Branaplam for SMA

Last updated Oct. 29, 2024, by Marisa Wexler
Fact-checked by Ana de Barros, PhD

What is branaplam for SMA?

Branaplam (also known as LMI070) is an orally available, small molecule that 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since 2016 — during which three disease-modifying therapies were approved — and the fact that the therapy would no longer represent a highly differentiated option for SMA patients.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 was also developing branaplam as a potential treatment for Huntington’s disease. However, in 2022 the company decided to stop this development program due to safety concerns observed in a Phase 2 trial.

Therapy snapshot

How does branaplam work?

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 the specialized nerve cells that control voluntary movement and that 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 while 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 that also can thwart potential therapies.

How was branaplam administered?

In clinical studies, branaplam was administered via oral dosing once a week.

Branaplam in clinical trials

Novartis 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, that is, the medication’s movement into, through, and out of the body, and its pharmacodynamics, which consists of its effects on the body.

The trial was testing multiple doses of branaplam in infants younger than 6 months with SMA type 1, a severe form of the disease, with the therapy being given orally once a week.

The study’s first part was 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.

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 orally, as well as through a feeding tube, and nerve tests were added as an additional safety measure.

Recruitment was completed in May 2019 with 32 infants, 25 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.

Interim findings from the first part of the trial showed that a once-weekly dose of branaplam effectively maintained the drug’s presence in the body. Some patients showed improvements in motor function and daily activities, along with preserved abilities to eat orally and breathe without assistance.

Several patients had reduced motor function when their dose was lowered due to the safety concerns raised in animal studies, however. In some cases, motor function partially recovered when the dosage was returned to its previous level.

Since Novartis’ decision to discontinue branaplam’s development in SMA was not related to any safety or efficacy issues, the company encouraged trial participants to continue the treatment until an alternative therapy could be arranged so as to maintain continuous care.

Common side effects of branaplam

Full results from the Phase 1/2 clinical trial of branaplam in SMA have not been published, so the therapy’s complete safety profile remains unknown. Interim results from the first part of the trial showed that adverse events were mostly mild, reversible and manageable, however.

A clinical trial testing the treatment in Huntington’s disease was paused in 2022 due to safety concerns of potential peripheral neuropathy, that is, damage to the nerves that run through the body outside the brain and spinal cord.

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