Centessa Pharmaceuticals (NASDAQ:CNTA) used remarks at a healthcare conference to highlight recent progress in its orexin agonist program and outline near-term priorities that include a Phase II update, the start of registrational studies in rare hypersomnias, and additional proof-of-concept work in broader neuropsychiatric and neurodegenerative indications.
CEO highlights ORX750 progress and near-term milestones
Chief Executive Officer Mario Accardi said the company has advanced ORX750 into patients and is aiming to commence registrational studies for rare hypersomnias during the current quarter. Accardi, who founded the original company behind the program in 2019, described the opportunity as building a multi-asset franchise of potent and selective orexin agonists across multiple potential indications, with a focus on being first-in-class in narcolepsy type 2 (NT2) and idiopathic hypersomnia (IH).
November data discussed across NT1, NT2, and IH
Accardi reviewed results the company previously disclosed in November from what he described as the lowest-dose cohorts: 1.5 mg in narcolepsy type 1 (NT1), 4 mg in NT2, and initial 2 mg language in IH.
- NT1: Accardi said ORX750 achieved a greater-than-20-minute change from baseline on a placebo-adjusted Maintenance of Wakefulness Test (MWT). He also said the Epworth Sleepiness Scale (ESS) dropped from 18 to five, and cited a 0.13 incidence rate ratio on weekly cataplexy rate, which he said suggested prolonged symptom control later into the day.
- NT2: He said the company reported a greater-than-10-minute change from baseline on the MWT, adding that he was not aware of approved standard-of-care drugs showing greater than a 10-minute change from baseline. He also said ESS was normalized, dropping from 15 to eight.
- IH: Accardi said the company disclosed statistically significant and clinically meaningful effects across multiple efficacy measures.
He emphasized that the November data were accompanied by what he characterized as a favorable safety and tolerability profile.
Dose escalation, dosing flexibility, and differentiation themes
Since the November disclosure, Accardi said Centessa has continued escalating doses—“multiples higher” in some instances—and evaluated both once-daily (QD) and split-dosing approaches across cohorts and indications. He framed the work as an effort to identify an optimal dose for registrational studies and to explore the mechanism’s full potential.
Accardi said ORX750 was designed as a QD drug with linear pharmacokinetics and rapid onset. He described split dosing as a way to provide flexibility for patients who may need additional coverage later in the day, noting that orexin agonism can act like a “binary switch,” where symptoms can return once exposure drops below a wakefulness threshold.
On potential differentiation versus other orexin agonists in development, Accardi said he views duration of action as a key opportunity—particularly for NT1—arguing that symptom control should extend beyond the timeframe captured by an MWT session and through later evening hours. He also pointed to exploratory endpoints the company is collecting in its Phase II study, including measures spanning cognition, executive function, fatigue, and other patient-reported outcomes, which he said the company hopes to share in the future.
Safety, visual events, and open-label extension participation
On tolerability, Accardi said the company would like to reach a maximum tolerated dose that manifests as insomnia, which he suggested could indicate sufficient duration of action to cover a wide range of patient needs and support monotherapy use. He said Centessa had not identified an adverse event that limited the therapeutic index since the November press release and expressed confidence in ORX750’s therapeutic window.
Addressing questions about visual disturbances, Accardi said there were three cases referenced in the November update, and that they were mild, transient, self-resolving, and did not show a dose-response relationship at that time. He said the company’s hypothesis is that such events may be related to mydriasis and photophobia and could be influenced by peak exposure (Cmax), adding that ORX750 was designed with a “relatively flat” Cmax profile. He also said titration could be a tool to further improve tolerability, noting that sleep physicians are familiar with titrated regimens.
Accardi also discussed the company’s open-label extension (OLE). He said Centessa expanded the Phase II treatment duration from two weeks to four weeks to better align with a potential registrational program and stated the company had seen no degradation of effect from two weeks to four weeks. While he did not provide specific OLE efficacy results, he said Centessa is collecting MWT data in the OLE and described uptake into the extension as significant.
Regulatory interactions and expansion beyond rare hypersomnias
Accardi said Centessa has had multiple interactions with the U.S. Food and Drug Administration and other regulatory bodies and described the company as having “very good alignment” on its registrational program.
Beyond NT1, NT2, and IH, Accardi said the company is building a “multi-asset orexin agonist franchise” and referenced follow-on orexin agonists ORX142 and ORX489. He said Centessa plans to initiate additional studies in other indications in the first quarter, describing them as proof-of-concept studies with timing dependent on the indication and emphasizing that the company intends to run robust trials.
Accardi also said Centessa is increasing its efforts to educate physicians—not only sleep specialists but also neurologists and psychiatrists—and described the company as “morphing into a pre-commercial company,” including plans to hire a commercial team this year to prepare for potentially fast-enrolling registrational studies.
About Centessa Pharmaceuticals (NASDAQ:CNTA)
Centessa Pharmaceuticals plc is a global clinical‐stage biopharmaceutical company focused on the discovery and development of innovative therapies across multiple disease areas. The company operates a modular R&D network, bringing together a portfolio of independent, specialist research entities under a single corporate umbrella. This structure is designed to accelerate decision‐making and resource allocation while leveraging deep scientific expertise in each therapeutic domain.
Centessa’s pipeline spans oncology, immunology, neuroscience, cardiovascular and metabolic diseases, as well as rare genetic disorders.
