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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. Mutations in TTR cause abnormal amyloid proteins to accumulate and damage body organs and tissue, such as the peripheral nerves and heart, resulting in intractable peripheral sensory neuropathy, autonomic neuropathy, and/or cardiomyopathy.
ATTR represents a major unmet medical need with significant morbidity and mortality; familial amyloidotic polyneuropathy (FAP) affects approximately 10,000 people worldwide and familial amyloidotic cardiomyopathy (FAC) affects at least 40,000 people worldwide. FAP patients have a life expectancy of five to 15 years from symptom onset, and the only treatment options for early stage disease are liver transplantation and tafamidis (approved in Europe). The mean survival for FAC patients is approximately 2.5 years, and there are no approved therapies. As a result, there is a significant need for novel therapeutics to treat patients who have inherited mutations in the TTR gene.
In October 2012, we formed an exclusive alliance with Genzyme, a Sanofi company, to advance our ALN-TTR program in the Japanese and broader Asian market, while we maintain our plans to develop and commercialize ALN-TTR in the North and South America, Europe, and rest of world.
ALN-TTR02 is an intravenously delivered RNAi therapeutic for the treatment of ATTR.
Our Phase I clinical trial with ALN-TTR02, initiated in March 2012, was designed to evaluate the safety and tolerability of ALN-TTR02 in healthy volunteers as well as the clinical activity of ALN-TTR02 based on measurements of serum levels of TTR, the disease-causing protein in patients with ATTR
In July 2012, we announced the achievement of positive clinical results from our Phase I trial. Preliminary data, presented at Boston University School of Medicine, showed that administration of ALN-TTR02 leads to robust knockdown of serum TTR protein levels of up to 94% (p<0.00001 by ANOVA). Reduction of TTR was found to be rapid, dose dependent, durable, and specific after just a single dose of ALN-TTR02, and a nearly 80% level of suppression was sustained at one month with just a single dose. ALN-TTR02 was found to be generally safe and well tolerated.
Knockdown of circulating TTR is a validated endpoint in ATTR based on data from patients receiving liver transplants. Evidence from other systemic amyloidotic diseases shows that as little as a 50% reduction of the disease-causing protein can result in disease improvement or stabilization. These new data with ALN-TTR02 provide key human proof of concept with associated clinical relevance as we advance this medicine to patients for the treatment of ATTR, a debilitating orphan genetic disease.
We are currently conducting a Phase II trial with ALN-TTR02 in Europe, and in the process of adding more sites in other geographies. The study is aimed at evaluating safety, tolerability, and potential clinical activity of multiple once-monthly doses of ALN-TTR02 in ATTR patients. We expect to report results from this trial in mid-2013.
Additionally, Alnylam intends to initiate an open-label extension study in mid-2013 for longer-term treatment of patients enrolled in the Phase II study. The new extension study will include a number of exploratory clinical endpoint measurements. We intend to provide periodic updates on results from the extension study starting in 2014.
Assuming positive results from our Phase II study, Alnylam expects to initiate a Phase III pivotal trial of ALN-TTR02 in ATTR patients with FAP in late 2013.
ALN-TTRsc is a subcutaneously administered RNAi therapeutic which utilizes our proprietary GalNAc-conjugate delivery platform. Pre-clinical studies have shown that once-weekly dosing with ALN-TTRsc enables robust and sustained silencing of TTR over a multi-week period.
In March 2013, we initiated dosing in a Phase I clinical trial with ALN-TTRsc, the first GalNAc-siRNA to enter clinical development stages. The Phase I trial of ALN-TTRsc is being conducted in the U.K. as a randomized, double-blind, placebo-controlled, single- and multi-dose, dose-escalation study, enrolling up to 40 healthy volunteer subjects. The primary objective of the study is to evaluate the safety and tolerability of single and multiple doses of subcutaneously administered ALN-TTRsc. Secondary objectives include assessment of clinical activity of the drug as measured by serum TTR levels.
We expect to present data from this trial in mid-2013.
Upon completion of the Phase I trial, we plan to start a Phase II clinical study of ALN-TTRsc in FAC patients by the end of 2013 and, assuming positive results, expect to start a pivotal trial for ALN-TTRsc in FAC patients in 2014.
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.
The Phase II trial is an open-label, multi-center, multi-dose, dose-escalation trial designed to enroll approximately 20 ATTR patients. Subjects will be enrolled into cohorts of increasing doses and will receive drug once every four weeks for two cycles. The primary objectives of the study are to evaluate the safety and tolerability of multiple doses of ALN-TTR02 and to measure clinical activity based on serial measurement of circulating serum TTR levels.
In May 2013, it was announced the study would be expanded to a total of about 30 patients with additional study sites to explore additional cohorts treated with a once-every-three week dosing regimen and a reduced steroid pre-medication regimen
Study results 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.
ALN-TTR02 was found to be generally safe and well tolerated. 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).
The Phase I trial, being conducted in the U.K., is a randomized, double-blind, placebo-controlled, single- and multi-dose, dose-escalation study, enrolling up to 40 healthy volunteer subjects. The primary objective of the study is to evaluate the safety and tolerability of single and multiple doses of subcutaneously administered ALN-TTRsc. Secondary objectives include assessment of clinical activity of the drug as measured by serum TTR levels. Alnylam expects to present data from this trial in mid-2013.