Alnylam Pharmaceuticals, Inc. (NASDAQ: ALNY) announced today that results from the Phase 1 study of givosiran, an investigational, subcutaneous RNAi therapeutic targeting aminolevulinic acid synthase 1 (ALAS1) for the treatment of acute hepatic porphyria (AHP), were published online today in The New England Journal of Medicine (NEJM). The full manuscript, titled “Phase 1 Trial of an RNA Interference Therapy for Acute Intermittent Porphyria,” will appear in the February 7, 2019 issue of NEJM.
In the Phase 1 study, the proportion of patients reporting adverse events (AEs) was similar across treatment groups with no clear relationship with givosiran dose. The majority of AEs were mild or moderate; the most common AEs included nasopharyngitis, abdominal pain, and diarrhea. Serious AEs (SAEs) were reported in six patients treated with givosiran (N=33), including – as previously reported – one fatal SAE of hemorrhagic pancreatitis, assessed as unlikely related to study drug by the study investigator. Additional unrelated SAEs included influenza infection, opioid bowel dysfunction, miscarriage, and two patients with abdominal pain. No SAEs were reported in the placebo group (N=10).
Results showed that basal ALAS1 messenger RNA (mRNA), aminolevulinic acid (ALA), and porphobilinogen (PBG) levels were associated with disease activity, with higher levels noted in those with recurrent attacks, confirming the central importance of liver ALAS1 induction and ALA and PBG in the pathophysiology of acute intermittent porphyria (AIP). Monthly givosiran administration resulted in sustained reductions of ALAS1 mRNA, urinary ALA, and PBG to near normal levels. In exploratory analyses, these reductions were associated with a 79 percent decrease in mean annualized attack rate and an 83 percent decrease in mean annualized hemin usage, compared with placebo.
“We are pleased to have our givosiran Phase 1 findings published in such a highly esteemed, peer-reviewed journal. Indeed, we are encouraged by the emerging safety and tolerability profile for givosiran, as well as the results of exploratory analyses suggesting favorable effects on porphyria attack rate and hemin use for acute attacks,” said Akin Akinc, Ph.D., Vice President and General Manager, Givosiran Program at Alnylam. “With no treatment options currently approved for the prevention of porphyria attacks, we believe givosiran has the potential to make a meaningful difference in the lives of AHP patients.”
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