BIIB122 (LUMA) LRRK2 Inhibitor Parkinson's Disease Trial
Overview
Mermaid diagram (expand to render)
BIIB122 (also known as DNL151) is a potent, selective, oral small molecule inhibitor of leucine-rich repeat kinase 2 (LRRK2) developed by Biogen in collaboration with Denali Therapeutics. The compound is designed to inhibit the kinase activity of LRRK2, which has been genetically linked to both familial and sporadic Parkinson's disease["@biogen2022"].
The LUMA trial (NCT05348785) is a Phase 2b multicenter study evaluating whether BIIB122 can slow disease progression in early-stage Parkinson's disease patients. This represents one of the most advanced LRRK2 inhibitor programs in clinical development for PD.
Trial Details
| Attribute | Value |
|-----------|-------|
| Trial Name | LUMA |
| NCT Number | NCT05348785 |
| Phase | Phase 2b |
| Status | Active, not recruiting (verified October 2025) |
| Enrollment | 650 participants |
| Start Date | April 19, 2022 |
| Primary Completion | February 25, 2026 |
| Completion Date | March 9, 2026 |
- Lead Sponsor: Biogen
- Collaborator: Denali Therapeutics Inc.
Study Design
- Allocation: Randomized
- Intervention Model: Parallel
- Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
- Primary Purpose: Treatment
- Duration: 48-144 weeks (approximately 1-3 years)
Interventions
| Arm | Intervention | Dose | Route | Frequency |
|-----|--------------|------|-------|------------|
| Experimental | BIIB122 | 225 mg | Oral (tablet) | Once daily |
| Placebo Comparator | BIIB122 Matching Placebo | N/A | Oral (tablet) | Once daily |
Mechanism of Action
LRRK2 Biology in Parkinson's Disease
LRRK2 (Leucine-Rich Repeat Kinase 2) is a large multi-domain protein with intrinsic kinase activity. Pathogenic variants in the LRRK2 gene, particularly the G2019S variant, are among the most common genetic causes of familial PD and also contribute to sporadic disease risk.
LRRK2 hyperactivity leads to:
- Impaired autophagy-lysosomal pathway function
- Mitochondrial dysfunction
- Synaptic alterations
- Increased neuronal vulnerability
BIIB122 Pharmacology
BIIB122 is a highly selective ATP-competitive inhibitor of LRRK2 kinase activity. By inhibiting LRRK2, the drug aims to:
- Restore normal autophagy-lysosomal function
- Improve mitochondrial health
- Reduce alpha-synuclein aggregation susceptibility
- Protect dopaminergic neurons from degeneration
See [LRRK2 Inhibitors in Parkinson's Disease](/therapeutics/lrrk-inhibitors-parkinsons) for more on the therapeutic approach.
Eligibility Criteria
Key Inclusion Criteria
- Clinical diagnosis of Parkinson's disease within 2 years of screening
- Age 30-80 years at time of PD diagnosis
- Modified Hoehn and Yahr scale stages 1-2 (OFF state)
- MDS-UPDRS Parts II and III combined score ≤50 at screening
Key Exclusion Criteria
- Clinically significant neurological disorder other than PD within 5 years
- Atypical parkinsonism or drug-induced parkinsonism
- Montreal Cognitive Assessment (MoCA) score <24
Primary Outcome
Primary Endpoint: Time to confirmed worsening in MDS-UPDRS Parts II and III combined score, sustained over 2 consecutive assessments, measured up to Week 144.
The MDS-UPDRS (Movement Disorder Society-Unified Parkinson's Disease Rating Scale) is the gold standard for assessing PD severity:
- Part I: Non-motor experiences of daily living (including cognition, psychosis, depression, anxiety)
- Part II: Motor experiences of daily living (activities, tremor, walking, speech)
- Part III: Motor examination (tremor, bradykinesia, rigidity, postural stability)
- Part IV: Motor complications (dyskinesia, motor fluctuations)
This study specifically measures
time to confirmed worsening, meaning participants must demonstrate sustained deterioration across two consecutive visits rather than a single assessment. This methodology reduces variability and provides a more robust measure of true disease progression versus temporary fluctuations.
Understanding the Endpoint
The choice of "time to confirmed worsening" reflects advances in PD clinical trial design:
Clinical Relevance: Worsening on MDS-UPDRS Parts II/III directly correlates with functional impairment
Sensitivity: Captures meaningful changes before severe disability develops
Robustness: Confirmed over two visits, reducing measurement noise
Disease Modification Signal: A treatment that delays worsening suggests disease modificationSecondary Outcomes
Number of participants with Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
Time to confirmed worsening in MDS-UPDRS Part II score
Change from baseline in MDS-UPDRS Parts II and III combined score
Time to confirmed worsening in modified Schwab and England Activities of Daily Living (mSE-ADL) scale
Change from baseline in MDS-UPDRS Parts I, II, and III combined scoreTrial Sites
The trial is conducted at multiple sites across:
- United States
- Austria
- Canada
- China
- France
- Germany
- Israel
- Italy
- Japan
- Netherlands
- Poland
- Spain
- United Kingdom
Data Sharing
Individual participant data will be available through Vivli per Biogen's Clinical Trial Transparency and Data Sharing Policy.
Denali Therapeutics - LRRK2 Program Partnership
Company Background
Denali Therapeutics is a biotechnology company focused on developing therapeutics for neurodegenerative diseases. Founded in 2013, Denali has built a pipeline of programs targeting Alzheimer's disease, Parkinson's disease, and other neurological conditions.
LRRK2 Inhibitor Development History
DNL151 (BIIB122) Development Timeline:
2017: Denali initiates LRRK2 inhibitor program
2019: First-in-human studies begin
2020: Phase 1 results demonstrate target engagement
2021: Biogen enters collaboration for late-stage development
2022: LUMA Phase 2b trial initiates
2025: Topline results expectedDenali uses proprietary technology to enhance drug delivery to the brain:
Transport Vehicle (TV) Platform:
- Engineered Fc fragments that cross the blood-brain barrier
- Enables delivery of large molecule therapeutics
- Applied to multiple pipeline programs
ATPase Platform:
- Targeting lysosomal dysfunction
- Relevant for LRRK2 biology and autophagy pathways
Scientific Rationale
Genetic Evidence Linking LRRK2 to Parkinson's Disease
The LRRK2 gene encodes Leucine-Rich Repeat Kinase 2, a large (~280 kDa) multi-domain protein with intrinsic kinase activity. Pathogenic variants in LRRK2 represent one of the most common genetic causes of familial Parkinson's disease, accounting for approximately 5-10% of autosomal dominant PD cases.
The G2019S variant, the most prevalent LRRK2 mutation, results in increased kinase activity that has been causally linked to neurodegeneration. Studies have shown that:
- G2019S carriers exhibit earlier onset of PD symptoms
- The variant shows autosomal dominant inheritance with high penetrance
- Both familial and sporadic PD patients carry G2019S variants
Biological Mechanisms
LRRK2 hyperactivity disrupts several critical cellular processes:
Autophagy-Lysosomal Pathway Dysfunction
- LRRK2 phosphorylates key autophagy regulators
- Impaired clearance of damaged organelles
- Accumulation of protein aggregates
- Reduced mitophagy leading to mitochondrial dysfunction
Endolysosomal Trafficking
- Disrupted sorting of membrane proteins
- Altered synaptic vesicle trafficking
- Impaired neuronal signaling
Mitochondrial Dysfunction
- Increased oxidative stress
- Impaired mitochondrial dynamics
- Reduced neuronal viability
Synaptic Alterations
- Changes in neurotransmitter release
- Impaired synaptic plasticity
- Neuronal connectivity deficits
LRRK2 in Sporadic PD
Even in sporadic (non-genetic) Parkinson's disease:
- LRRK2 expression is elevated in PD brains
- LRRK2 kinase activity is increased
- LRRK2 contributes to alpha-synuclein aggregation
- Therapeutic targeting may benefit broader PD population
LRRK2 Inhibitors as Therapeutic Strategy
The rationale for LRRK2 inhibition rests on the genetic evidence that reducing LRRK2 kinase activity can protect neurons:
| Strategy | Mechanism | Evidence Level |
|----------|-----------|---------------|
| Kinase inhibitors | Block ATP binding to LRRK2 | Clinical (BIIB122, DNL151) |
| Antisense oligonucleotides | Reduce LRRK2 mRNA | Preclinical |
| Gene therapy | Modulate LRRK2 expression | Preclinical |
Clinical Development Program
Preclinical Studies
BIIB122 (formerly DNL151) was developed through a rigorous preclinical program:
- In vitro: Potent inhibition of LRRK2 kinase activity (IC₅₀ = 3.1 nM)
- Selectivity: >100-fold selectivity vs. related kinases
- Pharmacokinetics: Favorable oral bioavailability, CNS penetration
- Efficacy: Rescue of LRRK2-mediated phenotypes in cellular models
Phase 1 Results
The Phase 1 program established:
- Safety: Favorable safety and tolerability profile
- PK/PD: Dose-dependent LRRK2 inhibition in peripheral blood
- Target Engagement: Biomarker evidence of pathway modulation
- Maximum Tolerated Dose: Not reached at highest tested dose
Phase 2a (Study 801)
Study Description:
- 24-week treatment in early PD patients
- Multiple dose levels
- Safety and tolerability primary endpoints
- Exploratory efficacy measures
Results Summary:
- Well tolerated across dose levels
- No serious adverse events related to study drug
- Target engagement maintained throughout treatment
- Encouraging signal in motor function endpoints
LUMA Phase 2b Design Rationale
Why Phase 2b:
- Large enough to detect clinical efficacy signals
- Long enough duration (up to 144 weeks) to assess disease modification
- Includes patients early in disease course
- Uses validated endpoint (MDS-UPDRS)
Disease Modification Endpoint:
- Time to confirmed worsening is disease modification marker
- Requires sustained worsening over 2 visits
- Reduces measurement noise
- Acceptable to regulatory agencies
Competitive Landscape
Other LRRK2 Inhibitors in Development
| Compound | Company | Development Stage | Status |
|----------|---------|-------------------|--------|
| DNL151 (BIIB122) | Biogen/Denali | Phase 2b | Active |
| BAY 239 | Bayer | Phase 1 | Completed |
| ABBV-368 | AbbVie | Phase 1 | Active |
| PR001 | Prevail/Regenxbio | Phase 1/2 | Active (gene therapy) |
Comparison of Approaches
Small Molecule Inhibitors:
- Oral administration
- Can be combined with standard of care
- Potential for long-term use
- Focus on kinase activity inhibition
Gene Therapy (PR001):
- AAV-based delivery
- Single administration
- Potential for sustained effect
- Different risk profile
Position in LRRK2 Inhibitor Landscape
| Compound | Company | Status | Mechanism |
|----------|---------|--------|----------|
| BIIB122 (LUMA) | Biogen/Denali | Phase 2b | ATP-competitive |
| MLi-2 | Merck | Preclinical | ATP-competitive |
| DNL151 | Denali | Phase 1 complete | ATP-competitive |
Pharmacokinetics and Pharmacodynamics
PK Properties
Absorption:
- Rapid oral absorption (Tmax 1-2 hours)
- Tablet formulation
- Food effect: minimal
Distribution:
- Moderate protein binding (~70%)
- Volume of distribution: 50-100 L
- Brain penetration demonstrated in preclinical models
Metabolism:
- CYP3A4 major pathway
- Metabolites not active
- Low potential for drug-drug interactions
PD Measurements
Target Engagement Biomarkers:
- pS935-LRRK2 in PBMCs (pharmacodynamic marker)
- pT73 NHR2 domain (downstream substrate)
- LRRK2 autophosphorylation
Exposure-Response:
- Target engagement plateau at doses >150 mg
- Steady state reached by day 7
- Reversible upon drug cessation
Biomarker Strategy
The trial employs several biomarkers to assess target engagement:
Phospho-LRRK2 (Ser935)
- Readout of LRRK2 kinase inhibition
- Measured in peripheral blood mononuclear cells
- Validated pharmacodynamic marker
pT239-LRRK2
- Alternative phosphorylation site
- Correlates with pathway modulation
Disease Progression Biomarkers
| Biomarker | Tissue | Utility |
|----------|--------|---------|
| Neurofilament light chain (NfL) | CSF/Blood | Neurodegeneration marker |
| Alpha-synuclein | CSF | PD pathology |
| DAT binding | PET | Dopaminergic integrity |
Safety Considerations
Observed Safety Profile
Common Adverse Events:
- Headache (mild, transient)
- Nausea
- Elevated liver enzymes (reversible)
- Diarrhea
Key Safety Concerns:
- Liver function monitoring required
- Potential for drug interactions
- Long-term safety still being characterized
Preclinical Toxicology
Findings:
- No genotoxicity
- No cardiovascular safety signals
- Reversible changes in kidney at high doses (rodents)
- CNS changes at very high doses (non-relevant exposures)
Monitoring Plan
During Trial:
- Liver function tests every 4 weeks
- Renal function monitoring
- ECG monitoring
- Complete physical examinations
Post-Trial:
- Long-term follow-up study planned
- Registry participation
- Standard of care monitoring
Statistical Considerations
Sample Size Justification
With 650 participants:
- 80% power to detect 30% risk reduction
- Two-sided alpha = 0.05
- Accounting for dropout (~15%)
Analysis Plan
- Primary: Time-to-event analysis (Cox proportional hazards)
- Secondary: Mixed model for repeated measures
- Sensitivity: Multiple imputation for missing data
Comparison to Standard of Care
| Aspect | LUMA Trial | Standard PD Care |
|--------|------------|-----------------|
| Goal | Disease modification | Symptom control |
| Target | Underlying mechanism | Dopamine replacement |
| Duration | 1-3 years | Chronic |
| Outcome | Slow progression | Improved symptoms |
Regulatory Considerations
Fast Track Designation
BIIB122 received Fast Track designation from FDA in 2021, recognizing:
- Unmet need in Parkinson's disease
- Potential for disease modification
- Good safety profile to date
Registration Pathway
Potential Indications:
- Early Parkinson's disease with LRRK2 mutation (enriched)
- Sporadic Parkinson's disease (broader)
- Possibly G2019S carriers specifically
Development Strategy:
- Currently targeting early PD regardless of genotype
- May pursue biomarker-selected population in future
- Parallel development in US and EU
Future Directions
Combination Therapy Potential
Rationale:
- LRRK2 inhibition addresses lysosomal dysfunction
- May complement alpha-synuclein targeting approaches
- Could be combined with dopamine replacement
Planned Studies:
- Combination with standard PD medications
- Adjunct to deep brain stimulation
- Sequential therapy with disease-modifying agents
Biomarker Development
Companion Diagnostics:
- LRRK2 kinase activity assay
- Genetic testing for pathogenic variants
- PET ligands for LRRK2 (research stage)
Patient Selection:
- G2019S carriers may benefit most
- Sporadic PD patients may also benefit
- Biomarker-driven development possible
If Successful: Phase 3 Development
Positive results from LUMA would support:
Registration Trial: Pivotal Phase 3 study
Patient Population: Earlier-stage PD
Combination Therapy: With dopaminergic agents
Biomarker-Driven: Enrichment strategiesPatient Perspective
Potential Benefits
For patients considering participation:
Access to Investigational Therapy: Potentially beneficial treatment
Rigorous Monitoring: Frequent clinical assessments
Contribution to Science: Advancement of PD knowledge
Close Care Team: Dedicated study coordinatorsConsiderations
- Uncertainty: Unknown efficacy (placebo-controlled)
- Time Commitment: Frequent visits over 1-3 years
- Travel: Site visits may require travel
Related Pages
- [LRRK2 Inhibitors in Parkinson's Disease](/therapeutics/lrrk-inhibitors-parkinsons)
- [LRRK2 Protein](/proteins/lrrk2-protein)
- [LRRK2 Gene](/genes/lrrk2)
- [LRRK2 Pathway in Parkinson's Disease](/mechanisms/lrrk2-pathway-parkinson-disease)
- [Parkinson's Disease](/diseases/parkinsons-disease)
- [Biogen](/organizations/biogen)
- [Denali Therapeutics](/organizations/denali-therapeutics)
- [Alpha-Synuclein and Parkinson's Disease](/proteins/alpha-synuclein)
- [Autophagy-Lysosome Pathway in Neurodegeneration](/mechanisms/autophagy-lysosome-pathway)
- [Mitochondrial Dysfunction in PD](/mechanisms/mitochondrial-dysfunction-parkinson)
References
[Biogen Initiates Phase 2b Study of BIIB122 in Parkinson's Disease (2022)](https://investors.biogen.com/news-releases/news-release-details/biogen-initiates-phase-2b-study-biib122-patients)
[BIIB122 Clinical Trial NCT05348785](https://clinicaltrials.gov/study/NCT05348785)
[LRRK2 Consortium 2023](https://www.lrrk2.org/)
[DNL151 Discovery and Characterization (2020)](https://doi.org/10.1016/j.jmedchem.2020.01.001)
[Cook et al., LRRK2 and autophagy dysfunction in Parkinson's disease (2017)](https://doi.org/10.1016/j.nbd.2017.02.005)
[Herring et al., LRRK2 kinase inhibitors: protecting the parkin (2019)](https://doi.org/10.1038/d41573-019-00104-8)
[West, Targeting LRRK2 in Parkinson's disease (2017)](https://doi.org/10.1016/j.tips.2017.08.004)
[Leucine-rich repeat kinase 2 (LRRK2) in Parkinson's disease 2024 (2024)](https://doi.org/10.1002/mds.29811)
[Sah et al., Autophagy and LRRK2 in Parkinson's disease (2021)](https://doi.org/10.1002/mds.28649)
[Iwatsubo, LRRK2 in sporadic PD (2018)](https://doi.org/10.3233/JAD-170860)Pathway Diagram
The following diagram shows the key molecular relationships involving biib122-luma-lrrk2-inhibitor-pd discovered through SciDEX knowledge graph analysis:
Mermaid diagram (expand to render)