Alnylam Receives Positive CHMP Opinion for GIVLAARI™ (givosiran) for the Treatment of Acute Hepatic Porphyria in Adults and Adolescents

− European Commission Decision Expected in March −

− Positive Opinion is Based on Data from the Pivotal ENVISION Phase 3 Study −

CAMBRIDGE, MA, USA I January 31, 2020 IAlnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi therapeutics company, today announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted a positive opinion recommending approval of givosiran, an RNAi therapeutic targeting aminolevulinic acid synthase 1 (ALAS1) for the treatment of acute hepatic porphyria (AHP) in adults and adolescents aged 12 years and older. If approved by the European Commission, givosiran will be commercialized under the brand name GIVLAARI™.

“Today’s CHMP positive opinion is very encouraging news for patients living with acute hepatic porphyria and recognizes the potential of givosiran to address the urgent unmet need that exists for those living with this ultra-rare, inherited disease,” said Barry Greene, President, Alnylam Pharmaceuticals. “We are committed to bringing givosiran to patients in Europe as rapidly as possible.”

“Acute hepatic porphyria is characterized by debilitating, potentially life-threatening attacks and chronic disease manifestations that dramatically impact the lives of patients and their families,” said Bernhard Kaumanns, Head of Medical Affairs, Europe, Middle East, Africa and Canada, at Alnylam. “We have seen in clinical trials that givosiran has the potential to reduce the frequency of attacks, reduce pain and improve patients’ quality of life. Today’s recommendation takes us a significant step closer to making an important new treatment option a reality for AHP patients in Europe.”

The positive opinion is based on efficacy and safety findings from the pivotal ENVISION Phase 3 study, including data on the reduction in the annualized rate of composite porphyria attacks compared with placebo. Findings were presented in April 2019 at the 54th Annual International Liver Congress of the European Association for the Study of the Liver (EASL).

Givosiran was granted Priority Medicines (PRIME) Designation by the EMA as well as Orphan Designation in the European Union. Givosiran was also granted an accelerated assessment by the EMA, which is awarded to medicines deemed to be of major public health interest and therapeutic innovation, and the award is designed to bring new treatments to patients more quickly. This positive CHMP opinion follows the recent approval of GIVLAARI™ (givosiran) by the Food and Drug Administration in November 2019.

About Givosiran
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 subcutaneous 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), toward 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.

About ENVISION Phase 3 Study
The ENVISION Phase 3 trial was a randomized, double-blind, placebo-controlled, global, multicenter study to evaluate the efficacy and safety of givosiran in patients with a documented diagnosis of acute hepatic porphyria (AHP). The primary endpoint was reduction relative to placebo in the annualized rate of composite porphyria attacks, defined as those requiring hospitalization, urgent healthcare visit, or hemin administration at home, in patients with acute intermittent porphyria (AIP, the most common subtype of AHP) over six months. Key secondary and exploratory endpoints evaluated reductions in neurotoxic heme intermediates, aminolevulinic acid (ALA) and porphobilinogen (PBG), usage of hemin, symptoms of AHP, such as pain, nausea, and fatigue, as well as impact on quality of life. The trial enrolled 94 patients with AHP, at 36 study sites in 18 countries around the world and is the largest-ever interventional study conducted in AHP. Patients were randomized 1:1 to givosiran or placebo, with givosiran administered subcutaneously at 2.5 mg/kg monthly. Upon completion of dosing in the double-blind period, all eligible patients (99 percent) enrolled in the ENVISION open-label extension (OLE) to receive givosiran on an ongoing basis.

About Acute Hepatic Porphyria
Acute hepatic porphyria (AHP) refers to a family of ultra-rare, genetic diseases characterized by debilitating, potentially life-threatening attacks and, for some patients, chronic manifestations that negatively impact daily functioning and quality of life. AHP is comprised of four subtypes: acute intermittent porphyria (AIP), hereditary coproporphyria (HCP), variegate porphyria (VP), and ALA dehydratase-deficiency porphyria (ADP). Each type of AHP results from a genetic defect leading to deficiency in one of the enzymes of the heme biosynthesis pathway in the liver. AHP disproportionately impacts women of working and childbearing age; symptoms of the disease vary widely. Severe, unexplained abdominal pain is the most common symptom, which can be accompanied by limb, back or chest pain, nausea, vomiting, confusion, anxiety, seizures, weak limbs, constipation, diarrhea, or dark or reddish urine. The nonspecific nature of AHP signs and symptoms can often lead to misdiagnoses of other more common conditions, such as viral gastroenteritis, irritable bowel syndrome (IBS), addiction withdrawal, and appendicitis. Consequently, patients with AHP can wait up to 15 years for a confirmed diagnosis. In addition, long-term complications and comorbidities of AHP can include hypertension, chronic kidney disease, or liver disease, including hepatocellular carcinoma. Currently, there are no treatments approved in Europe to prevent debilitating attacks or to treat the chronic manifestations of the disease.

About RNAi
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.

About Alnylam
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)/ocular 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 RNAi therapeutics platform. Alnylam’s commercial RNAi therapeutic products are ONPATTRO® (patisiran), approved in the U.S., EU, Canada, Japan, and Switzerland, and GIVLAARI™ (givosiran), approved in the U.S. Alnylam has a deep pipeline of investigational medicines, including five product candidates that are in late-stage development. Alnylam is executing 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 1,200 people worldwide and is headquartered in Cambridge, MA.

SOURCE: Alnylam Pharmaceuticals

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