Centessa Pharmaceuticals (NASDAQ:CNTA) Chief Executive Officer Mario Alberto Accardi told investors at the Leerink Partners Global Healthcare Conference that the company is aiming to establish its orexin-2 agonist program as a “best-in-class” and potentially “first-in-class” set of therapies for rare hypersomnias, while using that work as a foundation to broaden into a multi-asset neuroscience pipeline.
CEO outlines focus on orexin-2 agonists and rare hypersomnias
Accardi said he views the current moment as “defining” for neuroscience and for patients with rare hypersomnias, citing the potential for a “functional cure in NT1” and a “paradigm shift” in the treatment landscape. He said the company’s original premise, dating back to the company’s beginnings in 2019, was to design highly potent and selective orexin-2 agonists and advance candidates with profiles that could be used beyond rare hypersomnias by developing assets with different pharmacokinetic (PK) characteristics.
Recap of previously reported Phase 2 results for ORX750
- NT1 (1.5 mg cohort): Accardi said ORX750 produced a greater than 20-minute baseline-adjusted, placebo-adjusted improvement on the Maintenance of Wakefulness Test (MWT), describing this as normalization of wakefulness. He also said the Epworth Sleepiness Scale (ESS) decreased from 18 to 5 and that weekly cataplexy rate was reduced by 87% (0.13 incidence rate ratio).
- NT2 (4 mg cohort): He said ORX750 achieved greater than a 10-minute change from baseline on placebo-adjusted MWT and noted that, in his view, no approved NT2 drugs have shown more than a 10-minute placebo-adjusted change from baseline. He also said ESS was normalized to around 8.
- IH (2 mg cohort): Accardi said the company observed clinically meaningful and statistically significant differences across multiple efficacy measures at the first cohort in IH.
Accardi added that since November the company has evaluated “multiples higher” doses, and said management’s goal is to ensure ORX750 remains best-in-class not only relative to current development programs but also over time.
“Best-in-class” framed around efficacy and duration of action
Accardi said Centessa defines “best in class” as a holistic profile across efficacy, safety, and tolerability. However, he argued that, across the orexin agonist class, some on-target adverse events (AEs) such as polyuria and insomnia may be manageable and that differentiation may matter most on efficacy and duration of action.
He said Centessa is seeking dosing “bookends” that would support a monotherapy approach and sustained symptom control throughout the day. He emphasized the importance of demonstrating extended duration of action in endpoints such as MWT across its time points, noting the eight-hour nature of the test and the value of maintaining “normal wakefulness” at later time points.
On polyuria specifically, Accardi said the company did not see a marked dose response in the November update, and said it remains to be seen whether higher doses will show a dose relationship. He also said discussions with key opinion leaders and patient groups suggest polyuria may not be a major negative for patients and might attenuate over time in some cases. Accardi said Centessa is considering titration approaches—both in the remaining Phase 2 cohorts and potentially in registration studies—as a way to potentially reduce AE rates, noting that titration is common in narcolepsy standard of care.
Upcoming disclosure and plans for registration studies
Accardi said Centessa plans a Phase 2 update later in the quarter, potentially in one indication or across all three, depending on which cohorts are available at the time of disclosure. He described the Phase 2 design as one in which the company selects a dose for a cohort, unblinds results, and uses that information to select the next cohort, calling dose selection an important part of optimizing benefit for patients.
He also said the company aims to announce the start of registration studies “this quarter,” potentially across multiple indications, though he framed that decision as data-driven and said it could be at least one indication or all three depending on available results. Accardi said Centessa plans to share its registrational study designs and regulatory strategy, which he said are intended to support efforts to remain first-in-class in NT2 and IH.
Accardi also said Centessa may continue dose escalation even as registration studies begin, arguing that if the maximum tolerated dose has not been reached, the company could keep Phase 2 open, add a higher-dose cohort, and potentially add that higher dose into the registrational program later in the year if differences are “meaningfully” better.
Dosing flexibility, long-term follow-up, and differentiation claims
Accardi said the company is evaluating both once-daily (QD) and split dosing. While ORX750 was designed as a QD drug, he said split dosing could offer patients control over duration of action and potentially improve tolerability by lowering Cmax.
Regarding the open-label extension (OLE), he said it is open with a “large number” of patients rolling over, and that the company is collecting efficacy measures including MWT over weeks of dosing, with plans to provide an update at a later time.
On tachyphylaxis, Accardi said the company has seen no changes in efficacy from week two to week four, and said preclinical chronic studies showed no receptor internalization or signs of tachyphylaxis. He also referenced consistent data from other orexin agonists between week two, week four, and later time points in OLEs. Accardi argued that orexin’s tonic neurotransmitter biology implies a low risk of tachyphylaxis, while noting that longer-term data will continue to be important.
Accardi also discussed differentiation from another orexin program previously disclosed by Centessa, focusing on PK characteristics. He said ORX750 has shown linear PK across doses tested, a relatively flat Cmax-to-AUC profile, and no observed visual disturbances at the 1.5 mg dose reported in November. He added that the company has not observed a clinically meaningful food effect at some tested doses, and he linked ORX750’s duration of action to metabolic stability and sustained exposures.
Looking beyond rare hypersomnias, Accardi said Centessa has additional orexin agonists in development, noting that “142” is in the clinic and “489” is expected to enter the clinic this quarter, as the company pivots from a rare hypersomnia-focused effort to a broader neuroscience pipeline approach. He said the company plans to discuss additional indications and the rationale in its Q1 disclosure.
Accardi also described what he believes is a significant commercial opportunity across NT1, NT2, and IH, citing company estimates of an $18 billion market and patient counts of about 50,000 diagnosed and treated NT1 patients in the U.S., roughly double that in NT2, and about 120,000 diagnosed and treated in IH. He pointed to approximately 2,500 sleep centers in the U.S. and said Centessa is beginning to build a commercial team this year, describing the company as “morphing into a pre-commercial stage company.”
On pricing, Accardi referenced Xywav pricing as “north of $200,000 gross” with what he described as equal pricing across NT1, NT2, and IH. He said Centessa is evaluating exploratory endpoints such as cognition, executive function, and brain fog in Phase 2, and expressed hope that a broader data package could support a strong commercial narrative for orexin agonists.
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.
