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

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.   

ALN-TTR01 was found to be generally safe and well tolerated in ATTR patients. Mild-to-moderate acute infusion reactions were observed in 5 of 24 (20.8%) patients receiving ALN-TTR01 and were readily managed by slowing of the infusion rate where necessary. There were no significant increases in liver function test parameters. All patients on study drug completed the study; there were no discontinuations except for one patient in the placebo group who underwent elective hospitalization for a liver transplant, and was scored as a serious adverse event unrelated to study drug.

"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. The completed results of this study with ALN-TTR01 are promising, particularly the durable decreases in TTR levels after a single dose as well as the knockdown of both mutant and wild-type TTR in patients with the V30M mutation, since we believe that TTR protein suppression has the potential to lead to a reversal of amyloid plaques and clinical benefit," said Teresa Coelho, M.D., Director, Unidade Clinica de Paramiloidose. "Moreover, the emerging clinical data with second generation delivery technology are very encouraging for the ongoing development of ALN-TTR02. 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 orphan genetic disease."

Alnylam is developing ALN-TTR02 as its lead RNAi therapeutic for the treatment of ATTR. ALN-TTR02 uses the identical siRNA as ALN-TTR01 but employs a proprietary second-generation LNP formulation that has demonstrated improved potency and tolerability based on pre-clinical and clinical studies. ALN-TTR02 is currently being tested in a Phase I clinical study in normal healthy volunteers with results expected in the third quarter of 2012. Further, the company expects to start a Phase II study of ALN-TTR02 in ATTR patients in the second half of 2012 and expects to start pivotal studies in 2013.