2 research outputs found
Discovery of Risdiplam, a Selective Survival of Motor Neuron‑2 (<i>SMN2</i>) Gene Splicing Modifier for the Treatment of Spinal Muscular Atrophy (SMA)
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 <b>2</b> 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 <b>1</b> (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
Discovery of Risdiplam, a Selective Survival of Motor Neuron‑2 (<i>SMN2</i>) Gene Splicing Modifier for the Treatment of Spinal Muscular Atrophy (SMA)
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 <b>2</b> 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 <b>1</b> (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