Phase 1 Trial of an RNA Interference Therapy for Acute Intermittent Porphyria
Publication Details
New England Journal of Medicine
February 2019
Author(s)
Eliane Sardh1, Pauline Harper1, Manisha Balwani1, Penelope Stein1, David Rees1, D Montgomery Bissell1, Robert Desnick1, Charles Parker1, John Phillips1, Herbert L Bonkovsky1, Daphne Vassiliou1, Craig Penz1, Amy Chan-Daniels1, Qiuling He1, William Querbes1, Kevin Fitzgerald1, Jae B Kim1, Pushkal Garg1, Akshay Vaishnaw1, Amy R Simon1, Karl E Anderson1
Affiliations
1From the Porphyria Centre Sweden, Karolinska Institutet, Karolinska University Hospital, Stockholm (E.S., P.H., D.V.); Icahn School of Medicine at Mount Sinai, New York (M.B., R.D.); King's College Hospital, London (P.S., D.R.); University of California, San Francisco, San Francisco (D.M.B.); University of Utah, Salt Lake City (C. Parker, J.P.); Wake Forest University, Winston-Salem, NC (H.L.B.); Alnylam Pharmaceuticals, Cambridge, MA (C. Penz, A.C.-D., Q.H., W.Q., K.F., J.B.K., P.G., A.V., A.R.S.); and the University of Texas Medical Branch at Galveston, Galveston (K.E.A.)
Abstract
Background:
Induction of delta aminolevulinic acid synthase 1 (ALAS1) gene expression and accumulation of neurotoxic intermediates result in neurovisceral attacks and disease manifestations in patients with acute intermittent porphyria, a rare inherited disease of heme biosynthesis. Givosiran is an investigational RNA interference therapeutic agent that inhibits hepatic ALAS1 synthesis.
Methods:
We conducted a phase 1 trial of givosiran in patients with acute intermittent porphyria. In part A of the trial, patients without recent porphyria attacks (i.e., no attacks in the 6 months before baseline) were randomly assigned to receive a single subcutaneous injection of one of five ascending doses of givosiran (0.035, 0.10, 0.35, 1.0, or 2.5 mg per kilogram of body weight) or placebo. In part B, patients without recent attacks were randomly assigned to receive once-monthly injections of one of two doses of givosiran (0.35 or 1.0 mg per kilogram) or placebo (total of two injections 28 days apart). In part C, patients who had recurrent attacks were randomly assigned to receive injections of one of two doses of givosiran (2.5 or 5.0 mg per kilogram) or placebo once monthly (total of four injections) or once quarterly (total of two injections) during a 12-week period, starting on day 0. Safety, pharmacokinetic, pharmacodynamic, and exploratory efficacy outcomes were evaluated.
Results:
A total of 23 patients in parts A and B and 17 patients in part C underwent randomization. Common adverse events included nasopharyngitis, abdominal pain, and diarrhea. Serious adverse events occurred in 6 patients who received givosiran in parts A through C combined. In part C, all 6 patients who were assigned to receive once-monthly injections of givosiran had sustained reductions in ALAS1 messenger RNA (mRNA), delta aminolevulinic acid, and porphobilinogen levels to near normal. These reductions were associated with a 79% lower mean annualized attack rate than that observed with placebo (exploratory efficacy end point).
Conclusions:
Once-monthly injections of givosiran in patients who had recurrent porphyria attacks resulted in mainly low-grade adverse events, reductions in induced ALAS1 mRNA levels, nearly normalized levels of the neurotoxic intermediates delta aminolevulinic acid and porphobilinogen, and a lower attack rate than that observed with placebo. (Funded by Alnylam Pharmaceuticals; ClinicalTrials.gov number, NCT02452372.)
PMID
30726693
DOI
10.1056/nejmoa1807838
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