Eli Lilly expands from neuroscience to sleep medicine via USD 7.8b Centessa acquisition

Eli Lilly and Company has agreed to acquire UK-based Centessa Pharmaceuticals plc in an all-cash transaction valued at up to USD 7.8 billion, anchored by Centessa's selective orexin receptor 2 (OX2R) agonist pipeline. The deal extends Lilly's neuroscience franchise into sleep-wake disorders, a therapeutic area where approved mechanism-specific orexin-restoring options remain unavailable, and treatment gaps persist, especially in NT2 and IH.

Lilly will pay USD 38.00 per Centessa share or American Depositary Share upfront, representing a total guaranteed consideration of approximately USD 6.3 billion. Each Centessa shareholder also receives one non-transferable contingent value right (CVR) entitling them to up to USD 9.00 per share in additional cash payments, contingent on three U.S. FDA approval milestones. The first CVR tranche of USD 2.00 per share is payable upon FDA approval of cleminorexton or ORX142 for narcolepsy type 2 (NT2). The second tranche of USD 5.00 per share triggers on FDA approval for idiopathic hypersomnia (IH). A third tranche of USD 2.00 per share is payable upon the first FDA approval of either asset for any indication, provided this occurs before January 1, 2030. The upfront consideration represents a 40.5% premium to Centessa's 30-day average share price. Lilly acquires worldwide rights to all Centessa pipeline assets.

OX2R agonism and the orexin system

The acquisition centers on Centessa's OX2R agonist platform, which targets the orexin/hypocretin neuropeptide system. Orexin-A and orexin-B regulate arousal and wakefulness through two G protein-coupled receptors, OX1R and OX2R. In narcolepsy type 1 (NT1), orexin-producing neurons in the lateral hypothalamus are selectively destroyed, resulting in near-total orexin deficiency. NT2 and IH involve partial or functional orexin dysregulation. Selective OX2R agonism pharmacologically restores the downstream wakefulness signal without engaging OX1R, which is associated with cardiovascular and anxiety-related on-target effects seen with non-selective compounds.

The lead asset, cleminorexton (formerly ORX750), is an oral small molecule OX2R agonist currently in the Phase IIa CRYSTAL-1 study across NT1, NT2, and IH cohorts in the United States and Canada. Phase 1 data demonstrated that a 2.5 mg dose restored normative wakefulness, with a mean sleep latency of 32 minutes on the Maintenance of Wakefulness Test (MWT). Phase IIa data from 55 patients, with a cut-off of September 2025, showed wakefulness restoration across all three indications at doses ranging from 1.0 to 4.0 mg, with a favorable safety and tolerability profile and no on-target adverse events. Cleminorexton holds potential to be the first OX2R agonist approved for NT2 and IH, indications for which no selective OX2R agonist has yet received regulatory clearance.

Two additional OX2R agonists extend the platform's clinical reach. ORX142, currently in Phase I with IND cleared, targets neurological and neurodegenerative indications and has demonstrated antidepressive effects and enhanced wakefulness in preclinical models. ORX489, described as Centessa's most potent OX2R agonist, is currently Phase I stage and will target neuropsychiatric disorders.

Strategic outlook

The milestone-based structure of Lilly's acquisition reflects the regulatory uncertainty inherent in a Phase IIa asset while allowing Lilly to capture near-term pipeline value. The three-asset OX2R portfolio provides Lilly with staggered clinical readouts and indication expansion optionality across the CNS spectrum, from sleep-wake disorders through to neurodegenerative and neuropsychiatric conditions. Because Centessa held unencumbered worldwide IP across all pipeline programs at the time of signing, Lilly assumes full global development and commercial control without the complexity of pre-existing regional licensing arrangements.

---

Spot something wrong? Report an issue with this article