With the eye-catching commercial success of new treatments for wet age-related macular degeneration, venture capital investors as well as industry players are turning their attention to the non-exudative form of the disease, dry AMD.

Genentech Inc./Roche has been remarkably successful in wet AMD with its drug Lucentis (ranibizumab), as has Regeneron Inc.’s Eylea (aflibercept), which launched in November 2011 and is well on its way to being one of the strongest biotech launches ever Also see "Finally A FIBCO, Regeneron Sets Its Sights On Eylea And Beyond" - In Vivo, 26 March, 2012..

Although prevalence estimates vary widely in the medical literature, the consensus among researchers is that 85%-90% of the eight million people who suffer from AMD in the U.S. have the dry form. Unlike wet AMD, however, FDA has not approved any therapies for treatment of the dry form of the disease. The high unmet need coupled with a potentially huge market provides more than sufficient rationale for investors and drug companies to dig a stake in the development of therapies for this condition Also see "Biotechs Eye Macular Degeneration" - Scrip, 1 July, 2009..

Multivitamins For Early-Stage Disease But Little Else

Dry AMD develops when extensive drusen deposits of lipids and proteins accumulate between the retinal pigment epithelium and the underlying choroid (vascular layer) in the macular region of the retina. In its early stages, dry AMD may not produce noticeable symptoms. As the disease progresses, however, patients may experience glare intolerance, difficulties in light-to-dark adaptation, and a blurred spot in the center of their vision.

The late stage of the disease is characterized by geographic atrophy (GA), or loss of retinal pigment epithelium and photoreceptor cells in the macular region of the retina. Over time, central vision in the affected eye also can be lost as the atrophic lesions encroach on the center of the macula. In addition to progressing from early AMD to GA, some patients also develop abnormal blood vessel growth (also called neovascularization) under the macula, converting to wet AMD.

Patients diagnosed with early dry AMD may be advised to take high doses of vitamin supplements – formulation of antioxidant multivitamins used in the Age-Related Eye Diseases Study (AREDS) – as a preventive measure to reduce the risk of developing AMD-associated vision loss (AREDS was a randomized perspective study sponsored by the National Eye Institute to learn more about risks and natural history of AMD). The benefits and potential adverse effects of these nutritional supplements have been a subject of debate within the medical community. In addition, laser treatment to promote drusen regression was investigated but found to be ineffective in preventing disease progression.

“Dry AMD is a very large market with huge unmet need, so anything that does show efficacy will be a big winner,” says Emmett Cunningham, an adjunct clinical professor of ophthalmology at Stanford University School of Medicineand a partner at Clarus Ventures. “However, it is hard to show efficacy because to be effective, any treatment would have to modify disease progression, which means long, risky trials.”

A Slew of Failures, Now Some Hope

Unlike wet AMD where the natural history of vision loss is rapid and the resolution of the macular fluid can result in a profound visually acuity improvement, vision loss in dry AMD is slow and may be imperceptible in the short term. Even if a treatment is effective in stopping disease progression, changes in macular anatomy may take months to be appreciated. Trials designed with visual acuity as an endpoint may require years for any benefits to be demonstrated. It is therefore generally considered impractical to use visual acuity as an endpoint for dry AMD, particularly for early-stage trials.

Furthermore, because FDA has not approved drugs for this indication, the regulatory path remains uncertain. However, “the FDA has given consistent guidance that they will look at the change in the sizes of the atrophic lesions,” states Cunningham.

Although overshadowed recently by scientific advances in wet AMD treatment, current knowledge of dry AMD, particularly of the pathobiology of drusen formation in the early stage of disease, is significantly better compared to 5 to 7 years ago, likely a factor in investors’ and companies’ emerging interest.

“We now know enough about dry AMD that we can at least begin to focus on specific targets for therapeutic inhibition,” observes Scott Cousins, a professor of ophthalmology and immunology at the Duke Eye Center and Director of the Duke Center for Macular Diseases and chief scientific offer of the start-up Imagen Biotech, which is working in the field.

Emerging treatment strategies fall into five categories: prevention of photoreceptor and retinal pigment epithelium loss through neuroprotection; reduction of oxidative stress; reduction of toxic by-product accumulation; visual cycle modulation, and suppression of inflammation. Several drug candidates from each of these categories are being tested in clinical trials (see table).

Still, Cousins characterizes understanding of the disease process as “early and primitive.” Cunningham holds a similar view and believes that “the jury is still out on all of the approaches since none has shown convincing efficacy in human trials.”

Indeed, in discussions with experts, “early and primitive” is a term frequently used to describe drug development for dry AMD. Several companies have brought products to Phase II trials, but none has been able to meet the efficacy endpoints. Furthermore, the endpoints that are the most appropriate to use in clinical trials are still being debated.

An additional challenge for drug development in dry AMD seems to be the lack of consistently predictive animal models for the disease. Development of drug candidates, therefore, bears even higher risk than usual since drug developers may have to commit to the high cost of clinical trials without the indicative data that good animal models can provide. As Cunningham puts it, “If you don’t have a good animal model, each time you take a bet, it will be long and expensive. That’s risky from an investment perspective.”

Notable trial disappointments in dry AMD include Sirion Therapeutics’ Phase II trials for fenretinide, a visual cycle modulator; Neurotech Corp./Alcon Laboratories Inc.’s NT-501, an encapsulated cell implant with the ability to secrete a neuroprotectant, and, most recently, Alcon’s tandospirone, a serotonin 1A agonist shown to protect photoreceptor damage in animal models. Despite varied targets and mechanisms of action, these compounds unfortunately have all fallen short of meeting their trials’ primary endpoints or demonstrating clear efficacy signals.

Most recently, in May 2012, investigators presented results from two separate Phase I/II trials of Alexion Pharmaceuticals Inc.’s Soliris (eculizumab), an antibody against the complement component C5. In both cases, the drug, administered intravenously, failed to reach its primary six-month endpoint: reduction in drusen volume in the early AMD study and reduction in rate of GA progression in the late AMD study. Complement, a part of the innate immune system, is believed to play a key role in the pathogenesis of AMD and a number of compounds targeting various components of the complement system are under evaluation for the disease.

The high level of risk involved in developing therapeutics for dry AMD and the failure to overcome efficacy hurdles in clinical trials may well be the reason that it has been virtually quiescent in the partnering front since 2009 when Alcon licensed rights to POT4, an inhibitor of complement C3 activation, from Potentia Pharmaceuticals Inc. At the time, POT4 had finished Phase I for wet AMD and had also shown potential in the dry form of the disease. Cunningham believes that large pharmaceutical companies are waiting for clear efficacy signals in humans such as robust phase II results before committing to any significant amount of investment Also see "The New Ophthalmic Drug Players" - Scrip, 1 October, 2011..

However, despite these risks, large pharmaceutical companies such as Pfizer Inc., Genentech/Roche, and GlaxoSmithKline PLC, in addition to ophthalmology specialty players such as Allergan Inc. and Alcon (now a wholly owned subsidiary of Novartis AG) have maintained an R&D presence in dry AMD with drugs in Phase I or II clinical trials Also see "Venture Eyes Ophthalmology--And Likes What It Sees" - Scrip, 1 October, 2009.. At a recent R&D day, Allergan described its dry AMD program, highlighting a novel, potent corticosteroid as a new candidate for dry AMD. The company also detailed plans to couple brimonidine with its proprietary intravitreal implant technology Also see "Botox And Beyond: Allergan Lays Out Growth Strategy" - Pink Sheet, 2 April, 2012.. Allergan is planning a Phase IIb trial of brimonidine in patients with geographic atrophy. Pfizer, meanwhile, is preparing a Phase II trial of its antibody directed against amyloid, which studies suggest may be an important component of drusen.

Complement Inhibition Is Active Area Of Interest

At the other end of the spectrum is Imagen, which has identified dry AMD as its target area. The company secured $40 million in Series A financing from SV Life Sciences, Novo Ventures and Fidelity Biosciences to pursue treatments for blinding diseases with high unmet needs, with dry AMD as an initial focus Also see "Imagen's Ophthalmology In-Licensing Strategy Attracts $40M Series A" - Pink Sheet, 20 October, 2011.. Initially, much of the company’s activities will rely on in-licensing.

Imagen is staffed with veterans of Eyetech Inc., which brought the first anti-VEGF drug, Macugen, to market for wet AMD in 2005. In addition to Cousins, David Guyer, an ophthalmologist and the founder and former CEO of Eyetech, and a serial ophthalmology entrepreneur, serves as executive chairman of Imagen. Matt Feinsod, also an ophthalmologist and former SVP at Eyetech, is the chief medical officer. Indeed, while there does not appear to be a standard best of breed business model in the ophthalmology start-up world, a small group of experts led by Guyer seems to be behind some of the field’s most energetic companies, which are watched closely by the pharmacos they may eventually seek to work with.

More than six months after its launch, Feinsod says that Imagen has been very active in evaluating many promising technologies worldwide, from academia and industry. Many of these novel approaches are beyond the compounds currently in clinical trials.

Feinsod is confident that the collective experience of the management team gives Imagen a unique position in advancing the compounds once they are acquired. Having secured financing to fund the development initially of three programs, Imagen is in superior position compared to many other new start-ups in the sector. According to Cousins, many start-ups with very primitive and almost academic stage compounds are shopping for incubators with little success, which may well be a reflection of the current funding environment as well as the state of the technology itself.

While no effect on GA growth was seen in the recent eculizumab setback, complement inhibition remains an active area of research in this disease. “Complement inhibition is the therapeutic strategy with the most well-studied scientific rationale for treatment of dry AMD,” said Cousins. “Which part of the complement system is ‘druggable’ and whether systemic administration or local administration of a drug will be more effective – these questions still need to be answered.”

Philip Rosenfeld, a professor of ophthalmology at the Bascom Palmer Eye Institute of the University of Miami, and the lead investigator of the eculizumab trial, also indicated in his presentation that it was possible that a higher dose, different delivery method, or different target of complement might be needed to see an effect of complement inhibition on GA. In the same category as eculizumab but delivered intra-vitreally is Ophthotech Corp.’s anti-C5 aptamer ARC1905; data from a 6-month trial of this agent are currently being analyzed.

Dry AMD Market Could Surpass Wet AMD, Based On Prevalence

Five years after its launch, worldwide sales of Lucentis reached more than $3.7 billion in 2011, mostly from wet AMD. But the drug’s growth is slowing as it is believed to be significantly dampened by the off-label use of Genentech/Roche’s Avastin (bevacizumab), also a VEGF inhibitor approved for treatment of several cancer indications but not for wet AMD, and by Regeneron’s Eylea Also see "Regeneron Plays It Safe With Eylea, Aims To Undercut Lucentis" - Pink Sheet, 21 November, 2011..

Estimates put the prevalence of late stage dry AMD (i.e. patients with GA) at about 1.6 times of that for wet AMD. Thus, a successful therapy for advanced dry AMD should easily reach blockbuster status given that the market is entirely untapped at current time.

Notable Pharmaceuticals In Clinical Trials For Dry AMD

Company

Category

Drug

Mechanism Of Action

Delivery

Current Status

Allergan

Neuroprotection

Brimonidine tartrate

Alpha-2 adrenergic receptor agonist

Sustained-release implant (Novadur delivery system)

Phase I/II completed. Reformulation for longer-term release ongoing.

Pfizer

Anti-amyloid

RN6G

Humanized MAB against amyloid B40 & B42 to reduce amyloid deposition in drusen

Intravenous infusion

Phase II due to start June 2012.

Acucela

Visual cycle modulation

ACU-4429

Rpe65 inhibitor

Small molecule oral formulation

Phase II, due to complete Aug. 2012.

Genentech/Roche

Supression of inflammation

FCFD4514S

Humanized MAB Fab Fragment against factor D

Intravitreal injection

Phase II to start June 2012, due to complete Nov. 2014.

Potentia/ Alcon

POT-4

Synthetic peptide inhibitor of complement C3 activation

Intravitreal injection

Phase I completed.

Alexion

Eculizumab

Humanized IgG antibody against C5

Intravenous infusion

Phase II results presented May 2012 showed lack of efficacy.

Ophthotech

ARC1905

Anti-C-5 aptamer

Intravitreal injection

Phase I ongoing, due to complete Sept. 2012.

Illuvien, Alimera Sciences

Fluocinolone

Acetonide

Glucocorticoid steroid

Extended release implant

Phase II ongoing, due to complete Dec. 2014.

MacuCLEAR

MC-1101

Restore blood flow in choroidal vessels

Topically administered eye drop

Phase II/III to start in July 2012.

Allergan

AGN208397

Novel corticosteroid

Sustained release formulation, intravitreal injection

Phase IIa completed in macular edema. Phase II dry AMD study in planning.

Sources: www.clinicaltrials.gov; company reports, Association for Research In Vision and Ophthalmology presentation, May 2012

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