Phase 1 trial of an RNA interference therapy for acute intermittent porphyria

Eliane Sardh, Pauline Harper, Manisha Balwani, Penelope Stein, David Rees, D. Montgomery Bissell, Robert Desnick, Charles Parker, John Phillips, Herbert L. Bonkovsky, Daphne Vassiliou, Craig Penz, Amy Chan-Daniels, Qiuling He, William Querbes, Kevin Fitzgerald, Jae B. Kim, Pushkal Garg, Akshay Vaishnaw, Amy R. SimonKarl Anderson

Research output: Contribution to journalArticle

12 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)549-558
Number of pages10
JournalNew England Journal of Medicine
Volume380
Issue number6
DOIs
StatePublished - Feb 7 2019

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Acute Intermittent Porphyria
RNA Interference
Aminolevulinic Acid
Injections
Placebos
Porphobilinogen
Therapeutics
Porphyrias
Nasopharyngitis
Messenger RNA
Subcutaneous Injections
Random Allocation
Rare Diseases
Heme
Abdominal Pain
Diarrhea
Pharmacokinetics
Body Weight

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Sardh, E., Harper, P., Balwani, M., Stein, P., Rees, D., Montgomery Bissell, D., ... Anderson, K. (2019). Phase 1 trial of an RNA interference therapy for acute intermittent porphyria. New England Journal of Medicine, 380(6), 549-558. https://doi.org/10.1056/NEJMoa1807838

Phase 1 trial of an RNA interference therapy for acute intermittent porphyria. / Sardh, Eliane; Harper, Pauline; Balwani, Manisha; Stein, Penelope; Rees, David; Montgomery Bissell, D.; Desnick, Robert; Parker, Charles; Phillips, John; Bonkovsky, Herbert L.; Vassiliou, Daphne; Penz, Craig; Chan-Daniels, Amy; He, Qiuling; Querbes, William; Fitzgerald, Kevin; Kim, Jae B.; Garg, Pushkal; Vaishnaw, Akshay; Simon, Amy R.; Anderson, Karl.

In: New England Journal of Medicine, Vol. 380, No. 6, 07.02.2019, p. 549-558.

Research output: Contribution to journalArticle

Sardh, E, Harper, P, Balwani, M, Stein, P, Rees, D, Montgomery Bissell, D, Desnick, R, Parker, C, Phillips, J, Bonkovsky, HL, Vassiliou, D, Penz, C, Chan-Daniels, A, He, Q, Querbes, W, Fitzgerald, K, Kim, JB, Garg, P, Vaishnaw, A, Simon, AR & Anderson, K 2019, 'Phase 1 trial of an RNA interference therapy for acute intermittent porphyria', New England Journal of Medicine, vol. 380, no. 6, pp. 549-558. https://doi.org/10.1056/NEJMoa1807838
Sardh E, Harper P, Balwani M, Stein P, Rees D, Montgomery Bissell D et al. Phase 1 trial of an RNA interference therapy for acute intermittent porphyria. New England Journal of Medicine. 2019 Feb 7;380(6):549-558. https://doi.org/10.1056/NEJMoa1807838
Sardh, Eliane ; Harper, Pauline ; Balwani, Manisha ; Stein, Penelope ; Rees, David ; Montgomery Bissell, D. ; Desnick, Robert ; Parker, Charles ; Phillips, John ; Bonkovsky, Herbert L. ; Vassiliou, Daphne ; Penz, Craig ; Chan-Daniels, Amy ; He, Qiuling ; Querbes, William ; Fitzgerald, Kevin ; Kim, Jae B. ; Garg, Pushkal ; Vaishnaw, Akshay ; Simon, Amy R. ; Anderson, Karl. / Phase 1 trial of an RNA interference therapy for acute intermittent porphyria. In: New England Journal of Medicine. 2019 ; Vol. 380, No. 6. pp. 549-558.
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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.",
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T1 - Phase 1 trial of an RNA interference therapy for acute intermittent porphyria

AU - Sardh, Eliane

AU - Harper, Pauline

AU - Balwani, Manisha

AU - Stein, Penelope

AU - Rees, David

AU - Montgomery Bissell, D.

AU - Desnick, Robert

AU - Parker, Charles

AU - Phillips, John

AU - Bonkovsky, Herbert L.

AU - Vassiliou, Daphne

AU - Penz, Craig

AU - Chan-Daniels, Amy

AU - He, Qiuling

AU - Querbes, William

AU - Fitzgerald, Kevin

AU - Kim, Jae B.

AU - Garg, Pushkal

AU - Vaishnaw, Akshay

AU - Simon, Amy R.

AU - Anderson, Karl

PY - 2019/2/7

Y1 - 2019/2/7

N2 - 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.

AB - 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.

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