Last updated Dec. 8, 2022, by Marisa Wexler, MS
Fact-checked by Ana de Barros, PhD
What is branaplam for SMA?
Branaplam (also known as LMI070) is an orally available, small molecule Novartis had been developing as a potential therapy for spinal muscular atrophy (SMA).
In July 2021, the company decided to stop branaplam’s work for that indication based on the rapid advancements in the SMA treatment landscape since 2016 — during which three disease-modifying therapies were approved — and the fact that the therapy would no longer represent a highly differentiated option for SMA patients.
Novartis is continuing branaplam’s development as a potential treatment for Huntington’s disease.
How does branaplam work in SMA?
SMA is caused by low to no levels of SMN, a protein essential for motor neuron and muscle health, due to mutations in the SMN1 gene. Motor neurons are specialized nerve cells controlling voluntary movement and are progressively lost in SMA.
Humans have a “backup” SMN gene, SMN2, but a slight difference in its DNA sequence results in the production of a shorter, less stable, and poorly working SMN protein due to alternative splicing. Alternative splicing is a natural process that allows for a single gene to give rise to many different proteins by adding or removing pieces of genetic information, much like ingredients in a recipe.
Branaplam is thought to work by correcting SMN2’s alternative splicing, thereby increasing the production of full-length SMN protein. Although structurally different, the proposed mode of action is reportedly similar to that of the approved oral SMA treatment Evrysdi (risdiplam).
Branaplam was first discovered by Novartis when screening for compounds that could potentially increase SMN levels in lab-grown nerve cells, and it was shown to increase the levels of working SMN in the brain and spinal cord, leading to improvements in motor function and survival.
Branaplam is able to cross the blood-brain barrier to get to the brain and spinal cord, where motor neurons reside. The blood-brain barrier is a semipermeable membrane that shields the brain and spinal cord from the external environment but also can thwart potential therapies.
How is branaplam administered in SMA?
In clinical studies, branaplam was administered via once-per-week oral dosing.
Branaplam in SMA clinical trials
Novartis had launched a two-part Phase 1/2 clinical trial (NCT02268552) in 2014 to evaluate the candidate therapy’s safety, tolerability, and early effectiveness. It also sought to assess its pharmacokinetics — the medication’s movement into, through, and out of the body — and pharmacodynamics, comprised of its effects on the body.
The trial was testing ascending doses of branaplam in infants younger than 6 months with SMA type 1, a severe form of the disease, with the therapy being given once a week.
The study’s first part was meant to determine the maximum tolerated dose. This information would be used to determine up to three doses to be tested in its second part, which would include a new group of patients.
However, due to safety concerns raised by animal studies conducted while the trial was underway, Novartis in 2016 paused the trial’s enrollment. The safety concerns had included findings of damage to the nerves, spinal cord, testes, and kidney blood vessels of animals treated with a daily regimen of the therapy.
Enrollment was resumed in late 2017, with modifications in the study’s design: treatment was allowed to be given not only through a feeding tube, but also orally, and nerve tests were added as an additional safety measure.
Recruitment was completed in May 2019, with 13 infants in part 1 and 25 infants in part 2. Later that year, the company announced the study was progressing well, with 29 infants receiving the therapy, some for more than four years.
Results from the ongoing trial have not been disclosed.
Common side effects of branaplam
Full results from the Phase 1/2 clinical trial of branaplam in SMA have not been published, so the complete safety profile of the therapy remains unknown. However, interim results from the first part of the Phase 1/2 trial showed that adverse events were mostly mild, reversible, and manageable.
A clinical trial testing the treatment in Huntington’s disease was paused in 2022 due to safety concerns of potential peripheral neuropathy (damage to the nerves that run through the body outside the brain and spinal cord).
SMA News Today is strictly a news and information website about the disease. It does not provide medical advice, diagnosis, or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified healthcare providers with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.