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Alnylam Names TTR Amyloidosis Rx as Next IND Candidate, Posts Higher Q2 Losses on Increased Costs

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By Doug Macron

Alnylam Pharmaceuticals last week announced that it has advanced its preclinical TTR amyloidosis therapeutic candidate into its formal drug-development pipeline, aiming to file an investigational new drug application on the systemically administered drug by the end of 2009.

The company made the disclosure as part of an announcement of its second-quarter financial results, which included a roughly 77 percent jump in net loss as research and development spending swelled more than 30 percent.

TTR amyloidosis is a hereditary, systemic disease caused by a mutation in the transthyretin gene, according to Jared Gollob, Alnylam's senior director of clinical research.

"The two severest forms of the disease are familial amyloidotic cardiomyopathy, which occurs when the mutant TTR deposits in the heart, and familial amyloidotic polyneuropathy, which occurs when the mutant TTR deposits in the nerves," he said during a conference call held last week to discuss the financial results. "These severe forms of TTR amyloidosis are estimated to affect over 50,000 people worldwide, and the only treatment option for a subset of these patients is liver transplantation. Historically, [however], this is an inadequate approach for the majority of patients."

Alnylam's drug, ALN-TTR, is designed to inhibit both mutant and wild-type TTR.

Driving Alnylam's decision to put ALN-TTR onto a clinical track is preclinical data in rodents, transgenic mice, and non-human primates, which demonstrate that siRNAs targeting TTR can significantly reduce the levels of normal and mutant TTR mRNA in the liver and TTR protein in circulation, Gollob said.

Additionally, as an orphan disease, the company expects there will be "early opportunities for establishing human proof of concept by knocking down the mutant TTR gene that … are strong predictors of potential clinical benefit," Alnylam CEO John Maraganore said during the call.

Although Alnylam remains committed to its other preclinical programs, including one focused on lowering high cholesterol, "for many reasons, [TTR amyloidosis] has got some attractive features related to … what clinical trials might look like and what paths to the marketplace might look like that in many ways we view as more clear-cut than what might exist in the case of hypercholesterolemia," he added.

Commenting on the possible design of an initial clinical trial for ALN-TTR, Gollob said that "an IND-opening study "would, in all likelihood, be done in actual patients with TTR amyloidosis," probably in ones exhibiting different manifestations of the disease such as neuropathy, cardiomyopathy, and a combination of the two.

And while the first study would focus on the drug's safety and tolerability, it would also provide an opportunity for Alnylam to show that ALN-TTR can actually lower mutant and wild-type TTR levels in patients with TTR amyloidosis, he said.

The design of follow-on trials would "depend a lot on what we see in the … initial IND-opening study," Gollob added. "Whether those types of studies would focus more on patients with cardiomyopathy … or whether it would look at all comers, that would really be determined by what we see in the initial study."

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Clinical endpoints in the ALN-TTR effort, he said, would probably include peripheral neuropathy endpoints in patients with the disease's familial amyloidotic polyneuropathy syndrome, such as sensory or autonomic neuropathy endpoints.

"For patients who present with cardioneuropathy as the main part of the disease, there are a number of cardiac endpoints … such as looking at exercise tolerance for those with congestive heart failure or even looking at barriers for radiologic endpoints that give us a sense of whether we're improving cardiac function," Gollob said.

Alnylam's selection of ALN-TTR as its next IND candidate comes as no surprise in light of comments made by a company official earlier this summer.

Alnylam Vice President of Drug Discovery Muthiah Manoharan told RNAi News in June that it was "highly likely" that the company would choose to advance the drug into the clinic ahead of other candidates, in part because the delivery hurdles facing the TTR amyloidosis program were lower than those facing ones in hypercholesterolemia and Huntington's disease (see RNAi News, 6/11/2009).

ALN-TTR is expected to make use of the stable nucleic acid lipid particle delivery technology developed by Alnylam partner Tekmira Pharmaceuticals and which is currently being used with Alnylam's phase I liver cancer drug ALN-VSP.

During last week's conference call, Maraganore said that Alnylam remains committed to both the hypercholesterolemia and Huntington's disease programs, which could possibly yield INDs in 2010.

The Second Quarter

In the second quarter, Alnylam posted a net loss of $22.7 million, or $0.55 per share, versus a year-ago loss of $12.8 million, or $0.31 per share, an increase the company attributed to $11 million in license fees paid to acquire the rights to Isis Pharmaceuticals' single-stranded RNAi technology (see RNAi News, 4/30/2009).

Revenues in the quarter edged up slightly, to $24.6 million from $23.8 million, primarily as a result of $5.4 million in revenues received through Alnylam's collaboration with Takeda Pharmaceutical (see RNAi News, 5/29/2008).

R&D costs in the second quarter surged to $38.6 million from $29.6 million in the same period a year earlier, reflecting the fees paid to Isis for the ssRNAi license, expenses related to the ALN-TTR program, and clinical trials in liver cancer and respiratory syncytial virus.

General and administrative expenses rose to $8.4 million from $7.1 million.

As of June 30, Alnylam had cash, cash equivalents, and marketable securities totaling $473.8 million. The company said it expects this balance will be greater than $435 million by the end of the year.

Alnylam also said it expects to end 2009 with a cash operating loss of between $35 million and $45 million, excluding the $11 million paid to Isis under the ssRNAi deal.

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