Alnylam (ALNY) Reports Significant Results from ALN-TTR02 Phase I
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Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics company, announced today the achievement of positive clinical results from its Phase I trial with ALN-TTR02, an RNAi therapeutic targeting the transthyretin (TTR) gene for the treatment of TTR-mediated amyloidosis (ATTR). The data were presented today in a seminar by Alnylam scientists at Boston University School of Medicine. Results from this study show that administration of ALN-TTR02 leads to robust knockdown of serum TTR protein levels of up to 94%; the overall results were highly significant (p<0.00001 by ANOVA). Suppression of TTR, the disease-causing protein in ATTR, was found to be rapid, dose dependent, durable, and specific after just a single dose. Alnylam recently reported that it has initiated a Phase II study of ALN-TTR02 in patients with ATTR and has guided that its goal is to start a pivotal trial in 2013.
The Phase I trial of ALN-TTR02 was conducted in the U.K. as a randomized, single-blind, placebo-controlled, single-ascending dose study, and enrolled 17 healthy volunteer subjects. The primary objective of the study was to evaluate the safety and tolerability of a single dose of ALN-TTR02, with subjects being enrolled into five sequential cohorts of increasing doses ranging from 0.01 to 0.50 mg/kg. In addition, pharmacodynamic activity was evaluated with serial measurements of serum TTR protein levels through at least day 56. Serum TTR levels were measured by an ELISA assay and also by a turbidometric assay method.
Preliminary data from this study showed that a single dose of ALN-TTR02 resulted in rapid, dose-dependent, durable, and specific knockdown of serum TTR levels. Even at doses as low as 0.15 mg/kg, substantial serum TTR suppression was achieved, with a mean 81.9% knockdown at nadir. At a dose of 0.30 mg/kg, an 86.8% mean knockdown was achieved at nadir, with a mean 66.7% reduction still observed 28 days post-dose. In the one subject treated at 0.50 mg/kg, knockdown of 93.8% was observed at nadir, with 76.8% reduction maintained at day 28. ALN-TTR02 exhibited a rapid onset of action; over 50% knockdown in TTR was achieved by day three in all of the 0.15, 0.30, and 0.50 mg/kg subjects, and nadir levels were achieved by day 10 to 14. In addition, time courses for TTR reduction showed highly consistent pharmacologic effects, with minimal inter-subject variability in maximal levels of TTR suppression (<5% relative standard deviation among 0.15 and 0.30 mg/kg subjects). Using a turbidometric assay method to measure TTR, 3 of 4 (75%) subjects receiving ALN-TTR02 in the 0.30 and 0.50 mg/kg dose groups showed undetectable levels of serum TTR on one or more post-dose days. As expected, serum TTR reductions were highly correlated with parallel changes in retinol binding protein (RBP) (r2=0.83) and vitamin A levels (r2=0.86). The effects of ALN-TTR02 were also determined to be specific, as subjects (n=6) treated at a 0.4 mg/kg dose of an siRNA targeting PCSK9 in the identical lipid nanoparticle (LNP) formulation showed no significant serum TTR reduction in a separate, recently completed Phase I study. As a result of the positive pharmacology seen at doses as low as 0.15 mg/kg, dosing at 0.50 mg/kg was limited to one patient, allowing for the start of the Phase II study with ALN-TTR02 in ATTR patients. Alnylam believes that these robust and durable knockdown data support a once-a-month or possibly once-every-other month dosing regimen, and intends to examine this further in the ongoing Phase II study.
ALN-TTR02 was found to be generally safe and well tolerated in this Phase I study, consistent with Alnylam’s broader clinical experience with LNP-formulated siRNA which now includes 102 patients or subjects, 334 total doses administered, and a length of treatment exceeding two years. There were no serious adverse events or discontinuations in the study related to ALN-TTR02 and there were no significant adverse events associated with drug up through 0.30 mg/kg. A moderate acute infusion reaction was observed in one subject receiving ALN-TTR02 at 0.50 mg/kg who was able to complete dosing with slowing of the infusion rate. There were no laboratory abnormalities, including no changes in liver function tests, cytokines, or C-reactive protein (CRP).
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The Phase I trial of ALN-TTR02 was conducted in the U.K. as a randomized, single-blind, placebo-controlled, single-ascending dose study, and enrolled 17 healthy volunteer subjects. The primary objective of the study was to evaluate the safety and tolerability of a single dose of ALN-TTR02, with subjects being enrolled into five sequential cohorts of increasing doses ranging from 0.01 to 0.50 mg/kg. In addition, pharmacodynamic activity was evaluated with serial measurements of serum TTR protein levels through at least day 56. Serum TTR levels were measured by an ELISA assay and also by a turbidometric assay method.
Preliminary data from this study showed that a single dose of ALN-TTR02 resulted in rapid, dose-dependent, durable, and specific knockdown of serum TTR levels. Even at doses as low as 0.15 mg/kg, substantial serum TTR suppression was achieved, with a mean 81.9% knockdown at nadir. At a dose of 0.30 mg/kg, an 86.8% mean knockdown was achieved at nadir, with a mean 66.7% reduction still observed 28 days post-dose. In the one subject treated at 0.50 mg/kg, knockdown of 93.8% was observed at nadir, with 76.8% reduction maintained at day 28. ALN-TTR02 exhibited a rapid onset of action; over 50% knockdown in TTR was achieved by day three in all of the 0.15, 0.30, and 0.50 mg/kg subjects, and nadir levels were achieved by day 10 to 14. In addition, time courses for TTR reduction showed highly consistent pharmacologic effects, with minimal inter-subject variability in maximal levels of TTR suppression (<5% relative standard deviation among 0.15 and 0.30 mg/kg subjects). Using a turbidometric assay method to measure TTR, 3 of 4 (75%) subjects receiving ALN-TTR02 in the 0.30 and 0.50 mg/kg dose groups showed undetectable levels of serum TTR on one or more post-dose days. As expected, serum TTR reductions were highly correlated with parallel changes in retinol binding protein (RBP) (r2=0.83) and vitamin A levels (r2=0.86). The effects of ALN-TTR02 were also determined to be specific, as subjects (n=6) treated at a 0.4 mg/kg dose of an siRNA targeting PCSK9 in the identical lipid nanoparticle (LNP) formulation showed no significant serum TTR reduction in a separate, recently completed Phase I study. As a result of the positive pharmacology seen at doses as low as 0.15 mg/kg, dosing at 0.50 mg/kg was limited to one patient, allowing for the start of the Phase II study with ALN-TTR02 in ATTR patients. Alnylam believes that these robust and durable knockdown data support a once-a-month or possibly once-every-other month dosing regimen, and intends to examine this further in the ongoing Phase II study.
ALN-TTR02 was found to be generally safe and well tolerated in this Phase I study, consistent with Alnylam’s broader clinical experience with LNP-formulated siRNA which now includes 102 patients or subjects, 334 total doses administered, and a length of treatment exceeding two years. There were no serious adverse events or discontinuations in the study related to ALN-TTR02 and there were no significant adverse events associated with drug up through 0.30 mg/kg. A moderate acute infusion reaction was observed in one subject receiving ALN-TTR02 at 0.50 mg/kg who was able to complete dosing with slowing of the infusion rate. There were no laboratory abnormalities, including no changes in liver function tests, cytokines, or C-reactive protein (CRP).
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