Biogen Ends BIIB122 Program, Denali Continues Trial in LRRK2 Carriers

Biogen and Denali Therapeutics reported negative topline results from the Phase 2b LUMA study (NCT05348785) of BIIB122 (DNL151) in early-stage Parkinson’s disease. The investigational oral LRRK2 inhibitor failed to slow disease progression versus placebo on the primary endpoint of confirmed worsening in modified MDS-UPDRS Part II and III scores, with secondary endpoints also showing no meaningful benefit. Both companies will discontinue BIIB122 development in idiopathic Parkinson’s disease, while Denali continues to explore genetically defined patient populations.

Trial and Biomarker Findings

The global, randomized, double-blind, placebo-controlled LUMA study enrolled 648 adults aged 30–80 years with early-stage Parkinson’s disease, including patients with and without pathogenic LRRK2 variants. Participants received BIIB122 or placebo for at least 48 weeks and up to 144 weeks. Exploratory biomarker analyses confirmed robust target engagement, with >90% inhibition of peripheral LRRK2 kinase activity and approximate 30% reductions in phosphorylated Rab10 levels in cerebrospinal fluid. Drug exposure in blood and CSF remained sustained. BIIB122 was generally well tolerated with an acceptable safety profile.

Scientific and Clinical Context

 BIIB122 targets leucine-rich repeat kinase 2 (LRRK2), a protein implicated in familial and sporadic Parkinson’s disease. Mutations in LRRK2 increase kinase activity, disrupting lysosomal and intracellular trafficking pathways. Inhibition has been viewed as a potential disease-modifying strategy, given lysosomal dysfunction’s role in toxic protein accumulation and neurodegeneration. Parkinson’s disease affects more than 10 million people worldwide and remains one of the most difficult neurodegenerative disorders for drug development due to biological heterogeneity, variable progression, and limited biomarkers.

Executive Commentary

Diana Gallagher, Senior Vice President and Head of Neurodegeneration Clinical Development at Biogen, said the findings provide important data for the Parkinson’s research community despite the disappointing outcome.

Denali Chief Medical Officer Peter Chin added that the LUMA trial represented a rigorous test of LRRK2 inhibition in idiopathic Parkinson’s disease and may still inform future therapeutic strategies targeting genetically defined patient populations.

Next Steps in Genetically Defined Parkinson’s

Denali will continue independently advancing the Phase 2a BEACON study (NCT06602193) in Parkinson’s patients carrying pathogenic LRRK2 variants, a subgroup associated with elevated kinase activity. The study is evaluating safety, pharmacokinetics, and lysosomal pathway biomarkers to better define biological response to LRRK2 inhibition in genetically selected patients. Initial BEACON data are expected in the first half of 2027.

Reference

Biogen and Denali Therapeutics Provide Update on Phase 2b LUMA Study of BIIB122 (DNL151) in Early-Stage Parkinson’s Disease | Biogen

Study Details | NCT05348785 | A Study to Learn About the Safety of BIIB122 Tablets and Whether They Can Slow the Worsening of Early-Stage Parkinson’s Disease in Adults Between the Ages of 30 and 80 | ClinicalTrials.gov