A phase 2b trial of Biogen and Denali Therapeutics’ Parkinson’s disease candidate has missed its primary endpoint, prompting the partners to end development in the idiopathic form of the condition.
Biogen paid Denali $400 million in 2020 to partner on the LRRK2 program. The bet reflected evidence of LRRK2’s role in Parkinson’s, with researchers linking mutations that increase activity of the kinase to the aggregation of toxic proteins. In 2022, Biogen started a phase 2 trial in early-stage Parkinson’s and began a phase 3 study in a genetic subpopulation.
While Biogen made a quick U-turn on the phase 3, terminating the study after enrolling seven patients, it pushed ahead with the 650-subject midphase trial and delivered data after the markets closed Thursday. Analysts saw the study as a high-risk bet, with the William Blair team covering Denali modeling a 10% probability of success for the program.
BIIB122, also called DNL151, failed to slow the progression of Parkinson’s compared to placebo, causing the trial to miss its primary endpoint. Biogen reported more than 90% kinase inhibition of peripheral LRRK2 and a roughly 30% drop in a cerebrospinal fluid (CSF) biomarker of the kinase’s activity. Levels of the molecule in the blood and CSF were as expected.
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Yet the evidence of target activity failed to translate into improved outcomes, with secondary endpoints also finding no signs that BIIB122 provides benefits. The drug candidate was generally well tolerated with an acceptable safety profile, the partners said, but the absence of efficacy signals drove the companies to stop development of BIIB122 in idiopathic Parkinson’s.
Denali will continue to test the small molecule independently in a phase 2a trial that is enrolling people with LRRK2-associated Parkinson’s. The estimated primary completion date, according to the federal trials database, for the 12-week, 50-patient trial was late last month. The phase 2a data, coupled with the failed trial, will inform the next steps for development, Denali’s Chief Medical Officer Peter Chin, M.D., said in a statement.
With the failed study showing target activity, William Blair analysts said they are encouraged to see Denali continue the phase 2a trial “to further examine the LRRK2 dysfunction thesis.” LRRK2 mutations account for about 4% of familial and 1% to 2% of sporadic Parkinson’s cases.
Biogen axed an Ionis-partnered antisense oligonucleotide that targets LRRK2 last year. Other biotechs continue to work on the target, with Neuron23 enrolling patients with early Parkinson’s in a phase 2 trial of its LRRK2 inhibitor and Arvinas advancing a PROTAC in progressive supranuclear palsy.
