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Facing a Crowded AMD Field, Alnylam Considers Dropping Drug Program, Focusing on Others

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After Alnylam Pharmaceuticals' President and CEO John Maraganore announced last week that the company's wet age-related macular degeneration drug development program, the most advanced in its pipeline, might not proceed, investors reacted negatively. As of Thursday morning, about one week after news broke, the stock had lost about 10 percent of its value and was trading around $8.90.

But despite the negative near-term impact, a decision by Alnylam to exit an already over-crowded field may prove to be a smart move in the long run, saving the company's cash for drug-development programs in less competitive fields.

During a conference call last week to discuss the company's second-quarter financial performance, Maraganore said that Alnylam is currently on track to begin clinical testing of an AMD drug candidate before the end of this year. This would make the company the third firm to test an RNAi-based AMD treatment in humans behind Acuity Pharmaceuticals and Sirna Therapeutics.

However, he noted that "the [AMD] landscape has changed dramatically in the last month or so. In particular, we all need to take note of the recent Lucentis data presented at the American Society of Retina specialists."


"The [AMD] landscape has changed dramatically in the last month or so."

Lucentis, a drug being developed by Genentech and Novartis, is a humanized antibody fragment designed to bind to and inhibit VEGF-A. At ASR last month, Genentech presented 1-year data from a phase III study of 716 patients showing that monthly intraocular injections of the drug helped prevent vision loss. Importantly, Lucentis-treated patients also experienced an improvement in visual acuity compared with controls, whose vision continued to deteriorate.

Genentech has also submitted the drug for a fast-track designation and said it could begin the process of seeking regulatory approval for the drug as early as the end of this year if the designation is granted.

In addition, recently disclosed data show that Genentech's cancer drug Avastin, which also targets VEGF, has been used effectively off-label to treat AMD. Given these and other market conditions, Maraganore said Alnylam might shelve its AMD research in order to focus on other preclinical programs, namely its respiratory syncytial virus program, which is slated to enter the clinic in the first half of 2006.

Lowest-Hanging Fruit

AMD has become an increasingly popular starting point for RNAi drug developers for a number of reasons, the biggest of which being the relative ease with which RNAi agents can be delivered into the eye.

Another factor is the sizable market opportunity: the Macular Degeneration Partnership estimates that AMD affects between 14-24 percent of the US population aged 65-74 years and 35 percent of those aged over 75. And as the US population ages, these figures are only expected to increase.

Currently, there are two US Food and Drug Administration-approved treatments for AMD: Visudyne, a photodynamic therapy made by Novartis and QLT Phototherapeutics, and Macugen, made by Pfizer and Eyetech.

The first, which is dosed as often as every three months, is administered intravenously and activated with a light on the eyes. Because the drug is light activated, patients are advised to avoid sunlight for five days after treatment. The second is administered via direct intraocular injection every six weeks.

Both treatments slow the progression of AMD-associated vision loss, but neither has shown the ability to improve vision.

By November 2004, RNAi-based drugs for AMD began to gain hold. At that time, Acuity became the first company to advance an RNAi-based AMD drug — Cand5, which targets VEGF — into the clinic (see RNAi News, 11/12/2004). Weeks later Sirna initiated a phase I trial of its own RNAi-based AMD therapy, Sirna-027, which attacks VEGF receptor-1 (see RNAi News, 11/26/2004).

All the while Alnylam was working in collaboration with Merck (see RNAi News, 7/2/2004) to get its own VEGF-targeting AMD drug, called Aln-VEG01, into clinical trials before the end of 2005. Then, earlier this year, Quark Biotech entered the mix, announcing that it was pursuing the disease with an RNAi drug designed to silence the gene RTP801 (see RNAi News, 3/18/2005).


"If we don't see a fruitful path forward [in AMD], we will not waste our valuable resources to initiate clinical trials" in this indication.

Making a Choice

During last week's conference call, Maraganore said that any decision on the future of Alnylam's AMD program would be made after Merck and "key opinion leaders" reviewed the situation.

"If we don't see a fruitful path forward [in AMD], we will not waste our valuable resources to initiate clinical trials" in this indication, Maraganore said. As of June 30, Alnylam had $31.6 million in cash, cash equivalents, and marketable securities, and second-quarter operating expenses of $12.3 million, excluding reimbursements received from collaborators.

In response to an analyst's request for additional clarity on how a decision might be made on the future of the AMD program, Maraganore noted that "there are other ocular neovascular diseases that may be more appropriate to go after as the initial first step. That wouldn't affect anything as it relates to time into phase I, but it would certainly reflect our changes or thoughts on phase II studies. That includes diabetic macular edema and diabetic retinopathy," he said.

Additionally, Alnylam and Merck might say, "'Let's not go ahead and focus on the other two ocular disease targets that we have in our collaboration,'" he added.

These statements seem to indicate that Alnylam could continue development of Aln-Veg20, but substitute either diabetic macular edema or diabetic retinopathy for AMD, and still be in the clinic before year-end. They also imply that the company could drop VEGF as a target for its ocular diseases program with Merck altogether, and focus on two other undisclosed targets instead.

Officials from Alnylam declined requests for comment. An Alnylam spokeswoman said that the company would not be making any statements to the media regarding the AMD program beyond what Maraganore had said during the conference call.

— Doug Macron ([email protected])

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