Takeda Reports Breakthrough Phase 3 Results for Oveporexton in Narcolepsy Type 1

Takeda will present new data from its global Phase 3 studies of oveporexton (TAK-861)—a first-in-class oral orexin receptor 2 (OX2R)-selective agonist—at the World Sleep 2025 Congress in Singapore. The candidate is being developed for narcolepsy type 1 (NT1), a rare neurological disease caused by loss of orexin neurons.

Phase 3 Highlights: FirstLight & RadiantLight

Both FirstLight (TAK-861-3001) and RadiantLight (TAK-861-3002) trials met all primary and secondary endpoints, with p<0.001 across doses at week 12.

• Wakefulness
  - Significant improvement in mean sleep latency (MWT) and Epworth Sleepiness Scale (ESS).
  - Most patients on 2mg twice daily achieved MWT scores within normal range (≥20 min).
  - 85% reached ESS scores comparable to healthy individuals (≤10).
• Cataplexy
  - Median cataplexy rate reduced >80% vs placebo.
  - Patients reported 4–5 cataplexy-free days per week by week 12.
• Symptom Severity
  - Over 70% reached the lowest severity level (NSS-CT score 0–14).
  - 97% reported improvement on Patient Global Impression of Change (PGI-C).
• Quality of Life
  - Significant improvements on SF-36 scores, reaching normative range.
  - Gains confirmed by EQ-5D-5L exploratory endpoints.
• Safety Profile
  - Well-tolerated across both studies.
  - No treatment-related serious adverse events.
  - Most common: insomnia, urinary urgency, frequency (mild to moderate).

Why It Matters

Current NT1 treatments address symptoms but not the underlying orexin deficiency. Oveporexton directly targets OX2R signaling, potentially transforming the treatment paradigm with broad, durable symptom control.

Dr. Emmanuel Mignot, principal investigator of FirstLight, noted:

“These Phase 3 results bring us closer to the first orexin therapy addressing the root cause of NT1.”

Study Scope

• Design: Double-blind, placebo-controlled, 12 weeks.
• Participants: 273 patients across 19 countries.
• Endpoints: 14 clinical measures including wakefulness, cataplexy, symptom severity, QoL, safety.
• Continuation: >95% of participants entered the long-term extension study.

Takeda’s Orexin Franchise

• Oveporexton (TAK-861) – lead NT1 program; granted Breakthrough Therapy designation by US FDA and China’s NMPA.
• TAK-360 – oral OX2R agonist in Phase 2 for NT2 and idiopathic hypersomnia (IH).
• TAK-495 – preclinical orexin candidate entering clinic FY2025.
• Broader vision: Leveraging orexin biology in sleep, mood, metabolism, and cognition.

Looking Ahead

Takeda will present additional findings at World Sleep 2025, including:

• Impact of stigma in NT1.
• Advances in diagnostic algorithms and orexin biomarkers.
• Extended analyses from Phase 2b studies (cognition, microsleeps, treatment satisfaction).

Results from Phase 3 do not affect Takeda’s FY2026 financial forecast, but they mark a major milestone in orexin-targeted therapeutics.

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