Data from Pharmawand - Curated by EPG Health - Date added 10 February 2019

Alnylam Pharmaceuticals, Inc.announced hat 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 in The New England Journal of Medicine (NEJM). The full manuscript, titled “Phase 1 Trial of an RNA Interference Therapy for Acute Intermittent Porphyria,” appeared 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.

See- "Phase 1 Trial of an RNA Interference Therapy for Acute Intermittent Porphyria"_Eliane Sardh, M.D., Ph.D., Pauline Harper, M.D., Ph.D., Manisha Balwani, M.D., Penelope Stein, M.D., Ph.D., et al.-February 7, 2019. N Engl J Med 2019; 380:549-558 DOI: 10.1056/NEJMoa1807838.

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