DNL151 / Denali Therap, Biogen - LARVOL DELTA

BIIB122/DNL151 (small molecule LRRK2 inhibitor) for the treatment of Parkinson’s disease (PD) (GlobeNewswire) - "Denali and Biogen are jointly developing LRRK2 small molecule inhibitors for Parkinson’s disease (PD), with Biogen leading the global Phase 2b LUMA study evaluating the effect of BIIB122 on disease progression in early-stage PD. In May 2025, Biogen announced the Phase 2b LUMA study was fully enrolled with a readout expected in 2026."

P2b data • Parkinson's Disease

LUMA: 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) - P2 | N=650 | Active, not recruiting | Sponsor: Biogen | Recruiting ➔ Active, not recruiting

Enrollment closed • CNS Disorders • Movement Disorders • Parkinson's Disease

HOW THE THERAPEUTIC APPROACH TO EARLY PARKINSON'S DISEASE WILL CHANGE IN THE NEXT FUTURE (ADPD 2025) - "Levodopa remains the most efficacious drug, a better preparation of levodopa like IPX 203 can ensure more stable plasma levels of Levodopa...Tavapadon is a new dopamine agonist stimulating D1-D5 receptors which concluded the phase III. Other compounds such as CVN424 (Cerevance) orally active and selective GPR6 inverse agonist, piperamat (IRLAB 752) a cortical enhancer to improve balance, Clenbuterol/Nadolol for cognition, mesdopetam a D3 antagonist are under investigation...These include the monoclonal antibody prasinezumab, UCB0599 and buntanetap small-molecules α-synuclein aggregation inhibitor, the vaccine ACI-7104.056 by AC immune...The LRKK2 kinase inhibitor BIIB122/DNL151 is in phase IIb in PD. BIAL BIA 28-6156 activator of the GCase enzyme is under investigation in patients with GBA mutation. The combination of symptomatic and disease modifying therapy, the use of accurate biomarkers and more precise treatment will be the future in the treatment of PD."

CNS Disorders • Movement Disorders • Parkinson's Disease • GBA

RESPONSE OF CSF LYSOSOMAL PATHWAY BIOMARKERS TO BIIB122/DNL151 TREATMENT IN PH1 AND PH1B CLINICAL TRIALS (ADPD 2025) - P1, P1b | "The pharmacodynamic Results suggest that BIIB122/DNL151 treatment centrally modulates levels of lysosomal pathway proteins in PD patients, a finding requiring confirmation in a treatment study with greater participant numbers and longer treatment duration. In addition to lysosomal pathway modulation, GPNMB and CTSS pharmacodynamic responses may reflect modulation of neuroinflammation, a pathway similarly implicated in PD pathogenesis."

Biomarker • Clinical • CNS Disorders • Inflammation • Movement Disorders • Parkinson's Disease • CTSD • CTSS • GPNMB

BIIB122/DNL151 (small molecule LRRK2 inhibitor) for the treatment of Parkinson’s disease (PD) (GlobeNewswire) - "Denali and Biogen have a strategic collaboration to jointly develop and commercialize small molecule inhibitors of LRRK2. Biogen is conducting the global Phase 2b LUMA study, which is evaluating the ability of BIIB122 to slow disease progression as compared to placebo in approximately 640 participants with early-stage Parkinson's disease; completion of enrollment is expected in 2025."

Enrollment closed • CNS Disorders • Parkinson's Disease

Denali Therapeutics Announces First Participant Dosed in Phase 2a Study of LRRK2 Inhibitor, BIIB122, in LRRK2-Associated Parkinson’s Disease (GlobeNewswire) - "Denali Therapeutics Inc...announced initiation of dosing in a global Phase 2a clinical study, BEACON, of the investigational drug leucine-rich repeat kinase 2 (LRRK2) inhibitor BIIB122 (DNL151) in participants with LRRK2-associated Parkinson’s disease (LRRK2-PD)...The Phase 2a study is intended to evaluate safety and biomarkers associated with oral daily dosing of BIIB122 in approximately 50 participants with Parkinson’s disease and LRRK2 pathogenic mutations confirmed by genetic testing. The study is designed to enroll participants into a double-blind treatment period of three months followed by an open label extension."

Trial status • CNS Disorders • Parkinson's Disease

Safety and Pharmacodynamic Effects of BIIB122 in Participants With LRRK2-Associated Parkinson's Disease (LRRK2-PD) (clinicaltrials.gov) - P2 | N=50 | Recruiting | Sponsor: Denali Therapeutics Inc. | Not yet recruiting ➔ Recruiting

Enrollment open • CNS Disorders • Movement Disorders • Parkinson's Disease

Rationale for LRRK2 inhibition in sporadic Parkinson’s disease and the LUMA trial (MDS Congress 2024) - P2 | "The LUMA protocol is evaluating the safety and efficacy of BIIB122/DNL151 in eligible patients with early-stage sporadic PD, including those with or without a pathogenic LRRK2 variant. LUMA is the most advanced program in clinic for LRRK2 inhibition, with efficacy endpoints that measure clinical progression of PD and biomarker assessments that measure the biological impact of LRRK2 inhibition. LRRK2 in the pathogenesis of Parkinson's disease F2."

CNS Disorders • Parkinson's Disease • LRRK2

LRRK2 inhibition by BIIB122/DNL151 in participants with Pathogenic LRRK2 Variants and Parkinson's disease: Study Design to Evaluate Safety, Pharmacodynamics and Pharmacokinetics (MDS Congress 2024) - "LRRK2 inhibition is a promising target with the potential to improve lysosomal dysfunction and slow progression of PD. This study will enroll a broad population of LRRK2-PD participants and aims to complement safety and biomarker data derived from LUMA. Data from this study may inform the design of future studies with BIIB122/DNL151."

Clinical • PK/PD data • CNS Disorders • Parkinson's Disease • LRRK2

Safety and Pharmacodynamic Effects of BIIB122 in Participants With LRRK2-Associated Parkinson's Disease (LRRK2-PD) (clinicaltrials.gov) - P2 | N=50 | Not yet recruiting | Sponsor: Denali Therapeutics Inc.

New P2 trial • CNS Disorders • Movement Disorders • Parkinson's Disease

A Study to Assess the Potential for Gastric-pH Dependent Drug-Drug Interactions of BIIB122 With a Proton Pump Inhibitor in Healthy Participants (clinicaltrials.gov) - P1 | N=18 | Completed | Sponsor: Biogen | Active, not recruiting ➔ Completed

Trial completion

Denali Therapeutics Reports First Quarter 2024 Financial Results and Business Highlights (GlobeNewswire) - "In February, Sanofi discontinued development of SAR443820/DNL788 in ALS based on the results of the Phase 2 HIMALAYA study, which did not meet the primary endpoint. BIIB122/DNL151:...Denali plans to initiate the Phase 2a study in 2024....In January, Denali announced a voluntary pause in the DNL593 Phase 1/2 study in participants with FTD-GRN to implement protocol modifications and expects the study to resume this year."

Discontinued • New P2a trial • Trial status • Amyotrophic Lateral Sclerosis • CNS Disorders

A Study to Assess the Potential for Gastric-pH Dependent Drug-Drug Interactions of BIIB122 With a Proton Pump Inhibitor in Healthy Participants (clinicaltrials.gov) - P1 | N=18 | Active, not recruiting | Sponsor: Biogen | Recruiting ➔ Active, not recruiting

Enrollment closed

A Study to Assess the Potential for Gastric-pH Dependent Drug-Drug Interactions of BIIB122 With a Proton Pump Inhibitor in Healthy Participants (clinicaltrials.gov) - P1 | N=15 | Recruiting | Sponsor: Biogen | Not yet recruiting ➔ Recruiting

Enrollment open

LUMA: A Study to Assess the Safety of BIIB122 Tablets and if it Can Slow the Worsening of Early-Stage Parkinson's Disease in Participants Between the Ages of 30 and 80 (clinicaltrials.gov) - P2 | N=640 | Recruiting | Sponsor: Biogen | Trial completion date: Aug 2025 ➔ Dec 2025 | Trial primary completion date: Aug 2025 ➔ Dec 2025

Trial completion date • Trial primary completion date • CNS Disorders • Movement Disorders • Parkinson's Disease

Denali Therapeutics Reports Fourth Quarter and Full Year 2023 Financial Results and Business Highlights (GlobeNewswire) - "DNL343: eIF2B activator in development for the treatment of amyotrophic lateral sclerosis (ALS); Enrollment continues in Regimen G (DNL343) of the Phase 2/3 HEALEY ALS Platform Trial and is expected to be completed in 2024....Today Denali also announced the execution of a Collaboration and Development Funding Agreement in January 2024 with a third party related to a global Phase 2a study of BIIB122/DNL151, which Denali plans to solely operationalize to evaluate safety and biomarkers associated with BIIB122 in participants with Parkinson’s disease and confirmed pathogenic variants of LRRK2. This agreement includes committed funding of $75.0 million, of which $12.5 million was received in January 2024, and the remainder will be triggered based on time and operational milestones in the study."

Enrollment status • Licensing / partnership • Amyotrophic Lateral Sclerosis • CNS Disorders • Parkinson's Disease

A Study to Assess the Potential for Gastric-pH Dependent Drug-Drug Interactions of BIIB122 With a Proton Pump Inhibitor in Healthy Participants (clinicaltrials.gov) - P1 | N=15 | Not yet recruiting | Sponsor: Biogen

New P1 trial

LUMA: A Study to Assess the Safety of BIIB122 Tablets and if it Can Slow the Worsening of Early-Stage Parkinson's Disease in Participants Between the Ages of 30 and 80 (clinicaltrials.gov) - P2 | N=640 | Recruiting | Sponsor: Biogen | Phase classification: P2b ➔ P2

Phase classification • CNS Disorders • Movement Disorders • Parkinson's Disease

Recent advances in targeting leucine-rich repeat kinase 2 as a potential strategy for the treatment of Parkinson's disease. (PubMed, Bioorg Chem) - "Currently, five candidates, DNL201, DNL151, WXWH0226, NEU-723 and BIIB094, have advanced to clinical trials for PD treatment. In this review, we describe the structure, pathogenic mutations and the mechanism of LRRK2, and summarize the development of LRRK2 inhibitors in preclinical and clinical studies, trying to provide an insight into targeting LRRK2 for PD intervention in future."

Journal • Review • CNS Disorders • Movement Disorders • Parkinson's Disease • LRRK2

DNL151, DNL201 and BIIB094: experimental agents for the treatment of Parkinson's disease. (PubMed, Expert Opin Investig Drugs) - "Approval of Leucine-rich repeat kinase 2 inhibitors in case of positive clinical study outcomes will introduce personalized medicine for beneficial modification of progression as the most unmet need for treatment of patients with Parkinson's disease. In addition to the currently, preponderantly performed clinical rating with established scales, further clinical trial endpoints, such as dosing of dopamine substitution, may be considered in study designs to demonstrate therapeutic effects on the progression of Parkinson's disease."

Journal • Review • CNS Disorders • Inflammation • Metabolic Disorders • Movement Disorders • Parkinson's Disease • LRRK2

LIGHTHOUSE: A Study to Assess if BIIB122 Tablets Are Safe and Can Slow Worsening of Early-Stage Parkinson's Disease in Participants With Specific LRRK2 Genetic Variants Between the Ages of 30 and 80 Using the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (clinicaltrials.gov) - P3 | N=6 | Terminated | Sponsor: Biogen | Active, not recruiting ➔ Terminated; Sponsor Decision

Trial termination • CNS Disorders • Movement Disorders • Parkinson's Disease

LRRK2 Inhibition by BIIB122/DNL151 Demonstrates Robust Target and Lysosomal Engagement: Pharmacokinetics, Pharmacodynamics and Safety in Phase 1 and Phase 1b Studies in Healthy and (MDS Congress 2023) - "E-R analysis indicated BIIB122/DNL151 potently inhibited peripheral and central LRRK2 activity. Higher average concentrations associated with ~80-90% LRRK2 inhibition were required to impact downstream lysosomal pathways. These concentrations were achieved at doses that were generally well tolerated in HVs and PD participants."

Clinical • P1 data • PK/PD data • CNS Disorders • Parkinson's Disease

LIGHTHOUSE: A Study to Assess if BIIB122 Tablets Are Safe and Can Slow Worsening of Early-Stage Parkinson's Disease in Participants With Specific LRRK2 Genetic Variants Between the Ages of 30 and 80 Using the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (clinicaltrials.gov) - P3 | N=6 | Active, not recruiting | Sponsor: Biogen | Recruiting ➔ Active, not recruiting | N=400 ➔ 6 | Trial completion date: Jan 2031 ➔ Aug 2023 | Trial primary completion date: Jan 2031 ➔ Aug 2023

Enrollment change • Enrollment closed • Trial completion date • Trial primary completion date • CNS Disorders • Movement Disorders • Parkinson's Disease

Statement: Biogen Provides Update on Parkinson’s Disease Clinical Development Program (Biogen Press Release) - "...Biogen announced plans to revise the clinical development program for BIIB122, a small molecule inhibitor of leucine-rich repeat kinase 2 (LRRK2), which is being developed in collaboration with Denali Therapeutics Inc....The protocol for the LUMA study in patients with early-stage Parkinson’s disease will be amended to now include eligible patients with a LRRK2 genetic mutation in addition to continuing to enroll eligible patients with early-stage idiopathic Parkinson’s disease. The LIGHTHOUSE study of BIIB122 in patients with Parkinson’s disease associated with LRRK2 mutations will be discontinued. Patients currently enrolled and randomized in LIGHTHOUSE will be offered the opportunity to join the LUMA study."

Clinical protocol • Trial termination • CNS Disorders • Parkinson's Disease

LRRK2 Inhibition by BIIB122 in Healthy Participants and Patients with Parkinson's Disease. (PubMed, Mov Disord) - "At generally safe and well-tolerated doses, BIIB122 achieved substantial peripheral LRRK2 kinase inhibition and modulation of lysosomal pathways downstream of LRRK2, with evidence of CNS distribution and target inhibition. These studies support continued investigation of LRRK2 inhibition with BIIB122 for the treatment of PD."

Biomarker • Clinical • Journal • P1 data • CNS Disorders • Movement Disorders • Parkinson's Disease