Branaplam (LMI070)

Last updated Jan. 31, 2022, by Marta Figueiredo, PhD 

Fact-checked by Ana de Barros, PhD

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since 2016 — during which three disease-modifying therapies were approved — and the fact that the therapy would no longer represent a highly differentiated option for SMA patients.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 is continuing branaplam’s development as a potential treatment for Huntington’s disease, a rare, genetic neurodegenerative disease.

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 an event called 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 in a recipe.

Branaplam, a small molecule that can cross the blood-brain barrier and reach the brain and spinal cord — where motor neurons reside — works by correcting SMN2’s alternative splicing, thereby increasing the production of full-length SMN protein. Of note, 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.

As such, the therapy — first discovered by Novartis when screening for compounds that could potentially increase SMN levels in lab-grown nerve cells — was thought to have the potential to slow or prevent disease progression in people with SMA.

In mouse models of milder and severe SMA, branaplam was shown to increase the levels of working SMN in the brain and spinal cord, leading to improvements in the animals’ weight, muscle strength, and survival.

Branaplam in clinical trials

Novartis had launched a two-part Phase 1/2 clinical trial (NCT02268552) in 2015 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 six months with SMA type 1, a severe form of the disease, with the oral 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 that the study was progressing well, with a total of 29 infants receiving the therapy, some for more than four years.

Results from the ongoing trial have not been disclosed.

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.


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