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Alnylam Reports New 12-Month Interim Data From the ENVISION Phase 3 Study of Givosiran in Acute Hepatic Porphyria

− Long-Term Givosiran Dosing Showed Sustained Reduction in Annualized Rate of Composite Porphyria Attacks (AAR) With a Median AAR of Zero and Over 60 Percent of Patients Attack-Free in the Open-Label Extension Period −

− Safety Profile Consistent With That Observed in the 6-Month Double-Blind Period, With No New Safety Findings

Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi therapeutics company, today announced the presentation of new data from the open-label extension (OLE) period of the ENVISION Phase 3 study, reinforcing the long-term therapeutic benefit of givosiran in patients with acute hepatic porphyria (AHP)—an orphan disease that can be life threatening. The results were presented by study investigator Eliane Sardh, M.D., Ph.D., during a webinar hosted by Alnylam. In an interim analysis of the OLE period, givosiran, which is approved in the U.S. and EU and marketed as GIVLAARI®, demonstrated sustained efficacy and safety through 12 months of treatment, with evidence for potentially improved efficacy over time.

"Less than eight months after GIVLAARI’s first regulatory approval based on the ENVISION Phase 3 study results, we are pleased to share encouraging new data from our OLE program that we believe continue to support the sustained therapeutic benefit of this RNAi therapeutic. The improvements in daily worst pain and quality of life exploratory endpoints, and consistent safety profile, help us better understand the potential of GIVLAARI to provide ongoing and long-term benefit for patients living with AHP," said Akin Akinc, Ph.D., General Manager of Givosiran at Alnylam. "We remain committed to bringing GIVLAARI to patients with AHP around the world as we pursue marketing authorizations in additional countries and territories."

The ENVISION Phase 3 study evaluated the efficacy and safety of givosiran in patients with AHP. As previously reported and recently published in the New England Journal of Medicine, givosiran met the primary endpoint in the 6-month double-blind (DB) period, with a 74 percent mean reduction in the annualized rate of composite porphyria attacks (AAR) that required hospitalization, urgent healthcare visit or intravenous hemin administration at home, and a median AAR of 1.0. Givosiran also demonstrated an acceptable safety and tolerability profile in this high unmet need indication. Upon completion of dosing in the DB period, all eligible patients (93 out of 94; 99 percent) enrolled in the OLE period of the trial to receive monthly givosiran at either 2.5 mg/kg or 1.25 mg/kg. A dose of 1.25 mg/kg was initially studied in some patients to generate additional data at a lower dose level; all patients enrolled in the OLE period are now in the process of transitioning to the 2.5 mg/kg dose level, due to evidence for increased efficacy at the higher dose.

Results at 12 months showed that continued givosiran treatment led to sustained AAR reduction in the OLE period (6-12 months) with a median AAR of 0.0. The proportion of attack-free patients receiving givosiran increased from 50.0 percent in the DB period to 61.7 percent in the first 6 months of the OLE period. Sustained lowering of aminolevulinic acid and porphobilinogen in givosiran patients in the OLE period was accompanied by durable reductions in hemin use, lower levels of patient-reported daily worst pain and ongoing improvements in patient-reported quality of life and ability to function. Patients who crossed over from placebo in the DB period to givosiran in the OLE period experienced a mean reduction in AAR of 76 percent, similar to that experienced by givosiran patients in the DB period. Moreover, placebo crossover patients had reductions in hemin use and lower levels of patient-reported daily worst pain in the OLE period, consistent with the reductions observed in givosiran patients during the DB period.

The safety profile of givosiran in the OLE period was consistent with that observed in the DB period, and there were no new safety findings. In the combined DB and OLE periods, as of July 23, 2019 (median exposure of 11.2 months), the most common related adverse events (AEs) (reported in at least 10 percent of patients) on givosiran were injection site reactions, nausea and fatigue. Serious AEs (reported in at least 2 percent of patients) included chronic kidney disease in two patients during the DB period (as previously reported) and urinary tract infection in two patients during the OLE period. In the combined DB and OLE periods, hepatic and renal AEs were reported in 16 patients (17 percent) and 10 patients (11 percent), respectively. The majority of AEs were mild or moderate in severity, and there were no new treatment discontinuations due to AEs in the OLE period and no deaths.

"AHP is a tremendously burdensome disease, characterized by painful, often disabling attacks and chronic symptoms that can greatly impact a patient’s ability to function on a daily basis," said Eliane Sardh, M.D., Ph.D., Porphyria Centre Sweden, Centre for Inherited Metabolic Diseases, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden. "In the placebo-controlled period of the ENVISION Phase 3 study, givosiran showed a reduction in AAR and, based on secondary and exploratory measures, an improvement in patients’ health status, daily functioning and quality of life. These results, paired with the new long-term efficacy and safety data, provide further evidence that treatment with givosiran has the potential to significantly reduce the high burden of disease for patients and families affected by AHP."

GIVLAARI was approved by the U.S. Food and Drug Administration for the treatment of adults with AHP in November 2019 and by the European Commission for the treatment of AHP in adults and adolescents 12 years and older in March 2020. It is undergoing priority review by both Health Canada and the Brazilian Health Regulatory Agency (ANVISA).

To view the presentation recording and materials, please visit www.alnylam.com/capella.

About the ENVISION Phase 3 Study
The ENVISION Phase 3 study was a randomized, double-blind (DB), placebo-controlled, global, multicenter trial designed to evaluate the efficacy and safety of givosiran in patients with a documented diagnosis of acute hepatic porphyria (AHP). The primary endpoint of the trial was the annualized rate of composite porphyria attacks (AAR) in patients with acute intermittent porphyria (AIP) over the 6-month DB period. Secondary endpoints included: urinary aminolevulinic acid (ALA) and porphobilinogen (PBG) levels in patients with AIP, AAR in patients with AHP, hemin use and daily worst pain in patients with AIP. The trial enrolled 94 patients with AHP at 36 study sites in 18 countries around the world and is the largest interventional study ever 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 6-month DB period, 93 out of 94 patients (99 percent) enrolled in the ENVISION open-label extension period to receive givosiran on an ongoing basis.

About GIVLAARI® (givosiran)
GIVLAARI is an RNAi therapeutic targeting aminolevulinic acid synthase 1 (ALAS1) approved for the treatment of adults with acute hepatic porphyria (AHP) in the U.S. and for the treatment of AHP in adults and adolescents aged 12 years and older in the EU. In the pivotal ENVISION Phase 3 study, givosiran was shown to significantly reduce the annualized rate of composite porphyria attacks that required hospitalization, urgent healthcare visit 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 ALAS1 messenger RNA, leading to reduction of toxins associated with attacks and other disease manifestations of AHP.

GIVLAARI® (givosiran) Important Safety Information
Contraindications
GIVLAARI is contraindicated in patients with known severe hypersensitivity to givosiran. Reactions have included anaphylaxis.

Anaphylactic Reaction
Anaphylaxis has occurred with GIVLAARI treatment (<1 percent of patients in clinical trials). Ensure that medical support is available to appropriately manage anaphylactic reactions when administering GIVLAARI. Monitor for signs and symptoms of anaphylaxis. If anaphylaxis occurs, immediately discontinue administration of GIVLAARI and institute appropriate medical treatment.

Hepatic Toxicity
Transaminase elevations (ALT) of at least 3 times the upper limit of normal (ULN) were observed in 15 percent of patients receiving GIVLAARI in the placebo-controlled trial. Transaminase elevations primarily occurred between 3 to 5 months following initiation of treatment.

Measure liver function tests prior to initiating treatment with GIVLAARI, repeat every month during the first 6 months of treatment, and as clinically indicated thereafter. Interrupt or discontinue treatment with GIVLAARI for severe or clinically significant transaminase elevations. In patients who have dose interruption and subsequent improvement, reduce the dose to 1.25 mg/kg once monthly. The dose may be increased to the recommended dose of 2.5 mg/kg once monthly if there is no recurrence of severe or clinically significant transaminase elevations at the 1.25 mg/kg dose.

Renal Toxicity
Increases in serum creatinine levels and decreases in estimated glomerular filtration rate (eGFR) have been reported during treatment with GIVLAARI. In the placebo-controlled study, 15 percent of patients receiving GIVLAARI experienced a renally-related adverse reaction. The median increase in creatinine at Month 3 was 0.07 mg/dL. Monitor renal function during treatment with GIVLAARI as clinically indicated.

Injection Site Reactions
Injection site reactions were reported in 25 percent of patients receiving GIVLAARI in the placebo-controlled trial. Symptoms included erythema, pain, pruritus, rash, discoloration, or swelling around the injection site. One (2 percent) patient experienced a single, transient, recall reaction of erythema at a prior injection site with a subsequent dose administration.

Drug Interactions
Concomitant use of GIVLAARI increases the concentration of CYP1A2 or CYP2D6 substrates, which may increase adverse reactions of these substrates. Avoid concomitant use of GIVLAARI with CYP1A2 or CYP2D6 substrates for which minimal concentration changes may lead to serious or life-threatening toxicities. If concomitant use is unavoidable, decrease the CYP1A2 or CYP2D6 substrate dosage in accordance with approved product labeling.

Adverse Reactions
The most common adverse reactions that occurred in patients receiving GIVLAARI were nausea (27 percent) and injection site reactions (25 percent).

For additional information about GIVLAARI, please see full Prescribing Information.

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 or disease pathway 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 Pharmaceuticals
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 six 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 safety and efficacy of GIVLAARI® (givosiran) injection for subcutaneous use, as further demonstrated in the open-label extension (OLE) portion of the ENVISION study, its views that new data from its OLE program confirm the sustained therapeutic benefit of givosiran for patients living with AHP, its views regarding the clinical benefit of givosiran and the potential therapeutic impact of givosiran for patients afflicted with AHP, including the potential to significantly reduce the high burden of disease for patients and families, expectations regarding the regulatory review of GIVLAARI in Canada and Brazil, and expectations regarding the continued execution on 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: the direct or indirect impact of the COVID-19 global pandemic or a future pandemic, such as the scope and duration of the outbreak, government actions and restrictive measures implemented in response, material delays in diagnoses of rare diseases, initiation or continuation of treatment for diseases addressed by Alnylam products, or in patient enrollment in clinical trials, potential supply chain disruptions, and other potential impacts to Alnylam’s business, the effectiveness or timeliness of steps taken by Alnylam to mitigate the impact of the pandemic, and Alnylam’s ability to execute business continuity plans to address disruptions caused by the COVID-19 or a future pandemic; Alnylam's ability to discover and develop novel drug candidates and delivery approaches and 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, including lumasiran, or its marketed products; obtaining, maintaining and protecting intellectual property; intellectual property matters including potential patent litigation relating to its platform, products or product candidates; obtaining regulatory approval for its product candidates, including lumasiran, and maintaining regulatory approval and obtaining pricing and reimbursement for its products, including ONPATTRO and GIVLAARI; progress in continuing to establish a commercial and ex-United States infrastructure; successfully launching, marketing and selling its approved products globally, including ONPATTRO and GIVLAARI, and achieving net product revenues for ONPATTRO within its revised expected range during 2020; 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 within the ranges of guidance provided by Alnylam through the implementation of further discipline in operations to moderate spend and its ability to achieve a self-sustainable financial profile in the future without the need for future equity financing; Alnylam’s ability to establish and maintain strategic business alliances and new business initiatives, including completing an agreement for funding by Blackstone of certain R&D activities for vutrisiran and ALN-AGT; Alnylam's dependence on third parties, including Regeneron, for development, manufacture and distribution of certain products, including eye and CNS products, Ironwood, for assistance with the education about and promotion of GIVLAARI, and Vir for the development of ALN-COV and other potential RNAi therapeutics targeting SARS-CoV-2 and host factors for SARS-CoV-2; 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 Quarterly Report on Form 10-Q 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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