New clinical results for givosiran at the 2019 International Congress on porphyrins and porphyrias

Alnylam Pharmaceuticals, Inc. announced that the Company and its collaborators presented new clinical results at the 2019 International Congress on Porphyrins and Porphyrias (ICPP), held September 8-11, 2019 in Milan, Italy. Presentations included additional results from the ENVISION Phase III study and the Phase 1/II open-label extension (OLE) study of givosiran, an investigational RNAi therapeutic targeting aminolevulinic acid synthase 1 (ALAS1) in development for the treatment of acute hepatic porphyria (AHP).

ENVISION Phase III OLE Results : As of the data cut-off date of January 31, 2019, all eligible patients (N=93) from the ENVISION Phase III study of givosiran rolled over into the OLE phase of the study. Reduction in the composite porphyria attack rate with givosiran treatment, which had been observed in the ENVISION Phase III study as early as one month after dosing, was shown to be sustained with continued dosing in the OLE phase of the study. Sustained reduction in levels of aminolevulinic acid (ALA), an intermediate in the heme biosynthesis pathway believed to be the primary neurotoxic intermediate responsible for causing both porphyria attacks and ongoing symptoms in between attacks, was also observed with continued dosing. Rapid and sustained lowering of attack rate and ALA levels was also observed in placebo patients who crossed over after the six-month double blind phase of the ENVISION Phase III study to receive givosiran in the OLE phase of the study. Givosiran’s safety profile in the OLE phase has remained consistent with the profile observed in the double blind phase of the ENVISION study.

ENVISION Results of Select Patient Reported Outcome : A number of patient reported outcomes were collected as secondary and exploratory measures in the ENVISION study. Daily worst pain did not achieve statistical significance based on the prespecified ANCOVA analysis (p equals 0.0530), however, the data were found to not be normally distributed. A post-hoc analysis of daily worst pain was therefore performed using the non-parametric stratified Wilcoxon test. Based on the non-parametric test, patients on givosiran had a significant reduction in daily worst pain (nominal p equals 0.0455). In exploratory analyses, the reductions in pain were accompanied by fewer days of use of both opioid and non-opioid analgesics. Givosiran did not impact daily worst fatigue or daily worst nausea at six months, although these assessments will be repeated at twelve months to explore the effects of longer term dosing. Change from baseline at six months of the Physical Component Summary (PCS) of the Short Form 12 (SF-12) health and quality of life questionnaire was a secondary endpoint that showed a trend favoring givosiran compared to placebo (nominal p equals 0.0216). There was consistent evidence of effect favoring givosiran compared to placebo (nominal p less than 0.05 for each) in the SF-12 domains of bodily pain, social functioning, and role physical (a domain that assesses limitations in routine activity due to physical impairment). The Patient Global Impression of Change (PGIC) at six months was an exploratory endpoint. The majority (59 percent) of givosiran treated patients reported their health status as “very much improved” or “much improved” since the beginning of the study compared to 18 percent of placebo patients reporting their status as “much improved”. Similarly, the Porphyria Patient Experience Questionnaire (PPEQ) at six months was assessed as an exploratory endpoint. On all eight items of the PPEQ, a greater proportion of patients on givosiran, relative to patients on placebo, reported improvements. In particular, a higher proportion (67 percent versus 11 percent) of givosiran-treated patients versus those on placebo reported “always” or “most of the time” in response to the question about the role of the study drug in helping them return to a more normal life over the prior four weeks.

Updated Phase 1/II OLE Results : As of the data cut-off date of April 19, 2019, a robust treatment effect was maintained in givosiran-treated patients with continued dosing in the Phase 1/II OLE study (N=16), with a mean time on treatment of 22.8 months and total time on treatment across the Phase 1 and OLE studies of up to 35 months. Substantial mean reductions in annualized attack rate (AAR) and in annualized hemin use of greater than 90 percent were observed, with evidence for sustained or potentially enhanced clinical activity with continued dosing. Five out of twelve patients (42 percent) who received givosiran during the Phase 1 study and continued with givosiran dosing in the OLE study and two out of four patients (50 percent) who had been in the placebo arm of the Phase 1 study and crossed over to givosiran treatment in the OLE study achieved an AAR of zero for a mean of 18.1 and 24.9 months, respectively. The overall safety profile of givosiran in the Phase 1/II OLE as of the data cut-off date remains consistent with that previously reported. Serious adverse events (SAEs) were reported in six patients. Those SAEs not previously reported at earlier data cut-off dates included: one patient with synovitis, assessed as not related to study drug, and one patient with abdominal pain, assessed as unlikely related to study drug. No clinically significant laboratory changes, including liver function tests, were observed with ongoing dosing in the Phase 1/II OLE study.

The Company and collaborators also presented additional results on a drug-drug interaction study with givosiran, recent analyses from the EXPLORE natural history study, data on patient journey to diagnosis, real-world analysis of illness burden and management, and an overview of AHP symptomology based on peer-reviewed publications and patient narratives.