Alnylam Presents Updated Phase 1/2 Open-Label Extension (OLE) Results for Givosiran, an Investigational RNAi Therapeutic for the Treatment of Acute Hepatic Porphyria
− Givosiran Demonstrated Sustained Clinical Activity, with an Over 90 Percent Decrease in Mean Annualized Porphyria Attack Rate, Relative to Baseline –
− Safety Profile Encouraging with up to 25 Months of Treatment –
“We are encouraged by the sustained clinical activity and safety profile of givosiran in the ongoing Phase 1/2 OLE study, now with up to over two years of dosing. We believe these results demonstrate clinically meaningful reductions in neurotoxic biomarkers, porphyria attack rate, and hemin usage, supporting the potential of givosiran to be an important treatment option for AHP patients,” said Akin Akinc, Vice President and General Manager, Givosiran Program at Alnylam. “We remain committed to bringing givosiran to patients as rapidly as possible, and are on course to initiate a rolling submission for an NDA by the end of 2018, and report topline results from the ENVISION Phase 3 pivotal study in early 2019.”
“Patients with acute hepatic porphyria not only endure potentially
life-threatening neurovisceral attacks but often present with
debilitating chronic symptoms and a severely diminished quality of life,
highlighting the profound unmet need in this disease setting for both
patients and their caregivers,” said
Updated Phase 1/2 OLE Results
As of the data cut-off date of
Serious adverse events (SAEs) were reported in four patients. Previously reported SAEs included: a patient with an upper extremity deep vein thrombosis, assessed as unlikely related to study drug by the investigator; and one patient who had an anaphylactic reaction after the third dose of givosiran, assessed as definitely related to study drug, which resolved with medical management. New SAEs included: a patient with two episodes of pyrexia related to a suspected Port-a-Cath infection and chlamydia bronchitis, assessed as unlikely related to study drug; and one patient with a change in mental status due to a possible glucocorticoid toxicity from an acute bacterial sinusitis, both of which were assessed as unlikely related to study drug. Adverse events (AEs) occurring in three or more patients included abdominal pain, fatigue, injection site erythema, nausea, myalgia, diarrhea, headache, and nasopharyngitis. Six patients had injection site reactions, all mild to moderate. No clinically significant increases in liver function tests or lipase levels were noted with continued dosing in the OLE study.
Results presented at AASLD can be viewed on the Capella section of the Alnylam website.
*Attacks requiring hospitalization, urgent health care visit or hemin administration, which is the attack rate definition used in the ENVISION Phase 3 trial.
About Givosiran Phase 1 Study
The Phase 1 study of givosiran (Part C) was conducted as a randomized, double-blind, placebo-controlled study in 17 patients with acute intermittent porphyria (AIP) who experienced recurrent porphyria attacks. Patients were initially followed in a 3-month run-in phase, where the number and frequency of porphyria attacks and levels of ALA and PBG were measured prospectively. Patients who experienced at least one porphyria attack during the run-in phase were then eligible to enter the 6-month treatment phase of the study, where they were randomized to receive 2 once-quarterly doses or 4 once-monthly doses of placebo or givosiran at doses of 2.5 or 5.0 mg/kg. During the treatment phase, the effects of placebo or givosiran on the number and frequency of porphyria attacks, as well as on the levels of ALA and PBG, were measured prospectively in a blinded manner and then compared to run-in phase results. Additional measures included safety, tolerability, hospitalizations, use of hemin, levels of ALAS1 mRNA, and givosiran pharmacokinetics. Hemin is an
About the ENVISION Phase 3 Study
The ENVISION Phase 3 trial is a randomized, double-blind, placebo-controlled, global, multicenter study to evaluate the efficacy and safety of givosiran in patients with a documented diagnosis of an AHP. Patients were randomized on a 1:1 basis to receive 2.5 mg/kg of givosiran or placebo subcutaneously administered monthly, over a six-month treatment period. The primary endpoint is the annualized rate of porphyria attacks requiring hospitalization, urgent healthcare visit or hemin administration at home over the six-month treatment period. Key secondary and exploratory endpoints will evaluate reductions in the hallmark symptoms of AHP, such as pain, nausea, and fatigue, as well as impact on quality of life.
About Acute Hepatic Porphyrias
Acute hepatic porphyrias (AHPs) are a family of rare, genetic diseases characterized by potentially life-threatening attacks and for many patients chronic debilitating symptoms that negatively impact daily functioning and quality of life. AHPs are comprised of four subtypes, each resulting from a genetic defect leading to deficiency in one of the enzymes of the heme biosynthesis pathway in the liver: acute intermittent porphyria (AIP), hereditary coproporphyria (HCP), variegate porphyria (VP), and ALAD-deficiency porphyria (ADP). These defects cause the accumulation of neurotoxic heme intermediates aminolevulinic acid (ALA) and porphobilinogen (PBG), with ALA believed to be the primary neurotoxic intermediate responsible for causing both attacks and ongoing symptoms between attacks. Common symptoms of AHPs include severe, diffuse abdominal pain, weakness, nausea, and fatigue. Symptoms of AHPs can often resemble that of other more common conditions such as irritable bowel syndrome, appendicitis, fibromyalgia, and endometriosis and consequently, patients afflicted with an AHP are often misdiagnosed or remain undiagnosed for an average of 15 years. Currently, there are no treatments approved to prevent debilitating attacks and treat the chronic symptoms of the disease.
Givosiran is an investigational, subcutaneously administered RNAi therapeutic targeting aminolevulinic acid synthase 1 (ALAS1) in development for the treatment of acute hepatic porphyria (AHP). Monthly administration of givosiran has the potential to significantly lower induced liver ALAS1 levels in a sustained manner and thereby decrease neurotoxic heme intermediates, aminolevulinic acid (ALA) and porphobilinogen (PBG), to near normal levels. By reducing accumulation of these intermediates, givosiran has the potential to prevent or reduce the occurrence of severe and life-threatening attacks, control chronic symptoms, and decrease the burden of the disease. Givosiran utilizes Alnylam’s Enhanced Stabilization Chemistry ESC-GalNAc conjugate technology, which enables subcutaneous dosing with increased potency and durability and a wide therapeutic index. Givosiran has been granted Breakthrough Therapy designation by the
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 new class of medicines, known as RNAi therapeutics, is now a reality. 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, hepatic infectious, and central nervous system (CNS) 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. Alnylam’s first U.S.
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 benefits of givosiran, plans to initiate a rolling NDA submission in 2018 and pursue a full approval in 2019 based on the complete results of the ENVISION Phase 3 study of givosiran, the expected timing of the report of topline full results from the ENVISION study, and expectations regarding its “Alnylam 2020” guidance for the advancement and commercialization of RNAi therapeutics, 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, which may affect the design, initiation, timing, continuation and/or progress of clinical trials or result in the need for additional pre-clinical and/or clinical testing, delays, interruptions or failures in the manufacture and supply of its product candidates, 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 ex-
Givosiran has not been evaluated by the
Alnylam Pharmaceuticals, Inc.
(Investors and Media)
Christine Regan Lindenboom, 617-682-4340
Josh Brodsky, 617-551-8276