Rare Disease Report

Update on Alnylam Pharmaceutical's TTR Amyloidosis Studies

MAY 20, 2014
RDR Staff

At the recent Bank of America Merrill Lynch 2014 Health Care Conference, the CEO of Alnylam Pharmaceuticals presented an overview of the current data available from their pipeline. Much of the focus was on their two orphan designated drugs,  patisuran and ALN-TTRsc, but the company also has many other drugs in development for a variety of rare conditions.

All of Alylnam’s drugs in development are RNA interference (RNAi) therapies, which are small interfering RNAs (siRNA) that can disrupt the synthesis of disease causing proteins.
Examples of such disease causing proteins would be mutant or wild-type  Transthyretin (TTR) proteins that lead to TTR amyloidosis - an inherited, progressively debilitating, and often fatal disease. Two clinical syndromes that can develop from TTR amyloidosis are familial amyloidotic polyneuropathy (FAP) and familial amyloidotic cardiomyopathy (FAC). Alnylam has two RNAi drugs in development to treat FAP and FAC (patisuran and ALN-TTRsc, respectfully).

Patisiran - Phase 2 Study

An open-label, multicenter, multi-dose, does escalation study was conducted in 29 patient with TTR amyloidosis and the study found that multiple doses of patisiran led to robust and statistically significant knockdown of serum TTR protein levels of up to 96%, with mean levels of TTR knockdown exceeding 85%. Knockdown of TTR was found to be rapid, dose dependent, and durable. Further, similar activity was observed toward both wild-type and mutant protein. In addition, patisiran was found to be generally safe and well tolerated in this study. At the recent International Symposium on Amyloidosis in Indianopolis (April 27 – May 1, 2014), preliminary results from the open label extension showed the drug to maintain its efficacy in knocking out TTR over a 6 month period.

Patisiran - Phase 3 Study

The company is currently running a randomized, double-blind, placebo-controlled, global study in 200 FAP patients.
Primary endpoint will be a modified composite Neuropathy Impairment Score, termed "mNIS+7," which evaluates muscle weakness, sensory and autonomic function, and nerve conductance across a 304-point scale.
Secondary endpoints will include Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN) score; NIS-weakness; modified BMI; timed 10-meter walk; and the COMPASS-31 autonomic symptom score.
Alnylam has obtained protocol assistance for the Phase III study from the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) and has completed its End-of-Phase II meeting with the U.S. Food and Drug Administration (FDA).
It is not known when the trial will be completed.

ALN-TTRsc - Phase 2 Study

An open-label, multi-dose study in TTR cardiac amyloidosis will enroll approximately 25 patients with FAC and senile systemic amyloidosis (SSA) to test the safety and efficacy of ALN-TTRsc (qdx5 load,qwx5 maintenance).
The primary objectives are safety and tolerability.  Secondary objectives will include preliminary evidence for clinical activity.
The study is ongoing and initial data is expected the end of  2014.

About TTR Amyloidosis 

Transthyretin (TTR) is a protein that helps control the transportation of vitamin A in the body. Mutations of the TTR gene can lead to abnormal folding of the TTR protein that in turn results in deposits of the amyloid fibril proteins in various organs and tissues. Where they deposit will determine the symptoms. For example, patients with FAC have cardiac deposits and may show symptoms of congestive heart failure and/or severe postural hypotension whereas patients with FAP have neuropathic deposits and common symptoms will be hyperalgesia, lower or upper limb neuropathy, etc.
At present there is no pharmacologic therapy available for patients with TTR amyloidosis and treatment will be determined based on the organ involved.
Image of TTR protein courtesy of Wikimedia commons

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