− 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 −

CAMBRIDGE, Mass.--(BUSINESS WIRE)-- 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 (