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TTR Amyloidosis
ALN-TTR: TTR Amyloidosis
We are developing ALN-TTR, a systemically delivered RNAi therapeutic that targets the transthyretin (TTR) gene, to treat TTR-mediated amyloidosis (ATTR).
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.
As there are currently few options for patients suffering from this devastating disease, we aim to rapidly advance our ALN-TTR program and are committed to bringing this important medicine to ATTR patients in need.
ALN-TTR02
ALN-TTR02 is comprised of an siRNA formulated in a proprietary second-generation lipid nanoparticle (LNP). In March 2012, we initiated dosing in a Phase I clinical trial with ALN-TTR02. The trial is being conducted in the U.K. as a randomized, single-blind, single-ascending dose study, enrolling up to 32 healthy volunteer subjects. The study is aimed at evaluating the safety and tolerability of ALN-TTR02 in healthy volunteers. In addition, the study will evaluate the clinical activity of ALN-TTR02 based on measurements of serum levels of TTR, the disease-causing protein in patients with ATTR. ALN-TTR02 utilizes the company's proprietary second-generation lipid nanoparticle (LNP) technology using the "MC3" lipid. Alnylam expects to present data from this study in the third quarter of 2012 and, assuming positive results, expect to start a pivotal trial for ALN-TTR02 in 2013.
ALN-TTRsc
Alnylam also plans to advance ALN-TTRsc, which utilizes a GalNAc-conjugate delivery approach and subcutaneous dose administration. Pre-clinical studies have shown that once weekly dosing with ALN-TTRsc enables robust and sustained silencing of TTR over a multi-week period. We plan to file an investigational new drug (IND) application for ALN-TTRsc in the second half of 2012, with data expected in the first half of 2013. We believe that ALN-TTRsc represents an attractive opportunity for product differentiation in the ATTR clinical setting.
ALN-TTR01
ALN-TTR01 is comprised of an siRNA formulated in a first generation LNP. Preliminary results from our phase I human clinical study with ALN-TTR01 were presented at the International Symposium on Familial Amyloidotic Polyneuropathy in November 2011. The Phase I study was designed as a randomized, placebo-controlled, single-dose escalation study in patients with ATTR. The study was designed to enroll up to 36 patients. Data presented at that time were from 31 patients (8 received placebo and 23 received drug) and showed that administration of ALN-TTR01 resulted in statistically significant reductions in serum TTR protein levels in ATTR patients. Lowering of serum TTR protein was found to be dose dependent, rapid, and durable after just a single dose. We intend to complete its ongoing ALN-TTR01 Phase I study in the first quarter of 2012 and report final data in the first half of 2012.
ALN-TTR Clinical Timeline
This Phase I study was designed as a randomized, placebo-controlled, single-dose escalation study in patients with ATTR. Patients were enrolled in cohorts of increasing doses ranging from 0.01 to 1.0 mg/kg (3:1 drug/placebo ratio). 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, p=0.02). All five patients receiving drug in the 1.0 mg/kg group showed lowering of serum TTR protein which ranged from 25 to 81%. Nadir levels were achieved approximately 7 days after dosing and serum TTR levels remained decreased through at least 24 days. These effects were exemplified by one patient dosed at 1.0 mg/kg who showed 63% lowering at 48 hours, peak suppression of 81% at 7 days, and approximately 50% lowering of serum TTR protein at 28 days post dose. As expected, serum TTR reductions were well correlated with parallel changes in retinol binding protein and vitamin A levels. 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 parameters.
The Phase I trial of ALN-TTR02 is being conducted in the U.K. as a randomized, single-blind, placebo-controlled, single-ascending dose study, enrolling approximately 32 healthy volunteer subjects. The primary objective of the study is 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. Secondary objectives include serial measurement of circulating TTR serum levels through at least day 56 following a single dose. Additional secondary objectives include plasma and urine pharmacokinetics of ALN-TTR02.
