Novartis cans branaplam after seeing Huntington's safety signal, delays orphan drug over slow enrollment

Novartis has delivered the coup de grâce to its ailing branaplam program, stopping (PDF) development of the splicing modulator in Huntington’s disease in the wake of a safety signal. The Big Pharma disclosed the update alongside news of the delays and discontinuations that have hit oral factor B inhibitor iptacopan.

In August, Novartis stopped dosing in a phase 2b clinical trial of branaplam after seeing early signs that the candidate may be causing peripheral neuropathy, a condition characterized by damage to the nerves outside of the brain and spinal cord. Novartis spent the rest of the year going over the data on the drug candidate before reaching a decision on the next steps.

Now, the management team has revealed it is discontinuing the program based on the assessment of the potential risk-benefit profile seen in the phase 2b study. The news is another blow for the industrywide effort to develop treatments for Huntington’s, which has in recent years suffered setbacks including the failure of Roche and Ionis Pharmaceuticals’ antisense drug tominersen in phase 3 and the temporary pause of uniQure’s high-dose gene therapy arm.

Novartis’ decision to exit the race, which follows the termination of development of branaplam in spinal muscular atrophy, makes PTC Therapeutics’ PTC518 the most advanced Huntington’s splicing modulator. PTC plans to share 12-week phase 2 data on the candidate in the second quarter.

Novartis canned branaplam in a fourth-quarter pipeline update that featured details of changes to the R&D plan for iptacopan, the molecule the company is developing to challenge AstraZeneca’s Alexion for the blockbuster paroxysmal nocturnal hemoglobinuria (PNH) market. The company is on track to file for approval in PNH this year, but other aspects of the strategy have slipped.

Patient recruitment is going slower than expected in three late-phase clinical trials that are designed to support approvals in IgA nephropathy, C3 glomerulopathy and atypical hemolytic uremic syndrome (aHUS). Novartis still expects to deliver data in IgA nephropathy and C3 glomerulopathy this year, but its target filing date has slipped to 2024. The filing in aHUS has moved from 2025 to 2026 at the earliest.

Novartis has given up on membranous nephropathy entirely, discontinuing work on the phase 2 program after seeing an “uncompelling competitive profile,” but is moving forward in another rare kidney disease, immune complex membranoproliferative glomerulonephritis. A phase 3 trial in the indication is set to get underway this year to support a filing for approval in 2026 or later.