Novartis drops Huntington's drug on phase 2b data

Tucked away inside Novartis' fourth-quarter results update this morning is the news that the company has pulled the plug on a drug candidate for Huntington's disease after concluding that its risks may outweigh any potential benefit.

The decision to drop branaplam (also known as LMI070) comes three years after Novartis abandoned development of the drug for spinal muscular atrophy (SMA), saying it didn't see a commercial opportunity for the drug in that indication.

Like Roche's rival therapy Evrysdi (risdiplam) – which is already approved for SMA since 2020 and with sales more than doubling to around $865 million in the first nine months of 2022 – branaplam is a small-molecule RNA-splicing drug designed to reduce levels of disease-associated proteins.

Both drugs are designed to switch on the SMN2 gene, to compensate for the loss of the SMN1 gene that isn't working properly in SMA, but Novartis found that its drug also worked on another gene called HTT that is mutated in Huntington's.

HTT provides instructions to make the huntingtin protein, which is misfolded in Huntington's disease and involved in the damage to neurons that characterises the disorder – a devastating and fatal familial disease for which there are no disease modifying therapies that delay onset or slow progression.

In preliminary studies, branaplam was shown to cut levels of the protein in the central nervous system, and the drug was fast-tracked by the FDA in 2021.

Novartis was testing the therapy in a phase 2 clinical trial called VIBRANT-HD, but suspended dosing to patients last year, after becoming concerned about possible neurological side effects. Now, it has discontinued the study entirely "based on an overall assessment of potential benefit-risk."

In its third-quarter update, the company also said it was halting mid-stage studies of oral factor B inhibitor iptacopan (LNP023) in membranous nephropathy, due to an "uncompelling competitive profile", although the drug remains in development for other indications, including paroxysmal nocturnal haemoglobinuria (PNH) and C3 glomerulopathy (C3G).

Other pipeline casualties include a pair of phase 3 trials of Novartis' approved PI3K inhibitor Piqray (alpelisib) in triple-negative breast cancer and HER2-positive breast cancer, in order to "prioritise other programmes" in Novartis' pipeline.

The R&D update came as Novartis recorded fourth-quarter revenues of $12.69 billion, up 3% at constant currencies, with a stellar performance from relapsing/remitting multiple sclerosis therapy Kesimpta (ofatumumab), which saw sales grow 157% to reach $369 million in the three-month period and approach $1.1 billion for 2022 as a whole.