Alnylam Announces Approval of GIVLAARI® (givosiran) in the European Union for the Treatment of Acute Hepatic Porphyria (AHP) in Adults and Adolescents

“Today’s approval of GIVLAARI marks a historic moment for patients and families living with this devastating genetic disease, as there are currently no approved medicines in Europe proven to decrease the frequency of attacks and reduce the chronic pain that many patients suffer,” said John Maraganore, Ph.D., Chief Executive Officer of Alnylam. “We are proud to bring GIVLAARI, our second RNAi medicine to be approved in the last 18 months, to patients in Europe and we want to thank the patients, families, investigators and study staff whose support and involvement have made this achievement possible.”

“The fear of not knowing when an attack will strike, combined with ongoing symptoms between attacks, affects every aspect of patients’ lives, limiting their ability to work and maintain a social life,” said Dr Eliane Sardh, Head of the Porphyria Centre Sweden, Karolinska University Hospital, Sweden. “In our experience, life is very different for patients since they have been treated with givosiran. In addition to a reduction in the number of porphyria attacks which require hospitalization and urgent healthcare visits, we have seen improvements in how patients report their overall health status and quality of life, so this approval is truly meaningful for patients, their families and the healthcare professionals who treat them. Some of our patients have been able to achieve significant personal and professional milestones that would not have been possible before.”

“We are committed to bringing GIVLAARI to patients in Europe as rapidly as possible, and plan to build on our experience in the U.S. by proactively engaging with national authorities in Europe around a value-based agreement framework which we hope will accelerate patient and provider access to GIVLAARI,” said Barry Greene, President, Alnylam. “While every country has its own process for measuring the value of new medicines, we believe this framework will appeal in many countries as it combines payment based on performance with additional financial mechanisms to ensure the long-term financial sustainability of the treatment of all AHP patients in line with the authorized indication of GIVLAARI.”

GIVLAARI (givosiran) was granted Priority Medicines (PRIME) Designation by the European Medicines Agency (EMA) as well as Orphan Designation in the European Union. GIVLAARI was also granted an accelerated assessment, 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 EC approval follows the recent approval of GIVLAARI by the U.S. Food and Drug Administration in November 2019. Givosiran is also awaiting approval in Brazil where it is under priority review.

About ENVISION Phase 3 Study
The marketing authorization was based on positive data from the ENVISION Phase 3 trial, 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 intravenous hemin administration at home, in patients with acute intermittent porphyria (AIP, the most common subtype of AHP) over six months. 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%) enrolled in the ENVISION open-label extension (OLE) to receive givosiran on an ongoing basis.

• In the study, givosiran demonstrated a 74% reduction in the annualized composite rate of porphyria attacks in AIP patients relative to placebo.
• 50% of patients on givosiran were attack-free during the six-month treatment period as compared to 16.3% of placebo-treated patients.
• Patient-reported daily worst pain was significantly improved with givosiran vs placebo in patients with AIP (p<0.05).
• Givosiran reduced use of hemin, as well as urinary aminolevulinic acid (ALA), and urinary porphobilinogen (PBG).
• A greater proportion of patients on givosiran reported improvements in their overall health, pain, daily functioning, compared to placebo.

The most frequently occurring adverse reactions reported in patients treated with givosiran are injection site reactions (36%), nausea (32.4%) and fatigue (22.5%). Other adverse reactions seen in givosiran treated patients (occurring ≥10% more frequently than placebo) include transaminase elevations, rash and glomerular filtration rate decrease.

About GIVLAARI^® (givosiran)
GIVLAARI is an RNAi therapeutic targeting aminolevulinic acid synthase 1 (ALAS1) for the treatment of adults and adolescents with acute hepatic porphyria (AHP). In the pivotal study, givosiran was shown to significantly reduce the rate of porphyria attacks that required hospitalizations, urgent healthcare visits or intravenous hemin administration at home compared to placebo. GIVLAARI is Alnylam’s first commercially available therapeutic based on its Enhanced Stabilization Chemistry ESC-GalNAc conjugate technology to increase potency and durability. GIVLAARI is administered via subcutaneous injection once monthly at a dose based on actual body weight and should be administered by a healthcare professional. GIVLAARI works by specifically reducing elevated levels of aminolevulinic acid synthase 1 (ALAS1) messenger RNA (mRNA), leading to reduction of toxins associated with attacks and other disease manifestations of AHP.

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 a lack of certain enzymes needed to produce heme in the liver, which leads to an accumulation of porphyrins in the body to toxic amounts. AHP disproportionately impacts women of working and childbearing age, and 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. AHP is life-threatening due to the possibility of paralysis and respiratory arrest during attacks. The nonspecific nature of AHP signs and symptoms can often lead to misdiagnoses of other more common conditions such as gynecological disorders, viral gastroenteritis, irritable bowel syndrome (IBS), and appendicitis. Consequently, on a global perspective, patients with AHP can wait up to 15 years for a confirmed diagnosis, with the risk of addiction problems. In addition, long-term complications and comorbidities of AHP can include hypertension, chronic kidney disease or liver disease, including hepatocellular carcinoma.

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, Brazil and Switzerland, and GIVLAARI^® (givosiran), approved in the U.S and the EU. 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 is headquartered in Cambridge, MA.

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 approval of GIVLAARI^® (givosiran) injection for subcutaneous use, and the implications of such approval for patients and their caregivers, the results of the ENVISION Phase 3 clinical trial for givosiran, expectations regarding the review of GIVLAARI’s marketing authorization application under accelerated assessment by the EMA for the treatment of patients with AHP, and expectations regarding Alnylam’s “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, including GIVLAARI, progress in establishing a commercial and ex-United States infrastructure, successfully launching, marketing and selling its approved products globally, including GIVLAARI, Alnylam’s ability to successfully expand the indication for ONPATTRO in the future, competition from others using technology similar to Alnylam’s and others developing products for similar uses, Alnylam’s ability to manage its growth and operating expenses and achieve a self-sustainable financial profile in the future, obtain additional funding to support its business activities, and establish and maintain strategic business alliances and new business initiatives, Alnylam’s dependence on third parties, including Regeneron, for development, manufacture and distribution of products, and Ironwood, for assistance with the education about and promotion of GIVLAARI in the United States, the outcome of litigation, the risk of government investigations, and unexpected expenditures, as well as those risks more fully discussed in the “Risk Factors” filed with Alnylam’s most recent Annual Report on Form 10-K filed with the Securities and Exchange Commission (SEC) and in other filings that Alnylam makes with the SEC. In addition, any forward-looking statements represent Alnylam’s views only as of today and should not be relied upon as representing its views as of any subsequent date. Alnylam explicitly disclaims any obligation, except to the extent required by law, to update any forward-looking statements.

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