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Alnylam Racing to Prove RNAi Works, For a Disease You’ve Never Heard Of

Xconomy Boston — 

Alnylam Pharmaceuticals has been in the doghouse for a while now, as its technology of choice has fallen out of favor in the industry. But while many people have written it off, the Cambridge, MA-based company has started to show hints that it might—just might—be onto something that works against a rare and deadly disease.

The company (NASDAQ: ALNY) reported last month at a scientific meeting that one of its experimental RNA-interference drugs was able to shut down production of a protein that causes a disease called TTR amyloidosis. The findings, from an early-stage clinical trial of 31 patients, marked the first time that Alnylam has been able to show that an RNAi treatment can specifically block a disease-causing protein in human beings.

The potential of RNA interference has electrified scientists for years, because it offers the potential of blocking disease targets inside cells that can’t be effectively halted by conventional small-molecule or larger biotech drugs. But the excitement has faded the past couple years, as researchers have struggled to deliver these RNA-silencing molecules into cells, and major companies like Roche, Merck, and Novartis have cut back on their investments in the field. Through it all, Alnylam CEO John Maraganore has insisted that the only way to overcome the doubters is to deliver convincing proof from clinical trials, not just mouse or monkey experiments.

Alnylam has made some headway in the clinic the past couple years, and while it’s too early to say it has proved the skeptics wrong, it’s moving full steam ahead on this new flagship program, betting that it will prove that RNAi will someday live up to its promise.

“The level of confidence for us at Alnylam, and among our collaborators, has gone up enormously as a result of this data,” Maraganore says.

Based on the clinical findings (which I’ll get to in a minute), the company has raced ahead with a more potent-second generation delivery technology of its TTR drug, which it plans to move into its first clinical trial in early 2012. The plan is then to move ahead at breakneck speed by wrapping up that study before year’s end, starting a mid-stage study later in 2012, and then leaping all the way into the third and final phase of clinical trials normally required for FDA approval in 2013, Maraganore says.

There are scientific and business reasons why Alnylam has honed in on TTR to be its flagship program. The disease, transthyretin (TTR) amyloidosis, allows excessive amounts of amyloid proteins to build up in tissues throughout the body. Alnylam likes going after this disease partly because it’s a single gene disorder of the TTR protein, and the protein in question is concentrated in the liver, where RNAi therapeutics can be delivered. People typically start developing symptoms of this disease in their 30s and 40s, suffer progressive damage to their nerves and heart, and usually live nine to 11 years after symptoms appear, Alnylam has said.

In terms of the business, there’s little competition, other than a new Pfizer drug tafamadis (Vyndaqel) in Europe. And, while Alnylam has split the ownership of some of its other programs with partners, this drug’s worldwide commercial rights are 100 percent held by Alnylam. Only about 8,000 people in the world are thought to have the nerve-damaging form of amyloidosis, which creates a small community of doctors and patients that a small company like Alnylam can conceivably address on its own. An estimated 40,000 worldwide have the heart-damaging variation of the disease.

Before anybody gets too excited about changing the world for those patients, a lot needs to happen in clinical trials. But Alnylam got off to a promising start with its initial trial of ALNTTR01.

The company showed in animal experiments that the drug was progressively better at reducing the amount of TTR protein circulating in the bloodstream as doses went up. Researchers said that TTR dropped by an average of 41 percent, when the drug was given at the highest of seven different doses tested. That improvement was seen after patients got a single intravenous infusion of the experimental drug, and were followed for 28 days. No patients dropped out of the study because of side effects, and there was no increase in liver enzymes circulating in the blood, which can be a sign of liver damage.

One of the catches with this current data is that Alnylam uses a lipid nanoparticle made by Vancouver, BC-based Tekmira Pharmaceuticals as the delivery capsule to get its drug into the liver where it can inhibit TTR. Alnylam and Tekmira are currently fighting over this intellectual property in court, and nothing has been resolved yet, Maraganore says. While the argument continues, Alnylam is moving ahead with a second-generation proprietary lipid nanoparticle, which it says it developed with partners at Vancouver, BC-based AlCana Pharmaceuticals and the University of British Columbia. The second-generation delivery capsule is designed to be 10 times more potent, which should enable Alnylam to use smaller doses of its drug to achieve the therapeutic effect it wants. And lower doses usually translate to lower costs of manufacturing, which means higher profit margins.

But the data from Alnylam to date is only a scientific measure of progress, and not a sign that the drug is relieving patient’s symptoms. And Alnylam hasn’t shown yet that it can safely deliver the drug repeatedly for patients with a chronic condition. That kind of proof will have to come in further clinical trials.

The good news about the clinical landscape is that Pfizer helped validate one of the key clinical measurements of success through its trials—something called Neuropathy Impairment Score – Lower Limb, or NIS-LL. Essentially, that would be the main goal of a future Alnylam trial, in which physicians look to see if the experimental drug can improve neurological functioning in the legs, Maraganore says.

After interviewing Maraganore many times over the years, I can’t recall ever hearing him anything but upbeat. But the basic science, medical evidence, and business case for other RNAi programs have never quite coalesced like they have with this program. “It’s clear we can make this work,” Maraganore says. “We can deliver siRNAs [small interfering RNA molecules] in humans, and generate exciting effects. We’ve not been able to say that, frankly, ever.”

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