Data from Pharmawand - Curated by EPG Health - Date added 14 April 2019

Alnylam Pharmaceuticals, Inc. announced positive complete results from 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). The clinical data are being presented in an oral presentation at the European Association for the Study of the Liver (EASL) International Liver Congress™ being held April 10-14 in Vienna, Austria.

The full ENVISION results demonstrated a 74 percent mean and 90 percent median reduction in the primary endpoint measure of annualized rate of composite attacks in patients on givosiran relative to placebo during the six-month double-blind period. In addition, givosiran achieved statistically significant positive results for five of nine secondary endpoints, with an overall safety and tolerability profile that the Company believes is encouraging, especially in this high unmet need disease.

Adverse events (AEs) were reported in 89.6 percent of givosiran patients and 80.4 percent of placebo patients; serious adverse events (SAEs) were reported in 20.8 percent of givosiran patients and 8.7 percent of placebo patients. Ninety-three of 94 patients, or 99 percent, enrolled in the open-label extension (OLE) period of the study. Based on the ENVISION 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.Currently, there are no approved therapies aimed at preventing the painful, often incapacitating attacks and chronic symptoms associated with AHP.

Efficacy Results:Givosiran met the primary efficacy endpoint with a 74 percent mean 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 acute intermittent porphyria (AIP) over six months (p equal to 6.04x10-9). There was a corresponding 90 percent median reduction in composite annualized attack rate (AAR), with a median AAR of 1.0 in givosiran patients compared with a median AAR of 10.7 in placebo patients. Fifty percent of givosiran-treated patients were attack-free during the six-month treatment period as compared to 16.3 percent of placebo-treated patients. The reductions in attack rates were observed across all components of the primary endpoint. The treatment benefit for givosiran compared to placebo was maintained across all pre-specified patient subgroups, including age, race, geography, historical attack rates, prior hemin prophylaxis status, disease severity, and other baseline characteristics.Givosiran also demonstrated statistically significant differences in five of nine hierarchically tested secondary endpoints relative to placebo. These included mean reductions of: 91 percent in urinary aminolevulinic acid (ALA) in patients with AIP at three months (p equal to 8.74x10-14). 83 percent in urinary ALA in patients with AIP at six months (p equal to 6.24x10-7).73 percent in urinary levels of porphobilinogen (PBG) in patients with AIP at six months (p equal to 8.80x10-7). 77 percent in the number of annualized days on hemin in patients with AIP (p equal to 2.35x10-5). 73 percent in composite AAR for patients with any AHP (p equal to 1.35x10-8). The remaining four secondary endpoints did not meet the prespecified criteria for statistical significance in hierarchical testing.

Safety and Tolerability : AEs were reported in 43/48 (89.6 percent) of givosiran patients and 37/46 (80.4 percent) of placebo patients.SAEs were reported in 10/48 (20.8 percent) of givosiran patients and 4/46 (8.7 percent) of placebo patients.SAEs in givosiran patients consisted of two cases of chronic kidney disease (CKD; 4.2 percent), and one case (2.1 percent) each of asthma, device-related infection, gastroenteritis, hypoglycemia, abnormal liver function test, major depression, pain management, and pyrexia. Three SAEs in givosiran patients were reported as related to study drug: pyrexia, abnormal liver function test, and CKD (one case). The two SAEs of CKD noted above were considered serious due to elective hospitalization for diagnostic evaluation.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 (27.1 versus 10.9 percent), injection site reactions (16.7 versus 0 percent), CKD (10.4 versus 0 percent), and fatigue (10.4 versus 4.3 percent). Four of five of the patients with AEs reported as CKD had a prior history of CKD or a baseline estimated glomerular filtration rate (eGFR) less than 60 mL/min/1.73m2; no patients had clinically significant proteinuria and there were no treatment discontinuations due to renal AEs. Liver transaminase increases greater than three times the upper limit of normal (ULN) or baseline 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) level greater than eight times ULN, a protocol-defined stopping rule; this elevation did not meet Hy’s Law and subsequently resolved. In the other six givosiran-treated patients, peak ALT levels ranged from 3.0-5.4 times ULN and were not accompanied by bilirubin increases; the ALT elevations were asymptomatic and all events resolved with continued dosing (N=5) or after a brief pause in dosing (N=1).

Patient Perspectives : In exploratory measures of patient-reported outcomes, a greater proportion of patients reported an improvement in overall health status on givosiran (89 percent) than placebo (37 percent), as measured by the Patient Global Impression of Change (PGIC) Questionnaire. Similarly, patients on givosiran reported an overall higher level of treatment satisfaction on givosiran (72 percent) than placebo (14 percent) and an increased ability to perform activities of daily living, as measured by the Porphyria Patient Experience Questionnaire (PPEQ). Specifically, a greater proportion of patients on givosiran reported improvements in traveling for work or pleasure (35.1 versus 13.2 percent), participating in social activities (35.1 versus 7.9 percent), planning for future events (35.1 versus 10.5 percent), doing household chores (35.1 versus 5.3 percent), and exercising moderately (32.4 versus 5.3 percent), relative to patients on placebo.

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