Centessa Pharmaceuticals (NASDAQ:CNTA) CEO Mario Alberto Accardi told attendees at Guggenheim’s 2026 Emerging Outlook Biotech Summit that 2026 is “shaping up to be a transformational year” for the company as it moves its lead orexin agonist program toward registrational studies in rare hypersomnias and advances a next-generation asset into the clinic.
Positioning ORX750 for registrational studies
Accardi said Centessa is entering the year “from a position of strength” after what he described as an “incredibly positive year” in 2025. He pointed to data shared in November that he said supported a “potential best-in-class profile” for ORX750 in narcolepsy type 1 (NT1), narcolepsy type 2 (NT2), and idiopathic hypersomnia (IH).
As part of Centessa’s next update in the first quarter, Accardi said the company intends to provide a Phase II update from “at least one” indication, depending on which cohorts are completed by the time of disclosure, alongside details on the commencement of registrational studies.
Dose exploration and the role of split dosing
Accardi repeatedly emphasized the importance of exploring dose range before registrational trials, arguing that “dose selection… is absolutely critical.” He said the company may decide to add an additional cohort after the upcoming disclosure “not because we need to do that,” but to avoid leaving “some efficacy on the table,” particularly given what he characterized as Centessa’s lead versus competitors in NT2 and IH.
In discussing tolerability boundaries, Accardi suggested that if there is no discrete adverse event defining the therapeutic index, “your maximum tolerated dose may indeed be in the form of insomnia” as duration of action extends into 16–18 hours or more. He framed reaching that boundary as useful for establishing “bookends” that could give prescribers and patients flexibility to find an optimal dose, rather than being constrained by an inability to dose higher.
On split dosing, Accardi said ORX750 was designed as a QD drug and that the company believes it has demonstrated strong diurnal symptom control in NT1 with a single dose. He described split dosing as a way to put patients “in control” by allowing them to modulate duration of action—for example, taking a second smaller dose later in the day if they need extended coverage. He also drew a distinction between a drug that can be used QD but optionally split and one that “needs to be dosed BID.”
What Centessa highlighted from prior ORX750 results
During the discussion, Accardi cited several specific outcomes he said were observed in prior disclosures:
- NT1: At a 1.5 mg dose, he said ORX750 showed “greater than 20 minutes” change from baseline on the Maintenance of Wakefulness Test (MWT) and reduced Epworth Sleepiness Scale (ESS) from 18 to 5. He also cited a weekly cataplexy result he described as “best in class,” including an incidence rate ratio of 0.13 and an 87% reduction.
- NT2: He said that at 4 mg, ORX750 showed “greater than 10-minute change from baseline” on the MWT and reduced ESS to 8, which he characterized as normalization. He also stated there is no approved drug in NT2 that has shown a greater than 10-minute change from baseline on the MWT.
- IH: He said Centessa previously communicated a “statistically and clinically meaningful impact” on multiple efficacy measures, and noted the company is capturing IH-focused symptoms such as sleep inertia and brain fog using the Idiopathic Hypersomnia Severity Scale (IHSS) in addition to ESS.
Accardi said that for NT2, Centessa is enrolling a “sleepy patient” population and evaluating multiple endpoints beyond MWT, including patient-reported outcomes like ESS. For IH, he said ESS is the registrational endpoint, while IHSS is being used as an important additional measure; he mentioned that “dipping below 22” or a change of around “10” on IHSS would be “good,” while reiterating that ongoing dose exploration is intended to drive meaningful benefit.
Regulatory interactions and study design considerations
Asked whether any factors besides dose selection could delay initiation of registrational studies, Accardi said, “Not at all,” adding that Centessa has had “a number of interactions with the FDA” with “overall very positive feedback and overall alignment” on the development strategy.
On whether Centessa would consider including a randomized withdrawal design—an approach the interviewer noted is often favored by the European Medicines Agency (EMA)—Accardi said, “Watch this space,” indicating it is something the company has considered and suggesting more detail could be provided in the first-quarter disclosure.
He also said Centessa is evaluating “all potential regulatory measures to accelerate the development of the drug,” in response to a question about Breakthrough Therapy Designation (BTD).
Pipeline expansion: ORX142 and a broader neuroscience strategy
Accardi positioned orexin agonism as a mechanism that could extend beyond rare hypersomnias into symptoms such as fatigue, cognition, executive function, and mood, citing the broad CNS projections of orexinergic neurons. He compared the potential platform value to “a potential GLP-1 type in neurosciences,” where validation in one disease area supports expansion into others.
He said Centessa’s next-generation asset, ORX142, is expected to enter the clinic “this quarter” and has “completely different” pharmacokinetics from ORX750. While he did not provide further detail on the differentiated PK in the session, he said the company has “very good ideas” about where it may fit and indicated that strategy updates would be part of the forthcoming Q1 disclosure.
Accardi also described Centessa as “morphing into essentially a pre-commercial stage company” in rare hypersomnias and said the company is “already thinking about commercial,” including plans to hire commercially in 2026.
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.
