Alnylam Presents New Clinical Results from the APOLLO Phase 3 Study of Patisiran at the 16th International Symposium on Amyloidosis
− Patisiran Demonstrated Improvement of Cardiomyopathy in Prospectively Defined Subgroup of Patients with Cardiac Amyloid Involvement, Relative to Placebo −
− Long-term Treatment with Patisiran in Global Open-Label Extension (OLE) Study Demonstrates Maintenance of Efficacy and Consistent Safety −
− Degree of Patisiran-Mediated TTR Knockdown Found to Correlate with Neurologic Improvement –
− New Phase 1 Data on ALN-TTRsc02, an Investigational, Subcutaneously Administered RNAi Therapeutic for the Treatment of ATTR Amyloidosis, Support Low Dose and Volume, Quarterly Dosing Regimen −
“We are pleased to share important new data from our TTR program across
ten distinct presentations at ISA today. The clinical results presented
further highlight the robust profile of patisiran and provide evidence
supporting patisiran as a potentially transformative treatment approach
for patients with hATTR amyloidosis. We believe that, if approved, these
results position patisiran as a best-in-class therapeutic option for
patients with hATTR amyloidosis,” said
Cardiac Subpopulation Results
Fifty-six percent of the APOLLO study participants (N=126) were included in the predefined cardiac subpopulation*. The data presented at ISA highlighted that treatment with patisiran was associated with significant improvements in measures of cardiomyopathy, the leading cause of death in patients with hATTR amyloidosis, relative to placebo. Specifically, there were improvements in cardiac structure (reduction in mean left ventricular [LV] wall thickness) and function (reduction in LV-end diastolic volume and global longitudinal strain) at 18 months. Patisiran was also associated with a favorable effect on gait speed in the cardiac subpopulation, relative to placebo. Furthermore, patisiran treatment led to a significant reduction in levels of a cardiac stress biomarker, NT-proBNP, relative to placebo at 9 and 18 months (p = 7.7 x 10-8). Higher levels of NT-proBNP are associated with increased mortality in cardiac amyloidosis. The frequency of cardiac adverse events (AEs) and serious AEs (SAEs) were similar in patisiran- and placebo-treated patients in the overall APOLLO study population. Deaths occurred with similar frequency in the patisiran (4.7 percent) and placebo (7.8 percent) arms.
“The results presented at ISA highlight the potential of patisiran to
alleviate the cardiac manifestations of hATTR amyloidosis through
notable improvements in cardiac structure and function relative to
placebo-treated patients. These improvements, in conjunction with
demonstrated benefits in neurologic impairment, appear to be associated
with favorable effects on gait speed, an important indicator of
functional status,” said
Long-Term Use of Patisiran: Preliminary Results from Global OLE Study
The Company also presented preliminary results from the ongoing Global
OLE Study of patisiran evaluating the drug’s long-term efficacy and
safety in eligible patients who completed the Phase 2 OLE and Phase 3
APOLLO studies. The data presented were as of the
Relationship Between TTR Knockdown and Change in mNIS+7
Alnylam also presented results of an exploratory analysis from the Phase 2 OLE and Phase 3 APOLLO studies examining the relationship between the degree of patisiran-mediated TTR knockdown with changes in mNIS+7 – the primary endpoint in APOLLO, relative to baseline. A strong correlation between the degree of TTR knockdown and change in mNIS+7 was observed. Specifically, higher degrees of TTR knockdown resulted in greater levels of mNIS+7 improvement. At a population level, TTR knockdown of greater than 80 percent was associated with negative changes in mNIS+7, indicating reversal of disease manifestations, relative to baseline. The Company believes these data support the therapeutic hypothesis that reducing hepatic production of TTR by RNAi has the potential to halt or improve disease progression in patients with hATTR amyloidosis.
ALN-TTRsc02 Phase 1 Results
The Phase 1 study of ALN-TTRsc02 was a randomized, ascending fixed dose (5 mg to 300 mg) study in 80 healthy volunteers. Single doses of ALN-TTRsc02 demonstrated robust TTR knockdown (mean maximum up to 97 percent) maintained over 320 days. There were no SAEs or study discontinuations due to AEs. AEs were mild in severity and reported in 77 percent of ALN-TTRsc02 versus 50 percent of placebo patients. There were no reports of clinically significant changes in hematologic parameters (including platelets), renal function, electrocardiogram, vital signs or physical exam. One subject in the 200 mg dose group experienced a transient, asymptomatic elevation in liver alanine aminotransferase levels greater than three times the upper limit of normal that was not reported as an AE. Sustained TTR knockdown observed on study to date and modeling data both support the potential for a low dose (25 mg), low volume (less than 1 mL), and once quarterly subcutaneous dosing regimen for ALN-TTRsc02 to achieve levels of TTR knockdown comparable to those observed with patisiran in the APOLLO Phase 3 study. Consistent with previous guidance, the Company expects to advance ALN-TTRsc02 into a comprehensive pivotal Phase 3 program in late 2018.
All results presented at ISA can be viewed on the Capella section of the Alnylam website.
*Patients with baseline LV wall thickness ≥ 13 mm and no medical history of aortic valve disease or hypertension.
About the APOLLO Phase 3 Study
The APOLLO Phase 3 trial was 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 was the change from baseline in modified Neurologic Impairment Score +7 (mNIS+7) relative to placebo at 18 months. Secondary endpoints included: the Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN) score; NIS-weakness (NIS-W); Rasch-built Overall Disability Scale (R-ODS); timed 10-meter walk (10-MWT); modified BMI (mBMI); and the composite autonomic symptom score-31 (COMPASS-31). In addition, exploratory cardiac assessments included measurement of N-terminal pro-brain natriuretic peptide (NT-ProBNP) levels and echocardiography. The trial enrolled 225 hATTR amyloidosis patients from 19 countries with 39 genotypes who were randomized 2:1, patisiran:placebo, with patisiran administered at 0.3 mg/kg once every three weeks for 18 months. All patients who completed the APOLLO Phase 3 study were eligible to screen for the Global OLE study, in which they have the opportunity to receive patisiran on an ongoing basis.
Patisiran is an investigational, intravenously administered RNAi therapeutic targeting transthyretin (TTR) in development for the treatment of hereditary ATTR amyloidosis. It is designed to target and silence specific messenger RNA, potentially blocking the production of TTR protein before it is made. This may help to reduce the deposition and facilitate the clearance of TTR amyloid in peripheral tissues and potentially restore function to these tissues. Patisiran is currently under Priority Review as a Breakthrough Therapy with the
ALN-TTRsc02 is an investigational, subcutaneously administered RNAi therapeutic targeting transthyretin (TTR) in development for the treatment of ATTR amyloidosis. It is designed to target and silence specific messenger RNA, potentially blocking the production of TTR protein before it is made. This may help to reduce the deposition and facilitate the clearance of TTR amyloid in peripheral tissues and potentially restore function to these tissues. The safety and efficacy of ALN-TTRsc02 have not been evaluated by the
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 primarily produced in the liver and is normally a carrier of vitamin A. Mutations in the TTR gene 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, as well as other disease manifestations. hATTR amyloidosis represents a major unmet medical need with significant morbidity and mortality, affecting approximately 50,000 people worldwide. The median survival is 4.7 years following diagnosis, with a reduced survival (3.4 years) for patients presenting with cardiomyopathy. The only available treatment options for early stage disease are liver transplantation and, in some countries, tafamidis (approved in
RNAi (RNA interference) is a natural cellular process of gene silencing that represents one of the most promising and rapidly advancing frontiers in biology and drug development today. Its discovery has been heralded as “a major scientific breakthrough that happens once every decade or so,” and was recognized with the award of the 2006 Nobel Prize for Physiology or Medicine. By harnessing the natural biological process of RNAi occurring in our cells, 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, function upstream of today’s medicines by potently silencing messenger RNA (mRNA) – the genetic precursors – that encode for disease-causing proteins, thus preventing them from being made. This is a revolutionary approach with the potential to transform the care of patients with genetic and other diseases.
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 people afflicted with rare genetic, cardio-metabolic, and hepatic infectious diseases. Based on Nobel Prize-winning science, RNAi therapeutics represent a powerful, clinically validated approach for the treatment of a wide range of severe and 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 four product candidates that are in late-stage development. 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 to address the needs of patients who have limited or inadequate treatment options. Alnylam employs over 700 people in the U.S. and
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 data presented for patisiran and ALN-TTRsc02, and the potential implications of such data for patients, including patients with hATTR amyloidosis with cardiac involvement, its expectations regarding the timing of regulatory reviews and potential regulatory approvals for patisiran in
Neither patisiran nor ALN-TTRsc02 have been approved by the
Alnylam Pharmaceuticals, Inc.
Christine Regan Lindenboom, 617-682-4340
(Investors and Media)
Josh Brodsky, 617-551-8276