Positive preliminary results from Alnylam's ALN-TTR01 Phase I clinical trial for TTR-mediated amyloidosis

Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics company, announced today positive preliminary results from its Phase I clinical trial with ALN-TTR01, an RNAi therapeutic targeting transthyretin (TTR) for the treatment of TTR-mediated amyloidosis (ATTR). The data were presented at the VIIIth International Symposium on Familial Amyloidotic Polyneuropathy being held November 20 - 22, 2011 in Kumamoto, Japan. Data from this study show that administration of ALN-TTR01 resulted in statistically significant reductions in serum TTR protein levels in ATTR patients. Lowering of TTR was found to be dose dependent, rapid, and durable after just a single dose. To date, ALN-TTR01 has been generally safe and well tolerated in this study.

“RNAi therapeutics represent a novel and exciting approach for ATTR patients and have great potential to make a meaningful impact in the treatment of this devastating disease”

"We are very pleased with these Phase I data from our ongoing ALN-TTR01 clinical study. Importantly, we demonstrated rapid, dose-dependent, and durable lowering of serum TTR protein levels after a single dose in ATTR patients. These pharmacodynamic effects confirm our expectation for once-monthly dosing in humans with systemically delivered RNAi therapeutics. Further, we demonstrated that ALN-TTR01 was safe and well tolerated," said Akshay K. Vaishnaw, M.D., Ph.D., Senior Vice President and Chief Medical Officer of Alnylam. "We look forward to the continued advancement of our ALN-TTR program, including our upcoming ALN-TTR02 regulatory filing, and are committed to bringing this important medicine to ATTR patients in need."

This Phase I study was designed as a randomized, placebo-controlled, single-dose escalation study in patients with ATTR. Patients were enrolled in seven sequential cohorts of increasing doses ranging from 0.01 to 1.0 mg/kg. There were four patients per cohort, with patients randomized to receive drug or placebo in a 3:1 ratio. Following the completion of dose escalation, additional patients were enrolled at 1.0 mg/kg. The study was designed to enroll up to 36 patients. Data available to date were presented from 31 patients, including eight who received placebo and 23 who received drug.

Assessment of ALN-TTR01 clinical activity based on measurements of serum levels of circulating TTR protein was performed to demonstrate human proof of concept for the ALN-TTR program. ALN-TTR01 demonstrated a dose-dependent reduction in serum TTR levels with a statistically significant mean 41% reduction at the 1.0 mg/kg dose level (geometric mean relative to placebo).

To date, ALN-TTR01 has been found to be well tolerated and there were no serious adverse events related to study drug administration. Mild-to-moderate acute infusion reactions were observed in three of 23 (13%) patients receiving ALN-TTR01 and were readily managed by slowing of the infusion rate where necessary. There were no drug-related discontinuations from the study and there were no significant increases in liver function test (LFT) parameters. Further, pharmacokinetic studies showed that ALN-TTR01 administration was associated with approximately dose-proportional plasma exposure.

"RNAi therapeutics represent a novel and exciting approach for ATTR patients and have great potential to make a meaningful impact in the treatment of this devastating disease," said Teresa Coelho, M.D., Director, Unidade Clinica de Paramiloidose. "The results of this ongoing study are encouraging, particularly the evidence for dose-dependent decreases in TTR serum levels since we believe that TTR protein suppression has the potential to lead to a reversal of amyloid plaques and clinical benefit. Accordingly, I look forward to the continued advancement of RNAi therapeutics in clinical trials for the treatment of ATTR, as there are currently few options for patients suffering from this devastating disease."

ATTR is caused by mutations in the TTR gene, which is expressed predominantly in the liver and results in the accumulation of pathogenic deposits of mutant and wild-type TTR protein in multiple extra-hepatic tissues, including the peripheral nervous system, heart, and the gastrointestinal tract. ALN-TTR01 is a systemically delivered RNAi therapeutic that targets the TTR gene; it comprises an siRNA formulated in a first generation lipid nanoparticle (LNP). In addition, Alnylam is developing ALN-TTR02 which utilizes the company's second generation LNP technology and demonstrates an over 10-fold improvement in potency in animal models. The company plans to file an investigational new drug (IND) application, or IND equivalent, for ALN-TTR02 at or around year's end.

"These results represent a key milestone in the advancement of RNAi therapeutics as a new class of innovative medicines. Indeed, we believe that the lowering of serum TTR protein levels observed in this study demonstrates additional human proof of concept with a systemically delivered RNAi therapeutic. Moreover, we believe this result marks the first time RNAi has been shown to silence a disease-causing gene in humans," said John Maraganore, Ph.D., Chief Executive Officer of Alnylam. "In the coming weeks, we expect to report data from our ALN-PCS program which targets PCSK9 for the treatment of severe hypercholesterolemia and utilizes our second generation LNP technology. Collectively, we believe current data from our ALN-TTR01 study and pending data from our ALN-PCS study will strengthen our overall confidence in our 'Alnylam 5x15' product strategy, where we aim to advance RNAi therapeutics for the treatment of genetically defined targets and diseases."

The presentation of these data made at the VIIIth International Symposium on Familial Amyloidotic Polyneuropathy can be found on our website at www.alnylam.com/capella.

Source Alnylam Pharmaceuticals

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