Irv Arons' Journal

AMD Update 6: An Overview of New Treatments for Dry AMD

2009-12-14T16:42:00.005-05:00

Those of you who have been following this space know that I have been reporting on new drug and device treatments for wet age-related macular degeneration for the past several years. I haven’t paid much attention to the treatments under development for the dry form, basically because most are drug-related, and my knowledge of how drugs work is limited. However, I recently read an excellent overview of the new drugs that are being developed for dry AMD, written by Dr. Philip Rosenfeld (the father of Avastin for use in AMD) and John Legarreta, a medical student at State University of New York at Buffalo, which presents a clear picture of current developments in this important field.

I have previously written about the potential for the use of lasers to treat dry AMD by Iridex, but that attempt did not prove successful. I have also written about the Ellex 2RT (retinal regeneration) program that might hold potential in the early intervention in dry AMD. Links to both of these writeups are shown at the end of this posting.

With about 80% to 90% of newly diagnosed AMD cases being of the dry variety, and with no effective treatment currently in use, it is important to track the developmental work underway in this area. This review appeared in the November 2009 issue of Retinal Physician, and with the permission of the magazines publishers, here is the complete writeup:

Preclinical and Phase 1 Drugs in Development for Dry AMD: An Overview

Retinal Physician, November 2009

Philip J. Rosenfeld, MD, PhD ● John Legaretta, BFA

Philip J. Rosenfeld, MD, PhD, is professor of ophthalmology at the Bascom Palmer Eye Institute at the University of Miami Miller School of Medicine in Florida. He receives significant research support from Potentia and Alexion, and he has a minimal advisory relationship with Potentia. John Legarreta, BFA, is a medical student at the School of Medicine and Biomedical Sciences, State University of New York at Buffalo. He has no financial interest in any products mentioned in this article. Dr. Rosenfeld can be reached at prosenfeld@med.miami.edu.

The vast majority of AMD patients have the nonexudative or dry form of the disease, characterized by a constellation of clinical features, including drusen, disturbances of the retinal pigment epithelium (pigment clumping and/or dropout), and geographic atrophy (GA) of the macula. As defined by the Age-Related Eye Disease Study (AREDS), the severity of AMD can be classified into three categories: early, intermediate, and advanced.

[Editors Note: For a breakdown on the number of people in the three categories noted above in both dry and wet AMD in 2007, as estimated by Market Scope, please see the link to the table shown at the end of this posting.]

While drusen alone, particularly those of smaller size, do not seem to be associated with vision loss, at least one large druse measuring 125 μm in diameter is sufficient for the diagnosis of intermediate AMD. Dry AMD may remain static or progress slowly to produce a greater number and distribution of drusen with areas of GA. The increase in size or area of drusen or pigment abnormalities (focal hyper- or hypopigmentation of the retinal pigment epithelium [RPE]) predicts the likelihood of developing vision-threatening lesions in AMD, which include central GA and neovascularization, the advanced forms of AMD.(1)

CURRENT TREATMENT OPTIONS FOR DRY AMD

Antiangiogenic therapies have been developed to treat wet AMD. While drugs such as ranibizumab (Lucentis, Genentech) and bevacizumab (Avastin, Genentech) have revolutionized the care of patients with neovascular AMD, under the best of circumstances, treatment converts the neovascular form of AMD back to dry AMD. There is no evidence to suggest that these antiangiogenic drugs have any beneficial effect on the underlying degenerative process known as dry AMD. Currently, there is no proven drug treatment for dry AMD; however, the cessation of smoking and treatments based on nutritional recommendations and supplements can slow disease progression. Nutrient-based treatments for AMD were evaluated in the AREDS trial.(2)

TARGETING THE CAUSE OF AMD

The overall goal of treatment for dry AMD is to target the underlying cause of the disease and halt, or at least slow, the loss of vision. This approach has been hampered by two major issues. First, there are no reliable in vitro systems for testing the efficacy of any drug for dry AMD, and second, no true animal model exists for AMD. A well-developed macula is only found in primates and birds, and while numerous attempts have been made to develop nonprimate models for AMD, and these models highlight various pathological features of human AMD, none of these animal models truly replicates the disease process seen in humans. The only model that may be useful for potential drug testing is the naturally occurring monkey colonies that have been found to develop drusen.(3)

The second issue that has hampered drug development is the uncertainty surrounding the best molecular pathway to target for the treatment of dry AMD. However, several different strategies have evolved. These strategies have targeted three major therapeutic areas of investigation: preservation of photoreceptors and the RPE (neuroprotection), prevention of oxidative damage, and suppression of inflammation. Each strategy is supported by varying degrees of scientific evidence and will have to await validation based on clinical trial outcomes.

CLINICAL TRIAL ENDPOINTS IN DRY AMD

The most obvious study endpoint for dry AMD therapies would be the preservation of visual acuity; however, studies using visual acuity as an endpoint will take many years to complete. To decrease the time required to show a benefit from a drug, surrogate endpoints have been developed that might indicate a positive outcome without waiting the years required to show visual acuity benefit.

One surrogate endpoint is the prevention of disease progression from dry to wet AMD. This endpoint was first used in the study investigating anecortave acetate (Retaane, Alcon) for the treatment of dry AMD. While the drug failed to prevent progression of dry to wet AMD, the study demonstrated the feasibility of this study design. Another strategy is to assume that a treatment for dry AMD might also affect the underlying stimulus for neovascularization in wet AMD. If true, then a potential endpoint might be to demonstrate that a drug for dry AMD is able to decrease the need for retreatment with antiangiogenic therapy in wet AMD or improve the visual acuity outcome. This study design has not been tested.

A feature of dry AMD that could serve as a surrogate endpoint is the area of drusen in the macula. While drusen area as measured by fundus photography has already been explored as an endpoint in the failed laser-to-drusen trials, (4-6) the change in drusen volume in response to pharmacotherapy is a novel clinical trial endpoint that has not been explored previously. Spectral-domain optical coherence tomography has the potential to reliably and reproducibly identify drusen in the macula and provide truly automated volume quantification. The most likely surrogate clinical trial endpoint, based on a symposium held in Washington, DC, and sponsored by the National Eye Institute and the Food and Drug Administration, is an endpoint that assesses a drug’s effects on the growth of GA, since GA is a feature of dry AMD that directly causes loss of photoreceptors and the RPE. (7)

DRUGS TO PROMOTE SURVIVAL OF PHOTORECEPTORS AND THE RPE

No matter what the underlying cause of AMD, drugs that can preserve viable photoreceptors and maintain the RPE should preserve vision. One strategy to promote survival of photoreceptors and the RPE is to protect cells against ischemia and improve the choroidal circulation in patients with dry AMD. Two studies are currently using this strategy. In Europe, an ongoing multicenter, randomized, placebo-controlled study is investigating the use of an offlabel, generic drug known as trimetazidine (Vastarel MR, 35 mg tablet), a drug currently used for the treatment of angina pectoris. Trimetazidine improves myocardial glucose utilization by stopping fatty acid metabolism, and it is considered to have cytoprotective effects in ischemic conditions. Other uses for this drug include the treatment of vertigo, tinnitus, and vision loss and visual field loss due to vascular causes. The primary goal of this study is to slow the conversion of dry AMD to wet AMD.

Another drug being investigated for its vasodilatory effect is Alprostadil, also known as prostaglandin E1 (PGE1). The presumed rationale is based on the belief that improved circulation would slow the progression of AMD. This multicenter, randomized, placebo-controlled study is ongoing in Europe.

Another strategy to preserve the macular function is to prevent apoptosis by using neuroprotective agents. Ciliary neurotrophic factor (CNTF), a potent neuroprotective agent, has been shown to inhibit photoreceptor apoptosis in an animal model of retinal degeneration (8) and is being investigated as a treatment for dry AMD. Using encapsulated cell technology that permits CNTF-producing transfected cells to be implanted into the vitreous cavity, Neurotech Pharmaceuticals (Lincoln, RI) has developed a sustained-release platform that produces CNTF for a year or longer. The phase 2 study is completed and data analysis is currently under way. Other neuroprotective agents currently under investigation for dry AMD include a brimonidine tartrate intravitreal implant (Allergan, Irvine, CA) and topical tandospirone (Alcon, Fort Worth, TX).

Yet another strategy is to interfere with the normal visual cycle and preserve vision by decreasing the accumulation of toxic metabolites, such as lipofuscin and the retinal fluorophore A2E. This strategy is being pursued by Sirion Therapeutics (Tampa, FL) with the use of fenretinide - N-(4-hydroxyphenyl) retinamide - for the treatment of dry AMD. Fenretinide binds retinol-binding protein in the circulation and prevents uptake of retinol by the RPE, thus downregulating photoreceptor metabolism. The phase 2 study investigating fenretinide for the treatment of GA is fully enrolled and in its second year of follow-up.

Downregulation of photoreceptor activity is also being investigated using the drug ACU-4429 (Acucela, Bothell, WA). ACU-4429 is a small nonretinoid molecule that functions as a modulator of the isomerase (RPE65) required for the conversion of all transretinol to 11-cis-retinal in the RPE. By modulating isomerization, ACU-4429 slows the visual cycle in rod photoreceptors and decreases the accumulation of A2E. The ongoing phase 1 study has shown so far that the drug is safe and well tolerated in healthy volunteers. A phase 2 study for treatment of dry AMD is currently being planned.

A novel strategy for the preservation of photoreceptors and the RPE borrows a therapeutic strategy used for the treatment of Alzheimer's disease. An antibody against amyloid ß has completed a phase 1 study as an intravenous treatment for GA in AMD patients. This antibody, known as RN6G (Pfizer, New York, NY), was shown to decrease the amount of amyloid ß in the eye from a mouse model of AMD when given as a systemic therapy.(9) A phase 2 study is currently under way.

The therapies under investigation that seek to preserve photoreceptors and the RPE are summarized in Table 1.

(Note: I have reproduced the tables included with the article. By clicking on the tables they will open in a new window or tab in a larger more readable size. Or, go to the original online writeup for a clearer view of the table contents.)

DRUGS TO PREVENT INJURY FROM OXIDATIVE STRESS AND MICRONUTRIENT DEPLETION

In AMD, oxidative stress and the depletion of essential micronutrients are considered to be driving forces in disease progression. This disease paradigm assumes that AMD is caused by a lifelong exposure to free radicals - a byproduct of high oxygen consumption in the neural retina and RPE - combined with exposure to environmental toxins, such as those derived from smoking, in conjunction with inadequate levels of naturally occurring antioxidants. These exposures and deficits result in the accumulation of cellular debris - particularly oxidized lipids, which promote inflammation and may be directly toxic to the macular tissues - resulting in the clinical manifestations known as AMD. This paradigm is supported by epidemiologic studies showing that diets rich in antioxidants decrease the risk of AMD, while smoking was associated with an increased risk of AMD.(10)

Support for this nutrient-based paradigm was provided by the AREDS trial. This multicenter, NEI-sponsored study evaluated the effect of pharmacological doses of zinc and/or a formulation containing nutrients with antioxidant properties (vitamin C, vitamin E, and beta-carotene) on the rate of progression to advanced AMD and on visual acuity. The use of these vitamins and micronutrients reduced the risk of developing advanced AMD by about 25%.(2) The overall risk of moderate vision loss was reduced by 19% at five years. The theory of oxidative damage as a cause for AMD has also been supported by the findings that individuals have an increased risk of developing AMD if they carry a specific genetic polymorphism in mitochondrial DNA (A4917G), an organelle important for oxidative metabolism, and in nuclear DNA within the 5'-upstream region of a genetic locus important for DNA repair (ERCC6). DNA damage can be caused by oxidative stress.(11,12)

The AREDS2 trial, now under way, is designed to evaluate the effect of dietary xanthophylls (lutein/zeaxanthin) and/or omega-3 long-chain polyunsaturated fatty acids (LCPUFA), known as docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), on the progression to advanced AMD (www.areds2.org). These micronutrients are believed to function not only as antioxidants, but also as anti-inflammatory and antiangiogenic agents, according to epidemiologic and laboratory studies. In addition, AREDS2 will investigate the effects of eliminating betacarotene and the effects of reducing zinc in the original AREDS on the development and progression of AMD.

A topical antioxidant called OT-551 (Othera Pharmaceuticals, Exton, PA) was being explored as a treatment for dry AMD. OT-551 (4-cyclopropanoyloxy- 1-hydroxy-2,2,6,6-tetramethylpiperidine HCl) is a small lipophilic molecule that readily penetrates the cornea. OT-551 is converted by ocular esterases to TEMPOL-H (TP-H), the active metabolite that is a potent free-radical scavenger that does not penetrate the cornea. In animal studies, topical therapy has resulted in excellent ocular bioavailability, with significant levels of TP-H achieved in the retina.

The drug OT-551 was shown to possess antiinflammatory and antiangiogenic properties, as well as antioxidant properties. OT-551 was also shown to protect against oxidative damage in vitro, protect against light damage in vivo,(13) suppress photoreceptor cell death in animal models, and block angiogenesis stimulated by growth factors. Based on these preclinical data, OT-551 was being investigated as a therapy for GA in AMD. This two-year, phase 2 trial, known as the OMEGA (OT-551 Multicenter Evaluation of Geographic Atrophy) study, was stopped after 18 months, due to an apparent lack of efficacy in preventing the enlargement rate of GA in AMD.

The therapies under investigation that seek to prevent injury from oxidative stress and micronutrient depletion are summarized in Table 2.

DRUGS TO SUPPRESS INFLAMMATION

Genetic association studies using different populations have shown that inflammation appears to be the driving force behind AMD.(14) In 2005, four groups identified a genetic polymorphism in complement factor H (CFH), which was associated with an increased risk of developing AMD.(15-18) The documented risk-conferring single-nucleotide polymorphism (SNP) was a thymine (T) to cytosine (C) substitution at nucleotide 1277 in exon 9, which results in a tyrosine-to-histidine change at amino acid position 402 (Y402H) of the CFH protein.

Since complement is a system of serum proteins that comprise an important arm of the innate immune system, association studies have definitively linked AMD to the immune system. Also, two independent studies reported the association of the complement factor 3 gene with AMD, (19,20) as well as the complement factor B/component 2 gene.(21) An association between the complement factor 1 gene and AMD has been reported too.(22) Less robust associations have been reported between AMD and SERPING1, which regulates the first component of complement (C1), (23) and between AMD and C7 and mannose binding lectin 2 (MBL2) loci.(24) Protective alleles associated with the complement pathway have also been reported. Two of the five CFH-related genes (CFHR1-5), which lie within the regulators of complement activation (RCA) locus on chromosome 1q32, known as CFHR1 and CFHR3, are considered to be protective against AMD.(25)

These genetic association studies would imply that inhibition of complement activation would be a reasonable strategy for the treatment of AMD. However, after a lifetime of complement-mediated damage, such a strategy might have no effect on disease progression later in life. One drug being investigated is POT-4 (Potentia Pharmaceuticals, Louisville, KY), a cyclic peptide comprised of 13 amino acids, that is derived from compstatin. POT-4 binds reversibly to complement component 3 (C3) and prevents its proteolytic activation to C3a and C3b and the subsequent release of all downstream anaphylatoxins, as well as the formation of terminal membrane attack complex. As a C3 inhibitor, POT-4 inhibits all three major pathways of complement activation. POT-4 has unique slow-release properties due to the formation of an intravitreal gel at higher doses, which should permit less frequent intravitreal injections to achieve prolonged complement inhibition.

The phase 1 dose-escalation study, known as Assessment of Safety of Intravitreal POT-4 Therapy for Patients with Neovascular AMD (ASaP), was performed on patients with advanced neovascular lesions with the intention to pursue POT-4 as a treatment for dry AMD. To date, POT-4 appears safe up to a dose of 1.05 mg, with evidence of efficacy at the higher doses.

Another complement inhibitor under investigation is eculizumab (Soliris, Alexion Pharmaceuticals), a humanized monoclonal antibody derived from a murine antihuman C5 antibody. Eculizumab specifically binds the terminal complement protein C5, thereby inhibiting its cleavage to C5a and C5b during complement activation. The strategic blockade of the complement cascade at C5 prevents the release of the downstream anaphylatoxin C5a and prevents the formation of the cytolytic membrane attack complex.

Eculizumab is FDA-approved for the intravenous treatment of another complement-mediated disease known as paroxysmal nocturnal hemoglobinuria. At the Bascom Palmer Eye Institute, we are performing a phase 2 investigation with eculizumab for the treatment of patients with dry AMD, known as the COMPLement Inhibition with Eculizumab for the Treatment of Non-Exudative Age-Related Macular Degeneration (COMPLETE) Study. Patients with GA or high-risk drusen are being randomized 2:1 to receive intravenous infusions of eculizumab or placebo.

Ophthotech's ARC-1905 (Princeton, NJ), an anti-C5 aptamer, is another complement inhibitor being tested in AMD. ARC-1905 is being administered by intravitreal injection. The phase 1 dose-escalation study was performed in combination with ranibizumab therapy for the treatment of wet AMD. Genentech/Roche are developing an anti-Complement Factor D antibody Fab (FCFD4514S), which is in a phase 2 trial. Another phase 1 study using ARC1905 for dry AMD is currently under way.

Another complement inhibitor in preclinical studies is JPE1375 (Jerini Ophthalmic, New York, NY), a small, peptidomimetic molecular antagonist against the C5a receptor, which prevents binding of C5a, thus inhibiting the biological activity of C5a. Additional complement inhibitors are being pursued in preclinical studies by several companies, but details are not yet available.

More generalized immune suppression for the treatment of dry AMD is being pursued with the use of subcutaneous glatiramer acetate (Copaxone, Teva Pharmaceuticals, Kfar- Saba, Israel), intravitreal sustained-release fluocinolone acetonide (Iluvien implant, Alimera Sciences, Alpharetta, GA), and subcutaneous sirolimus (rapamycin), a macrolide fungicide with immunosuppressive properties.

The therapies under investigation that seek to suppress inflammation are summarized in Table 3.

SUMMARY

Several different strategies are being investigated, but it will take years before we know if any of them are successful. While we await positive outcomes, these clinical trials will produce a wealth of natural history data on the progression of dry AMD and provide us with extensive experience using several different imaging modalities to track disease progression. With this experience, our clinical trial designs will improve over time and the appropriate clinical trial endpoints should become obvious. With all the drugs in development, there is a good chance that a treatment breakthrough should occur within the next decade. RP

REFERENCES

1. Ferris FL, Davis MD, Clemons TE, et al. A simplified severity scale for agerelated macular degeneration: AREDS Report No. 18. Arch Ophthalmol. 2005;123:1570-1574.
2. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no. 8. Arch Ophthalmol. 2001;119:1417-1436.
3. Kaidzu S, Tanito M, Ohira A, et al. Immunohistochemical analysis of aldehydemodified proteins in drusen in cynomolgus monkeys (Macaca fascicularis). Exp Eye Res. 2008;86:856-859.
4. Laser treatment in patients with bilateral large drusen: the complications of age-related macular degeneration prevention trial. Ophthalmology. 2006;113:1974-1986.
5. Friberg TR, Musch DC, Lim JI, et al. Prophylactic treatment of age-related macular degeneration report number 1: 810-nanometer laser to eyes with drusen. Unilaterally eligible patients. Ophthalmology. 2006;113:622 e1.
6. Owens SL, Bunce C, Brannon AJ, et al. Prophylactic laser treatment hastens choroidal neovascularization in unilateral age-related maculopathy: final results of the drusen laser study. Am J Ophthalmol. 2006;141:276-281.
7. Csaky KG, Richman EA, Ferris FL 3rd. Report from the NEI/FDA Ophthalmic Clinical Trial Design and Endpoints Symposium. Invest Ophthalmol Vis Sci. 2008;49:479-489.
8. Tao W, Wen R, Goddard MB, et al. Encapsulated cell-based delivery of CNTF reduces photoreceptor degeneration in animal models of retinitis pigmentosa. Invest Ophthalmol Vis Sci. 2002;43:3292-3298.
9. Ding JD, Lin J, Mace BE, et al. Targeting age-related macular degeneration with Alzheimer's disease based immunotherapies: anti-amyloid-beta antibody attenuates pathologies in an age-related macular degeneration mouse model. Vision Res. 2008;48:339-345.
10. Risk factors associated with age-related macular degeneration. A case-control study in the age-related eye disease study: Age-Related Eye Disease Study Report Number 3. Ophthalmology. 2000;107:2224-2232.
11. Canter JA, Olson LM, Spencer K, et al. Mitochondrial DNA polymorphism A4917G is independently associated with age-related macular degeneration. PLoS One. 2008;3:e2091.
12. Tuo J, Ning B, Bojanowski CM, et al. Synergic effect of polymorphisms in ERCC6 5' flanking region and complement factor H on age-related macular degeneration predisposition. Proc Natl Acad Sci U S A. 2006;103:9256-9261.
13. Tanito M, Li F, Elliott MH, et al. Protective effect of TEMPOL derivatives against light-induced retinal damage in rats. Invest Ophthalmol Vis Sci. 2007;48:1900-1905.
14. Patel M, Chan CC. Immunopathological aspects of age-related macular degeneration. Semin Immunopathol. 2008;30:97-110.
15. Edwards AO, Ritter R, 3rd, Abel KJ, et al. Complement factor H polymorphism and age-related macular degeneration. Science. 2005;308:421-424.
16. Hageman GS, Anderson DH, Johnson LV, et al. A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. Proc Natl Acad Sci U S A. 2005;102:7227-7232.
17. Haines JL, Hauser MA, Schmidt S, et al. Complement factor H variant increases the risk of age-related macular degeneration. Science. 2005;308:419-421.
18. Klein RJ, Zeiss C, Chew EY, et al. Complement factor H polymorphism in agerelated macular degeneration. Science. 2005;308:385-389.
19. Maller JB, Fagerness JA, Reynolds RC, et al. Variation in complement factor 3 is associated with risk of age-related macular degeneration. Nat Genet. 2007;39:1200-1201.
20. Yates JR, Sepp T, Matharu BK, et al. Complement C3 variant and the risk of age-related macular degeneration. N Engl J Med. 2007;357:553-561.
21. Gold B, Merriam JE, Zernant J, et al. Variation in factor B (BF) and complement component 2 (C2) genes is associated with age-related macular degeneration. Nat Genet. 2006;38:458-462.
22. Fagerness JA, Maller JB, Neale BM, et al. Variation near complement factor I is associated with risk of advanced AMD. Eur J Hum Genet. 2009;17;100-104.
23. Ennis S, Jomary C, Mullins R, et al. Association between the SERPING1 gene and age-related macular degeneration: a two-stage case-control study. Lancet. 2008;372:1828-1834.
24. Dinu V, Miller PL, Zhao H. Evidence for association between multiple complement pathway genes and AMD. Genet Epidemiol. 2007;31:224-237.
25. Hughes AE, Orr N, Esfandiary H, et al. A common CFH haplotype, with deletion of CFHR1 and CFHR3, is associated with lower risk of age-related macular degeneration. Nat Genet. 2006;38:1173-1177.

Links:

Laser Treatments for AMD Show Promise; Ocular Surgery News, January 15, 2000.

Ellex 2RT Retina Regeneration Therapy: A First Report

AMD Cases in the U.S. by Type and Stage in 20007

Preclinical and Phase 1 Drugs in Development for Dry AMD: An Overview

The First Ophthalmic Innovation Summit

2009-11-27T16:11:00.008-05:00

Earlier this year, two venture capitalists, Emmett Cunningham of Clarus Ventures and Bill Link of Versant Ventures, came up with the idea to hold a meeting prior to this year’s AAO Meeting, to enable start up and other small and early-stage ophthalmic companies to present new innovations that they were working on to a group of “angels” and other potential investors, key ophthalmic industry leaders, and other interested parties. Thus was born the first Ophthalmic Innovation Summit (OIS). The day-long event was held at the Palace Hotel in San Francisco on October 22nd, co-chaired by the above mentioned venture capitalists.

Over 400 attendees listened to 10 minute presentations from 25 early stage and small companies, including twelve ophthalmic device companies, and thirteen working on ophthalmic pharmaceutical products to battle various disease states.

The device companies presenting included:

-- AcuFocus, Inc. – (a corneal inlay) Jim Socks, SVP Clinical & Regulatory Affairs
-- ReVision Optics, Inc. – (the Presby corneal inlay) J. Randy Alexander, President & CEO
– PowerVision, Inc. – (a fluid-filled accommodating IOL) Barry Cheskin, President & CEO
– NuLens Ltd. – (an accommodating IOL) Ori Gal, CEO
– LenSx Lasers, Inc. – (femtosecond laser for cataracts) Ron Kurtz, MD, President & CEO
– VisionCare Ophthalmic Technologies, Inc. – (implantable telescope for AMD) Allen Hill, President & CEO
– WaveTec Vision – ( wavefront aberrometer) Tom Berryman, President & CEO
– Ocular Therapeutix, Inc. – (hydrogel bandage lens) Amar Sawhney, PhD, President & CEO
– OptiMedica Corporation – (pattern-scan laser for retina, and a femtosecond laser for cataracts) Mark Forchette, President & CEO
– NeoVista, Inc. – (Epi-Rad 90 brachytherapy for AMD) John Hendrick, President & CEO
– Oraya Therapeutics – (IRay X-ray therapy for AMD) Jim Taylor, President & CEO
– Second Sight Medical Products, Inc. – (retinal prosthesis) Rob Greenberg, MD, PhD & CEO

[Editor’s note: I have written extensively on NeoVista and its Epi-Rad 90 treatment for AMD. Please see the links at the end of this posting. I have also just written a comprehensive report on the Oraya IRay X-ray treatment for AMD. That link is also included at the end of this posting.]

The pharmaceutical companies presenting included:

– MacuSight – (pharma for AMD) David Weber, PhD, President & CEO
– Ophthotech Corporation – (pharma for AMD) Samir Patel, MD, President & CEO
– Taligen Therapeutics – (pharma for inflammatory disease) Abbie Celniker, PhD, CEO
– Eyetech Inc. – (Macugen for AMD) Michael Atieh, Executive Chairman*
– NeuroTech – (pharma for AMD) Ted Danse, President & CEO
– Aerie Pharmaceuticals, Inc. –(pharma for glaucoma) Tom van Haarlem, MD, President & CEO
– Panoptica, Inc. – (seeking early-stage ophthalmic drugs) Paul Chaney, President & CEO
– SARCode Corporation – (pharma for inflammatory disease) Tom Gadek, PhD, CEO
– Lux Biosciences, Inc. – (dry eye/uveitis) Ulrich Grau, PhD, President & CEO
– Applied Genetic Technologies Corporation (AGTC) – (gene therapy) Sue Washer, CEO
– ESBATech – (Alcon - biotech) Dominik Escher, PhD, CEO
– Sirion Therapeutics – (anti-inflam/uveitis, GA in AMD)Barry Butler, President & CEO
– iCo Therapeutics – (antisense for diabetic & macular edema) Andrew Rae, MBA, President & CEO

[Editor's Note: Some of the above presentations have been put online. Follow the links of the highlighted companies to see their presentations. In addition, some of the other presentations -- mentioned below -- are also shown online. Again, follow the highlighted text to see the presentations.]

In addition to the company presentations, industry leaders participated in panel discussions on topics ranging from views of the private and public sectors, financing of ophthalmic device and pharmaceutical companies, what established ophthalmic companies are seeking in smaller companies, and regulatory issues (ophthalmic devices, ophthalmic drugs).

Executives from larger companies weighed in with criteria that, for them, makes a new idea worthy of investment. These included proof of concept in animal studies as well as some characteristics that will distinguish the drug or device from competitors’ products. None of the individual investors in the audience thought that a slow economy was a bad time, per se, to make investments, and, in fact, several commented that putting assets on the table now will enhance their potential returns when capital starts flowing again.

As a wrap up to the meeting, two prominent ophthalmic practitioners, Richard Lindstrom and Mark Blumenkranz took a look at what the next five years might hold in the posterior segment (Blumenkranz) and the anterior segment (Lindstrom).

Dr. Lindstrom said that glaucoma surgeries may become a safe and more effective first-line alternative to medical management in patients who are regularly non-adherent with, or whose disease is refractory to, topical therapies. He also suggested that efforts to prevent cataractogenesis and presbyopia may someday preempt efforts to treat them.

Dr. Blumenkranz said that ophthalmologists are learning what oncologists discovered years ago – combination therapy is often superior to monotherapy. He also noted that virtually all retinal diseases conform to one of four avenues of pathogenesis, and that all four of those are in some part VEGF-dependent.

With the success of this first meeting, Dr. Cunningham hopes to make the OIS an annual event.

Prior to the meeting, Dr. Cunningham sat down with Jim Stommen, the recently retired editor of Medical Device Daily, to discuss both the upcoming OIS meeting and issues related to ophthalmic device and drug development. Here, presented with permission of The Healthcare Syndicate, a website devoted to healthcare information for the venture capital community, is the full interview:

EYE ON INNOVATION – AN INTERVIEW WITH: DR. EMMETT CUNNINGHAM, OPHTHALMOLOGIST AND VENTURE CAPITALIST

Dr. Emmett Cunningham is a Partner at Clarus Ventures. He will be Co-Chairing the upcoming Ophthalmology Innovation Summit scheduled for October 22nd at San Francisco’s Palace Hotel along with Dr. Bill Link of Versant Ventures. Prior to Clarus, Dr. Cunningham was senior vice president, medical strategy, at Eyetech Pharmaceuticals, where he helped build and lead the development and commercialization of Macugen, the first pharmacotherapy for age-related macular degeneration (AMD). Prior to Eyetech, he was at Pfizer. Dr. Cunningham is an ophthalmologist, an internationally recognized specialist in infectious and inflammatory eye disease, and an Adjunct Clinical Professor of ophthalmology at Stanford University.

Dr. Cunningham discussed both the upcoming Ophthalmology Innovation Summit and issues related to ophthalmic drug and device development with Jim Stommen, recently retired editor of Medical Device Daily.

HS: What are the key marketplace challenges for firms – and their investors – operating in the ophthalmic space?

Cunningham: The ophthalmic space has become relatively crowded in the past 5 years, which means there are more people and companies chasing the same end-points and indications. That’s a good thing for the patients who need new and improved treatments, but it makes investing a little more challenging because it’s harder to predict what the competitive landscape will look like 5 to 10 years down the road. In addition, the cost of running clinical trials continues to rise, and trials take more time enrolling. Perhaps the biggest challenge, however, is the overall financial environment. Investors, including venture investors, have responded to recent changes by becoming less willing to take on risk. For those companies developing drugs, many investors want to see randomized Phase II data. Similarly, for commercial-stage companies, many investors like to see enough of a sales ramp to be able to predict profitability. This has effectively left some companies “stranded” between financings.

HS: Aside from the format for trials and trial approvals, etc., are there any specific regulatory issues that apply broadly within the ophthalmic pharma space?

Cunningham: There are lots of very nuanced regulatory issues in the space. Really, ophthalmology has four big indications: wet AMD, dry AMD, diabetic macular edema/diabetic retinopathy, and glaucoma/neuroprotection. Everyone would agree that these each have the potential to be billion-dollar-plus markets. The next-largest indication is dry eye, which currently is about a $500 million-sized market in the U.S., but could be much larger once drugs with improved efficacy are available.

If you look at AMD, the first drug approved was Eyetech’s Macugen. It had modest efficacy, but was clearly more efficacious than placebo or the standard of care at the time. Next to come along, about a year later, was Lucentis, which had much greater efficacy. And by greater efficacy, if you looked at the primary endpoint response range, Macugen was in the 70% range and Lucentis was above 90%. So once you have a therapy that has a 90% efficacy rate, however you define that, it becomes very challenging to develop a drug that’s superior. So from the perspective, of having a very effective drug on the market, it’s harder to develop new drugs in the wet AMD space.

Dry AMD also is a very large market, but no one to date has developed a drug for it, so the regulatory and clinical development issues are still to be worked out. There are trials underway, and people are very enthusiastic about them, but until it actually happens, it’s unknown territory.

Dry eye has also historically been a very difficult indication. Allergan has Restasis approved for dry eye, but no other company has been able to get a drug approved for that indication. My guess is that it is difficult because the pathogenesis is complex – most companies go after things that are anti-inflammatory, or that increase tear production, but inflammation on the one hand and tar production on the other each contribute only partially to the pathogenesis of dry eye, so targeting either mechanism might be treating only part of the disease.

It’s a lot easier to develop a drug for glaucoma, where you have a very clear endpoint of pressure reduction, but because we have so many drugs available for pressure reduction, the hurdle has been raised to where the absolute pressure reduction for any given agent needs to be pretty pronounced. The hot area right now appears to be the so-called ROCK inhibitors, and a few companies are looking at those, but to be real winners in this space, they have to have good tolerability and compelling efficacy.

The are lots of other indications, such as infectious conjunctivitis, allergic conjunctivitis, etc., that are much smaller markets.

HS: Are those smaller markets worth getting involved with?

Cunningham: Yes and no. There are certain costs of developing a drug, no matter how big the market is, so if the market doesn’t justify those costs, then people don’t do it. They might do it as a second indication once it’s gotten approval for a lead indication, but they typically don’t bet the ranch on small indications.

HS: The agenda for your upcoming conference addresses the development of both device and drug solutions. Are there more opportunities for innovation, especially by smaller companies, on the device side?

Cunningham: Some problems are more amenable to devices, such as optical problems – those problems that have to do with focusing the image on the retina. One example is reversing presbyopia with accommodating intraocular lenses, currently pursued by Visigen, NuLens, and PowerVision. On the instrument side, WaveTec has a device that is used for accurately measuring the refractive area of the eye at the time of surgery to try to help improve placement of intraocular lenses, among other things. Devices also play a role in glaucoma management, particularly for patients who fail medical therapy. Examples would be Glaukos and Transcend, among others. There are lots of other examples, but generally I would say there’s considerable activity in both devices and drugs in ophthalmology.

HS: We have talked quite a bit about AMD, so I’m wondering where we’re headed with Lucentis, which has the huge market penetration, and then Avastin, which has made strides on an off-label basis.

Cunningham: Just by way of history, it’s not that long ago that we had no good therapies for neovascular AMD. I have friends who are retinal specialists who say, frankly, that practicing in that era was depressing, because patients would come in, they would have had a huge vision loss in one eye and oftentimes both eyes, and the physicians would have nothing to do except hold their hands and try to get them through it. So this whole era of anti-VEGF therapy has truly been a revolution in therapy for what is the leading cause of blindness in the developed world. Lucentis is a phenomenal drug. Genentech really outdid itself. Their commercial issue, however, is that Lucentis is basically an enhanced fragment of Avastin. So, once the Lucentis data came out, but when there was still a year or so until approval, people had the idea to compound Avastin and inject it into the eye, and experience with Avastin and Lucentis over the past 4 years has led many to assume that the two drugs have equivalent efficacy. To address this point directly, there’s an ongoing trial, called CATT, that is designed to rigorously compare the relative efficacy of Lucentis vs. Avastin for neovascular AMD. If Avastin is shown to be non-inferior, many assume that Lucentis sales will drop dramatically.

So now you have two very good drugs that are available for AMD – Lucentis and Avastin. You also have Macugen and lasers – specifically photodynamic therapy and thermal laser therapy. The first question, therefore, has to be, what is the unmet need? I think it’s clear that there’s a proportion of patients who don’t respond very well to intraocular VEGF inhibitors. Maybe it’s 20%, maybe it’s 30%. It depends on who you talk to. Maybe it’s only 10%. But it’s in that range. In addition, even those who respond to anti-VEGF agents find it difficult to tolerate these injections every month or two. They tend to be older patients, many have to be brought to the office by family members, the eye has to be prepared in a sterile fashion -- just as though they were going to undergo surgery, and then the injection is given.

I think a big movement in the space now is trying to find novel targets that can either supplement the efficacy of Lucentis or Avastin, which is a high hurdle because they have up to a 90% response rate, or treat those who are not responsive to Lucentis/Avastin. One such agent is the aptameric PDGF inhibitor being developed by OphthoTech. Others include a raft of complement inhibitors being developed for wet and dry AMD. The other thing that people are looking at is getting agents into a sustained-release format so that injections might only be every three months or six months instead of every month or two, to save the patient burden and the physician burden, because these injections have become so frequent that doctors are spending a significant portion of their time just doing injections. That’s the two big pushes in the AMD area right now.

HS: Two device-based approaches being studied as possible solutions for AMD involve the use of ionizing radiation delivered via systems developed by NeoVista and Oraya Therapeutics, both of which will present at the Summit. How would you characterize their progress?

Cunningham: If you had asked me five years ago whether I thought radiation would work, I would have said no. I would have said no because there had been trials that had looked at various radiation therapies for AMD, and they had basically failed. What NeoVista and Oraya would tell you, I believe, is that the radiation in those earlier trials was external radiation, and so wasn’t very focused. NeoVista actually puts the radioactive device very, very close to the retina and Oraya gives a finely focused external beam. I haven’t seen all the data for NeoVista -- and I think Oraya’s device is fairly early in development -- but the data that I have seen looks very intriguing.

HS: The laser refractive surgery (LASIK) segment has been dramatically impacted by the overall economic decline, but within that space, one intriguing segment is that of premium intraocular lenses. How is the market going for P-IOLs? Are some patients and practitioners taking a “wait and see” approach toward whatever improvements are forthcoming in what is a first-generation product market?

Cunningham: Premium IOLs have been much less affected than refractive surgery. The reasons are probably multiple and complex, but at base I think older retirees have more discretionary funds and tend to be more willing to spend the money for optimal vision.

HS: An intriguing area on the device side of ophthalmic therapy lies in the femtosecond laser technology for cataract removal that is under development by LenSx, another company slated to present at the Summit. Does this have the potential to be a “disruptive” technology in the space?

Cunningham: They’re early in their innovation curve, but the technology looks very impressive. If they’re able to do what they plan to be able to do, I think it could be disruptive.

HS: You talked a little earlier about glaucoma, and obviously you have surgical approaches, but there are some other innovative approaches that look to me making inroads because of the falloff in patient compliance on the drug side. Docs often talk about the difficult time they have keeping their patients compliant in use of drugs for glaucoma.

Cunningham: A few points: A) Glaucoma is very, very common; B) many patients are to a greater or lesser extent non-compliant; and C) many patients – perhaps up to 50% -- need more than one drug, which speaks both to how refractory the disease can be and, as mentioned, the issue with compliance. For all those reasons, new therapies are always welcome, and it could be another drop with a novel mechanism of action, that had the potential to be additive to current drops, another drop that was just so effective that it could supplant what is out there, or a device that could either supplant some of those patients who are on multiple drops or treat some of those downright treatment failures who don’t respond to any number of drops. For all of those reasons, glaucoma still is a very attractive space.

HS: Could you talk about the current funding environment in the ophthalmic space?

Cunningham: I don’t know if it’s the end of the beginning or the beginning of the end, as Churchill said, but I think people are beginning to see the light at the end of the tunnel. That said, credit and investments are still tight, and since the third quarter of last year, people have just been much more circumspect about their investments. I’d like to think that over time, things would get back to where they were a couple of years ago, which is to say staged investors willing to help shepherd these companies from inception through exit.

HS: What do you hope to accomplish with this new Ophthalmology Innovation Summit?

Cunningham: I’ve thought for some time now that it would be great to have a venue that would bring together early-stage companies, investors and the larger, later-stage public companies to facilitate the development and delivery of new drugs and devices to improve therapies for vision-threatening disorders. We also welcome entrepreneurs, physicians and vision scientists who are interested in company building and the process of developing ophthalmic drugs and devices. As you look at the agenda, I think you’ll agree that it really is a “who’s who” in the ophthalmology space, from the large companies, to the most promising private companies, to the VCs who invest in this space. Our hope is that this will be the first of what becomes an annual tradition.

References:

The Ophthalmic Innovation Symposium Agenda

An Overview of the OIS Meeting of October 22, 2009
Academy Alive – email from the AAO to its members for October 23, 2009.

Eye on Innovation Interview
The Healthcare Syndicate

Links to Previous Postings:

NeoVista Writeups:

NeoVista Epi-retinal Strontium 90 Treatment for Wet AMD (2-14-07)

NeoVista Epi-retinal Strontium 90 Treatment for AMD Update (7-10-07)

NeoVista Epi-Retinal Strontium 90 Treatment for AMD: Update 2 (11-19-07)

NeoVista Epi-Retinal Strontium 90 Treatment for AMD: Update 3 (10-1-08)

Oraya Writeup:

Oraya IRay In-office Stereotactic X-ray Treatment for AMD: A First Report

Avastin/Lucentis Update 35: The CMS Does the Full Monty on Code Q2024 for Avastin!

2009-11-17T12:08:00.002-05:00

According to an email received yesterday by Jack Mitchell of the Senate Committee on Aging, “Effective immediately, CMS is no longer going to recognize code Q2024 for payment of non-outpatient hospital claims. Practitioners are directed to return to their previous reporting practice for small intraocular doses of Bevacizumab (Avastin®) furnished prior to October 1, 2009.”

“The Medicare claims processing contractors will post the following information on their websites within 5 days to inform providers of this policy: “Effective immediately, the Centers for Medicare & Medicaid Services (CMS) no longer recognizes Healthcare Common Procedure Coding System (HCPCS) Code Q2024 Bevacizumab (Avastin®) for payment of non-outpatient hospital claims. Practitioners shall return to their previous reporting practice for small intraocular doses of Bevacizumab (Avastin®) furnished prior to October 1, 2009. HCPCS Code Q2024 will be deleted as of January 1, 2010, and, therefore, it will be removed from the Average Sales Price (ASP) pricing file effective with the January 2010 Release.”

In addition, the Medicare contractors have been instructed to reprocess any claims from physicians for Avastin administered in their offices that were paid based on the Q2024 code if requested by the physician.

In plain English, this reverses the prior reversal and the policy goes back to the original policy in effect before the reduction in reimbursement took place. Good news for both retinal physicians using Avastin and for patients and Medicare!

According to a spokesperson for the AAO, Dr. William L. Rich, the AAO's Medical Director for Health Policy, "The AAO, all three retinal societies, Congress and our patients are all very thankful for this reversal. It benefits patients, doctors, and taxpayers."

Oraya IRay In-office Stereotactic X-ray Treatment for AMD: A First Report

2009-11-16T16:47:00.005-05:00

Another new company with a treatment for wet AMD has come out of “stealth mode”, and presented information on how it’s system works and the results of it’s initial clinical trials. Here is an in-depth presentation of the Oraya IRay radiotherapy system.

Introduction

Over the past few years, several drug-based treatments have been suggested and tried to prevent visual loss due to neovascular age-related macular degeneration. Two anti-VEGF drugs, Avastin and Lucentis are now available to prevent significant vision loss in a majority of wet-AMD patients who are treated. However, it appears that repeated intravascular injections over an indefinite time period are required to keep the disease at bay.

One promising approach to reducing the number of injections needed is the synergistic use of radiation in conjunction with intravascular injections, to prevent the proliferation of vascular tissue and to induce visual acuity gains.

The idea of using radiation as a treatment modality for wet AMD has been around for years, but its use has been limited due to the potential damage that can be done to sensitive tissue within the eye without localization of the radiation beam and treatment area. Two companies now claim to have systems that achieve that aim.

The NeoVista Epi-Rad 90 System

The first of the two new therapy systems is the NeoVista Epi-Rad 90, which involves delivery of a target dose of 24 Gy of beta radiation to the center of the choroid neovascularization (CNV) following a partial vitrectomy for placing the strontium 90 tip close to the choroid. Several controlled clinical trials with this system are currently underway to determine if the combined use of radiation therapy and anti-VEGF injections can result in AMD control with fewer injections, compared to drug use alone.

(For more on the NeoVista Epi-Rad 90 system and the clinical trials underway, please see my four reports already posted on this site – links noted at the end of this writeup.)

The Oraya IRay System

Now, a second, office-based system has been proposed and is in early stages of testing. This is the Oraya IRay system, that uses a table-top source of low-energy X-ray beams, directed through the sclera onto the macula to treat CNV secondary to AMD. Unlike the NeoVista system, the Oraya IRay system delivers three doses of highly localized low energy X-ray radiation to the macula non-invasively, using a robotic positioning system, targeting algorithm and a device, I-Guide, for eye stabilization and motion detection. This office-based procedure can be performed in about 10-20 minutes, under a topical anesthetic. The IRay device delivers three beams of up to 8 Gy each through three different locations on the sclera (roughly at 7 o’clock, 6 o’clock and 5 o’clock), delivering up to 24 Gy to a single spot on the macula.

The unique method of delivering the three beams of radiation to the macula was chosen to avoid other sensitive eye structures such as the lens and optic nerve. In addition, the angle of the beam path minimizes collateral damage to radiosensitive structures, while enabling the delivery of the appropriate dosage of radiation (24 Gy) to the choroidal neovascularization that was found clinically useful in the NeoVista studies.

Details of the System

The IRay system consists of three parts: the robotically-controlled X-ray generation and eye imaging workstation (Figs. 1-3); the I-Guide, which is coupled to the patient’s eye via suction, and aligns and optically connects the eye to the X-ray generator (Figs. 5, 6); and the adjoining shielded operator workstation (Figs.3, 4).

To minimize the effects of eye motion during therapy, the I-Guide is used, which consists of a contact lens coupled to the eye with syringe-generated suction, and attached to a central post. The post is mounted to a stabilizer bar via a ball joint. The purpose of the I-Guide is to steady the eye and act as a target for the imaging system to monitor the eye’s position and gaze angle. During treatment, the automated positioning software continuously evaluates the deviation of the eye from nominal. Motion of the eye already is substantially reduced by the I-Guide and is monitored in real-time using a two-camera imaging system. When necessary, the beam is automatically gated off by an algorithm that incorporates time as well as displacement, allowing brief eye excursions while still maintaining effective targeting. The I-Guide is designed with a breakaway feature that allows emergency exit of the patient from the system.

Targeting is achieved on the basis of a calculated position of the fovea, as determined by the simple geometric relationship of the center of the I-Guide lens to the back of the eye. Oraya determined its targeting algorithm based on extensive pre-clinical studies, mathematical modeling of the eye, and subsequent developmental work. Pre-procedure fundus imaging, obtained via spectral-domain OCT, is used to verify targeting and ensure that patients with “outlier” fundus anatomy are identified.

In performing the procedure, the operator, after protecting the lower lid with a specially designed self-retaining retractor, places the I-Guide on the anesthetized eye. The patient’s head is secured in a chin rest/head restraint, which incorporates a radiation shield.

The operator at the shielded operator workstation obtains a visual lock on the eye and applies the appropriate X-ray dose to the three designated spots on the sclera. The three 3.5 mm collimated X-ray beams are sequentially and automatically delivered to converge onto a single 4 mm target spot on the fovea (Figs. 7-11).

This office-based, low-voltage (100 keV) X-ray radiation therapy is a 10-20 minute procedure with no appreciable external shielding required. For patients, the exposure is comparable to the radiation received in getting an X-ray of the head and neck. For operators, the radiation exposure would be equivalent to ~0.14 mrem/hour or one-quarter of the radiation from a transcontinental airline flight. Each patient would get just one lifetime dose, not repeated exposures. Even though doctors might experiment, after FDA approval, with pulse or repeat dosing at some interval, Oraya is not studying repeat dosing at this time.

The following illustrations show the elements of the system:

Figure 1. The Table-top X-ray Generator System

Figure 2. The 3-Part System Platform

Figure 3. The I-Ray System

Figure 4. The I-Ray System (showing operator station and shielding)

Figure 5. The I-Guide Assembly

Figure 6. The I-Guide in Position

Figure 7. The Robotic System and Spot Distribution

Figure 8. Spot Positioning on the Sclera

Figure 9. The X-Ray Beam Size on Sclera and Macula

Figure 10. X-Ray Beam Distribution within the Eye and Brain

Figure 11. X-Ray Beam Intensity on Fovea

Clinical Trials

Phase I (CLH001)

There are three clinical trials planned. The Phase I Trial (CLH001) has been initiated and is fully recruited with over 60 patients to having been treated at either 16 or 24 Gy.

The Phase I trial is a pilot study to evaluate the safety and tolerability of the IRay stereotactic, radiosurgery system in patients with Choroidal Neovascularization (CNV) secondary to AMD. The study aims to determine safety, preliminary efficacy, and dose evaluation.

The study includes two cohorts: those without previous treatment and those previously treated with anti-VEGF therapy requiring additional treatment due to persistent or recurring disease activity.

Monthly retreatment with additional anti-VEGF drug, if needed, is based on any of the following criteria:

– Increase of >100 microns central subfield thickness using SD-OCT
– Evidence of new macula hemorrhage on clinical exam
– New area of classic CNV on FA
– ≥10 EDTRS letter decrease in BCVA vs. previous visual acuity score, with associated fluid on SD-OCT

The initial results, on 28 patients with up to a year followup, treated in Mexico City, were presented by Dr. Peter Kaiser of the Cleveland Clinic Foundation at the Retina Sub-Specialty pre-meeting held prior to the main 2009 AAO Meeting. Dr. Kaiser reported on patients treated with 16 Gy of radiation plus Lucentis (following two monthly injections) in 15 anti-VEGF-naïve patients and in 13 prior Avastin or Lucentis patients (who had had on average 2.9 injections prior to entry into the study).

There were no device-related serious adverse events and no evidence of radiation-related abnormalities, but there were a few device related adverse events, all superficial keratopathy − which Dr. Kaiser attributed mostly to placement of the I-Guide. These superficial events required no intervention by the physician.

The efficacy results are shown in Figures 12, 13 and 14 below:

Figure 12. CLH001 Efficacy Results after 12 months

Figure 13. CLH001 Efficacy Results for Treatment Naive and Previously Treated Patients

Figure 14. Loss or Gain in Letters

The results of this feasibility study, while meant to evaluate primarily safety and tolerability of the IRay therapy, demonstrated a number of encouraging efficacy signals, including substantial preservation and gain of vision in both the treatment-naïve and previously treated cohorts, as well as low numbers of required anti-VEGF retreatment injections. The rate of the anti-VEGF retreatment injections (following the two mandatory “baseline” doses) was found to be only 0.9 per patient over 10 months, and ~56% of patients needed no additional anti-VEGF injections, while still demonstrating visual acuity preservation and gain at least comparable to that seen in other studies, such as MARINA and PrONTO, with much greater injection burdens.

(For a refresher on the MARINA, PrONTO – and ANCHOR studies, please see my NeoVista Update report of July 11, 2007, linked at the end of this report.)

Anti-VEGF retreatments, as described by Dr. Kaiser, are shown in the following graph:

Figure 15. Anti-VEGF Retreatments

Dr. Kaiser concluded that IRay extends the durability of Lucentis, reduces the number of injections, and appears safe and effective.

The company concluded that its non-invasively delivered, ionizing radiation in combination with Lucentis appears to:

– Extend the durability effect
– Limit the number of anti-VEGF injections
– Work in both treatment n ive and previously treated patients, and,
– Be safe and well tolerated

Phase II Clinical Trial (CLH002)

Oraya expects to enroll the first patients in a multi-center, randomized, masked, sham-controlled European trial before the end of the year, using a 16 Gy dose. (The company continues to evaluate the possibility of adding a higher-dose treatment arm.) It is expected that 8-10 sites in Europe will participate.

Phase III Pivotal (CLH003)

This larger randomized, masked, sham-controlled study is expected to initiate in mid-2010 and plans to enroll approximately 450 patients in 15-20 sites in both the U.S. and Europe

Questions and Answers

During the recent 2009 AAO Meeting in San Francisco, CEO of Oraya, Jim Taylor, was interviewed by Lynne Peterson of Trends-in-Medicine. She asked him the following questions:

Asked about the long-term safety of IRay, Taylor said, “I’d be the last person to say we have absolute certainty we know the outcome (with IRay). The comfort comes from the ample data and research from ocular oncology and from some early work done in radiotherapy for AMD that suggest the incidence of radiation retinopathy is low. Years of study in ocular oncology have given comfort that the doses here (are safe). We know that AMD has an inflammatory component to it, and we know that AMD causes scarring and building of lesions in the eye that don’t respond to anti-VEGF therapy. We also know that radiation is anti-vascularization and antifibrotic as well. Lastly, we know that if you combine an anti-VEGF agent with radiation, you get a synergistic effect”.

Taylor explained that radiation works best on concentrated lesions in an atmosphere of oxygenation. So, stopping leaking capillaries with an anti-VEGF, tends to make the center of the lesion more robust, and a better target for radiotherapy. Oraya has worked with radiation and oncology researchers and experts around the world to determine the dose and the approach. The science looks good. And the radiation is not delivered through the cornea but through the sclera. Taylor said one advantage of IRay over NeoVista’s therapy is that IRay is robotically delivered while NeoVista has a hand-held system. “We have a robot that is a wonderfully designed sniper, shooting low energy in tightly collimated beams with 3 beams going through the sclera at separate points, all converging at the same point on the fovea”. The IRay goal is to deliver either 16 Gy or 24 Gy to a spot centered on the fovea covering approximately 6 mm in diameter.

The three elements of IRay that Taylor highlighted were:

1. Robotic positioning.

2. Continuous tracking and management of eye motion with the I-Guide.

3. Collimation of the beam.

Does IRay make financial sense for retina specialists? Probably, if CMS reimburses for it. There would be an initial machine cost plus a per-procedure disposable cost. Taylor believes the procedure will be cost-effective because it should reduce both diagnostic testing and anti-VEGF injections. IRay is not currently being tested in dry AMD, but that might be an area for research in the future, as drusen formation has been demonstrated to have an inflammatory component which may be amenable to radiotherapy.

References:

1. Office-based External Beam Radiation Therapy for Age-related Macula Degeneration; Hsu, Jason and Regillo, Carl; Retinal Physician, September 2009.

2. Stereotactic Radiotherapy for AMD; Taylor, James; Ophthalmology Innovation Summit, October 2009.

3. Motion Management for a Novel Ophthalmic Stereotactic Radiosurgical Device; Chell, E. et al; AAPM, July 2009.

4. 2009 AAO Meeting; Peterson, Lynne and Woods, Diane; Trends-in-Medicine, November 2009. (Subscribers, only, contact Trends-in-Medicine)

Links to the NeoVista Writeups:

NeoVista Epi-retinal Strontium 90 Treatment for Wet AMD (2-14-07)

NeoVista Epi-retinal Strontium 90 Treatment for AMD Update (7-11-07)

NeoVista Epi-Retinal Strontium 90 Treatment for AMD: Update 2 (11-19-07)

NeoVista Epi-Retinal Strontium 90 Treatment for AMD: Update 3 (10-1-08)

Avastin/Lucentis Update 34: More on the Comparative Studies

2009-11-07T12:01:00.002-05:00

In my constant search for new information about AMD treatments, I happened across a blog devoted to all things retina: The Retina Blog. In one posting, following the recent AAO Meeting, author David Khorram reported on Dan Martins talk during the Retina SubSpecialty Day Meetings. Apparently, the Academy sent out an email on its Academy Live network describing Dan’s talk in more detail than I had received.

Anyway, The Retina Blog had the up-to-date details on both the CATT Study and most of the other head-to-head studies – although, news about the Spanish study appears to be missing.

Here, thanks to David Khorram, is the latest information on the comparative studies.

Head-to-head Lucentis vs. Avastin Trials
10-25-09
The Retina Blog – David Khorram, MD

This bit of news just came in from the annual meeting of the American Academy of Ophthalmology, which is being held right now in San Francisco. There is a lot happening in terms of these two drugs. The results will be important, both clinically and economically. Lucentis costs $2,000 per dose. Avastin costs less than 10% per dose. Both drugs are made by Genentech — that’s a whole different story. Here is a list of the current clinical trials as described in the article from the “Academy Live” email of Friday October, 23, 2009, a service of the American Academy of Ophthalmology.

Bevacizumab vs. ranibizumab: Initial results expected in 2011

Bevacizumab (Avastin) and ranibizumab (Lucentis) are competing in a hefty schedule of six head-to-head randomized clinical trials directly comparing their use in AMD patients, said Daniel F. Martin, MD. This year, researchers hope to complete enrollment in the studies, which compare varying doses and treatment schedules of the drugs. Initial study results are expected to be available in early 2011, according to Dr. Martin.

Here’s the status of each of the studies:

* The NEI-sponsored CATT (Comparison of AMD Treatments Trial) study began enrolling an estimated 1,200 wet AMD patients at 44 sites in the United States in February 2008. The four-arm study comparing bevacizumab and ranibizumab on fixed and variable schedules is proceeding well, according to Dr. Martin, with one-year results targeted for 2011.

[Editors Note: According to Dr. Martin, enrollment is expected to be completed by the end of November, at which time enrollment will be closed. For more on the CATT Study, see my CATT Study Update 10.]

* In April 2008, researchers in the United Kingdom began enrolling an anticipated 600 patients at 17 sites in the IVAN (Inhibit VEGF in Age-related choroidal Neovascularization) study. This four-armed study compares monthly bevacizumab 1.25 mg and ranibizumab 0.5 mg injections given over two years with three monthly injections followed by PRN dosing.

* The four-site German VIBERA study started enrolling 360 AMD patients in 2008 to receive three monthly bevacizumab 2.0 mg or ranibizumab 0.5 mg injections and additional injections as needed.

* The Austrian MANTA study began assigning an anticipated 320 AMD patients in June 2008 to three monthly bevacizumab or ranibizumab injections, with additional treatment as needed.

* Researchers in Norway began enrolling an anticipated 450 patients in the 12-site LUCAS study in March. Subjects receive bevacizumab 1.25 mg or ranibizumab 0.5 mg monthly as needed until dry, with intervals between doses decreasing over time.

* French investigators opened enrollment this fall in the 600-patient, 20-site GEFAL study. Subjects are randomized to receive three initial monthly injections of one of the two drugs.

[See my Update 25 for more on the French study.]

David Khorram, MD is the co-founder of Marianas Eye Institute, and the medical director of the Center for Advanced Diabetic Eye Care. A US-trained Board Certified ophthalmologist, he is listed in "Guide to America's Top Ophthalmologists."

Avastin/Lucentis Update 33: The Wording of the CMS Order for Repricing of Avastin

2009-11-02T19:24:00.001-05:00

The following note was received this morning by my contact in Senator Kohl’s office, from the director of CMS’ Office of Legislation, along with the wording, shown below, taken from the Federal Register of October 30th.

From the Office of Legislation of CMS:

“The excerpt from the CY 2010 hospital outpatient PPS final rule follows below. I have also attached the relevant page (page 615) from the copy of the rule that went on display at the Federal Register on Friday afternoon.

As requested, I am also checking with our program experts to see if we have any flexibility regarding the timing of this coding change (i.e., whether it can be applied retroactively or whether it can go into effect before January 1). If you have any questions, please let me know. “

From page 615 of the Federal Register, October 30, 2009:

We note that HCPCS code Q2024 (Injection, bevacizumab, 0.25 mg) was implemented effective October 2009 and represents a different dosage descriptor for the same drug described by HCPCS code J9035 (Injection, bevacizumab, 10 mg). Further, HCPCS code Q2024 has been replaced with HCPCS code C9257 (Injection, bevacizumab, 0.25 mg) effective January 1, 2010. In accordance with our CY 2010 policy to make a single packaging determination for a single drug, we are applying the methodology described above to bevacizumab and are assigning the applicable bevacizumab HCPCS codes the same packaging status for CY 2010. HCPCS codes C9257 and J9035 are included in Table 35 below.

In what I read from this in plain English, the reimbursement for the 0.25 mg dosage of Avastin, used in treating AMD, will revert on January 1st to the reimbursement in place before the change over on October 1st, or about $50.00, which I believe is what it was before the change.

Further, both CMS and Senator Kohl’s office, along with several ophthalmic organizations (AAO, ASRS, among others), continue to look into/request that the change in policy be implemented before January 1st.

Menu – Part 14: Some Updates and a Few New Posts

2009-10-30T16:38:00.002-04:00

Since the last menu posting on June 12th, I have added two new updates on the CATT Study; eight updates on Avastin vs. Lucentis; and three new postings. The new postings include a writeup on the use of femtosecond lasers in cataract surgery; a review of the history of customized ablation, and a little about an upgraded endoscope for use in ophthalmology (including some history on this device).

First, the CATT Study Updates:

CATT Study Update 9: The CATT Study is On Track

In June I learned that the CATT Study was on track, with 850 of the intended 1200 patients enrolled. I also included a review of the first eight updates (including links).

CATT Study Update 10 – From the 2009 AAO Meeting

In October, I received a report from the AAO meeting that enrollment was nearly completed, and that first results wouldn’t be published until all 1200 enrollees had completed their first year of results.

And, the Avastin/Lucentis Updates:

Avastin/Lucentis Update 25: Comparative Studies Proliferate – France Joins the Fray

In September I learned that France had started a comparative study, to join studies underway in five other countries.

Avastin/Lucentis Update 26: CMS Ups the Ante

In early October, I learned that Medicare was tilting the table towards Lucentis by lowering the reimbursement for Avastin.

Avastin/Lucentis Update 27: Dr. Rosenfeld’s Remarks at Retina Congress 2009

Dr. Phil Rosenfeld gave an interesting presentation about the search for optimal dosing for anti-VEGF drugs at the 2009 Retina Congress.

Avastin/Lucentis Update 28: Sustained Release Lucentis May Eventually Change the Equation

Roche and Genentech announced their licensing and developmental deal with Surmodics for a sustained release/delivery system for Lucentis. I provided a few comments.

Avastin/Lucentis Update 29: Six-Month Results of Controlled Comparison Study Published

The Boston University School of Medicine and the Veterans Administration of Boston announced their six-month results of comparative study of Avastin and Lucentis. This was the first published prospective, double-masked, randomized, controlled comparative study of the two drugs. However, this study only contains 20 subjects!

Avastin/Lucentis Update 30: A Followup to Update 26 – Sen. Herb Kohl Queries CMS

Following the implementation of the reimbursement cut for Avastin to ophthalmologists, and its implication for Medicare, Senator Herb Kohl got into the act, asking CMS why this cut took place and if Genentech had any involvement?

Avastin/Lucentis Update 31: Problems with Pharmacy Compounding of Avastin?

During the 2009 AAO Meeting in San Francisco, one ophthalmologist presented on problems he had experienced with compounded Avastin. (There is, however, one problem with this presentation – the good doctor is a paid consultant for Genentech.)

Avastin/Lucentis Update 32: More on the CMS Repricing of Avastin

Finally, just after posting a good summary of the pricing of Avastin reimbursement, I learned about the CMS reversal of its policy. I posted both the summary and the breaking new information.

Some New Postings on Other Subjects:

Femtosecond Lasers Proposed for Use in Cataract Surgery

In June, I received a writeup from old friend Larry Haimovitch, writing about femtosecond lasers under investigation for cataract surgery, his report from ASCRS 2009. After receiving permission from Larry and the publisher of his piece, Biomedical Business & Technology, I reproduced it in my Journal.

By the way, this is my third writeup on femtosecond lasers.

A Review of the History of Customized Corneal Ablation (Custom LASIK)

In July, I noticed an approval for an iris-tracking laser from Technolas Perfect Vision and decided that it would be a good time to review the history of what I had written about customized corneal ablation, basically, its history. So, I listed the nine articles I had written on this subject, along with links to each piece.

Endoscopy in Ophthalmology: The Latest News and Some History

And, finally, a brief note about an improved ophthalmic endoscopic system from Endo Optiks, and my 1992 writeup about this interesting company and product.

INDEX/SEARCH

2009-10-30T06:00:00.000-04:00

INDEX/SEARCH

For your convenience, and because only the last ten posts are shown on the opening page, here is a means for finding all of my posts in an easy-to-use fashion.

Use the Blog Search box in the upper left-hand corner of the header above, enter in "Menu" and click on "search this blog" and menus for all of my 120 or so postings will come up in an easy to search/find method (including short descriptions and live links.)

Avastin/Lucentis Update 32: More on the CMS Repricing of Avastin

2009-10-27T17:07:00.002-04:00

During the 2009 AAO Meeting in San Francisco, there was much discussion of the CMS cuts in reimbursement of Avastin beginning at the beginning of October.

Crystal Phend of MedPage Today provided a good summary of what has been transpiring in this controversy, including comments from the AAO. Now we await the results of Sen. Herb Kohl’s meeting with CMS officials.

Late Breaking News: (Courtesy of Dr. John Kitchens of Retina Associates of Kentucky)

According to CMS....

Effective January 1, we will be replacing the temporary HCPCS code, Q2024 (Injection, bevacizumab, 0.25 mg), with a new HCPCS C code with the same descriptor as Q2024. Because the C codes are only used by hospitals to bill for outpatient services, effective January 1, 2010, physicians should return to their billing practices prior to October 1, 2009 for small doses of Avastin, when administered in their offices to treat macular degeneration. If they have any questions, they should contact their local contractor.

AAO: CMS Payment Cuts for Eye Drug Counterproductive, Group Says

By Crystal Phend, Senior Staff Writer, MedPage Today
Published: October 27, 2009

SAN FRANCISCO -- The recent cut in Medicare reimbursement for intravitreal bevacizumab (Avastin) will hurt both patients and taxpayers by forcing a shift to more expensive options, according to American Academy of Ophthalmology officials.

The rule change that went into effect on Oct. 1 created a code to account for the tiny doses used in ophthalmology, requiring practices to bill in 0.25 mg increments at $1.25 each. That dropped reimbursement for the standard 1.25-mg intravitreal dose from about $50 to $6.25.

Reimbursement for its competitor ranibizumab (Lucentis) -- a closely related molecule generally considered to have equal efficacy -- remained unchanged at a whopping $2,039. Since ranibizumab costs under $2,000 for a single dose, ophthalmologists usually make around $120 with each injection.

But even at the prior reimbursement level, they usually didn't profit from choosing bevacizumab. One vial of bevacizumab -- originally developed for cancer treatment -- contains more than one intravitreal dose, but drawing multiple doses from the same container almost doubles the risk of infection. So, compounding pharmacies divide up the drug into individual doses, repackage, and sterilize them -- but at a price that typically pulled even with reimbursement before the Oct. 1 cut.

So the new rule actually creates a disincentive for using the drug that has been estimated to save Medicare $1.5 billion each year in treating macular degeneration alone, said William Rich, MD, the medical director for health policy at the AAO. The AAO and other ophthalmology organizations immediately started negotiating for a change that would reflect compounding charges, he said. One argument for the new rule is that CMS cannot legally pay for pharmacist costs, but that's not true, according to Rich, who said it is allowed for some asthma and pain management treatments.

Early talks were positive but led nowhere except to a Congressional inquiry, according to George Williams, MD, of William Beaumont Hospital in Royal Oak, Mich., and a member of the AAO Health Policy Committee. "We thought we had a solution," he told retinal surgeons at the AAO meeting here. After daily talks with CMS, "we were told two weeks ago it would be fixed. Two weeks have passed, and it is still not fixed."

Sen. Herb Kohl, D-Wis., who chairs the Senate Committee on Aging, has demanded an explanation for the change and questioned the role of Genentech, which manufactures both drugs and would stand to gain financially from greater use of its more expensive product.

The company has denied any part in the CMS decision, according to media reports.

CMS officials are set to meet with the Senate Committee on Aging later today, and Kohl has reportedly asked for a copy of all communication between CMS and Genentech. However, Rich was skeptical that CMS would have a remedy in place soon. "If the current policy is left in place, physicians lose, patients lose, and taxpayers lose," he said.

He has already heard reports of some ophthalmologists switching to the more expensive drug in order to avoid losing money. Because most patients with conditions treated off-label with bevacizumab are on Medicare, their 20% copays have increased dramatically. "Physicians who changed are getting tremendous pushback from patients," Rich said.

He urged a quick solution to avoid the shift in practice patterns from becoming set. As of 2007, bevacizumab held about 60% of the market share. "We're not interested in assigning blame, we just want to get it fixed" Rich said.

Avastin/Lucentis Update 31: Problems with Pharmacy Compounding of Avastin?

2009-10-27T12:50:00.001-04:00

A disturbing report from the 2009 AAO Meeting, as described on the OSN Supersite. Dr. Malik Kahook, speaking at the joint meeting, said that he had seen 16 cases of IOP spikes following injection of Avastin in his clinic, and has seen reports of at least 74 additional cases in five states. He went on to say that investigation was ongoing with both Lucentis and Avastin, but that "cases are overwhelmingly in the Avastin corner."

"By no means am I saying that Avastin is doing something to the trabecular meshwork or the eye cells, [but] certain compounding techniques are affecting the components that you're getting in the syringe, whether it's aggregation of proteins, formation of dimers and trimers, or other components that could be as large as 20 μm."

Inflammation and toxicity related to delivery of Avastin have been suggested as potentially causing IOP spikes. However, microflow imaging showed significant differences in total particle number in samples of Avastin drawn directly from a multidose vial, from the vehicle and from a dose supplied by a compounding pharmacy, Dr. Kahook said. The compounding pharmacy was selected because it [had] supplied doses to a Utah clinic that saw 42 post-injection IOP spikes.

This bears further watching.

November 10, 2009: A Update to the original story posted on October 27th.

I just received a copy of an email alert, Academy Alive, sent to Academy of Ophthalmology members during the recent meeting in San Francisco. One of the excerpts referenced the story above that I had originally sourced from Ocular Surgery News.

Here is more on this potentially troubling story:

Investigations continue into reports of IOP spikes following VEGF inhibitor use

Research is ongoing into the causes of cases of IOP spikes following bevacizumab (Avastin) or ranibizumab (Lucentis) use that have been reported around the United States, Malik Y. Kahook, MD, said at Glaucoma Subspecialty Day on Saturday. An active researcher on this topic, Dr. Kahook said he knows of more than 50 cases of IOP spikes after bevacizumab use and a smaller number after ranibizumab use. He said most of these patients don’t experience obvious inflammation, have no previous history of glaucoma or ocular hypertension, and sustain high IOP levels for weeks or months that often require laser therapy or surgery.

In an effort to elucidate the causes of these IOP elevation cases, Dr. Kahook and his colleagues tested bevacizumab samples from multiple compounding pharmacies and found noticeable variability in the concentration of the active monomer IgG, which in many cases was much less than the expected 25 mg/ml. Further investigations showed that some of the particles were much larger than expected.

“We believe that these molecules either plug the outflow pathway or may result in subclinical inflammation in the outflow pathway that then leads to elevation in eye pressure,” Dr. Kahook said during an interview. “We do not think that this is an issue with the active IgG monomer of Avastin, and we are not saying that people should stop using Avastin.”

Dr. Kahook recommends further study of the Avastin compounding and shipping processes to ensure greater product consistency between compounding pharmacies and to decrease the chances that high molecular weight adducts cause aqueous outflow obstruction and subsequent IOP elevation in additional patients. Studies are also being conducted to examine the potential link between IOP spikes and ranibizumab use.

Dr. Kahook has previously received research support from Genentech but has not received funding from Genentech for studies on this topic.

Reproduced from Academy Live, October 25, 2009, an e-mail service of the Academy of Ophthalmology to its members.

Q&A

I contacted Dr. Kahook several times asking him to name the five states that he said had reported at least 74 other occurrences; was there an online reference to these other reports; and who was doing the investigation – the FDA, NIH, or Genentech?

He refused to answer, responding that we would have to “await his further publications”.

CATT Study Update 10 – From the 2009 AAO Meeting

2009-10-23T21:28:00.002-04:00

According to Dr. J. Kitchens, Tweeting from the Retina SubSpecialty Day Session at the 2009 AAO Meeting, Dan Martin, head of the CATT Study, reported this morning that the study is almost finished recruiting. To date, 1130 patients are enrolled and the 44 clinics involved hope to have 1200 patients by the end of next month, at which time the study will be closed.

First one-year results on all enrolled patients expected in Spring of 2011.

Avastin/Lucentis Update 30: A Followup to Update 26 – Sen. Herb Kohl Queries CMS

2009-10-14T16:41:00.001-04:00

As reported by Alicia Mundy in a Wall Street Journal Health Blog yesterday evening, Senator Herb Kohl wants to know if Genentech had any input into the CMS decision to reduce the Medicare reimbursement rate for Avastin when used in small doses in the treatment for AMD.

Here is a copy of the WSJ blog and a link to Senator Kohl’s letter to CMS.

WSJ Health Blog
October 13, 2009, 5:41 PM ET

Senator Wants to Know About Medicare Shift on Eye Drugs
By Alicia Mundy

Sen. Herb Kohl wants to know whether Genentech was involved in a recent Medicare shift that could prompt eye doctors to use a more expensive drug. Genentech, which recently became part of Roche, says it wasn’t involved.

As we noted recently, Medicare introduced a new payment code that cut payments to doctors for small doses of Avastin, a cancer drug that many doctors use off-label to treat patients with macular degeneration. That could prompt doctors to switch to Lucentis, a similar but far more expensive drug approved for macular degeneration. (When used to treat the eye, Avastin costs less than $50 per dose; Lucentis costs about $2,000.)

Genentech had “no involvement” in the government’s decision to create a new payment code, a company spokeswoman told the Health Blog

Ophthalmologists are now using Avastin about as much as Lucentis, according to Dr. Philip Rosenfeld, a retina specialist in Florida. Both drugs are sold by Genentech, so its revenues would increase if eye doctors used less Avastin and more Lucentis. Rosenfeld, who was an early proponent of using Avastin in the eye, told us he thinks the change could cost the government nearly $500 million a year, based on estimates of usage he and other eye doctors have compiled.

In a recent letter to CMS, the agency that oversees Medicare, Kohl wrote that he was “disturbed to learn from members of the medical eye care community that Genentech may have communicated directly with CMS officials about this proposed coding change, reportedly suggesting that CMS was over-paying for the small amounts of Avastin being used off-label for intraocular treatments.”

Kohl wants all communication between Genentech and CMS on the matter. CMS says it is currently reviewing the letter and will respond to the senator.

Here is a link to Sen. Kohl’s letter.

Avastin/Lucentis Update 29: Six-Month Results of Controlled Comparison Study Published

2009-10-09T16:44:00.002-04:00

Apparently, Boston University School of Medicine and the VA Boston, have published the first six-month results of a comparison study of Lucentis vs. Avastin, and found no difference in effectiveness. An abstract of the results have just been published online in the American Journal of Ophthalmology.

NOTE: This study is NOT part of the CATT Study, but an independent study.

Here is the news release from BU/VA as published on Science Codex:

Cancer drug is no different in effectiveness as gold standard treatment for macular degeneration

Posted On: October 9, 2009 - 1:50pm

(Boston) - Investigators from Boston University School of Medicine (BUSM) and the VA Boston Healthcare System have shown, at 6 months in a small group of patients, that there is no difference in efficacy between Bevacizumab (Avastin) and Ranibizumab (Lucentis) for the treatment of age-related macular degeneration (AMD). The study, which appears currently on-line in the American Journal of Ophthalmology, is the first to report early outcomes of a prospective, double-masked, randomized, controlled trial comparing Bevacizumab to Ranibizumab for the treatment of exudative (wet) age-related macular degeneration.

AMD is the leading cause of blindness over the age of 50 in developed Western countries. It can present in 2 forms, exudative (wet) or nonexudative (dry). While dry AMD can lead to severe vision loss, wet AMD is often more visually devastating with a higher risk of blindness. The gold standard of treatment is ranibizumab (Lucentis, Genentech Inc.), which was FDA approved for AMD in 2006. Bevacizumab (Avastin, Genentech Inc.) was FDA approved for colo-rectal cancer in 2004, and has since been used worldwide as an off-label, local intravitreal treatment for wet AMD. Both have shown to be efficacious in the treatment of AMD, however, it is unknown which one is more effective.

This study was supported with resources and the use of facilities at the Veterans Affairs Boston Healthcare System, Jamaica Plain, MA. The VA funded the cost of medications for this study. Patients were enrolled by a 2:1 randomization to either the bevacizumab (2) or ranibizumab (1) arm of the study. Once inclusion criteria were met, patients were given intravitreal injection of bevacizumab or ranibizumab every month for the first three months (as they began the trial, month one, and month two). Following the third injection, patients returned for monthly examination and testing and received further injections on an as needed basis for one year.

"Our study aimed to offer early, six-month results of a randomized, double-masked, single center clinical trial comparing the off-label use of bevacizumab with the current gold standard ranibizumab. With a total of 20 subjects and a 2:1 randomization, early results of this trial suggest that at 6 months, visual outcomes of bevacizumab appear to be no different from ranibizumab," said lead author and Principal Investigator Manju Subramanian, MD, an assistant professor in Ophthalmology at BUSM.

Genentech Pharmaceuticals (the manufacturer of both drugs) has refused to sponsor a head to head trial comparing the 2 treatments. The open market cost of a single injection of Ranibizumab (Lucentis) is approximately $2000.00. Comparatively, the cost of a single injection of Bevacizumab (Avastin) for AMD is $40.00. Patients potentially undergo up to 13 injections per year, leading to a large cost differentiation for treatment of this common eye disease.

The National Eye Institute is sponsoring the Comparison of AMD Treatment Trials Study (CATT Study), a multi-centered, randomized, double-masked, clinical trial designed to assess the efficacy of bevacizumab compared to ranibizumab therapy and will be conducted in 44 clinical centers throughout the United States. Early results are expected in 2011.

Source: Boston University Medical Center

Avastin/Lucentis Update 28: Sustained Release Lucentis May Eventually Change the Equation

2009-10-06T18:42:00.000-04:00

In an announcement this morning, Roche and Genentech announced that they had struck a licensing and development deal with Surmodics, Inc., for the latter’s proprietary, biodegradable microparticle drug delivery system. The companies plan on developing a sustained release delivery formulation for Lucentis to treat age-related macular degeneration.

The agreement also provides Roche and Genentech with the opportunity to develop additional compounds, using a sustained drug delivery system, for the treatment of other ophthalmic diseases.

If the new sustained release version of Lucentis provides a better mechanism for delivering this anti-VEGF drug to the retina, acting over a sustained period, it could change the number of doses required for treatment. If one long-lasting Lucentis treatment provides a better outcome than several monthly injections, the patient and doctor interaction could be drastically reduced from the current need for five or six injections per year, to possibly a single or two doses!

However, a development program of this type will probably require a full Phase 3 study and might take close to five years to reach the market.

So, for now, don’t hold your breath!

Avastin/Lucentis Update 27: Dr. Rosenfeld’s Remarks at Retina Congress 2009

2009-10-05T19:46:00.001-04:00

The following abstract of Dr. Rosenfeld’s remarks were reported by OSN Supersite in their continuing coverage of Retina Congress 2009.

Search for optimal anti-VEGF dosing strategy in AMD continues

Although the optimal dosing of anti-VEGF therapy remains unknown, pharmacokinetics of the two most popular agents suggest that adjusting the current dosing strategies may better serve patient needs.

Head-to-head trials of Lucentis (ranibizumab, Genentech) and Avastin (bevacizumab, Genentech) should help steer future treatment decisions, Philip J. Rosenfeld, MD, PhD, said during the J. Donald M. Gass Award Lecture, sponsored by the Retina Society, here at the Retina Congress 2009.

Yet, despite the absence of definitive clinical trials at the present time, there is suggestive evidence that either shortening the dosing frequency to 2 weeks, at least during the loading phase, or increasing the dose strength may result in significantly improved biological activity, Dr. Rosenfeld said.

Lucentis has a 5- to 20-fold higher binding affinity than Avastin, and Avastin has a longer half-life than Lucentis; correspondingly, studies have shown that Lucentis has greater biological activity on day 0 than Avastin.

"But it's not how we start the month, it's how we finish the month," Dr. Rosenfeld said.

Studies of decay kinetics suggest similar activity of the two agents out to 30 days. However, Dr. Rosenfeld said, increasing either the dosing strength or dosing frequency of Lucentis or Avastin, provided it is safe, would yield significantly higher biological activity at 30 days.

A novel anti-VEGF agent, VEGF Trap-Eye (Regeneron and Bayer), may convey even greater affinity and result in 450 times the amount of biological activity at the end of 1 month than either Avastin or Lucentis.

Avastin/Lucentis Update 26: CMS Ups the Ante

2009-10-02T12:24:00.003-04:00

A few days ago, Dr. Philip Rosenfeld told me that Medicare was slashing the reimbursement for Avastin to $7.20 a dose, an unintended consequence of their new Avastin code for small doses, as used by ophthalmologists. He also told me that the AAO is fighting this, but it would go into effect on October 1st.

Today, two stories describing the impact of this new ruling on ophthalmologists, their patients, and Medicare were published by both The New York Times and The Wall Street Journal

October 2, 2009
New York Times

A Rule on Eye Treatment Is Likely to Cost Millions
By Andrew Pollack

Medicare is putting in place a new policy that may sharply curtail the use of the cancer drug Avastin as a treatment for eye diseases. But the way the bureaucratic gears mesh in this case, the move could end up costing Medicare itself hundreds of millions of dollars a year, and individual patients thousands of dollars.

For several years, eye doctors have been using Avastin off-label as a treatment for retinal diseases, particularly age-related macular degeneration, the leading cause of blindness in the elderly. Avastin is similar in its mechanism of action to Lucentis, a drug approved to treat macular degeneration. Both drugs are made by Genentech, a subsidiary of Roche.

Lucentis costs about $2,000 per injection — with an injection needed as often as every month. Although Avastin can cost thousands of dollars a month as a cancer treatment, when used in the tiny portions required for eye-disease injections, it costs only about $30 to $50 per shot. But it was unclear how Medicare should reimburse eye doctors for that use of Avastin. Payment policies varied regionally, though ophthalmologists say their costs for the drug were essentially covered.

Medicare has now introduced a special reimbursement code just for the smaller doses of Avastin. And starting Thursday (October 2nd), the reimbursement of Avastin dropped to about $7.20 for the dose typically used in the eye. That would mean eye doctors — who purchase Avastin and then are reimbursed when using it on patients — would lose money administering the drug.

The new policy would give eye doctors a financial incentive to switch to Lucentis, for which they would be fully reimbursed even though that drug is significantly more expensive. If doctors do shift to Lucentis, “this will have a huge economic impact on Medicare, in the range of hundreds of millions of dollars,” said Dr. David W. Parke II, chief executive of the American Academy of Ophthalmology. “Members view this as a bureaucratic decision that is maybe necessary, based on statutes, but highly short-sighted.”

Dr. Parke said about a million injections a year were given for macular degeneration, about half of them Avastin and the other half Lucentis. He said there was no indication that Genentech, which would make more money if more patients used Lucentis, had anything to do with Medicare’s policy change.

Dr. George A. Williams, an ophthalmologist at William Beaumont Hospital in Royal Oak, Mich., said patients themselves could also be affected. The 20 percent Medicare co-payment for Lucentis is about $400, compared with only a few dollars for Avastin.

Medicare apparently calculated the reimbursement rate for the tiny eye doses based on the average sales price of Avastin for cancer. But it did not take into account the markup charged to eye doctors by compounding pharmacies — the chemists that divide up the Avastin into tiny doses under sterile conditions.

The ophthalmology academy (AAO) has talked to Medicare this week and is hopeful the situation can be resolved, Dr. Parke said. “They truly do understand the problem and are looking for solutions,” he said.

A spokesman for Medicare said in an e-mail message, “We don’t know why the drug is only available to doctors through compounding pharmacies.” He said Medicare would continue to monitor the use of Lucentis and Avastin.

October 2, 2009, 9:28 AM ET
WSJ Health Blog

How Cutting Payments for a Drug Could Cost Medicare More
Jacob Goldstein

EyeMedicare just started reimbursing doctors less for very small amounts of the cancer drug Avastin. Oddly enough, that could mean Medicare will start spending lots more money on the eye drug Lucentis. Here’s why.

Lucentis and Avastin are very similar molecules. A few years back, before Lucentis was on the market, eye doctors realized that they could inject Avastin in patients’ eyes to treat macular degeneration, a condition that can lead to significant loss of vision and occurs mostly in the elderly.

Avastin costs tens of thousands of dollars to treat cancer patients, but the tiny dose doctors inject into patients’ eyes costs a very small fraction of that –the specialty pharmacy chain The Apothecary Shops repackages Avastin for use in the eye and sells it to doctors for $27 per dose, John Musil, the company’s CEO, told the Health Blog.

This week, Medicare cut its reimbursement for the dose of Avastin commonly used in the eye to about $7. Previously, when there was no specific billing code for tiny doses of Avastin, doctors could get reimbursed about $50 for using the drug in the eye, Philip Rosenfeld, an eye doctor at the University of Miami, told the Health Blog.

For a dose of Lucentis, Medicare reimburses doctors $2,039. Doctors pay just under $2,000 for a dose of Lucentis, Rosenfeld said. That means that eye doctors will now lose a bit of money when they use Avastin to treat patients’ eyes, and make a bit of money when they use Lucentis. Avastin hasn’t been approved for use in the eye, but it’s legal for doctors to use it in that way. Many eye doctors use both Avastin and Lucentis, depending on patient preference, Rosenfeld said.

Rosenfeld, like many docs, believes both drugs work equally well to treat macular degeneration; the NIH is currently sponsoring a head-to-head trial. But the new payment structure could push eye docs away from Avastin and toward the far more expensive Lucentis.

“Doctors will do what’s in the best interest of the patients,” Rosenfeld said. “Given that both drugs are equal, it’s not surprising that they’ll do what’s in their financial interest.” That could mean a hit for Medicare, as well as for Medicare patients who are on the hook for co-pays.

Both Lucentis and Avastin were developed by Genentech, now owned by Roche. U.S. sales of Lucentis were over $550 million in the first half of this year, Roche reported. Because the drug is primarily used by the elderly, much of that is paid for by Medicare.

Until now, there was no specific Medicare billing code for small doses of Avastin. A Medicare spokeswoman said the new reimbursement level is based on a formula that is determined by law, and doesn’t take into account the costs of repackaging the drug.

Update October6, 2009 – as reported from the Retina Congress 2009 by OSN SuperSite:

Retina specialists could face compensation issues regarding bevacizumab, other procedures

NEW YORK — A new rule currently under review by the Centers for Medicare and Medicaid Services (CMS) could drastically reduce the compensation for bevacizumab, while other billing codes germane to the practice of retina are also being reconsidered.

A new rule passed last week by the CMS mandates compensation for Avastin (bevacizumab, Genentech) based on average price of the drug. According to Trexler M. Topping, MD, however, the new rate does not account for associated expenses.

"They recently announced the development of code Q2024 for Avastin at a $1.24 per 0.025 mg, giving you a little over $7 for a typical intravitreal dose," Dr. Topping said here during a presentation at the Retina Congress 2009. "The particular methodology that CMS used ignores the medical, legal and risk management issues of separating individual doses from a large vial of drug."

The decision could significantly affect reimbursement for practicing retinal specialists, and it comes at a time when other codes are being revalued by the relative value update committee, the body that recommends code reimbursement rates to the CMS.

According to Dr. Topping, both the injection code and the code for optical coherence topography have been called up for review, and while the American Academy of Ophthalmology is working closely with the relative value update committee, there is early indication that both codes will be significantly devalued.

Endoscopy in Ophthalmology: The Latest News and Some History

2009-09-22T18:19:00.001-04:00

I saw a brief writeup in the current OSN Supersite (September 22, 2009) about Endo Optiks launching a new series of high-resolution micro-endoscopes and it brought to mind the first time I learned and wrote about this company.

I first learned about video endoscopic techniques being used in ophthalmology in the Spring of 1991. At that year’s ASCRS Meeting I learned about Summit Technology’s OmniView and at the Fall AAO Meeting, about Escalon’s InnerView.. In the Summer of 1992, I learned about the newest technology in this field, to be introduced at that Fall’s AAO Meeting, the MicroProbe video endoscope from Endo Optiks. The story about these endoscopes was published in the October 15, 1992 issue of Ocular Surgery News.

I thought that some of you might be interested in both the latest news and a little bit of history.

Here is the latest news from Endo Optiks, followed by the original writeup published in October 1992.

Endo Optiks launches series of high-resolution micro-endoscopes

LITTLE SILVER, N.J. — Endo Optiks has added a new series of high-resolution micro-endoscopes to its existing endoscopes line, providing improved image quality and increased field of view, according to a press release from the company.

"We designed the new high-resolution scopes to help surgeons better visualize the anatomy of the eye," Martin Uram, MD, endoscope creator and co-founder of Endo Optiks, said in the release. "Surgeons will find improved visualization when performing endoscopic cyclophotocoagulation, panretinal photocoagulation and diagnostics."

Two new versions have been launched: the Triple Function Micro-Endoscope and the Dual Function Micro-Endoscope. Both combine light and imaging, but the Triple Function Micro-Endoscope model also offers laser, the release said. The Triple Function Micro-Endoscope has a 19-gauge probe, while the Dual Function Micro-Endoscope has a 20-gauge probe.

The high resolution of the devices is a 70% increase in pixels from the company's existing scopes, from the current 10,000 pixels to a 17,000 pixel fiber optic bundle, the release said.

In addition, the devices offer an expanded 160̊ field-of-view.

Source: OSN SuperSite 9/22/09

Original writeup as submitted July 17, 1992 to Ocular Surgery News and published in the October 15, 1992 issue:

Technology Update

MIS TECHNIQUES REACH OPHTHALMOLOGY

Irving J. Arons
Ophthalmic Consulting Group
Arthur D. Little

It was inevitable that video endoscopic techniques, now widely practiced in general laparoscopic/endoscopic surgery, should finally reach ophthalmology. True, most inner parts of the eye are readily viewed through the pupil and minimally invasive surgery has been a part of the ophthalmologist's armamentarium for some time, but certain parts of the eye are not easily viewed, much less treated, and this new technology seeks to correct this oversight. With the new technology, eye structures such as the back of the iris, the ciliary body, the far reaches of the retina, and sites at or near the zonule attachment points can now be clearly seen and treated. Further, with the magnification and visual detail available with today's video endoscopic equipment, enhanced views of cellular level structures are now possible for other areas of the eye as well.

Over the past two years, at least two video endoscopic techniques have been introduced into ophthalmology. At the 1991 ASCRS meeting, Summit Technology announced its OmniView, an ophthalmic fiberendoscopic system containing between 50 to 70 illuminating fibers surrounding an image guide, all bundled into an 0.8 mm probe. It was introduced for viewing of sutures placed into the ciliary body, for inspection of the integrity of the posterior capsule, and to verify IOL haptic placement. Other applications suggested were for viewing retinal and glaucoma surgery, for otolaryngology, lacrimal duct surgery and for neurosurgery. Summit expected to sell the system for about $18,000.

The second ophthalmic endoscopic system was InnerView, launched by Escalon Ophthalmics at last fall's AAO meeting. This again is a small (20 gauge, 0.9 mm) flexible endoscope probe that can be coupled to a high resolution video display. Although the price had not been fixed at the time of introduction last fall, it was estimated that the system would sell for between $16,000 to $18,000 complete.

However, the newest endoscopic technology, to be launched at this fall's Academy Meeting, is the MicroProbe, an integrated diode laser treatment device combined with a high resolution microendoscope. The new device is from Endo Optiks, a two-year old Little Silver, NJ startup company, founded by Dr Martin Uram, a retinal surgeon in New Jersey. Endo Optiks has been able to couple an endoscopic viewing system with a diode laser and is working on incorporation of an aspirator system, all into a 20 gauge (0.89 mm) probe that can both view and treat formerly inaccessible parts of the eye. Further, with its high resolution color capabilities, the system can be used for diagnosis of difficult to view intraocular structures.

The heart of the system is a unique, patented, lens delivery system that combines a high illumination light source, a high resolution video endoscopic pickup, and a 0.1 to 2 watt 810 nm diode laser photocoagulation delivery system, all contained within a 20 gauge probe. This will allow the surgeon to view and treat a variety of eye structures including the peripheral retina, the pars plana, ciliary body and the posterior aspects of the iris in vivo.

The MicroProbe consists of a compact console containing the light source, the high resolution video monitor, a VCR recorder, the aspirator pump, the diode laser (including a red diode aiming beam), and simple keyboard controls. The system has been undergoing clinical evaluation trials, has received 510 (k) marketing clearance, and will be officially launched at this years AAO Meeting (1992) in Dallas.

By integrating the viewing and treating modalities into a 20 guage handpiece, the new system is truly a breakthrough in ophthalmology. In addition to viewing and treating the peripheral retina and ciliary processes, the unique system can be used for up close and personal diagnoses of other eye structures, giving high resolution colored views of the retina, lens, iris, and other ocular structures (and implants).

The primary application for the new device is expected to be for retinal surgeons for performing all types of vitreoretinal procedures. However, it is expected that glaucoma specialists will also find use for the device in pursuing direct visualization and laser treatment of the ciliary processes, as an alternative treatment for intractable glaucoma. The technology holds great promise for use in other medical fields as well. It is anticipated that the MicroProbe integrated endoscopy and laser system will sell for between $50,000 to $60,000 when it comes to market this fall.

Avastin/Lucentis Update 25: Comparative Studies Proliferate – France Joins the Fray

2009-09-14T12:19:00.006-04:00

According to a story just published in APM Health Europe (September 14, 2009), a French study comparing Roche's Avastin (bevacizumab) and Novartis' Lucentis (ranibizumab) in the treatment of wet age-related macular degeneration (AMD) has enrolled its first patients.

The U.S. CATT Study (Comparison of Age-Related Macular Degeneration Treatment Trials) was launched in February 2008, and a U.K. study is also underway as well as similar studies being carried out in Austria, Germany and Spain.

In France, Professor Gisèle Soubrane of the Creteil hospital outside Paris suggested a comparative study as early as 2006 but failed to secure financing. Early in 2008, the Lyon group of hospitals (HCL) put forward a new protocol and applied for financing. There were various delays and setbacks but the GEFAL (Groupe d'Evaluation Français Avastin versus Lucentis) study is now underway.

The study is sponsored by an academic hospital in Lyon (Hospices Civils de Lyon), the government (via a national research founding program), and the national health insurance system (which reimbursed for Lucentis).

The first recruiting centre in Lyon enrolled an initial patient at the end of June. Contacted by APM last week, Professor Laurent Kodjikian of HCL said: "We have now enrolled 10 patients and by autumn we shall have at least 40 centres."

The GEFAL study is due to enroll 600 patients over a period of 12 to 18 months and they will be monitored for one year.

The French health products safety agency (Afssaps) has been notified that the study involves 46 centres (34 hospitals and 12 private centres).

The study will evaluate the safety and efficacy of Avastin. Provided Avastin is shown to be comparable to Lucentis, the findings should bring down the cost of AMD treatment. This is important since the disease affects elderly people, a population group set to increase.

According to IMS Health figures published in July, in 2008, Lucentis was the 15th most sold drug in France. Turnover was just below 150 million euros. Sales practically tripled between 2007 and 2008.

AFSSAPS RECOMMENDATIONS

Contacted by APM on the off-label use of Avastin since July 2006, Afssaps initially responded by saying it was not in a position to control such use and said it did not intend to communicate with doctors on the matter but later decided to look into the problem.

On Thursday, Afssaps published an information sheet on the off-label use of Avastin, drawing attention to the fact that in its current pharmaceutical form, the product is not adapted to intravitreal administration (insufficient stability data, etc.) and pointing out that the safety data on the use of Avastin in ophthalmology are limited.

The agency says adverse effects with the off-label use of Avastin have been "under-notified" but notes the risk of endophthalmitis/uveitis linked with the injection, and risk of tearing or detachment of the pigment layer of the cornea. Cases of thrombotic side-effects have also been reported.

The agency points out that other products have been authorised for the treatment of wet AMD. Until the results of the GEFAL study and others are available, Afssaps recommends caution in the use of intravitreal Avastin.

Reported by: Sylvie Lapostolle

With the AAO Meeting coming up next month, I expect to hear about the first results of the CATT Study, and perhaps more from some of these other comparative studies as well.

Stay tuned and I will continue to update findings on both the drugs and other technologies for treating AMD.

A Review of the History of Customized Corneal Ablation (Custom LASIK)

2009-07-09T13:07:00.002-04:00

With the recent announcement by Technolas Perfect Vision of the FDA approval of its iris-tracking laser to improve LASIK outcomes, it reminded me that I was among the first to report on customized ablation (or Wavefront Driven LASIK), from its birth at the 1998 AAO Meeting, and subsequent blossoming at the 1999 ASCRS Meeting.

I was also the first to write about LASEK, the technique of pushing aside the epithelium and performing PRK on the surface of the cornea – as opposed to first making a flap with a microkeratome or laser, and then zapping the cornea to reshape it.

Here, in chronological order, is a series of writeups on these techniques that were first published in Ocular Surgery News, under my “Technology Update” byline:

1. I’ve Seen the Future....and its Custom Cornea, OSN, June 15, 1999.

I first learned about custom ablation at the 1998 AAO meeting, but it was at the 1999 ASCRS meeting that I came to realize that it was the future of refractive surgery.

2. Customized Ablation: the Future is Close, OSN, February 15, 2000.

Here is my report on my first encounter with wavefront and ray tracing diagnostics as a pre-cursor to customized ablation.

3. Customized Ablation: Getting Closer Yet, OSN, August 1, 2000.

At the 2000 ASCRS meeting I learned first-hand of the early results on the initial human clinical trials using wavefront combined with LASIK.

4. Customized Ablation: The Wave Moves Forward.....but Keep an Eye on a Newly Developed Technique....LASEK!, OSN, January 1, 2001.

My first exposure to LASEK – laser epithelial keratoplasty, as I explained it in detail.

5. AAO Report: LASEK, Customized Ablation Draws Interest, OSN, January 1, 2002.

More results from the ongoing custom LASIK trials and a new technique for performing LASEK.

6. AAO Refractive Pre-Meeting Focuses on LASIK, LASEK, OSN, January 15, 2002.

An overview of what was reported at the 2001 Refractive Surgery pre-AAO meeting.

7. ASCRS Report: Customized Ablation, Hyperopia & More, OSN, August 1, 2002.

An overview from the 2002 ASCRS meeting.

8. An AAO 2002 Update: Classic vs. Custom LASIK -- The Battle Continues, OSN, January 1, 2003.

And finally, my last report for OSN, reviewing the latest developments occurring at the 2002 AAO meeting.

9. Custom Ablation #9: Questions......and Answers

An update and answers to the question – Custom vs Classic Lasik.

Along with its April 2006 issue, CRS Today published a supplement (sponsored by an unrestricted grant from Advanced Medical Optics) that answered the questions I had raised in previous columns on customized ablation concerning whether wavefront-optimized LASIK was as good as wavefront-guided ablation. (And, were either better than conventional LASIK?)

CATT Study Update 9: The CATT Study is On Track

2009-06-21T13:30:00.002-04:00

I first learned of the possibility of there being a comparative study of Avastin vs. Lucentis in June 2007. I then followed its progress until it finally became a reality in February 2008. The eighth installment traces how it became a reality in the author's own words.

According to an official with the CATT Study, it is on track and proceeding well. The 44 participating centers have recruited over 850 of the called-for 1200 enrollments and anticipate completing patient enrollment by the end of the year.

One-year results from the study are expected to be released in early 2011.

The study began enrolling patients in February 2008.

For more on this historic study, please see my prior Updates listed below:

CATT Study Update (June 2007)
The first hint that there might be a study.

CATT Study Update 2: Avastin vs. Lucentis – It’s Official! (September 2007)
Confirmation that the study will get underway.

CATT Study Update 3: Avastin vs. Lucentis – To Get Underway by Year’s End! (September 2007)
Additional information from the September meeting of potential clinical participants. Patient enrollment was supposed to begin by end of 2007 – it was delayed by announcements from Genentech

CATT Study Update 4: Avastin vs. Lucentis Study Ready to Roll (November 2007)
.UPenn gets its official website up and running.

CATT Study Update 5: First Official Listing of Clinical Trial Sites (January 2008)
NIH gets its website up and running.

CATT Study Update 6: Official Announcement of Trial Start from NEI (February 2008)
NEI releases press release announcing official start of the program.

CATT Study Update 7: An Interesting Commentary by Dr. James Folk (September 2008)
Interesting commentary by Dr. James Folk on the CATT Study.

CATT Study Update 8: The Story Behind The CATT Study (October 2008)
The story behind the story of how the CATT Study really happened – by the people who made it happen.

Femtosecond Lasers Proposed for Use in Cataract Surgery

2009-06-17T19:31:00.011-04:00

As readers of this Journal know, I’ve been actively following developments in the use of femtosecond (FS) lasers. An old friend of mine, Larry Haimovitch, who contributes to Biomedical Business & Technology, just sent me a copy of his ASCRS 2009 report that was included in the June issue of BB&T. It features what he learned about the three companies proposing the use of FS lasers to perform cataract surgeries.

I requested and received permission from both Larry and the powers-to-be at AHC Media, the publishers of BT&T, to reproduce Larry’s report in its entirety.

Please note that the table numbers shown in the report are those used in the original writeup.

Femtosecond Laser Technology May Mark a Quantum Leap

By LARRY HAIMOVITCH

BB&T Contributing Editor

SAN FRANCISCO– The annual gathering of the American Society of Cataract and Refractive Surgery (ASCRS; Reston, Virginia) was held here this spring as specialists from three key ophthalmic specialties – cataract, refractive and glaucoma surgery – gathered to hear the latest clinical information.

With the economy reeling and laser vision corrections (LASIK) procedures down about 35% from last year, the expectation was that physician attendance would decline. However, the allure of a meeting in the spring in San Francisco, one of the great cities in the world, overcame the economic concerns and physician attendance was at record levels.

It is rare that any medical specialty experiences a revolution in new technology. More typically it is a gradual, evolutionary process. However, in a presentation titled “Initial Clinical Experience with a Femtosecond Laser System in Cataract Surgery” at a session on cataract removal techniques and technology, a potentially disruptive new technology was presented.

The talk, which was delivered to a captivated and standing room audience, was given by Zoltan Nagy, MD, an associate professor at Semmelweiss Medical University in Budapest, Hungary. He presented initial human results with a cataract removal system that has been developed by privately owned, venture capital-backed LenSx (Aliso Viejo, California). The company is describing this new technology as the “next-generation femtosecond laser phaco for refractive cataract surgery.”

Femtosecond (FS) lasers have been widely used in refractive surgery over the past several years. The technology was pioneered by IntraLase (Irvine, California) as a laser-based alternative to manual microkeratomes for the precise creation of a corneal flap prior to LASIK. After a slow start, the technology gained tremendous momentum and in the past couple of years had become the “standard of care” for LASIK procedures. This led to its acquisition in April 2007 by Advanced Medical Optics (AMO; Santa Ana, California) for $850 million.

AMO, which was purchased earlier this year for about $2.8 billion (including assumption of its debt) by Abbott laboratories (Abbott Park, Illinois), is now known as Abbott Medical Optics.

The removal of the cloudy natural lens, commonly referred to as a cataract, with today’s technology is manual and requires several steps. The surgical skill to do a “perfect” removal of the cataract is considerable and the procedure is fraught with risks. These adverse events, which are well-documented in the ophthalmic surgical literature, include posterior capsule rupture, the loss of endothelial cells, macular edema, retinal detachment, compromised zonules (ligaments that hold the lens in place) and perhaps most serious of all, the dreaded infection in the eye (endophthalmitis).

The basic concept behind this new approach is to convert the several manual and multi-steps in today’s cataract removal procedure into one that utilizes laser created, surgeon-controlled precision. The belief is that laser-accuracy will significantly enhance the results that are achieved by the surgeon’s hands.

Nagy outlined the several clinical applications of FS laser technology for the cataract removal procedure and these are shown in Table 4.

As an example, Nagy showed a comparison between the gold standard of today’s approach to cataract removal — ultrasonic phaco-emulsification — with the LenSx device. Phaco, which became popular about 20 years ago, is used in virtually every one of the estimated 3 million cataract procedures performed annually in the U.S. Nagy’s analysis showed that the LenSx system was extremely accurate for capsulotomy diameter, with 100% achieving the desired diameter. Conversely, manually performed procedures attained an accuracy of +/- 0.25 millimeters in only 20% of the time. Nagy also pointed out that the LenSx system required less power and effective phaco time to complete the procedure.

A less obvious but potentially huge benefit of this new technology is that it will provide a better capsulotomy prior to implantation of a “premium” intraocular lens (IOL). Premium IOLs encompass both multifocals and accommodating IOLs and enable most patients to either reduce or eliminate their need for reading glasses after cataract surgery. They are significantly premium-priced compared to standard monofocal IOLs and therefore patient expectations of an excellent outcome are far higher.

In part because most cataract surgeons are unable to perform a “perfect” cataract removal, the results from these premium IOLs has been mediocre. According to Andy Corley, global president of the Bausch & Lomb (B&L; Rochester, New York) Surgical Products division, the modest 5% domestic market penetration of premium IOLs is partially due to the limitations of today’s cataract removal process, which has caused some patients to experience disappointing results.

A list of the myriad potential benefits of a femtosecond laser cataract procedure is displayed in Table 5.

The cataract surgery market is a very large and significant ophthalmic market. According to MarketScope (St. Louis), the global market for cataract equipment and related disposable packs approximated $840 million in 2008, with the U.S. accounting for about one-third of this total.

Replacing manual cataract surgery with a highly precise FS laser could have dramatic impact on the competitive landscape in cataract surgery. Alcon Laboratories (Fort Worth, Texas) dominates this market with an estimated 60% global share. Other key players in the sector are AMO and B&L.

In addition to LenSx, which has assembled an outstanding and experienced management team and highly respected board of directors, two other private companies with VC backing are developing similar femtosecond laser technology.

LensAR (Winter Park, Florida) was founded by Randy Frey, who successfully started and sold his former excimer laser vision correction company, Autonomous Technologies. LensAR has also began its human clinical trials several months ago.

OptiMedica (Santa Clara, California) is expected to be another contender in this fledgling sector. This company has been in business for several years, successfully addressing the retinal market with its Pattern Scan Laser (PASCAL). Its proprietary approach to diabetic retinopathy photocoagulation features laser delivery technology that utilizes a short pulse duration, uniform predictable pulses and a precise pattern spacing. The benefits of the PASCAL technology and are shown in Table 6.

OptiMedica has demonstrated very robust growth in recent years, despite a price point for its laser that is approximately twice as much as conventional single-spot lasers. Clearly, its superior technology has enabled it to gain market share and become a force in this segment.

In addition to leveraging PASCAL into the glaucoma market, OptiMedica is ramping up a major effort to become a key player in the FS cataract market. The company has completed its pre-clinical studies and has recently initiated its human trials. Like LensAR and LenSx, OptiMedica hopes that its FS laser technology will enable it to perform an “all laser” procedure that will ultimately supplant manual cataract extractions.

All three companies will need to complete extensive clinical trials prior to entering the U.S. market but it appears that they will be able to file a 510(k) rather than a full PMA to achieve approvals. Based on their progress to date, it is unlikely that entry in the U.S. market will be attained until late 2010 or early 2011.

Glaucoma, Cornea programs

Before the exhibits opened, ASCRS sponsored two meetings, “Glaucoma Day” and Cornea Day” which provided attendees with the latest clinical, legislative and reimbursement from these two important areas.

Glaucoma is a group of disorders that is characterized by elevated intraocular pressure (IOP) that progressively damages the optic nerve in the eye. Without treatment, this can cause visual disability and eventually result in blindness. It affects an estimated 65 million people worldwide and is the second-leading cause of blindness globally. In the U.S., glaucoma currently afflicts at least 2 million Americans.

The risk of glaucoma increases dramatically with age. People who are 80 years old are nearly seven times more likely to have glaucoma than those who are 50. The U.S. Census Bureau has projected that Americans who are 60 and older will increase in number from 40 million to 76 million by 2025. Given this growth, the incidence of glaucoma is expected to increase to at least 3 million by the year 2020. This disease is typically managed medically, and it is estimated that a panoply of pharmaceuticals account for more than 90% of the treatment costs in the U.S. Glaucoma medications account for roughly 40% of the global market for ophthalmic pharmaceuticals, which exceeds $10 billion annually.

The shortcomings of the medical management of glaucoma are numerous and include:
1) Annual costs that for some patients can exceed $3,000.
2) Inconvenient dosage regimens.
3) Lack of efficacy, that is, the drugs often fail to control the elevated IOP.
4) Myriad side effects, including blurred vision, ocular irritation, pain, headaches, elevated blood pressure and gastrointestinal problems.

The disease is completely pain-free and asymptomatic, causing many patients to stop their regimens while their condition deteriorates. It is estimated that less than half of glaucoma patients are even aware they are afflicted. The result of all these barriers is that the compliance rate for patients on glaucoma medications is abysmally low, well below 50%. And, as one physician wryly observed years ago at an ophthalmic conference “drugs do not work when patients do not take them.”

The drawbacks of glaucoma drugs would appear to provide fertile ground for surgery and/or device based solutions. But, this has not occurred, as the mainstays of devices and surgery — drainage devices such as shunts, and filtration surgery (also known as trabeculectomy or trab) — have had modest efficacy and a relatively high level of adverse effects.

The number of trabs has declined from about 50,000 procedures in the mid-1990s to about 20,000 today. It is a complex surgery, and suffers from numerous adverse effects. The number of shunts has not grown either, as they are relegated as a “last resort” for patients in whom all other modalities have failed.

At this year’s “Glaucoma Day,” an interesting debate on the merits of selective laser trabeculoplasty (SLT) compared to medical management took place. SLT, which generally is regarded as the best form of laser therapy, creates tiny holes in the trabecular meshwork, allowing outflow from within the eye and thus reducing IOP.

Taking the side of promoting SLT was Douglas Rhee, MD, a glaucoma specialist from the Massachusetts Eye & Ear Infirmary (Boston), who provided a host of data to support the use of SLT as a primary option for treating glaucoma. He concluded by saying, “Based on effectiveness, compliance, impact on quality of life, risk comparison and cost, I think we’ve settled the argument of medical therapy over SLT.”

Defending medical management was Anissa Jamil, MD, from Glaucom Consultants North West (Seattle), who said that drugs are very effective for the vast majority of patients and are more reliable than a laser intervention.

During a Q & A period following the formal debate, the moderator asked Dr. Rhee what percentage of his patients actually received SLT as primary therapy. Much to the surprise of the audience, his answer was “less than 1% of the time.” When questioned as to why his treatment regimen so heavily favored drugs, he responded that “my patients expect me to prescribe drugs. This is a cultural expectation.” This rather surprising revelation perhaps best explains why prescription drugs utterly dominate the glaucoma therapy landscape today.

One of the more interesting concepts discussed during the program was the possible use of phacoemulsification (ultrasonic emulsification of the natural lens) as a means to lower IOP. It is estimated that in the U.S. about 10% of patients have co-existing cataracts and glaucoma.

There have been numerous studies over the past decade suggesting that phaco can lower elevated IOP. For example at last year’s ASCRS annual meeting in Chicago, Brooks Poley, MD, presented a retrospective study on nearly 600 eyes of the long-term effect of phaco in normotensive and ocular hypertensive eyes. Poley and colleagues found that the eyes with the highest pre-surgical intraocular pressure showed the biggest improvement. He compared this study with the landmark Ocular Hypertensive Treatment Study (OHTS), which was a prospective trial that examined the use of prescription eye drops in more than 1,600 patients, who were followed for over five years.

In the OHTS trial, 817 patients were treated with glaucoma drops and 819 were not. Of those treated with medication, 4.4% converted to glaucoma, compared to 9.5% converted to glaucoma not treated with drops. This compares unfavorably to the 1.1% the rate of glaucoma conversion after phaco alone.

After his presentation at ASCRS a year ago, Poley was adamant about phaco vs. drugs, saying that “drops don’t solve the problem, they just slow the progression. On the other hand . . . the patients that had ocular hypertension, their pressures went down after surgery for the 10 years of our study. We returned them to a normal status. How many patients treated with drops did that? None. That’s mind-boggling.”

These data were corroborated by Reay Brown, MD, who was inspired to conduct his own study to see how phaco reduces IOP. His data was presented at the March meeting of the American Glaucoma Society (AGS; San Francisco).

Brown and his colleagues examined 83 patients with angle-closure glaucoma or narrow angles who had phaco and IOL implantation. They found that 90% of the patients showed an improvement in pressure. At this year’s ASCRS, Brown said that “if you did a multicenter study and found what we had found in our highest pressure group, the FDA would approve cataract surgery as a treatment for angle-closure glaucoma. In other words, if cataract surgery came in a bottle, the label could say that cataract surgery has been found to be effective in the treatment of angle closure glaucoma.”

Several device companies, many venture-capital backed, are hoping to impact the glaucoma market with innovative devices. Some of these companies exhibited at this year’s ASCRS meeting, while some are too early stage to be making a public presence.

Prominent companies include iScience Interventional (Menlo Park, California), which features an innovative and new category of therapy, which it calls interventional ophthalmology. This encompasses microcatheter-based therapies designed to access a wide range of anatomical structures within the eye to aspirate ocular fluids or deliver sterile ophthalmic solutions to the eye. Specific to glaucoma, iScience features iCat canaloplasty, which is the first and only microcatheter-based procedure that safely reduces intraocular pressure (IOP) and dependence on medications in open-angle glaucoma patients. While specific information is not available, it is believed that this procedure is catching on slowly, due to its steep learning curve.

The company recently announced the closing of a Series “F” venture capital financing raising more than $20 million.

Another VC-backed company is Glaukos (Laguna Hills, California), which has developed an
implantable titanium stent called the iStent. This tiny implant, with a 120 mm lumen, is implanted through a tiny corneal incision and positioned so that aqueous fluid can bypass the clogged area of the eye and flow out through another route called Schlemm’s canal. Glaukos has completed its U.S. pivotal trial and filed its PMA in late 2008. Based upon this filing date, final FDA approval could be received in late 2009 or early 2010. The company’s initial marketing strategy will be to address patients who are undergoing a cataract procedure and who have an elevated IOP. These patients would receive an iStent concomitant to their cataract removal and IOL implant.

Another VC-backed company is Transcend Medical (Menlo Park, California), which has also developed a stent-like device. The company’s describes glaucoma as “ophthalmology’s greatest unmet need” and is hoping to begin its U.S. clinical trial in the near future. Like iStent, Transcend intends to initially address the cataract patient with elevated intraocular. The “perfect” glaucoma device, as described by the company, is shown in Table 7.

About the Author

Larry Haimovitch is president of Haimovitch Medical Technology Consultants, a Mill Valley, CA-based health care consulting firm. His firm specializes in the analysis of the medical device industry, with particular emphasis on the current trends and the future outlook for emerging medical technology. The current areas of emphasis are ophthalmology, interventional medicine (cardiology, electrophysiology, radiology and neuroradiology), urology, ophthalmology, minimally-invasive surgical technologies and medical lasers.

He can be reached at: Larry Haimovitch

Menu – Part 13: A Few Updates and Some New Posts

2009-06-12T16:54:00.001-04:00

Since the last menu posting, I have added two updates for AMD; a new approach for treating myopia with femtosecond lasers; a list of my private client studies while at Arthur D. Little and with Spectrum Consulting; revisited thermal keratoplasty as a technique for treating myopia; and posted two columns, one on my early contact lens days written for Vision Monday and the second on cast-molded eyeglass lenses, done for Ocular Surgery News.

First, the AMD Updates:

AMD Update 4: Does Visualizing RPE Cells Hold the Key to Understanding AMD?

David Williams and his team at the Center for Visual Sciences at the University of Rochester came up with a method of visualizing RPE cells in the retina in vivo, using adaptive optics. This could be a breakthrough in understanding how drugs and other treatments for AMD effect these important cells in the retina.

AMD Update 5: Emerging Technologies for Treating AMD

In this posting, I summarized some of the important techniques and technologies under development in the treatment of AMD – including the Ellex 2RT retinal regeneration technique; the potential use of stem cells to regenerate healthy retinal tissue by two research efforts; and a recap of the visualization techniques described in AMD Update 4 that could play an important role in showing the changes in RPE cells affected by some of these techniques.

Another Approach to Intrastromal Ablation

Dr. Rupal Shah, responding to my history of ISA*, told me of her research in using a femtosecond laser to form and remove a lenticle in the corneal stroma to correct myopia. She kindly allowed me to reproduce a report she had written on her research, describing her use of the Zeiss-Meditec VisuMax femtosecond laser in the FLEx technique (Femtosecond Lenticle Extraction).

* Intrastromal Ablation: A Technology Whose Time Has Come?

Private Client Studies – Arthur D. Little (1972 - 1994) and Spectrum Consulting (1994 - 2001)

In addition to the hundreds of articles and columns written over my 30-plus years of consulting, I led over 100 client-sponsored studies, covering a variety of topics. In this posting I have listed the titles of most of the reports I either wrote or was in charge of producing.

Thermal Keratoplasty Revisited

In reading about the work being done by John Marshall and his colleagues at King’s College in London, as well as by old friend David Muller with his new company Avedro, in trying to use microwave energy to flatten the cornea to correct myopia, I was reminded that I had written about earlier attempts do the same thing with a variety of thermal techniques. I looked up the column I had written for Ophthalmology Management in October 1990 and decided it was time to reproduce it on the web.

Vision Monday Columns: A Bit of Nostalgia

In searching for the columns I had written for Vision Monday back in the early 1990s, I came across this piece that described my early history with soft contact lenses. Again, I decided that it should be available online for contact lens historians and researchers, so I posted it to my online Journal.

Cast-Molded Eye Glass Lenses

I recently heard from a couple of old friends back from my contact lens days. They are starting a new company, QSpex Technologies, to produce ophthalmic lenses in an eye care professional’s office. I had done some consulting work on in-office plastic lens molding in the early 1990s and had also studied the high-index plastic lens business. I wrote about one of the innovative in-office lens molding companies in an Ocular Surgery News Technical Update column in 1993, and my friends were wondering if I still had a copy of the column. I managed to find it and have reproduced it on my Journal.

Another Approach to Intrastromal Ablation

2009-06-06T06:17:00.008-04:00

I have heard from several people since I wrote about intrastromal ablation. Some believe that incisions in the stroma to affect corneal shape can be done, as described by Dr. Ruiz, and others believe, in the long term, that it will not succeed.

I have just heard from Dr. Rupal Shah from the New Vision Laser Centers in India. She is amongst the latter. However, she has been involved over the past ten months in a lenticle removal technique using the VisuMax Femtosecond laser and has agreed to allow me to reproduce the paper she has written about this procedure in my Journal.

Note: The technique of forming and removing a lenticle from within the cornea is not a new approach. I wrote about developmental work on shaped lenticles by IntraLase in my 2000 AAO Meeting Roundup, that appeared in the January 15, 2001 issue of Ocular Surgery News. However, as has been pointed out by Dr. Shah, the method of planar applanation and the strong scleral suction used by the Intralase could compress the cornea in an unpredictable way, and therefore reduce the chances of success with such a procedure. The curved interface of the VisuMax Femtosecond Laser, as shown below in her article, along with the light corneal suction and low pulse energy of the VisuMax system seems to be necessary to get good results with such a technique.

Here is what Dr. Shah has written:

FLEx®- A New Paradigm for Laser Refractive Surgery

Dr. Rupal Shah, Clinical Director, New Vision Laser Centers-LaseRx

Trokel and Srinivasan first proposed the use of the excimer laser for corneal photoablation in 1983. Corneal Photoablation involves breaking the intermolecular bonds between tissue molecules, thus enabling precise removal of corneal tissue from the surface of the cornea. In 1988, the first sighted eyes were treated for refractive errors with the excimer laser using a procedure known as photorefractive keratectomy (PRK). PRK was performed by first removing the epithelial cells from the cornea, and then ablating a precise lens from the cornea, using repeated pulses of the excimer laser. PRK allows the safe and predictable correction of refractive errors. However, the procedure has certain limitations, particularly because the corneal epithelium is removed during the procedure. There is extreme pain for the first 24 hours after the procedure, visual acuity is impaired for several weeks after the procedure, there is typically a hyperopic shift during the first few weeks after PRK, and finally there is the risk of corneal haze and regression, particularly in the case of large refractive error correction.

To overcome these limitations, a new procedure called Laser In-Situ Keratomeleusis (LASIK) was developed in the early 1990’s. LASIK married the excimer laser with the microkeratome, an instrument designed for lamellar keratectomy. In LASIK, the microkeratome is used to create a hinged flap at about 130 microns depth on the cornea. The flap is then lifted to one side, and subsequently, excimer laser keratectomy is performed on the stromal bed. After the keratectomy is finished, the flap is then replaced, where it sticks back in its original location, initially by surface tension forces, and later by epithelial “glue” around the flap edges. LASIK overcame most of the limitations of PRK, and thus led to a sharp rise in the popularity and appeal of laser vision correction, both for physicians and patients.

It quickly became clear that the Achilles heel of the LASIK procedure is the microkeratome itself. It is prone to error, particularly due to the demands placed on what is a really precise but ultimately mechanical instrument. Free Caps, incomplete flaps, irregular flaps, button-hole flaps, displaced flaps, epithelial abrasions and other complications occur in approximately 1% of all LASIK cases. In most of these cases, it is not surgeon error but a result of malfunction, or mechanical error or other infirmities (related to blade quality, for example). In addition, the microkeratome flap is prone to thickness variation. This increases the risk of corneal ectasia, particularly for large corrections and thin corneas.

The Femtosecond Laser was introduced to overcome these limitations of mechanical microkeratomes. The Femtosecond Laser is capable of delivering laser energy in an extremely short time (femtosecond pulse width) and very tightly focused in space (in the μm regime). It causes photodisruption within corneal tissue, converting a tiny volume of corneal tissue into a gas bubble, with every laser pulse. When millions of such pulses are laid down in a precise plane at a fixed depth around the center of the cornea, it is possible to create a lamellar slice of the cornea. Thus, the Femtosecond Laser can be used to substitute the mechanical microkeratome in the LASIK procedure. Over the last few years, the Femtosecond laser has developed an excellent safety profile, and is increasingly replacing the mechanical instrument as the instrument of choice for making LASIK flaps. It has several advantages over mechanical microkeratomes in this respect-the flap thickness is more precise, there is little or no chance of flap complications such as button-holes, free caps and irregular flaps, and there is less chance of a displacement, since the Femtosecond laser creates a deep gutter in which the flap “fits” back, thus making it less likely that eyelid movements and such will displace the flap from its place. There is also some evidence that flaps made with the Femtosecond Laser induces lesser higher order aberrations in the eye.

While the Femtosecond Laser is very useful for the LASIK procedure, it is not without issues of its own. It means that the surgeon or eye hospital must invest in two rather expensive lasers, i.e. the Femtosecond Laser and the Excimer Laser. The Femtosecond Laser is used to make the flap, while the Excimer Laser is used to ablate the corneal surface to provide the refractive correction. They must pay for the consumables, license fees and maintenance of two lasers. There are also workflow issues related to a two step procedure as well. The patient must at best be moved only from one laser to another while lying on a pivoting patient bed. Due to the two laser configuration extra space is required in the surgery theatre, and the overall procedure time for a complete LASIK procedure is increased. Moreover, now that the Femtosecond Laser has removed the likelihood of flap problems during LASIK, attention is drawn to the limitations of the excimer laser itself. The excimer laser performance is affected by environmental factors such as humidity, there is peripheral energy loss during laser ablation, and the laser ablation is affected by the environment and other factors like corneal hydration, humidity, and the presence of organic vapors.

Recently, Carl Zeiss Meditec has introduced a new Femtosecond Laser into the ophthalmic market, the VisuMax® (Fig 1). Unlike other popular Femtosecond Lasers, like the Intralase (e.g. FS60, iFS) or the Zeimer Femto LDV, the VisuMax® has a curved (as opposed to a planar) contact glass (Fig 2). It has special optics to create a very precise spot focused in the cornea with extremely high accuracy (Fig 3). The scanning and focusing optics of the VisuMax® make it capable of placing the laser spot at a specified 3 dimensional position almost anywhere in the cornea. It is already a popular instrument to make LASIK flaps.

Figure 1. Zeiss-Meditec VisuMax FS Laser

Figure 2. Curved Contact Glass of the VisuMax Laser

Figure 3. Difference Between Conventional Optics and Zeiss Optics

However, the Visumax is also capable of a procedure, which is called Femtosecond Lenticule Extraction (FLEx®). FLEx® first involves the calculation of the kind of lenticule which needs to be removed for correcting the refractive error of the patient. The VisuMax® is then used to lay down pulses within the corneal stroma to form the lenticle, illustrated in the four steps shown in Fig 4. In the first step, the lenticule backside cut is created. The second step creates the lenticle frontside cut. In another step, the VisuMax® is used to lay down pulses which separate the anterior surface (upper cut) of the lenticule from the stroma. The upper cut of the lenticule is extended a fraction of a millimetre beyond the edge required for the lenticule. It thus serves as the flap. In the third step, the flap side cut is then created to make a hinged flap.

Figure 4. Steps in Formation of the Lenticle

The flap is lifted (Fig 5), and the lenticule extracted from the stroma (Fig 6 & 7). The flap is then replaced (Fig 8). The corneal tissue which otherwise would have been ablated off by the excimer laser is removed physically as a whole in the FLEx® procedure (lenticule extraction instead of tissue ablation). Thus, there is no need for an excimer laser for the refractive correction. FLEx® represents the first “All in One” procedure which uses only the Femtosecond laser to complete all steps of the LASIK procedure.

Figure 5. Flap Pushed Aside

Figure 6. Lenticle Lifted

Figure 7. Lenticle Removed

Figure 8. Flap Replaced

FLEx® promises to change the way eye surgeons perform LASIK. It requires investment in only one laser, and paying for only one laser’s consumables and maintenance. It simplifies workflow within the laser suite. There is less total energy incident on the cornea, and there are none of the limitations of excimer lasers, such as the dependence on corneal hydration levels and environmental humidity. It thus represents a possible paradigm shift in the way laser vision correction is carried out.

Since 2006, Dr. Walter Sekundo and Dr. Marcus Blum have performed FLEx® in Germany on more than 250 eyes, with a follow-up period of more than 2 years for some cases. They established the initial feasibility and safety of the procedure. The Femtosecond laser, of course, does not need new safety tests related to laser-tissue interaction, since it is routinely used for making flaps on the cornea. New Vision Laser Centers’ Vadodara Center was the third center in the world to start FLEx® and, moreover, also represented the first high volume site to test reliability and performance for high patient throughput clinical environments. We have recently completed a prospective study on 250 eyes, and have at least one month follow-up for all patients. This is an ongoing pre-commercial study supported by from Carl Zeiss Meditec. All patients were informed that the procedure was relatively new, with very little worldwide experience, and with results that were not very certain. A single surgeon (Dr. Rupal Shah) did all the procedures. All the procedures were done within a 5 month period, starting from August 2008. Complete pre-operative and post-operative testing was done.

We treated myopia and myopic astigmatism, with a high limit of -10 Diopter Spherical Equivalent. Theoretically, there is no limit on the kind of error that could be treated. Practically, the currently available software limits the treatments to -10 Diopters for safety reasons during the approval phase.

The results of the study are quite satisfying. The refractive stability is excellent. There was hardly any change in the refractive status of the patients from the first day onwards. The refractive predictability is also excellent. 96% of all eyes at one month were within a half diopter of the intended correction, which is at least comparable to or superior to all U.S. FDA trials of excimer lasers. There was a very slight tendency towards overcorrection in the low myopes and a very slight under correction for the high myopes. Interestingly, this was all we found in terms of nomogram optimization so far, although we started with a zero nomogram! It demonstrates the capabilities of the FLEx® and shows that FLEx® is more neutral and less sensitive to factors that normally affect excimer laser ablation (e.g. hydration state of the cornea). At three months, more than 85% of all eyes had an uncorrected visual acuity which was the same or better than their preoperative best corrected visual acuity. At three months, more than 90% of eyes had a best corrected visual acuity which was better than or the same as their pre-operative best corrected visual acuity. However, at one month, this figure was only 67%, which indicates that the visual acuity recovers more slowly than with standard LASIK. There were very few adverse events. One eye suffered from DLK, which resolved over time, while we aborted treatment in another patient, because of a suction loss appearing during the procedure. There were hardly any induced wavefront aberrations, and also an excellent topography outcome (Fig 9).

Figure 9. Topography Maps for an Eye with High Myopic Astigmatism

Thus, FLEX® compares very well with standard LASIK on stability, predictability, efficacy and safety. However, the visual acuity at the time being recovers more slowly than with standard LASIK. With an improvement in the laser energy parameters, as well as an improvement in surgical technique, visual recovery improved even during the study itself. However, we continue to do more work to find out the origin of the slower visual recovery, and a correction thereof. We are also doing more studies to study the biomechanical stability of the cornea post FLEx®, since there are good reasons to believe that the biomechanical stability after FLEx® would be better than with standard LASIK.

In conclusion, FLEx® represents a completely new way of doing laser refractive correction. It takes a familiar technology (Femtosecond Laser) with an excellent safety profile, and uses it exclusively for refractive correction, thus eliminating today’s two laser solution. Although studies in terms of hyperopia correction or the implementation of methods to perform retreatments are currently still ongoing, we clearly see FLEx® becoming part of the refractive surgery main stream. Based on our current results, FLEx® seems to represent a paradigm shift on the way in the field of refractive surgery.

Dr. Rupal Shah.

Dr. Shah is the Clinical Director of New Vision Laser Centers, and LaseRx, Institute of Laser Medicine. She practices in both Mumbai and Vadodara, India and is a consultant for Carl Zeiss Meditec.

Dr. Shah can be reached at: Email: Dr. Rupal Shah

Addendum: Since the above article was prepared, Dr. Shah informed me that she has now treated over 350 eyes in this study. Today, with optimization of laser parameters, she gets excellent refractive results, but visual recovery is also nearly similar to standard Femto-LASIK.

PRIVATE CLIENT STUDIES – Arthur D. Little (1972 - 1994) and Spectrum Consulting (1994 - 2001)

2009-05-21T17:42:00.002-04:00

In addition to the hundreds of articles and columns written over my 30-plus years of consulting, I led over 100 client-sponsored studies, covering a variety of topics. Here are the titles of most of the reports I either wrote or led the effort in producing. Some of the titles have been partly redacted to prevent identification of the client.

Note that nearly all of the studies until 1985 involved contact lenses, at which time I began consulting in medical lasers.

(Bolded studies can be found online.)

1972
● Worldwide Review of Soft Contact Lenses Made of Hydron (B&L Soflens), August 1972

1974
● Technological Developments in Ophthalmic Lens Materials and Processes, February 1974

1976
● The Contact Lens Business--An Emerging Opportunity, June 1976
● Investigation of the Coating Buildup Problem on Soft Contact Lenses, November 1976
● The Soft Contact Lens Business--Profile of an Opportunity, December 1976

1978
● Technical Assessment of a Soft Contact Lens Automated Machining Center, April 1978

1979
● The Contact Lens Solutions Business: An Opportunity for -- --, January 1979
● An Evaluation of Wesley-Jessen's Contact Lens Technology, August 1979
● Identification of a Soft Contact Lens Licensing Partner for -- --, November 1979
● Current and Future Developments in the Contact Lens Industry, December 1979
● An Evaluation of Titmus Eurocon's Contact Lens Technology, December 1979

1980
● A Technology Forecast: Vision Devices 1980-2000, January 1980
● The Development of an Improved Eyeglass Frame Material and Manufacturing Process, March 1980

1981
● Projections of the Markets for Hard Gas Permeable Contact Lenses, January 1981
● The Technical Evaluation of Frontier Contact Lenses Inc., January 1981
● An Overview of the U.S. Contact Lens Business, January 1981
● The Development of Novel Low Cost Disinfection Systems for Soft Contact Lenses, February 1981
● A Worldwide Review of Hard Gas Permeable Contact Lenses, February 1981
● Technical Evaluation of a New Contact Lens Manufacturing Process, February 1981
● An Analysis of the Contact Lens Business of -- --, March 1981
● A Worldwide Overview of the Ophthalmic Industry for the Scottish Development Authority, June 1981
● A Comparison of Low, Medium, and High Water Content Contact Lens Systems, July 1981

1982
● Technical Evaluation of an IOL Research and Manufacturing Operation, January 1982
● The Offering of a Contact Lens Company to Prospective Buyers, Winter 1982
● The Offering of a Retail Optical Business (Inventory, Lab Equipment and Fully-Equipped Dispensing Offices) to Prospective Buyers, Spring 1982
● The Development of a Low Cost Chemical Disinfection System for Soft Contact Lenses, February 1982
● An Overview of Diagnostic and Surgical Ophthalmic Equipment, July 1982
● Current Developments in Hard Gas Permeable Contact Lenses, December 1982

1983
● Assessment of a New Contact Lens Manufacturing Technology, January 1983
● Evaluation of a Soft Lens Cleaning Device, February 1983
● Technological Developments in the U.S. Contact Lens Industry, April 1983
● Near Term Trends in the U.S. Contact Lens Industry, June 1983
● Technological Assessment of -- --, October 1983
● Packaging of a Peroxide Neutralization System, November 1983
● Analysis of R&D and Regulatory Capabilities of Major U.S. Contact Lens Companies, December 1983

1984
● Background Papers on Soft Contact Lenses and Care Products, January 1984
● A Background Report on the Contact Lens Industry in the U.S., January 1984
● The Establishment of a Transfer Price for Contact Lens Blanks, January 1984
● Development of a Tensile Testing Method for Contact Lens Materials, January 1984
● An Overview of Trends and Developments in Eyeglasses and Contact Lenses, March 1984
● The Offering of a Contact Lens Laboratory and Fitting Clinic, April 1984
● The Establishment of a Transfer Price for Intraocular Lenses, April 1984
● The Outlook for the Ophthalmic Products Industry, May 1984
● An Assessment of Competitive Soft Lens Tinting Technologies, June 1984
● Current Trends in the U.S. Contact Lens Industry, September 1984
● Survey of Practitioner Attitudes Toward Cosmetic Extended Wear, November 1984

1985
● Comparison of Estimated Soft Lens Manufacturing Costs, February 1985
● An Update of Near Term Trends in the U.S. Contact Lens Industry, May 1985
● Contact Lens Manufacturing Techniques, August 1985
● The Offering of a New Soft Bifocal Contact Lens for Licensing, September 1985
● Entry Strategy to the U.S. Contact Lens Market, October 1985
● Update of the U.S. Ophthalmic Industry, November 1985
● Technology Assessment of the Green YAG Laser, November 1985

1986
● The Outlook for Refractive Surgery: The Impact of the LRK Technique, March 1986
● The Valuation of an IOL and a Surgical Instrument Companies, June 1986
● The Valuation of an Ophthalmic Products Company, November 1986
● A Brief Study of the CL Market in Japan, November 1986
● The Valuation of an Ophthalmic Instrument Company, December 1986

1987
● Ophthalmology Technical Alert Service, 1987
● An Overview of the Presbyopic Market Place: The Prospects for a New Viable Bifocal Contact Lens Design, February 1987
● A Detailed Survey of the CL Market in Japan, February 1987
● The Outlook for Viscoelastic Substances in Ophthalmology, May 1987
● An International Overview of Contact Lenses, June 1987
● The Nature and Evolution of the Soft Contact Lens Industry in the United States, August 1987 (B&L vs. the IRS)

1988
● The Current and Theoretical Production Capacity of the U.S. Contact Lens Industry, April 1988
● Evaluation of CooperVision, June 1988
● Medical Laser Overview, August, 1988
● Technical and Market Analysis of -- --, July 1988
● Ophthalmic Market Overview, September 1988
● Technology Overview: Ultrasound Catheter Market, December 1988

1989
● Ophthalmic Surgical Equipment Overview, March 1989
● U.S. Market for Soft Contact Lens Lubricant/Rewetting Drops, March 1989
● Contact Lens and Care Product Market Overview, May 1989
● Update: The Outlook for Laser Refractive Surgery, August 1989

1990
● Development of a Manufacturing Plan for Medical Lasers: Product Selection, January 1990
● Technology Overview: Phoenix Laser Systems, March 1990
● Current Developments in Laser Refractive Surgery, July 1990
● Opportunities for Collaboration, September, 1990
● An Evaluation of a New Eyeglass Lens Molding Process, Phase I: Technology Overview, September 1990
● Overview of High-Index Plastic Eyeglass Lens Materials, November 1990
● Background Information on the Contact Lens Industry, December, 1990
● Profitability in the Ophthalmic Industry, December, 1990

1991
● Contact Lens and Care Product Overview, January, 1991
● Current Developments in Laser Refractive Surgery, March 1991
● An Overview of the U.S. IOL Industry, April 1991
● Ophthalmic Industry Overview, August 1991
● Overview of Current Developments in Refractive Surgery, August 1991
● Technology Overview: Phoenix Laser Systems, October 1991
● Overview of the IOL Industry, September 1991

1992
● Excimer Lasers in Surgery, February 1992
● Current Developments in Laser Refractive Surgery, March 1992, updated July 1992
● New Ophthalmic Laser Technologies, June 1992
● Historical Overview of Ophthalmic Lasers in the Mid-1980s (legal case), July 1992
● Medical Laser Technology Alert Reports, monthly, July 1992 - April 1993

1993
● Technology Overview and Strategic Partnering for Unique Medical Laser Product Company, September 1993
● The Outlook for Refractive Surgery Centers, September 1993
● A Cost Comparison of Refractive Surgery vs. Eyeglasses and Contact Lenses, October 1993
● An Overview of Current Developments in Refractive Surgery, December 1993

1994
● An Assessment of a Laser-based Method to Alleviate Heart Attacks, February 1994
● The Outlook for a Laser-based Technique to Cure Psoriasis, March 1994
● Current Developments in Laser Refractive Surgery, August 1994, updated April 1995
● An Assessment of an Unique Laser-based Technique to Diagnose Severe Burns, August 1994

1995
● Estimated Market for a New Mid-IR Laser Delivery Fiber, February 1995
● The Outlook for Refractive Surgery, March 1995
● An Analysis of the Hawaii PRK Market, May 1995

1996
● Potential Laser (and non-laser) Sources for Activating Photofrin, March 1996
● Search for a Diode Laser Source for Activating Photofrin, April 1996
● A White Paper -- Laser Hair Removal: An Application Whose Time has Come, October 1996
● Worldwide Market Overview of Ophthalmic and Dermatologic Lasers, December 1996

1997
● U.S. Market Opportunities for ICON Centers for Cosmetic Surgery, March 1997
● Refractive & Cosmetic Surgery -- Any Synergies?, November 1997
● An Overview of the Medical Laser Industry, December 1997

1998
● Worldwide Medical Laser Marketplace, May 1998
● An Investigation into the Use of "Bermuda Cards", July 1998
● Review of Photodynamic Therapy for Treating ARMD, December 1998

1999
● Update: Trends in Refractive and Cosmetic Laser Surgery, November 1999
● An Evaluation of ThermoLase's Technologies, December 1999

2000
● A Look at the Future of Refractive Surgery, February 2000

2001
● A Brief Overview of the Opportunities for a 3 micron Medical Laser System, July 2001
● Adoption Rates of Soft Contact Lenses, IOLs, and Refractive Surgery, September 2001

Cast-Molded Eye Glass Lenses

2009-05-20T10:53:00.001-04:00

I recently heard from a couple of old friends back from my contact lens days. They are starting a new company to produce ophthalmic lenses in an eye care professional’s office. I had done some consulting work on in-office plastic lens molding in the early 1990s and had also studied the high-index plastic lens business. I wrote about one of the innovative in-office lens molding companies in an OSN Technical Update column in 1993, and my friend was wondering if I still had a copy of the column.

I managed to find the column I had written on my old computer, and since my friends were developing a new company based on this type of process, I decided to reproduce the original column as it relates the history of in-office lens casting.

As a salute to my old friends Tim Rogers and Steve Martin, and their new company QSpex Technologies and its Lens Transformation Process, here is what I wrote about Innotech and its Excaliber lens molding system back in the March 15, 1993 issue of Ocular Surgery News.

TECHNOLOGY UPDATE

The Excalibur SurfaceCasting System from Innotech: "He who has the sword shall be King!"

Irving J. Arons
Ophthalmic Consulting Group
Arthur D. Little

Over the years, several groups of innovative people have attempted to bring techniques for making "instant" ophthalmic lenses in the office or dispensary to market. These attempts reached their peak about five years ago with the advent of LensCrafters' advertisements for "1 Hour Service".

Since the LensCrafter claims to make most Rxs in about an hour were based on having an in-store processing lab, to stay competitive both independent dispensers and other chain retailers explored the options for making "fast" lenses offered by the likes of Vision Sciences and Technavision, the then (barely) surviving in-the-office lens casters.

Technavision, originally known as Orplex, was born in 1982, while Vision Sciences came along a few years later. And then there is Henry Earle, the grandpappy of lens casting, with his Duralens process, which was started in the early 1950s. Later on in 1988 Larry Joel developed his "Fast Cast" system, which he sold to Pearle Vision allegedly for $25 million. Pearle is still working to get the bugs out of the system before releasing it to its retail outlets.

Along the way, both Henry Earle (in about 1985) and Norman Rips, perhaps a year or so later, each developed wafer bonding methods -- the gluing of a thin lens carrying the Rx and/or bifocal correction onto a base stock lens. The Rips' system, originally called the Krom-X process, is now known as the Dicon Instalens process and is still being sold, now by Dicon/Visimed (San Diego). And other wafer systems are being developed by such as Tandem Optics (Rochester, NY), Pentax (Japan) and Sola Optical (Petaluma, CA).

Now, a new company, Innotech (Roanoke, VA), founded by Ron Blum and a group of people formerly associated with Vision Sciences, have come up with a hybrid technology, half way between the old thermal cast molding technique and the newer UV adhesive wafer technology. It is called SurfaceCasting using the Excalibur Office-Based Lens Fabrication System.

This patented process involves a single glass mold -- with either a progressive or flat-top 28 design, a proprietary, thin CR-39-based backup wafer (single vision lens) or Power Plate as the company calls it, a specially formulated CR-39 liquid monomer containing UV curing initiators, and a UV curing apparatus.

In use, two flat-top or progressive molds are placed into a holding tray, about a teaspoonful of the monomer is added to each mold, and the appropriate power plates positioned on top. No gaskets or pressure holding devices are used. The sandwiches are placed into a small UV curing chamber polymerizing the resin which bonds to the power plate backup wafer (back surface of the lens), and assumes the shape (and power) of the mold surface (front lens surface). This resin polymerization process takes about 27 minutes. The cured sandwiches are then placed into a demolding apparatus which separates the finished lenses from the molds in about two minutes. The whole process to produce a pair of bifocal or progressive lenses, including selection of the appropriate molds and wafers, assembly, curing, and demolding, takes about 35 minutes.

According to industry experts from LensCrafters and Texas State Optical who have observed the process close up, operating the system at three beta sites each, the system produced first quality, thin lenses (that the company claims exceed ANSI lens standards) at affordable prices. Innotech claims that the new UV processed lens is about 20% harder than conventional CR-39 lenses and therefore may not require a scratch-resistant coating. Innotech further claims that lenses made using the technique can save a dispenser an average of about 65% of the cost of buying progressive lenses from a lab, and about 35-40% of the cost of typical flat tops. (In the company's calculations, this worked out to about $15 per pair versus $45 for unfinished 75mm progressives and $12 versus $18 for the 75mm flat tops.) Further, the finished lenses can be hard coated, tinted, and anti-reflection coated similarly to standard CR-39 lenses.

For now, a series of 108 core molds can be obtained to make either flat-top 28s (54 molds) or their proprietary progressive design lenses (another 54 molds), with spherical powers from -4.00D to +4.00D, cylinder powers of -0.25 to -2.00D, and add powers of +1.00 to +3.00D. The progressive lens design is a "semi-soft" style according to company executives.

As noted, the system has been beta tested for a minimum of three months at seven sites, including three LensCrafters and three Texas State Optical retail locations. It will sell for approximately $32,000, plus an additional $3000 for an initial supply of monomer and a customized inventory of power plates depending on the practice size and lens type usage. The price includes two days training, service and a one-year warranty. The company claims the system is capable of producing up to 12 pairs of multifocal lenses per day, and that a typical dispenser using the Excalibur SurfaceCast System to produce 6-8 pairs of multifocals per day would pay for it in less than 2 years.

The Excalibur is self-contained with a microprocessor control unit, built in resin dispenser (and reservoir), curing chamber, and mold and wafer inventory holding drawers.

For those interested in seeing the system up close and personal, it will have its first public demonstration at Vision Expo in New York city at the end of March.

A number of question remain to be answered:

● Will high-index resin material and back up wafers be available any time soon to produce high-index lenses?

● The company claims to be able to produce "thin" lenses. How thin is thin?

● What is the life time of the molds? For how many cycles can they be used? What is the cost of replacement molds?

● What is the real cost per lens pair when labor, mold replacement, cleanup and other miscellaneous costs are included?

● What is the yield of high quality lenses? How much breakage/spoilage can be expected over a years usage?

● What skills are required to run the system? Can a lab tech run it, or is special training/education required?

● Will proprietary progressive lens designs such as Varilux be made available in the future?

The company's R&D plans are to extend the SurfaceCasting technology to include production of IOLs, bifocal and toric contact lenses, and consumer and aerospace optics in the future.

Although our initial impression of the system is that it appears promising, perhaps even "revolutionary", as with all things new, only time will tell if this "better mousetrap" will conquer the world (i.e., "He who holds the sword", etc.). But, with the announced initial sales of over 135 systems to LensCrafters and TSO, the company is off to an auspicious start!