Centessa Pharmaceuticals Charts New Direction Under Fresh Leadership as Orexin Portfolio Expands into Multiple Neuroscience Frontiers

A Strategic Pivot: From Diversified Pipeline to Pure-Play Orexin Focus

Centessa Pharmaceuticals has executed a significant management reshuffle that signals its commitment to a narrower, more specialized therapeutic strategy. Effective January 1, 2026, Mario Alberto Accardi PhD—the visionary who architected the company’s orexin program—assumes the role of Chief Executive Officer and joins the Board of Directors. This transition replaces Saurabh Saha MD PhD, who shepherded the organization through its foundational phase and will transition to an advisory capacity.

The shift underscores Centessa Pharmaceuticals’ deliberate transformation from a diversified clinical-stage enterprise into a specialized player betting heavily on orexin receptor biology. Francesco De Rubertis PhD, Chair of the Board, framed this as a natural evolution: “We’ve moved from being an R&D-driven startup juggling multiple early-stage programs to an organization singularly devoted to advancing a best-in-class orexin portfolio at the vanguard of an emerging therapeutic frontier.”

The Orexin Opportunity: Why Now?

Orexin—a neuropeptide governing the sleep-wake cycle—has emerged as a compelling target for addressing excessive daytime sleepiness, cognitive fog, attention deficits, and fatigue across neurological, neurodegenerative, and neuropsychiatric conditions. Centessa Pharmaceuticals’ portfolio of OX2R agonists positions the company to capitalize on this increasingly recognized therapeutic gap.

The company is developing multiple candidates tailored to different indications. ORX750, its most mature asset, has already demonstrated a potentially best-in-class profile in narcolepsy type 1, narcolepsy type 2, and idiopathic hypersomnia. A registrational-stage program for ORX750 is expected to commence in Q1 2026, marking a critical inflection point.

Beyond ORX750, Centessa Pharmaceuticals is advancing ORX142 and ORX489, aimed at neurodegenerative and neuropsychiatric disorders, with substantial milestones anticipated throughout 2026. This multi-asset approach reflects the company’s confidence in orexin’s therapeutic range and its ability to differentiate its molecules from competitors’ offerings.

Why Mario Accardi Is the Right Leader for This Moment

Accardi’s appointment isn’t ceremonial—it reflects deep institutional knowledge. As President of the Orexin Program, he has been the driving force behind Centessa Pharmaceuticals’ strategic pivot. Before joining the company, Accardi founded and led Orexia Therapeutics, where he successfully raised €40M in Series A funding, forged key partnerships, and orchestrated the 2021 acquisition by Centessa Pharmaceuticals. His pedigree in advanced structural biology and orexin science makes him uniquely suited to navigate the company’s next phase.

His educational credentials—a PhD in Biomedical Engineering and a degree in Mechanical Engineering from Imperial College London, along with postgraduate training in Genomic Medicine—complement his entrepreneurial track record.

The Pipeline in Focus: What to Expect from Centessa Pharmaceuticals in 2026

Centessa Pharmaceuticals has outlined an ambitious timeline:

• ORX750 for sleep-wake disorders: The Phase 2a CRYSTAL-1 study is currently underway (NCT06752668 and NCT07096674). Registration-stage trials are slated to begin in Q1 2026, a critical milestone for potential regulatory approval in narcolepsy and idiopathic hypersomnia.

• ORX142 and ORX489: These novel OX2R agonists target distinct neurological, neurodegenerative, and neuropsychiatric indications. Key data readouts are expected during 2026, which will be instrumental in determining their competitive positioning.

The organization has essentially placed its chips on orexin, a bet that hinges on both the scientific merit of OX2R agonism and the company’s ability to bring differentiated molecules to market ahead of competitors.

What This Means for Investors and Patients

The leadership transition signals confidence rather than distress. Centessa Pharmaceuticals’ board determined that Accardi—as the principal architect of the OX2R agonist program—is positioned to unlock the franchise’s full potential. Saurabh Saha’s contributions in building the organizational foundation are acknowledged, and his advisory role suggests a collaborative, rather than contentious, transition.

For Centessa Pharmaceuticals, 2026 represents a make-or-break year. ORX750’s registrational program initiation, combined with readouts from ORX142 and ORX489, will shape investor sentiment and competitive positioning within the emerging orexin therapeutics landscape. The appointment of Accardi as CEO amplifies the company’s commitment to executing this strategy with precision and speed.

The orexin class remains relatively underpenetrated compared to other neuroscience modalities, creating substantial whitespace for differentiated players like Centessa Pharmaceuticals to establish market leadership.