Mevidalen

Centessa had been aiming for cleminorexton to become the first OX2R agonist to treat narcolepsy type 2 and idiopathic hypersomnia.\n Eli Lilly has gone big in the name of neuroscience, paying $6.3 billion in a front-loaded deal for Centessa Pharmaceuticals and its sleep disorder pipeline.In recent years, U.K.-based Centessa has been focused on a portfolio of orexin receptor 2 (OX2R) agonists, which the biotech has been targeting at conditions related to the sleep-wake cycle. Centessa’s lead program is cleminorexton, formerly known as ORX750, which is undergoing a phase 2 study for two types of narcolepsy as well as idiopathic hypersomnia (IH).Last year, the biotech touted phase 2 data for cleminorexton that it said showed “statistically significant, clinically meaningful and dose-dependent results” across key measures of wakefulness, sleepiness and cataplexy—a symptom of narcolepsy that involves a sudden, temporary loss of muscle tone.Centessa had been aiming for cleminorexton to become the first OX2R agonist to treat narcolepsy type 2 (NT2) and IH. In this morning’s deal announcement, Lilly agreed that cleminorexton had “demonstrated a potential best-in-class profile” in the mid-stage study.Behind cleminorexton, Centessa also has another candidate in the clinic in the form of ORX142. Last year, the biotech reported that the drug had achieved statistically significant and dose-dependent improvements in mean sleep latency in a phase 1 study of healthy adults. There is also a third asset, dubbed ORX489, in preclinical development for neuropsychiatric disorders.“Orexin receptor biology represents one of the most compelling mechanistic opportunities in neuroscience as a direct intervention on the master switch of the sleep-wake cycle,” Carole Ho, the head of Lilly Neuroscience, said in the March 31 release. “Centessa has assembled a portfolio with the breadth and depth to improve wakefulness across a broad array of indications,” Ho added.To get its hands on this portfolio, Lilly is shelling out $38 per share of Centessa—a 27% markup on the biotech’s Monday closing price of $27.58. The deal also includes a nontransferable contingent value right (CVR) that entitles Centessa shareholders to a total of an additional $9 per share related to approval milestones for cleminorexton and ORX142 in the next several years.On top of the $6.3 billion upfront payment, the CVR could also require Lilly to pay an additional $1.5 billion within the next five years. Lilly said this morning’s deal “expands [its] neuroscience portfolio.” As well as the company’s approved Alzheimer’s disease med Kisunla, its clinical-stage portfolio includes the likes of mevidalen, a dopamine D1 receptor positive allosteric modulator being developed for various neurodegenerative disorders, and a GBA1 gene therapy for Parkinson’s disease.Centessa only fully focused its attention on its OX2R franchise in late 2024, having slowly shed various hemophilia B, alpha-1 antitrypsin deficiency and autosomal dominant polycystic kidney disease prospects over previous years.“Centessa is at the forefront of orexin science, and we\'ve built a potential best-in-class portfolio of OX2R agonists with a level of depth and breadth that could help redefine what\'s possible in neuroscience,” CEO Mario Alberto Accardi, Ph.D., said in this morning’s release.Accardi, who founded Centessa’s orexin program, took on the CEO role at the end of last year as part of a strategic decision to focus the company on the OX2R pipeline.

None The confetti is still flying from Eli Lilly’s party celebrating the approval of Alzheimer’s disease therapy donanemab, but the company is yet again facing the harsh reality of the neurodegenerative disease with the failure of an early tau-targeting med.Lilly Chief Scientific Officer and President, Lilly Research Laboratories Daniel Skovronsky, M.D., Ph.D., said the O-GlcNAcase Inhibitor called LY3372689 failed on the primary endpoint of a phase 2 clinical trial recently. The therapy, which targets the OGA enzyme, did not spur a change in baseline to endpoint time in a rating scale of Alzheimer’s severity in either dose tested.“While this negative outcome was disappointing, we remain committed to tap as a high conviction target in Alzheimer's disease and plan to continue studying tau biology,” Skovronsky said, speaking on a second-quarter earnings call Thursday. The executive said the company is currently reviewing the data for presentation at an upcoming medical conference.LY3372689 was a key part of Lilly’s next wave of Alzheimer’s efforts. After getting donanemab approved in July, to be marketed as Kisunla, the company was hoping that tau would be the next front in the fight against the memory-robbing disease. Behind Kisunla, Lilly has remternetug in phase 3 development, which targets amyloid plaques in the brain. Positive allosteric modulator mevidalen is in phase 2 testing. The company also has two undisclosed neurodegeneration medicines in phase 1.Lilly also trimmed around the edges of other programs after getting some early data on a few candidates.They include LOXO-783, a highly mutant-selective, brain-penetrant, allosteric small molecule PI3Kα H1047R inhibitor that was acquired as part of the acquisition of Loxo Oncology. The drug was being investigated in a phase 1 study in patients with PIK3CA H1047R-mutant advanced breast cancer and other solid tumors.Lilly had taken LOXO-783 into the clinic on the basis of preclinical data showing activity without on-target wild-type PI3Kα mediated toxicity.“We evaluated the ongoing clinical data for the program and compared the molecule to next-generation candidates that we have progressed from our discovery efforts,” Skovronsky said on the call. “We believe our next molecules have greater potential benefits to patients.”Also on the discard pile is an unnamed NRG4 agonist. Neuregulin 4 acts locally on brown and white adipose tissue and works to protect against obesity-related inflammatory and hypoxic events. The Big Pharma had halted work on the asset as “the profile is insufficient for further clinical development,” Skovronsky explained. A GITR antagonist has also been removed from the phase 1 immunology pipeline “due to insufficient efficacy,” Skovronsky said. At the time of publication, Lilly had not confirmed to Fierce whether this was LY3461767, a GITR antagonist that was being evaluated in a phase 1 trial of the drug in patients with chronic heart failure with reduced ejection fraction.Acadamic researchers have named glucocorticoid-induced tumor necrosis factor receptor (GITR), a co-stimulatory immune checkpoint protein, as playing a pivotal in cardiovascular disease. It’s also been suggested as a potential target to enhance immunotherapy, in particular immune checkpoint inhibitors.