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Alnylam Reports Positive Phase I Data on ATTR Drug; Sees Pfizer Drug Setback as FDA Guide

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Alnylam Pharmaceuticals this week released positive phase I data on its investigational TTR-mediated amyloidosis treatment ALN-TTR02, reporting that the drug triggered up to 94 percent reductions in levels of its target protein after a single dose.

The effects were also found to be rapid, dose-dependent, and durable, putting Alnylam on track to begin a phase III pivotal trial of the drug should data from a recently initiated phase II study prove positive, CMO Akshay Vaishnaw said during a conference call.

Notably, Vaishnaw said that the recent US Food and Drug Administration rejection of Pfizer's compound tafamidis, which was submitted as a treatment for patients with familial amyloid polyneuropathy-associated ATTR, should help guide Alnylam as it advances its drug toward regulatory approval.

Although the FDA was impressed with some of the tafamidis data, he said, the agency objected to the fact that efficacy data come from “a single study, with most of the data being derived from one center” and little supporting data coming from the other seven sites in the trial.

The FDA recently asked Pfizer to complete a second efficacy trial to establish tafamidis' effectiveness before market approval will be granted.

According to Vaishnaw, “tafamidis paved a clear path for future clinical development of therapeutics to treat ATTR.

“We're going to have a strong international, multi-center [study] … [and] aim to balance enrollment across sites,” he said during the conference call. “We've learned a lot about powering studies in TTR from the tafamidis experience, and we're going to power [our trials] in a way that accounts for potential dropouts.”

Alnylam has also “learned a lot about the subtleties from some of the trends that were seen in tafamidis,” such as the kinds of polyneuropathies that were responsive to treatment and which domains of the neuropathy impairment score-lower limb scoring system, a common diagnostic method for ATTR, were “particularly helpful,” he added.

The Data

In the phase I trial, a single dose of ALN-TTR02, which targets both the mutant and wild-type forms of transthyretin, was administered to 17 healthy volunteers. Study subjects were enrolled into five sequential cohorts of increasing doses ranging from 0.01 to 0.5 mg/kg.

The primary endpoint of the study was safety and tolerability, but pharmacodynamic activity was evaluated with serial measurements of serum TTR protein levels through at least day 56.

“The overall results were highly statistically significant,” Viashnaw said. “Even at doses as low as 0.15 milligram per kilogram, substantial serum TTR suppression was achieved, where a mean 82 percent reduction was observed at nadir.

“In the next cohort of 0.3 milligram per kilogram, an 87 percent mean TTR knockdown was achieved at nadir, with a mean of 67 percent reduction still observed 28 days post-dose,” he added. “In the one subject treated at 0.5 milligram per kilogram, a reduction of 94 percent was observed at nadir, with 77 percent suppression maintained at day 28.”

He noted that only one patient received the highest dose because of the “very substantial knockdown” observed at the 0.15 and 0.3 mg/kg dose levels.

“Using a turbidometric assay method to measure TTR, three of four subjects receiving ALN-TTR02 in the 0.3 and 0.5 mg/kg dose groups showed undetectable levels of serum TTR on one or more post-dose days,” Alnylam said. “As expected, serum TTR reductions were highly correlated with parallel changes in retinol binding protein and vitamin A levels.”

Vaishnaw also said that a single dose of ALN-TTR02 maintained “substantial” TTR knockdown for weeks, supporting a once-a-month or even a once-every-other-month dosing regimen. This dosing schedule will be examined in Alnylam's phase II study, which was initiated last month. It is a multi-center, multi-dose, dose-escalation trial that is expected to enroll approximately 20 ATTR patients (GSN 6/7/2012).

Vaishnaw added that “a rather striking result of the [phase I] study [came from] an analysis performed to look at the correspondence of TTR knockdown in humans as compared to non-human primates. Specifically, we observed essentially superimposible curves for TTR knockdown at the same milligram per kilogram dose.

“Certainly, these preliminary results give us great confidence on the human translation of RNAi therapeutics based on non-human primate preclinical studies,” he said.

Delivery Debate

During the conference call, Alnylam CEO John Maraganore attributed the robust TTR knockdown observed in the phase I study to the proprietary second-generation lipid nanoparticle delivery technology used with the agent. The company had tested a previous a version of the drug called ALN-TTR01, which used an earlier lipid nanoparticle licensed from Tekmira Pharmaceuticals, in a phase I trial, but disclosed it only intends to advance ALN-TTR02.

“These [new phase I] results illustrate the very significant potency improvements that we have made with second-generation LNPs,” which stem from “the discovery of novel lipids," he said — work that was described in a paper published earlier this month by Alnylam scientists in Angewandte Chemie.

In light of an ongoing legal battle between Alnylam and Tekmira over the rights to their respective delivery technologies, it is not surprising that Tekmira issued a statement this week staking claim to the delivery technology used with ALN-TTR-2.

"These positive ALN-TTR02 results further validate Tekmira's industry-leading LNP delivery platform as the gold standard for enabling RNAi therapeutics — both within our own pipeline and those of our partners — for a variety of clinical indications," Tekmira President and CEO Mark Murray said in the statement.

Tekmira noted that the initiation of the phase II trial of ALN-TTR02 triggered a milestone payment from Alnylam.

The litigation began in early 2011 when Tekmira sued Alnylam for allegedly stealing trade secrets related to its proprietary lipid nanoparticles (GSN 3/17/2011). The suit, which includes counterclaims from Alnylam, was later expanded by Tekmira to include Alnylam collaborator AlCana Technologies.

A few months ago, Tekmira's Murray said that a trial date for the dispute has been set for Oct. 30, and that he expects the matter to be resolved before the end of 2012.

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