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Alnylam May Seek Approval for TTR Amyloidosis Rx in 2017 as Other Programs Advance

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NEW YORK (GenomeWeb) – Officials from Alnylam Pharmaceuticals last week provided updates on the two drug candidates from the company's flagship transthyretin-mediated amyloidosis program, stating that the intravenously delivered agent patisiran is proceeding toward a possible market approval in three years, while a subcutaneously administered version called ALN-TTRsc is poised to enter Phase III testing before the end of the year.

Meanwhile, Alnylam is set to advance a handful of preclinical therapies into human studies in short order, including ones for complement-mediated diseases, hypercholesterolemia, and porphyria.

The officials made their comments during a conference call held to discuss Alnylam's second-quarter financial results.

ATTR is caused by a mutation in the TTR gene, which normally produces a protein that acts as a carrier for retinol binding protein and is characterized by the accumulation of amyloid deposits in various tissues. Alnylam's drugs are designed to silence both the mutant and wild-type forms of TTR.

Patisiran, which is delivered using lipid nanoparticles developed by Tekmira Pharmaceuticals, is currently in a Phase III study in patients with a form of ATTR called familial amyloid polyneuropathy (FAP) affecting the peripheral nervous system. Running at over 20 sites in nine countries, that study is set to enroll up to 200 patients and compare treatment to placebo based on improvements in neuropathy symptoms.

According to Alnylam Chief Medical Officer Akshay Vaishnaw, Alnylam expects to have final data from the study in two to three years, which would put patisiran on track for a new drug application filing in 2017.

Meanwhile, ALN-TTRsc, which is under development for a version of ATTR that affects cardiac tissue called familial amyloidotic cardiomyopathy (FAC) and uses Alnylam's proprietary GalNAc conjugate delivery technology, is set to enter Phase III by year-end as Alnylam holds "active discussions" with US and European regulators on the design of that study, CEO John Maraganore noted during the call.

In the interim, Alnylam continues to enroll patients in a pilot Phase II study of ALN-TTRsc, which is designed to test the drug's efficacy for FAC or senile systemic amyloidosis (SSA), a condition caused by the idiopathic accumulation of wild-type TTR protein in the heart.

Based on "encouraging" data thus far, Vaishnaw said that Alnylam has upped the expected enrollment in this study to 25 patients from 15. Available data from the trial is slated for release in November, he noted, stressing that "any clinical endpoint result needs to be considered exploratory given the small sample size and the very limited duration of treatment of only six weeks" in the trial.

Vaishnaw added that an open-label extension (OLE) study for patients in the ALN-TTRsc study will kick off in the coming weeks, allowing the company to gather long-term dosing tolerability and clinical activity data on the drug.

Enrollment in an OLE study of patisiran has been completed with 27 patients, he said, and, "as of today, with up to nine months of therapy … there have been no study drug discontinuations." Clinical endpoint data from approximately 20 patients in this study will be presented at the American Neurological Association meeting in October.

As part of its ATTR efforts, Alnylam has also been conducting natural history of disease studies in both FAP and FAC patients. Data from the 283-patient FAP study was presented earlier this year and showed a rapid progression in neuropathy impairment scores and a high correlation of this measurement with disease severity.

During last week's conference call, Vaishnaw said that clinical endpoint and biomarker data on about 400 patients with either FAC or SSA have already been collected in a nature history study on cardiac ATTR. Maraganore said that these findings would likely be released sometime next year.

Elsewhere in its pipeline, Alnylam is aiming to file investigational new drug (IND) applications for ALN-CC5 in complement-mediated disease and ALN-PCSsc for hypercholesterolemia in 2014. An IND for its porphyria treatment ALN-AS1 is set for either late this year or early next year.

The newest addition to Alnylam's drug-development roster, the hepatitis B treatment ALN-HBV that was acquired when the company bought Merck's RNAi assets earlier this year, is also set to yield an IND in late 2014 or early 2015.

Maraganore noted during the call that while data on the drug generated by Merck are very encouraging, Alnylam is currently working to formulate it with its GalNAc technology.

Q2 financials

For the three-month period ended June 30, Alnylam posted a net loss of $48 million, or $.63 a share, versus a year-ago loss of $18.2 million, or $.29 a share. Included in the figures for the second quarter of 2014 is a $3.9 million expense related to the deal for Merck's RNAi assets.

Also contributing to the loss increase was a rise in research and development spending to $44.7 million from $24.2 million a year earlier as Alnylam pushed ahead with clinical and preclinical initiatives.

General and administrative costs, meantime, jumped to $11.5 million from $5.8 million.

Revenues in the quarter, derived primarily from collaborators, slipped to $7.3 million from $8.7 million.

At the end of the second quarter, Alnylam had cash, cash equivalents, and marketable securities totaling $955.9 million. Boosting its cash position was the sale of $700 million in stock to Genzyme pursuant to the companies' broad drug development alliance signed in January.

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