Alnylam Reports Final 24-Month Results from Phase 2 Open-Label Extension Study of Patisiran, an Investigational RNAi Therapeutic in Development for the Treatment of Hereditary ATTR (hATTR) Amyloidosis
- Patisiran Achieves Mean 7.0 Point Decrease in Modified Neuropathy Impairment Score (mNIS+7), Comparing Favorably with Expected Mean 26-30 Point Increase Estimated from Historical Data -
- In New Post-Hoc Analysis, Evidence for Potential Halting or
- In Addition, Company Reports First-Ever Histological Evidence for
Decrease in Dermal TTR Amyloid Burden Associated with
"We are encouraged to see the final 24-month results from our Phase 2
OLE which provide continued evidence suggesting that patisiran can
potentially halt or improve neuropathy progression in patients with
hATTR amyloidosis. We are also pleased to present the first-ever
clinical evidence that patisiran administration is associated with a
decrease in dermal TTR amyloid burden, which we believe further supports
the therapeutic hypothesis that TTR knockdown can potentially lead to
reduction of amyloid deposits in the body," said
Final 24-month results from the Phase 2 OLE study showed a mean decrease
in mNIS+7 of 7.0 points after 24 months of patisiran administration.
This compares favorably to an expected mean increase in mNIS+7 of 26 to
30 points at 24 months estimated from an analysis of historical data
sets in untreated hATTR amyloidosis patients with similar baseline
Over the 24-month period, patients with evidence of cardiac amyloid
involvement at study entry (N=11) showed stability in their cardiac
biomarkers, echocardiographic measures, and 10-meter walk test (gait
speed). Additional results for patisiran in these hATTR amyloidosis
patients with cardiac involvement will be presented at the
Serum TTR levels were also measured throughout the Phase 2 OLE study and showed patisiran-mediated TTR knockdown of up to 97 percent, with mean maximal knockdown of 93 percent and a mean knockdown of approximately 82 percent over 24 months.
In the first post-hoc exploratory analysis of its kind, the change in dermal TTR amyloid content over 24 months was assessed through blinded evaluation of tandem skin punch biopsies from the distal thigh and distal leg. Patisiran administration was associated with a median reduction of up to 78 percent in dermal amyloid content over time as compared to baseline, with statistically significant mean decreases in dermal amyloid content at 24 months in both the distal thigh and distal leg (p less than 0.05). This decrease in mean dermal amyloid content is consistent with the statistically significant mean increase in sweat gland nerve fiber density observed from the same skin biopsy samples over 24 months. Taken together, these exploratory analyses support the therapeutic hypothesis that reduction of mutant and wild-type TTR can potentially lead to reduction of TTR amyloid deposition and increased nerve regeneration.
Patisiran administration was found to be generally well tolerated in
patients with hATTR amyloidosis out to 25 months, with no drug-related
serious adverse events (SAEs) reported. Drug-related or possibly
drug-related adverse events (AEs) in four or more patients were flushing
(22.2%) and infusion-related reactions (22.2%), all of which were mild
in severity and did not result in any discontinuations. There were ten
reports of serious adverse events (SAEs) in seven patients, all of which
were unrelated to study drug, including two previously reported deaths.
There were no clinically significant changes in liver function tests,
renal function, or hematologic parameters, including platelets.
Following treatment in the Phase 2 OLE study, all 25 eligible patients
enrolled in the APOLLO-OLE study; 20 have received at least 36 months of
dosing as of
About the Patisiran Phase 2 OLE Study
The patisiran Phase 2 OLE study was an open-label, multi-center trial designed to evaluate the long-term safety and tolerability of patisiran administration in patients with polyneuropathy due to hereditary ATTR (hATTR) amyloidosis that were previously enrolled in a Phase 2 study. Patisiran was administered once every 3 weeks at a dose of 0.3 mg/kg by intravenous infusion. The study measured a number of clinical endpoints every six months, including mNIS+7, which is an evaluation of muscle weakness, sensory and autonomic function, and nerve conductance, where neuropathy progression leads to an increased score over time. The change in the mNIS+7 measurement from baseline to 18 months is the primary endpoint in the Company's APOLLO Phase 3 trial of patisiran in patients with hATTR amyloidosis. Patients who completed the Phase 2 OLE study were eligible to screen for the global APOLLO-OLE study, in which they have the opportunity to receive patisiran on an ongoing basis.
About the APOLLO Phase 3 Study
The APOLLO Phase 3 trial is a randomized, double-blind, placebo-controlled, global study designed to evaluate the efficacy and safety of patisiran in hATTR amyloidosis patients with polyneuropathy. 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 enrolled 225 hATTR amyloidosis patients that were 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 percent power to conservatively detect as little as a 37.5 percent 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 hATTR amyloidosis patients. All patients completing the APOLLO Phase 3 study are eligible to screen for the global APOLLO-OLE study, in which they have the opportunity to receive patisiran on an ongoing basis.
About hATTR Amyloidosis
Hereditary transthyretin (TTR)-mediated amyloidosis (hATTR) 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 of vitamin A. 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. hATTR amyloidosis represents a major unmet medical need with significant morbidity and mortality, affecting approximately 50,000 people worldwide. hATTR amyloidosis patients have a life expectancy of 2.5 to 15 years from symptom onset, and the only approved treatment options for early stage disease are liver transplantation and tafamidis (approved in Europe, Japan, and certain countries in Latin America). There is a significant need for novel therapeutics to treat patients with hATTR amyloidosis.
About LNP Technology
Alnylam has licenses to Arbutus Biopharma LNP intellectual property for use in RNAi therapeutic products using LNP technology.
RNAi (RNA interference) is a revolution in biology, representing a breakthrough in understanding how genes are turned on and off in cells, and a completely new approach to drug discovery and development. Its discovery has been heralded as "a major scientific breakthrough that happens once every decade or so," and represents one of the most promising and rapidly advancing frontiers in biology and drug discovery today which was awarded the 2006 Nobel Prize for Physiology or Medicine. RNAi is a natural process of gene silencing that occurs in organisms ranging from plants to mammals. By harnessing the natural biological process of RNAi occurring in our cells, the creation of a major new class of medicines, known as RNAi therapeutics, is on the horizon. Small interfering RNA (siRNA), the molecules that mediate RNAi and comprise Alnylam's RNAi therapeutic platform, target the cause of diseases by potently silencing specific mRNAs, thereby preventing disease-causing proteins from being made. RNAi therapeutics have the potential to treat disease and help patients in a fundamentally new way.
Alnylam (Nasdaq: ALNY) is leading the translation of RNA interference (RNAi) into a whole new class of innovative medicines with the potential to transform the lives of patients who have limited or inadequate treatment options. Based on Nobel Prize-winning science, RNAi therapeutics represent a powerful, clinically validated approach for the treatment of a wide range of debilitating diseases. Founded in 2002, Alnylam is delivering on a bold vision to turn scientific possibility into reality, with a robust discovery platform and deep pipeline of investigational medicines, including three product candidates that are in late-stage development or will be in 2017. Looking forward, Alnylam will continue to execute on its "Alnylam 2020" strategy of building a multi-product, commercial-stage biopharmaceutical company with a sustainable pipeline of RNAi-based medicines. For more information about our people, science and pipeline, please visit www.alnylam.com and engage with us on Twitter at @Alnylam.
Alnylam Forward Looking Statements
Various statements in this release concerning Alnylam's future
expectations, plans and prospects, including, without limitation,
Alnylam's views with respect to the potential for RNAi therapeutics,
including the continued development of patisiran in the ongoing APOLLO
Phase 3 study and APOLLO-OLE study, its expectations regarding the
expected timing for reporting top-line data from the APOLLO study of
patisiran, and its expectations regarding the safety and tolerability of
its products in clinical development, including patisiran, constitute
forward-looking statements for the purposes of the safe harbor
provisions under The Private Securities Litigation Reform Act of 1995.
Actual results and future plans may differ materially from those
indicated by these forward-looking statements as a result of various
important risks, uncertainties and other factors, including, without
limitation, Alnylam's ability to discover and develop novel drug
candidates and delivery approaches, successfully demonstrate the
efficacy and safety of its product candidates, the pre-clinical and
clinical results for its product candidates, which may not be replicated
or continue to occur in other subjects or in additional studies or
otherwise support further development of product candidates for a
specified indication or at all, actions or advice of regulatory
agencies, including actions by regulators concerning product candidates,
which may affect the initiation, timing and progress of clinical trials,
obtaining, maintaining and protecting intellectual property, Alnylam's
ability to enforce its intellectual property rights against third
parties and defend its patent portfolio against challenges from third
parties, obtaining and maintaining regulatory approval, pricing and
reimbursement for products, progress in establishing a commercial and
The scientific information discussed in this news release relating to
Alnylam's investigational therapeutic patisiran is preliminary and
investigative. Patisiran has not been approved by the
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