Centessa’s ORX750 Shows Strong Phase 2a Results for Narcolepsy and Hypersomnia—Robust Clinical Gains and Favorable Safety Profile Stand Out

Lead Candidate ORX750 Achieves Statistically Significant Clinical Improvements Across Multiple Sleep Disorders

Centessa Pharmaceuticals (NASDAQ:CNTA) delivered a notable clinical update alongside its third-quarter 2025 financial results, underscoring the momentum behind its OX2R agonist pipeline. The company’s flagship candidate, ORX750, produced what management described as the first robust demonstration of an oral OX2R agonist’s benefit across narcolepsy type 1 (NT1), narcolepsy type 2 (NT2), and idiopathic hypersomnia (IH).

Initial cohorts in the Phase 2a CRYSTAL-1 study (55 participants as of September 23, 2025) showed ORX750 led to statistically significant, clinically meaningful, and dose-dependent gains in wakefulness and symptom management:

• NT1, 1.5 mg dose: >20-minute increase in mean sleep latency (MWT) vs placebo (p=0.0026); 87% relative reduction in weekly cataplexy rate (WCR, p=0.0025); 13.6-point improvement in Epworth Sleepiness Scale (ESS) score (p=0.0001).
• NT2, 4.0 mg dose: >10-minute gain in mean sleep latency (p=0.0193); 9.2-point ESS improvement (p=0.0023).
• IH, 2.0 mg dose: Statistically significant mean sleep latency increase on MWT (p=0.0213).

Favorable Safety and Tolerability: Most Adverse Events Were Mild to Moderate

Safety data showed ORX750 was generally well-tolerated across all tested doses. The most common adverse events (=10%) were pollakiuria (51%), insomnia (22%), dizziness (13%), and headache (11%). Nearly all adverse events were mild to moderate and transient; one participant discontinued due to urinary urgency. There were no notable cardiac, liver, renal, or vision-related issues reported, suggesting a potentially wide therapeutic window.

Pipeline Momentum: ORX142 and ORX489 Set for Patient Studies in 2026

Centessa also reported that ORX142 showed rapid onset and favorable safety in a Phase 1 study with 89 healthy volunteers, supporting advancement into patient studies in Q1 2026. The third program, ORX489, the company’s most potent OX2R agonist to date, is expected to enter clinical testing pending IND clearance, also in Q1 2026.

This diversified approach may help Centessa position itself as a leader in developing new treatments for disorders marked by excessive daytime sleepiness, impaired attention, and fatigue across multiple neurological and neuropsychiatric diseases.

Financial Position: Strong Cash Runway into Mid-2027

As of September 30, 2025, Centessa held $349.0 million in cash, cash equivalents, and investments, with the company expecting this to fund operations into mid-2027. R&D expenses rose to $41.56 million in Q3 2025, up from $33.90 million in the prior year’s quarter, reflecting increased investment in clinical progress. General and administrative costs remained stable, and net loss for the quarter was $54.89 million.

Takeaway: Advancing Toward Registrational Programs, Eyes on 2026

The clinical results reinforce Centessa’s claim of a best-in-class potential for ORX750, particularly for narcolepsy and idiopathic hypersomnia—two patient populations with major unmet needs. With additional studies set to start in 2026 and a solid financial foundation, the next twelve months will be pivotal for translating these clinical gains into longer-term pipeline value and possible market leadership in sleep/wake therapeutics.

For investors and those tracking neuroscience drug innovation, Centessa’s ability to advance all three OX2R agonists on schedule—and potentially deliver differentiated efficacy—makes the coming quarters especially worth watching.

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