ENVISION Phase III study of givosiran met its primary efficacy endpoint for the treatment of acute hepatic porphyria

Alnylam Pharmaceuticals, Inc. announced that the ENVISION Phase III study of givosiran, an investigational RNAi therapeutic targeting aminolevulinic acid synthase 1 (ALAS1) in development for the treatment of acute hepatic porphyria (AHP), met its primary efficacy endpoint and the majority of secondary endpoints. Specifically, givosiran met the primary endpoint of reduction in the annualized rate of composite porphyria attacks relative to placebo (p less than 0.00000001) and achieved statistically significant results for five of nine secondary endpoints (p less than 0.0001), with a safety and tolerability profile that the Company believes is encouraging, especially in this high unmet disease. Based on these results, the Company plans to complete its rolling submission of a New Drug Application (NDA) and file a Marketing Authorisation Application (MAA) in mid-2019.

ENVISION Study Results : ENVISION, a randomized, double-blind, placebo-controlled trial, enrolled 94 patients with AHP (including 89 with genetically-confirmed acute intermittent porphyria [AIP], the most common subtype of 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. The primary endpoint for the study was reduction relative to placebo in the annualized rate of composite porphyria attacks, defined as those requiring hospitalization, urgent healthcare visit, or hemin administration, in patients with AIP over six months. At six months, givosiran met the primary endpoint in patients with AIP (p less than 0.00000001). All the components of the composite primary endpoint and all subgroup analyses for the primary endpoint favored givosiran. Secondary endpoints listed below also demonstrated statistically significant favorable differences in the givosiran arm compared to placebo (p less than 0.0001): Urinary ALA levels at three months in AIP patients; Urinary ALA levels at six months in AIP patients; Urinary PBG levels at six months in AIP patients; Annualized days of administered hemin doses in AIP patients; and Annualized attack rate in patients with AHP (including AIP). The remaining four secondary endpoints did not meet the hierarchical threshold for significance and included: daily worst pain (p equal to 0.053), daily worst fatigue (p equal to 0.29), daily worst nausea (p equal to 0.25), and the physical component summary of the SF-12 health survey in AIP patients (p equal to 0.022)

Adverse events (AEs) were reported in 43/48 (89.6 percent) of givosiran and 37/46 (80.4 percent) of placebo patients and serious adverse events (SAEs) were reported in 10/48 (20.8 percent) of givosiran and 4/46 (8.7 percent) of placebo patients. There were no deaths in the study. One patient, described below, in the givosiran arm (2.1 percent) discontinued treatment due to an AE. AEs reported in greater than 10 percent of givosiran patients and seen more frequently compared to placebo were: nausea, injection site reactions, chronic kidney disease and fatigue; those reported in greater than 10 percent of placebo patients and seen more frequently than in givosiran-treated patients were headache, urinary tract infection, vomiting and pyrexia. The AEs of chronic kidney disease were reported in five givosiran-treated patients (10.4 percent) and no placebo patients; these events were all in patients with renal dysfunction at baseline and patients continued dosing throughout the study. Liver transaminase increases greater than three times upper limit of normal (ULN) were observed in 7/48 (14.6 percent) patients on givosiran and 1/46 (2.2 percent) patients on placebo; all had evidence of iron overload or liver disease at baseline. As previously reported and as noted above, one patient on givosiran discontinued treatment due to an increase in alanine aminotransferase (ALT) levels greater than 8 times ULN, a protocol-defined stopping rule; this elevation did not meet Hy’s Law and subsequently resolved. Peak ALT levels in the other six givosiran-treated patients ranged from 3.0-5.4 times ULN and were not accompanied by bilirubin increases. The patients were asymptomatic, and all events resolved with continued dosing (n=5) or after a brief pause in dosing (n=1).

Upon completion of dosing in the ENVISION double-blind period, all eligible patients (93/94 or 99 percent) enrolled in the ENVISION open-label extension (OLE) study, receiving monthly givosiran administration. In addition, patients continue dosing in the Phase 1/II OLE study with over two years of exposure to givosiran..