REASON
(2026)Objective
Evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of intrathecal BIIB094 (ION859), a LRRK2-targeting antisense oligonucleotide, in adults with Parkinson's disease with or without pathogenic LRRK2 variants.
Study Summary
• Three Grade 3 events occurred in Part B (all in the 80 mg arm); 3 SAEs (a-fib, post-LP syndrome, pre-existing breast lesion) were investigator-assessed as unrelated to study drug; no deaths.
• CSF LRRK2 protein fell up to 59% (80 mg arm, 95% CI 47–69%) and CSF phosphorylated Rab10 up to ~50% (95% CI 35–61%) at week 12, irrespective of LRRK2 variant status, with concomitant reductions in CSF cathepsins B/D/L/S and LAMP1.
• No effect on motor signs (MDS-UPDRS III), NfL, pTau217 or neuroimaging — the trial was not powered for efficacy.
Intervention
Intrathecal BIIB094 (ION859), an antisense oligonucleotide complementary to LRRK2 mRNA exon 6 — single ascending doses 10–150 mg (Part A) and four doses of 40, 80 or 120 mg every 4 weeks (Part B), vs intrathecal placebo (artificial CSF).
Inclusion Criteria
Adults 35–80 yr with PD diagnosed within 7 years, Modified Hoehn & Yahr stage ≤3, no major motor fluctuations/dyskinesia, treatment-naive or on stable symptomatic PD therapy ≥8 weeks; documented LRRK2 variant status required for Part B 80 mg and 120 mg cohorts.
Study Design
Arms: BIIB094 dose cohorts versus pooled IT placebo. Part A: 6 ascending single-dose cohorts (10, 30, 40, 80, 120, 150 mg, 3:1 active:placebo). Part B: 40 mg (unstratified) and 80 mg / 120 mg cohorts stratified by LRRK2 variant status (8:2 or 6:2 active:placebo) every 4 weeks × 4 doses.
Patients per Arm: Part A: 31 BIIB094 / 9 placebo (N=40). Part B: 33 BIIB094 / 9 placebo (N=42). Total enrolled N=82 (20 rolled over from Part A to Part B).
Outcome
• Target engagement: CSF LRRK2 –59% (80 mg, 95% CI 47–69%) and –51% (120 mg, 95% CI 36–63%) from baseline at week 12; CSF pRab10 ≈–50% (95% CI 35–61%), independent of LRRK2 variant status.
• Lysosomal biomarkers: dose-related decreases in CSF cathepsins B/D/L/S and LAMP1 at week 24 (e.g. cathepsin S –35% 95% CI 20–47%, LAMP1 –31% 95% CI 17–43% in 80 mg arm) versus increases in placebo.
• No effect on MDS-UPDRS II/III, MoCA, SCOPA-Aut, ABC-16, PDQ-39, NfL, pTau217, or MRI biomarkers.
Clinical Question
In adults with Parkinson's disease (with or without pathogenic LRRK2 variants), is intrathecal BIIB094, an antisense oligonucleotide that degrades LRRK2 mRNA, safe and able to lower CSF LRRK2 protein and downstream pRab10?
Bottom Line
Intrathecal BIIB094 was generally well tolerated with no drug-related serious adverse events and produced robust, dose-related lowering of CSF LRRK2 protein (up to 59%) and phosphorylated Rab10 (up to ~50%) across LRRK2-PD and non-LRRK2-PD patients, supporting further clinical development.
Major Points
- First-in-human Phase 1 (REASON) of BIIB094/ION859, a LRRK2-targeting ASO delivered intrathecally to PD patients.
- 82 participants across 16 international sites in 6 countries; Part A single ascending doses (10–150 mg) and Part B four monthly doses (40, 80 or 120 mg) stratified by LRRK2 variant status.
- Most AEs were mild-to-moderate and related to lumbar puncture (procedural pain, post-LP syndrome, headache); no SAEs were judged related to BIIB094 in either part.
- CSF LRRK2 protein fell by up to 59% (80 mg arm) and CSF phosphorylated Rab10 by ~50% at week 12, returning toward baseline after the last dose at week 12.
- Concomitant CSF decreases in lysosomal proteins (cathepsins B/D/L/S, LAMP1) support engagement of a LRRK2–pRab10–endolysosomal axis implicated in PD.
- No effect on motor scales, MoCA, autonomic or QoL measures, MRI, NfL or pTau217 — study not powered for efficacy.
- Findings support advancement to longer/larger trials to test disease modification.
Study Design
- Study Type
- Phase 1 Randomized, Double-Blind, Placebo-Controlled, Dose-Escalation Trial (SAD + MAD)
- Randomization
- Yes
- Blinding
- Double-blind (participants, investigators and assessors blinded; unblinded pharmacist dispensed study drug). ClinicalTrials.gov classifies masking as triple (participant, investigator, outcomes assessor).
- Sample Size
- 82
- Follow-up
- Part A: 8 weeks after single dose; Part B: ~36 weeks (4 doses every 4 weeks then 24-week follow-up)
- Centers
- 18
- Countries
- USA, Canada, Israel, Norway, Spain, United Kingdom
Primary Outcome
Definition: Incidence of adverse events and serious adverse events in participants receiving ≥1 dose of BIIB094 or placebo (Part A through Day 85; Part B through Day 253).
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| Part A pooled placebo: 5/9 (55.6%) any AE, 0 SAE, 0 grade 3, 0 deaths. Part B pooled placebo: 9/9 (100%) any AE, 0 SAE, 1 grade 3 (post-LP syndrome). | Part A BIIB094 (n=31): 20 (64.5%) any AE, all mild/moderate, 0 SAE, 0 grade 3, 2 (6.5%) study drug-related, 0 withdrawals. Part B BIIB094 (n=33): 28 (84.8%) any AE, 12 (36.4%) mild / 13 (39.4%) moderate / 3 (9.1%) severe; 3 (9.1%) SAEs (a-fib, post-LP syndrome, intraductal proliferative breast lesion) all judged unrelated to study drug; 4 (12.1%) study drug-related AEs; 1 withdrawal due to AE; no deaths. | - | Not formally tested (Phase 1, descriptive safety endpoint) |
Limitations & Criticisms
- Small Phase 1 sample (N=82 total; N=33 BIIB094-treated in Part B) limits power to detect rare AEs and any clinical efficacy signal.
- Short follow-up (≈12 months in Part B) is likely too brief to capture disease-modifying effects.
- Most participants (90.5%) on PD symptomatic therapy at baseline and 10 had on-study medication changes, adding variability to motor outcomes.
- Biomarker analyses were exploratory, with multiple endpoints and no adjustment for multiple comparisons — CIs not for inference.
- 20 participants rolled over from Part A to Part B (with re-randomization but no stratification by prior exposure), potentially complicating safety/PD interpretation.
- No clinical efficacy signal demonstrated; downstream lysosomal protein changes are surrogate biomarkers with unclear clinical relevance.
- Heterogeneous LRRK2 variants (G2019S most common) limit conclusions about variant-specific response.
Citation
Nat Med 2026;32(4):1421-1431