Due to rapid advancements in the SMA treatment landscape since 2016, however, and because branaplam — if approved — would no longer represent a highly differentiated treatment option for SMA patients, the company decided to stop work on branaplam as a potential SMA therapy in 2021, while pursuing a clinical path for it in treating Huntington’s disease, a rare and genetic neurodegenerative disease.
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 SMN2 is unstable and quickly degraded.
Branaplam was designed to increase the amount of functional SMN protein produced from the SMN2 gene. It was first discovered by Novartis after testing compounds that could increase SMN protein production in the laboratory. Researchers then tested it in mouse models of SMA, and found that amounts of SMN protein rose, leading to improvements in the animals’ body weight and survival. This work supported studies in patients.
Branaplam in clinical trials
A Phase 1/2 study (NCT02268552) opened in 2015 to evaluate the safety, tolerability, pharmacokinetics (movement in the body), pharmacodynamics (effect on the body), and early efficacy of branaplam after 13 weeks of treatment (at varying doses) in babies with SMA type 1 up to 6 months old. The trial, taking place in Europe, also aimed to determine the maximum tolerated dose and an optimal dosing regimen for the treatment.
In May 2016, Novartis had to pause trial enrollment 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.
Novartis announced a resumption of trial enrollment in September 2017. The company also modified the trial design, giving participants a choice of a weekly oral treatment or delivery through a feeding tube.
The trial was declared fully enrolled, with 25 infants placed in part 2 of the study, in May 2019, and treatment continuing for seven of the 13 children initially enrolled in part 1.
With the 2021 decision to discontinue work on branaplam, Novartis announced that children still in this study would be able to continue with the treatment until an alternative therapy could be offered. Treatment alternatives will be determined on a case-by-case basis, tailored to the needs of each child in collaboration with trial investigators, the company stated in its announcement.
Safety and efficacy concerns with branaplam’s use had no role in the stoppage decision, Novartis stated.
Last updated: July 26, 2021
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