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 Genetic Medicine Strategic Therapeutic Area (STAr) product development and commercialization strategy, which is focused on advancing innovative RNAi therapeutics toward genetically defined targets for the treatment of rare 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.

In April 2014, we presented results of a 283-patient natural history study of patients with FAP.  This cross-sectional analysis demonstrated a rapid progression in Neuropathy Impairment Score (NIS) and a high correlation of this measurement with disease severity.  These results give us confidence that our APOLLO Phase 3 trial of patisiran in FAP patients is robustly powered to show the potential impact of TTR lowering on the mNIS+7 endpoint used in that study.

Also in April 2014, we presented pre-clinical data showing that the degree of TTR knockdown in a mouse disease model was highly correlated with regression of TTR tissue deposits.  In addition, comparative studies performed with a TTR stabilizer and a TTR-specific antisense oligonucleotide (ASO) showed RNAi therapeutics targeting TTR to have superior pharmacologic profiles.  These data suggest that the 80% TTR knockdown target level achieved in clinical studies with patisiran could facilitate a reduced pathogenic accumulation of TTR amyloid, and possibly even a regression of TTR amyloid, in patients with ATTR.  The comparative data demonstrate the superior activity of RNAi therapeutics over stabilizers toward regression of TTR deposits, and establish greater TTR knockdown with over 100-fold lower tissue exposure for RNAi therapeutics versus ASOs. Taken together, we believe that these new pre-clinical data highlight the potential for RNAi therapeutics targeting TTR to emerge as an optimal approach for the treatment of ATTR.

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.

Patients participating in the Phase 2 study described above were eligible to participate in an open-label extension (OLE) study; 27 patients rolled into the OLE. In October 2014, we presented six-month clinical data from this ongoing Phase 2 OLE study at the American Neurological Association’s 2014 Annual Meeting held October 12 – 14 in Baltimore. With these results, we are very encouraged to see what we believe to be evidence for possible stabilization of neuropathy progression after the first six months of treatment. Specifically, results showed a mean 0.95 point decrease in modified Neuropathy Impairment Score (mNIS+7) at six months in 19 patients. This decrease in neuropathy progression compares favorably with the 7 to 10 point increase in mNIS+7 at six months that can be estimated from historical data sets in untreated FAP patients with similar baseline characteristics (Adams et al., International Symposium on Amyloidosis, April 2014; Berk et al., JAMA 310: 26588-67, 2013; Tafamidis European Medicines Agency Assessment Report, 2011). In addition, patisiran treatment showed robust knockdown of serum TTR of up to 90% for over nine months, and was associated with a favorable tolerability profile out to one year of treatment. We believe the potent, rapid, and durable knockdown of TTR achieved by patisiran could be important since TTR protein reduction in patients with ATTR may have the potential to delay or even reverse disease progression with associated clinical benefit.

In addition, in the ongoing Phase 2 OLE study, patisiran administration was found to be generally well tolerated in FAP patients (N=27), with minimal adverse events reported for a period of up to one year. As of the time of the data cutoff on September 8, 2014, 282 doses had been administered with a median of 11 doses per patient. Mean treatment duration was seven months and the longest treatment duration was out to one year. There were no drug-related serious adverse events. Infusion-related reactions were infrequent (14.8%), mild in severity, and did not result in any discontinuations. All other reported adverse events were mild to moderate, and there were no clinically significant changes in liver function tests, renal function tests, or other laboratory or hematological parameters.

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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 Genetic Medicine STAr pipeline, which is focused on advancing RNAi therapeutics toward genetically defined targets for the treatment of rare 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 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 revusiran, 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.

First-Ever Evidence that Patisiran Reduces Pathogenic, Misfolded TTR Monomers and Oligomers in FAP Patients

First-Ever Evidence that Patisiran Reduces Pathogenic, Misfolded TTR Monomers and Oligomers in FAP Patients

We reported data from our ongoing Phase 2 open-label extension (OLE) study of patisiran, an investigational RNAi therapeutic targeting transthyretin (TTR) for the treatment of TTR-mediated amyloidosis (ATTR amyloidosis) patients with familial amyloidotic polyneuropathy (FAP). Alnylam scientists and collaborators from The Scripps Research Institute and Misfolding Diagnostics, Inc. were able to measure the effects of patisiran on pathogenic, misfolded TTR monomers and oligomers in FAP patients. Results showed a rapid and sustained reduction in serum non-native conformations of TTR (NNTTR) of approximately 90%. Since NNTTR is pathogenic in ATTR amyloidosis and the level of NNTTR reduction correlated with total TTR knockdown, these results provide direct mechanistic evidence supporting the therapeutic hypothesis that TTR knockdown has the potential to result in clinical benefit. Furthermore, complete 12-month data from all 27 patients that enrolled in the patisiran Phase 2 OLE study showed sustained mean maximum reductions in total serum TTR of 91% for over 18 months and a mean 3.1-point decrease in mNIS+7 at 12 months, which compares favorably to an estimated increase in mNIS+7 of 13 to 18 points at 12 months based upon analysis of historical data sets in untreated FAP patients with similar baseline characteristics. Importantly, patisiran administration continues to be generally well tolerated out to 21 months of treatment.

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