How branaplam works
SMA is caused by a mutation in a gene called survival motor neuron 1, or SMN1. The mutation leads to little or no SMN protein being produced from this gene. SMN is an essential protein that maintains the health of motor neurons, nerve cells that control the activity of muscles.
Humans have a second gene called SMN2 that is closely related to SMN1. This gene is also able to produce some SMN protein, but most of the SMN protein produced from this gene is unstable and quickly degraded.
Branaplam is designed to increase the amount of functional SMN protein produced from the SMN2 gene. It was first discovered by Novartis after about 1.4 million compounds that could increase the production of SMN protein were tested in the laboratory. After identifying branaplam, researchers tested it in mouse models of SMA and found that it increases amounts of SMN protein, leading to improvements in body weight and survival of the animals. More information about the discovery of the compound is available in a study published in 2018.
Branaplam in clinical trials
A Phase 1/2 study (NCT02268552) was initiated to evaluate the safety, tolerability, pharmacokinetics (movement in the body), pharmacodynamics (effect on the body), and efficacy of branaplam after 13 weeks of treatment in babies with SMA type 1 up to 182 days old. The trial also aimed to determine the maximum tolerated dose and optimal dosing regimen of the treatment.
In May 2016, Novartis had to pause enrollment for this trial because animal studies conducted while the human trial was underway showed unexpected injuries to the peripheral nerves, spinal cord, testes, and blood vessels in the kidney.
On Sept. 20, 2017, Novartis released an update announcing resumption of enrollment for the trial in Europe, where different doses of branaplam are being tested. The company also modified the trial design, giving participants a choice of a weekly oral treatment or delivery through a feeding tube.
Novartis announced on May 16, 2019, that enrollment was closed for the Phase 1/2 trial after enrolling 25 infants in part 2 of the study. The company also said that seven of the original 13 children who started part 1 of the trial still continue treatment after three to four years. The study is expected to be completed in July 2020.
An investigational new drug (IND) application was recently accepted by the U.S. Food and Drug Administration (FDA) for branaplam, which means that U.S. participants will also be allowed to participate in the study.
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