Novartis is returning to the alpha-synuclein protein as a possible treatment for Parkinson鈥檚 disease, signing a licensing deal worth up to $2.2bn for Arrowhead Pharmaceuticals鈥� preclinical candidate.
Novartis, which experienced a Phase II failure with its own alpha-synuclein-targeting candidate late last year, will pay $200m upfront for the exclusive worldwide licence to research, develop, manufacture, and commercialise Arrowhead鈥檚 siRNA therapy ARO-SNCA.
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As part of the deal, Arrowhead is in line to receive a further $2bn in milestone payments, along with royalties on sales if the drug is approved in the future. The transaction is expected to close in the second half of 2025.
Arrowhead鈥檚 ARO-SNCA is built upon the company鈥檚 targeted RNAi molecule (TRiM) platform. Arrowhead uses RNAi, a natural mechanism used by your cells to regulate the expression of genes, to silence specific mRNAs and reduce the production of proteins that cause disease.
ARO-SNCA itself silences the alpha-synuclein gene 鈥� abnormal forms of the alpha-synuclein protein can misfold and clump together in the brain, leading to neurological diseases.聽
Treatment of Parkinson鈥檚 disease will be the first indication targeted by Novartis when it has its hands on ARO-SNCA. Further synucleinopathies will follow as part of the collaboration, the company stated.
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By GlobalDataArrowhead鈥檚 CEO Christopher Anzalone said the candidate has already 鈥済enerated impressive preclinical results鈥�, including distribution to deep brain regions via subcutaneous injection.
Anzalone said: 鈥淲e look forward to working with Novartis to bring ARO-SNCA for the treatment of synucleinopathies, such as Parkinson鈥檚 disease, into clinical trials as soon as possible and to collaborate on additional programs in the future.鈥�
Arrowhead鈥檚 platform has already been tapped by several big pharma companies in recent years, with Takeda, GSK and Sanofi all agreeing deals with the RNA-specialist. There was also a deal with rare disease specialist Sarepta Therapeutics that involved a hefty $500m upfront payment to Arrowhead. In terms of its own pipeline, the US biotech is currently awaiting an approval decision from the US Food and Drug Administration (FDA) due in November 2025 for plozasiran to treat the rare genetic disorder familial chylomicronemia syndrome.
Alpha-synuclein鈥檚 many suitors
For Swiss drugmaker Novartis, the licensing deal marks a second attempt at unlocking the alpha-synuclein target, following a setback for one of its own candidates earlier this year. Minzasolmin, an oral drug co-developed with UCB, in December 2024. The alpha-synuclein misfolding inhibitor missed the study鈥檚 primary and secondary endpoints, resulting in programme termination.
Novartis鈥� biomedical research president Fiona Marshall said: 鈥淲e believe that one way to effectively target core drivers in Parkinson鈥檚 and other neurodegenerative diseases requires completely novel approaches to deliver RNA medicines to the brain.
“We see Arrowhead鈥檚 TRiM technology as having great potential to achieve the type of widespread and effective delivery in key brain structures that will be necessary to see the full benefit of RNA medicines in neurodegeneration.鈥�
Alpha-synuclein has proved a tricky target to successfully harness, with Novartis far from the only company struggling with the neuronal protein. Roche and Prothena鈥檚 alpha-synuclein-targeting antibody prasinezumab in a Phase II trial (NCT04777331) in early-stage Parkinson鈥檚 disease patients in the same month as minzasolmin鈥檚 data readout. Nevertheless, Roche decided to proceed with Phase III development of prasinezumab, as per an announcement earlier this year.
In a Phase II trial (NCT05104476) readout in February 2024, Lundbeck’s alpha-synuclein-targeting Lu AF82422 showed no statistically significant difference in patients with multiple system atrophy (MSA), a neurodegenerative disease with symptoms similar to Parkinson’s disease. As with Roche, Lundbeck advanced the candidate to a Phase III trial (NCT06706622).
