2. Academic Validation
  3. Discovery of Risdiplam, a Selective Survival of Motor Neuron-2 ( SMN2) Gene Splicing Modifier for the Treatment of Spinal Muscular Atrophy (SMA)

Discovery of Risdiplam, a Selective Survival of Motor Neuron-2 ( SMN2) Gene Splicing Modifier for the Treatment of Spinal Muscular Atrophy (SMA)

  • J Med Chem. 2018 Aug 9;61(15):6501-6517. doi: 10.1021/acs.jmedchem.8b00741.
Hasane Ratni 1,  Martin Ebeling 1,  John Baird 2,  Stefanie Bendels 1,  Johan Bylund 1,  Karen S Chen 3,  Nora Denk 1,  Zhihua Feng 4,  Luke Green 1,  Melanie Guerard 1,  Philippe Jablonski 1,  Bjoern Jacobsen 1,  Omar Khwaja 1,  Heidemarie Kletzl 1,  Chien-Ping Ko 4,  Stefan Kustermann 1,  Anne Marquet 1,  Friedrich Metzger 1,  Barbara Mueller 1,  Nikolai A Naryshkin 2,  Sergey V Paushkin 3,  Emmanuel Pinard 1,  Agnès Poirier 1,  Michael Reutlinger 1,  Marla Weetall 2,  Andreas Zeller 1,  Xin Zhao 2,  Lutz Mueller 1
Affiliations

Affiliations

  • 1 F. Hoffmann-La Roche Ltd., pRED, Pharma Research & Early Development , Roche Innovation Center Basel , Grenzacherstrasse 124 , 4070 Basel , Switzerland.
  • 2 PTC Therapeutics, Inc. , 100 Corporate Court , South Plainfield , New Jersey 07080 , United States.
  • 3 SMA Foundation , 888 Seventh Avenue, Suite 400 , New York , New York 10019 , United States.
  • 4 Section of Neurobiology, Department of Biological Sciences , University of Southern California , Los Angeles , California 90089 , United States.
PMID: 30044619 DOI: 10.1021/acs.jmedchem.8b00741
Abstract

SMA is an inherited disease that leads to loss of motor function and ambulation and a reduced life expectancy. We have been working to develop orally administrated, systemically distributed small molecules to increase levels of functional SMN protein. Compound 2 was the first SMN2 splicing modifier tested in clinical trials in healthy volunteers and SMA patients. It was safe and well tolerated and increased SMN protein levels up to 2-fold in patients. Nevertheless, its development was stopped as a precautionary measure because retinal toxicity was observed in cynomolgus monkeys after chronic daily oral dosing (39 weeks) at exposures in excess of those investigated in patients. Herein, we describe the discovery of 1 (risdiplam, RG7916, RO7034067) that focused on thorough pharmacology, DMPK and safety characterization and optimization. This compound is undergoing pivotal clinical trials and is a promising medicine for the treatment of patients in all ages and stages with SMA.

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