TTR Amyloidosis (FAP)

Transthyretin (TTR)-mediated amyloidosis (ATTR) is an inherited, progressively debilitating, and often fatal disease caused by mutations in the TTR gene.  TTR protein is produced primarily in the liver and is normally a carrier for retinol binding protein – one of the vehicles to transport vitamin A around the body.  Mutations in the TTR gene cause misfolding of the protein and the formation of amyloid fibrils that typically contain both mutant and wild-type TTR that deposit in tissues 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. There are over 100 reported TTR mutations; the particular TTR mutation and the site of amyloid deposition determine the clinical manifestations of the disease which include two clinical syndromes: familial amyloidotic polyneuropathy (FAP) and familial amyloidotic cardiomyopathy (FAC).

It is estimated that FAP affects approximately 10,000 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 TTR stabilizers such as tafamidis (approved in Europe) and diflunisal.  Unfortunately liver transplantation has limitations, including limited organ availability as well as substantial morbidity and mortality. Furthermore, transplantation eliminates the production of mutant TTR but does not affect wild-type TTR, which can further deposit after transplantation, leading to cardiomyopathy and worsening of neuropathy. There is a significant need for novel therapeutics to treat patients who have inherited mutations in the TTR gene.

Our ATTR program is the lead effort in our “Alnylam 5×15″ product development and commercialization strategy, which is focused on advancing innovative RNAi therapeutics toward genetically defined targets for the treatment of diseases with high unmet medical need.  We are developing patisiran (ALN-TTR02), an intravenously administered RNAi therapeutic, to treat the FAP form of the disease.

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Patisiran (ALN-TTR02) for the Treatment of FAP

Our approach to the treatment of ATTR is to employ the RNAi mechanism to knockdown the disease-causing TTR protein, which is primarily synthesized in the liver.  Patisiran employs a TTR-targeting siRNA that knocks down both wild-type and all mutant forms of TTR in a lipid nanoparticle formulation that targets delivery to the liver; it is administered by intravenous infusion.  The therapeutic hypothesis that lowering TTR will result in clinical benefit is supported by data from FAP patients receiving liver transplants, and from other systemic amyloidotic diseases, which show that as little as a 50% reduction of the disease-causing protein can result in disease improvement or stabilization.

In November 2013, we presented positive Phase 2 data, which showed 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, and similar activity was observed toward both wild-type and mutant protein. In addition, patisiran was found to be generally well tolerated in this study. We have recently initiated an open label extension (“OLE”) study for patients that participated in the Phase 2 study; the study includes a number of clinical endpoints, and initial data are expected to be reported in 2014.

In August 2013, Alnylam and collaborators published results of its Phase 1 study of patisiran in the New England Journal of Medicine (Coelho et al., N Engl J Med 2013;369:819-29.) The Phase 1 study, performed in normal human volunteers, was the first ever to demonstrate human proof of concept for RNAi therapeutics. In the study, patisiran administration resulted in rapid, dose-dependent, and durable knockdown of serum TTR of up to 94%. In addition, the effects of patisiran were shown to be specific and mediated by an RNAi mechanism of action.

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APOLLO Phase 3 Trial

In November 2013, we initiated the APOLLO Phase 3 trial of patisiran in ATTR patients with FAP; this study is now ongoing. As our first Phase 3 study, this is a very significant milestone in Alnylam’s history and also for the entire field of RNAi therapeutics. Initiation of our Phase 3 trial with patisiran highlights continued execution on our “Alnylam 5×15″ and genetic medicine product development and commercialization strategy, which is focused on advancing RNAi therapeutics toward genetically defined targets for the treatment of diseases with high unmet medical need.

The APOLLO Phase 3 trial is a randomized, double-blind, placebo-controlled, global study designed to evaluate the efficacy and safety of patisiran in ATTR patients with FAP. The primary endpoint of the study is the difference in the change in mNIS+7 between patisiran and placebo at 18 months. Secondary endpoints include: the Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN) score; NIS-weakness; modified BMI; timed 10-meter walk; and the COMPASS-31 autonomic symptom score. The trial is designed to enroll up to 200 FAP patients with a baseline NIS in the range of 10 to 100, which represents patients with Stage 1 or Stage 2 disease. Patients will be randomized 2:1, patisiran:placebo, with patisiran administered at 0.3 mg/kg once every three weeks for 18 months. The study was designed with 90% power to conservatively detect as little as a 37.5% difference in change in mNIS+7 between treatment groups, with a two-sided alpha of 0.05. The placebo mNIS+7 progression rate was derived from an Alnylam analysis of natural history data from 283 FAP patients. We have obtained protocol assistance for the patisiran Phase 3 study from the European Medicines Agency (EMA) and have completed our End-of-Phase 2 meeting with the U.S. Food and Drug Administration (FDA). All patients completing the APOLLO Phase 3 study will be eligible to enroll in a Phase 3 OLE study.

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In 2012, Alnylam entered into an exclusive alliance with Genzyme, a Sanofi company, to develop and commercialize RNAi therapeutics, including patisiran and ALN-TTRsc, for the treatment of ATTR in Japan and the broader Asian-Pacific region. In early 2014, this relationship was extended as a significantly broader alliance to advance RNAi therapeutics as genetic medicines. Under this new agreement, Alnylam will lead development and commercialization of patisiran in North America and Europe while Genzyme will develop and commercialize the product in the rest of world.

Positive Phase II Data with Patisiran (ALN-TTR02)

Positive Phase II Data with Patisiran (ALN-TTR02)

We presented positive data from our Phase II clinical trial of patisiran (ALN-TTR02) for the treatment of transthyretin-mediated amyloidosis (ATTR) at the International Symposium on Familial Amyloidotic Polyneuropathy, November 10 – 13, 2013. Results showed 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, the disease-causing protein in ATTR, was found to be rapid, dose dependent, and durable, and 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.



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Positive Clinical Trial Results with ALN-TTR01 and ALN-TTR02 Published in the “New England Journal of Medicine”

Positive Clinical Trial Results with ALN-TTR01 and ALN-TTR02 Published in the “New England Journal of Medicine”

We have published complete study results from Phase I trials with ALN-TTR01 and ALN-TTR02 in the New England Journal of Medicine. RNAi therapeutics targeting transthyretin (TTR) achieved rapid, dose-dependent, durable, and specific knockdown of TTR, the disease-causing protein in TTR-mediated amyloidosis (ATTR). The Phase I studies of ALN-TTR01 and ALN-TTR02 demonstrate key human proof of concept for RNAi therapeutics targeting TTR as well as liver-expressed target genes in general.



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Positive Phase II Clinical Data with ALN-TTR02

We presented positive data from our Phase II clinical trial of ALN-TTR02 for the treatment of transthyretin-mediated amyloidosis (ATTR) at the Biennial Meeting of the Peripheral Nerve Society being held June 29 – July 3. Interim results show that multiple doses of ALN-TTR02 led to robust and statistically significant knockdown of serum TTR protein levels of up to 93%. Knockdown of TTR, the disease-causing protein in ATTR, was found to be rapid, dose dependent, and durable, and similar activity was observed toward both wild-type and mutant protein. In addition, ALN-TTR02 was found to be generally safe and well tolerated in this study.




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