Alnylam Reports Positive Phase II Data for ALN-TTR02, an RNAi Therapeutic

Alnylam Pharmaceuticals, Inc. announced the achievement of positive clinical results from its Phase II trial of ALN-TTR02, an RNAi therapeutic targeting the transthyretin (TTR) gene for the treatment of TTR-mediated amyloidosis (ATTR). The data were presented today at the 2013 Biennial Meeting of the Peripheral Nerve Society, held June 29 – July 3 in St. Malo, France. Interim results show that multiple doses of ALN-TTR02 led to robust and statistically significant (p<0.001) knockdown of serum TTR protein levels of up to 93%. Knockdown of TTR, the disease-causing protein in ATTR, was found to be rapid, dose dependent, and durable, and similar activity was observed toward both wild-type and mutant protein. In addition, ALN-TTR02 was found to be generally safe and well tolerated in this study.

“These new ALN-TTR02 results are a major milestone in our TTR program, where – for the first time in ATTR patients – we have demonstrated robust knockdown of up to 93% of circulating wild-type and mutant TTR in a multi-dose study. The clinical relevance of lowering circulating TTR has been demonstrated in ATTR patients who have benefited from the elimination of mutant TTR through liver transplantation. In addition, we are very encouraged with the continued safety profile of ALN-TTR02 which has now been extended with this experience in ATTR patients and with multi-dose regimens,” said Jared Gollob, M.D., Vice President, Clinical Research at Alnylam. “This Phase II trial continues in patients receiving a once-every-three-week dosing regimen and we plan to share the complete data set at the International Symposium on Familial Amyloidotic Polyneuropathy in Rio de Janeiro this November.”

“I am very encouraged by these new clinical activity and safety data with ALN-TTR02, an RNAi therapeutic for the treatment of ATTR. Specifically, I am impressed with the potent, rapid, and durable knockdown of both mutant and wild-type TTR, which is important since TTR protein reduction in patients with ATTR has the potential to delay or even reverse disease progression with associated clinical benefits,” said Professor David Adams, M.D., Ph.D., Neurology Department Head at CHU de Bicetre (APHP), Le Kremlin-Bicetre Cedex, France. “I very much 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 debilitating, progressive disease.”

The Phase II trial with ALN-TTR02 is an open-label, multi-center, multi-dose, dose-escalation trial to evaluate the safety and tolerability of two doses of ALN-TTR02 and to demonstrate clinical activity based on serial measurement of circulating serum levels of wild-type and mutant TTR. The study was designed to treat up to 30 ATTR polyneuropathy patients with ALN-TTR02 administered at doses of 0.01 to 0.30 mg/kg, using either a once-every-four-week or once-every-three-week dosing regimen. To date, 25 patients in eight cohorts have been dosed in the study, and all patients for the final cohort have been scheduled for dosing. The international study is being conducted at 10 sites in Portugal, France, Sweden, Germany, Spain, Brazil, and the U.S.

Data from the first 19 patients enrolled and analyzed in this study showed that multiple doses of ALN-TTR02 resulted in rapid, dose-dependent, and durable knockdown of serum TTR levels. As compared with the lowest dose group of 0.01 mg/kg, there was a statistically significant knockdown of serum TTR at doses of 0.15 mg/kg (p<0.01) and 0.30 mg/kg (p<0.001). At 0.30 mg/kg administered once every four weeks, mean TTR knockdown at nadir of 82.6% and 84.8% was observed following the first and second doses, respectively, and maximum TTR knockdown was up to 90.8%. At 0.30 mg/kg administered once every three weeks, mean TTR knockdown at nadir of 83.1% and 87.4% was observed following the first and second doses, respectively, and maximum TTR knockdown was up to 92.8%.