Ulotaront

Pictured: Girl student having trouble concentrating/iStock, PeopleImages Otsuka Pharmaceutical on Friday posted top-line data from two Phase III studies, demonstrating that its attention deficit/hyperactivity disorder candidate centanafadine significantly improves symptoms in children and teenagers. Friday’s readouts come from attention deficit/hyperactivity disorder (ADHD) trials that are largely similar in design, employing three arms and fixed high or low doses of centanafadine which were given compared to placebo on a double-blinded basis. The main difference is in the study populations: one enrolled adolescent participants between the ages of 13 and 17 years, while the other included children aged six to 12 years. In the adolescent study, patients treated with high-dose centanafadine saw significantly better scores on the ADHD Rating Scale version 5 (ADHD-RS-5), a validated tool used to assess the severity of ADHD and the study’s primary endpoint. The average effect of both the high and low centanafadine doses was also significantly better than placebo. Centanafadine was similarly effective in children. ADHD-RS-5 scores significantly improved in patients who were treated with high-dose centanafadine, and the average treatment effect in both high-dose and low-dose groups was likewise statistically better than placebo. In the adolescent and pediatric trials, the benefits of high-dose centanafadine became apparent as early as the first post-baseline timepoint at week one, which was sustained for the rest of the study periods. However, both low-dose arms did not see significantly improved ADHD-RS-5 scores versus placebo. In terms of safety, pooling data from both studies demonstrated a tolerability pro was consistent with centanafadine’s broader clinical development program. The most common side effects included nausea, upper abdominal pain, somnolence and fatigue. While the full results from both studies are not yet available, these data “demonstrate centanafadine has the potential to offer a new treatment option for children and adolescents who live with ADHD,” John Kraus, chief medical officer of U.S. subsidiary Otsuka Pharmaceutical Development and Commercialization, said in a statement. Otsuka will submit complete data and analyses from both trials for scientific publication. The company will also use these findings, along with clinical pharmacology studies and long-term stability data, to build a New Drug Application for centanafadine in this indication. Friday’s ADHD readout comes months after Otsuka and partner Sumitomo Pharma suffered two late-stage defeats in another psychiatric indication. In July 2023, the companies announced that its investigational TAAR1 agonist ulotaront failed the Phase III studies DIAMOND 1 and DIAMOND 2 in schizophrenia patients with acute psychosis. Tristan Manalac is an independent science writer based in Metro Manila, Philippines. He can be reached at tristan@tristanmanalac.com or tristan.manalac@biospace.com.

Pictured: Conceptual drawing of the right and left sides of the brain/iStock, Warrenrandalcarr Karuna Therapeutics announced Thursday it has submitted a New Drug Application to the FDA for KarXT, which, if approved, would offer the first new mechanism of action to treat schizophrenia in more than 50 years. The NDA submission for KarXT, an investigational agonist of muscarinic acetylcholine 1 receptors M1 and M4, is backed by three registrational trials from the EMERGENT program. The candidate hit the primary endpoint in the EMERGENT-1, EMERGENT-2 and EMERGENT-3 trials, demonstrating a “statistically significant and clinically meaningful” reduction in total score on the Positive and Negative Syndrome Scale (PANSS) compared to placebo, according to Karuna’s press release. This effect on negative symptoms sets KarXT apart as all currently approved therapies for schizophrenia focus on the disorder’s positive symptoms, which relate to psychosis; negative symptoms of the disease include social withdrawal, lack of motivation and apathy toward normal interests. KarXT also reduced both positive and negative symptoms on the PANSS positive, PANSS negative and PANSS negative Marder factor subscales, each of which were secondary endpoints in the trials. In an interview with BioSpace Thursday, Karuna founder and Chief Operating Officer Andrew Miller highlighted KarXT’s safety profile. “We see some of the most substantial considerations around current antipsychotics of weight gain and metabolic dysfunction, sedation and somnolence, motor symptoms ... and we don't see those things with KarXT because of the underlying mechanism,” he said. Miller added that KarXT comes with its own safety and tolerability considerations, but said they are limited to “generally mild-to-moderate GI side effects that are transient and resolve with time.” The NDA submission is also the first for Karuna, which was founded in 2009 and closed a $42 million Series A financing in August 2018. At the time, Robert Nelsen, co-founder and managing director of lead investor ARCH Venture Partners, said Karuna “has all of the characteristics we look for in a game-changing CNS company.” Karuna is expecting a standard 10- to 12-month review period for KarXT, Miller said, but added, “I do think there's the possibility that we could get a priority review period based on how differentiated the product is.” While the schizophrenia space has seen recent disappointments, including the Phase III failure of Sumitomo Pharma and Otsuka Pharmaceutical’s ulotaront and the termination of a second Phase II trial of Roche’s ralmitaront, there are a couple of companies hot on Karuna’s trail. Fellow Massachusetts company Cerevel Therapeutics is developing emraclidine, a positive allosteric modulator selectively targeting the M4 receptor while also minimizing the side effects associated with pan-muscarinic agonists. Emraclidine is currently in Phase II trials. Graig Suvannavejh, senior biopharmaceuticals and biotechnology equity research analyst at Mizuho Americas, told BioSpace in a previous interview that he anticipates combined peak sales for KarXT and emraclidine to be $7 billion. Another contender, Acadia Pharmaceuticals’ pimavanserin specifically targets the negative symptoms of schizophrenia. In a Phase II trial of adults with predominantly negative symptoms, the candidate elicited significant improvements versus placebo on the 16-item Negative Symptom Assessment (NSA-16) when added to existing regimens of antipsychotics. Pimavanserin is currently being assessed in the Phase III ADVANCE 2 study, for which Acadia anticipates topline results in 2024. Heather McKenzie is a senior editor at BioSpace. You can reach her at heather.mckenzie@biospace.com. Follow her on LinkedIn and X @chicat08.