Final results from Alnylam’s ALN-TTR01 Phase I trial on TTR-mediated amyloidosis

Published on May 11, 2012 at 4:59 AM · No Comments

Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics company, announced today final results from its completed 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 XIII International Symposium on Amyloidosis held May 6-10, 2012 in Groningen, The Netherlands. Data from this study show that administration of ALN-TTR01 resulted in statistically significant reductions in serum TTR protein levels, including both wild-type and mutant TTR protein, in ATTR patients. Knockdown of TTR, the disease-causing protein, was found to be dose dependent, rapid, and durable after just a single dose. The full time course for TTR knockdown reveals the potential for once monthly or possibly once every other monthly dose regimens in further studies. ALN-TTR was found to be generally safe and well tolerated in this study.    

"These Phase I data from our ALN-TTR01 clinical study demonstrate rapid, dose-dependent, and durable lowering of TTR protein levels after a single dose in ATTR patients. The observed reduction of mutant and wild-type TTR in patients with the V30M mutation is important, since both contribute to amyloid deposition. Further, the full time course for TTR knockdown after a single dose confirms our expectations for a once a month or possibly even a once every two month dosing regimen in our further studies," said Jared Gollob, M.D, Senior Director, Clinical Research. "We believe these data with ALN-TTR01 provide key human proof of concept as we advance ALN-TTR02 as our 'go-to-market' RNAi therapeutic for the treatment of ATTR, a debilitating orphan genetic disease. ALN-TTR02 uses our proprietary second-generation LNP formulation which has demonstrated markedly improved potency in human clinical studies, and we look forward to presenting results from an ongoing Phase I clinical study in the third quarter of 2012. Alnylam is committed to bringing this high impact medicine to patients afflicted with ATTR."

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. Data were presented from 32 patients, including eight who received placebo and 24 who received drug.

ALN-TTR01 clinical activity was assessed based on measurements of serum TTR protein levels. ALN-TTR01 demonstrated a dose-dependent reduction in serum TTR levels with a statistically significant mean reduction of 38% at approximately day 7 to 10 in the 1.0 mg/kg group (geometric mean relative to placebo, p=0.01). The rapid onset and durable effect of ALN-TTR01 after a single dose was exemplified by one patient dosed at 1.0 mg/kg who showed 63% TTR lowering at 48 hours, peak TTR knockdown of 81% at day 10, approximately 50% lowering at 30 days post dose, and full recovery only at 60 days. In addition, analysis of serum samples by a liquid chromatography-mass spectrometry method revealed that both mutant and wild-type TTR were knocked down to the same extent in V30M patients; both wild-type and mutant TTR have been shown to cause amyloid plaques in ATTR patients.   

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