Depressive Disorder, Major

Boehringer Ingelheim today announced top-line results from the Phase III CONNEX clinical program in cognitive impairment in adults with schizophrenia, showing primary and key secondary endpoints were not met.1–6 Overall, no statistically significant effects on cognition or functioning were observed in patients treated with iclepertin versus placebo at six months.1 All three trials demonstrated that iclepertin, a glycine transporter 1 (GlyT1) inhibitor, was generally well tolerated, with a safety profile that remains consistent with previous studies.1,2,7 “While these findings are disappointing, we remain dedicated to finding effective solutions for those living with serious mental illnesses. Our innovative pipeline includes over 20 additional investigative therapies in all stages of development and in different disease areas including schizophrenia and major depressive disorder,” said Shashank Deshpande, Member of the Board of Managing Directors and Head of Human Pharma at Boehringer Ingelheim. “In the near future more can be expected. Our gratitude goes to the patients and clinical investigators whose time and commitment made this research possible.” CONNEX was the largest program for cognitive impairment in schizophrenia to date. Boehringer believes that the results will aid scientific understanding and inform future research for patients living with cognitive impairment in schizophrenia, an area of high unmet need with no approved targeted pharmaceutical treatment options available.8,9 Full efficacy and safety data will be submitted for presentation at an upcoming medical meeting. Schizophrenia affects approximately 24 million people worldwide.10 Cognitive impairment is one of the three core symptom domains of schizophrenia, along with positive and negative symptoms.11 Cognitive impairment affects more than 80% of people with this condition, manifesting early in patients’ lives, and representing a leading cause of disability and impairment in daily functioning.8,9,12 People with schizophrenia often face cognitive challenges that impact their problem-solving abilities, attention and memory.8,9 These problems can make it difficult to live an independent and productive life.8,9 They can also cause a person to struggle with simple tasks such as attending appointments, which can make treatment difficult.8,9 There are no approved targeted pharmaceutical treatments for cognitive impairment in schizophrenia.8,9 Iclepertin (BI 425809), an investigational oral inhibitor of glycine transporter 1 (GlyT1), was studied as a potential treatment for cognitive impairment in adults with schizophrenia.1–6 Iclepertin has not been approved by any regulatory authorities. CONNEX was a Phase III clinical program designed to assess the safety and efficacy of iclepertin for improving cognitive impairment in adults with schizophrenia.2–6 The program comprised three clinical trials, all of which were randomized, double-blind, placebo-controlled parallel group trials investigating treatment with oral iclepertin 10 mg once daily over a 26-week period in adults with schizophrenia who received stable antipsychotic treatment.2–6 The CONNEX clinical program enrolled 1,840 patients in 41 countries.4–6 Boehringer Ingelheim decided to discontinue the long-term extension trial, CONNEX-X, effective immediately.13 Boehringer Ingelheim is a biopharmaceutical company active in both human and animal health. As one of the industry’s top investors in Research and Development, the company focuses on developing innovative therapies in areas of high unmet medical need. Independent since its foundation in 1885, Boehringer takes a long-term perspective, embedding sustainability along the entire value chain. More than 53,500 employees serve over 130 markets to build a healthier, more sustainable, and equitable tomorrow. Learn more at https://www.boehringer-ingelheim.com. References: Boehringer Ingelheim. Data on File. Rosenbrock H, Desch M, Wunderlich G. Development of the novel GlyT1 inhibitor, iclepertin (BI 425809), for the treatment of cognitive impairment associated with schizophrenia. Eur Arch Psychiatry Clin Neurosci. 2023;273(7):1557–1566. doi:10.1007/s00406-023-01576-z. Falkai P, Reuteman-Fowler C, Blahova Z, Ikezawa S, Marder SR, Krystal JH. Efficacy and safety of iclepertin (BI 425809) in patients with schizophrenia: CONNEX, a Phase III randomised controlled trial programme. Eur Psychiatry. 2023;66(Suppl 1):S637. doi:10.1192/j.eurpsy.2023.1325. ClinicalTrials.gov. NCT04846868. Clinical Trial of Iclepertin Effect on Cognition and Functional Capacity in Schizophrenia (CONNEX-1). Available from: https://clinicaltrials.gov/study/NCT04846868. Accessed January 2025. ClinicalTrials.gov. NCT04846881. Clinical Trial of Iclepertin Effect on Cognition and Functional Capacity in Schizophrenia (CONNEX-2). Available from: https://clinicaltrials.gov/study/NCT04846881. Accessed January 2025. ClinicalTrials.gov. NCT04860830. CONNEX-3: A Study to Test Whether Iclepertin Improves Learning and Memory in People With Schizophrenia. Available from: https://clinicaltrials.gov/study/NCT04860830. Accessed January 2025. Fleischhacker WW, Podhorna J, Gröschl M, et al. Efficacy and safety of the novel glycine transporter inhibitor BI 425809 once daily in patients with schizophrenia: a double-blind, randomised, placebo-controlled phase 2 study. Lancet Psychiatry. 2021;8(3):191–201. doi:10.1016/S2215-0366(20)30513-7. Kitchen H, Rofail D, Heron L, Sacco P. Cognitive impairment associated with schizophrenia: a review of the humanistic burden. Adv Ther. 2012;29(2):148–162. doi:10.1007/s12325-012-0001-4. Bowie CR, Harvey PD. Cognitive deficits and functional outcome in schizophrenia. Neuropsychiatr Dis Treat. 2006;2(4):531–536. doi:10.2147/nedt.2006.2.4.531. World Health Organization. Schizophrenia. Available from: https://www.who.int/news-room/fact-sheets/detail/schizophrenia. Accessed January 2025. Stahl SM. Stahl’s Essential Psychopharmacology. 4th ed. Cambridge University Press; 2013. Mosiołek A, Gierus J, Koweszko T, Szulc A. Cognitive impairment in schizophrenia across age groups: a case-control study. BMC Psychiatry. 2016;16:37. doi:10.1186/s12888-016-0749-1. ClinicalTrials.gov. NCT05211947. A Study to Test Long-term Safety of Iclepertin in People With Schizophrenia Who Took Part in a Previous CONNEX Study. Available from: https://clinicaltrials.gov/study/NCT05211947. Accessed January 2025. 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The phase 3 program missed primary and key secondary endpoints, with no statistically significant effects on relevant measures observed, Boehringer said.\n Boehringer Ingelheim’s investigational schizophrenia candidate has failed to improve cognitive impairment or functioning in a trio of late-stage trials.The phase 3 program missed both primary and key secondary endpoints, with no statistically significant effects on relevant measures observed for patients receiving investigational treatment compared to placebo at six months, according to a Jan. 16 release.Given the results, Boehringer is discontinuing a related long-term extension study effective immediately.Boehringer’s phase 3 program, called CONNEX, was made up of three double-blinded and placebo-controlled studies evaluating oral iclepertin, an investigational GlyT1 inhibitor. The program enrolled 1,840 adults with schizophrenia who received stable antipsychotic treatment. It was the largest trial program of its kind in patients with cognitive impairment tied to schizophrenia, according to Boehringer.The FDA had granted iclepertin a breakthrough therapy tag for the indication, citing the lack of targeted pharmaceuticals currently available for cognitive impairment in schizophrenia.“While these findings are disappointing, we remain dedicated to finding effective solutions for those living with serious mental illnesses,” Shashank Deshpande, Boehringer’s head of human pharma, said in the release. “Our innovative pipeline includes over 20 additional investigative therapies in all stages of development and in different disease areas including schizophrenia and major depressive disorder. In the near future, more can be expected.”Boehringer plans to present full data from the late-stage program at an upcoming medical conference.  The clinical flop comes just a few days after Johnson & Johnson’s $14.6 billion buyout of Intra-Cellular Therapies. In that deal, the pharma giant picked up the CNS biotech’s schizophrenia and bipolar treatment Caplyta.On the heels of the deal—biopharma’s biggest acquisition since Novo Nordisk’s $16.5 billion Catalent buy in February 2024—Alto Neuroscience founder and CEO Amit Etkin, M.D., Ph.D., argued that there\'s a need for new approaches in the neuro sector. Caplyta, first approved in 2019, represents \"more of the same\" in the traditional antipsychotic space, he said.“With all the recent failures across companies, how do we actually go forward in this high-need place?” Etkin told Fierce Biotech at the J.P. Morgan Healthcare conference yesterday. Going into 2025, the biotech’s mantra is to “rethink everything,” the CEO said. That includes reimagining how drug development happens, reconsidering challenges in trial execution and conduct that has plagued the field, and rethinking how tech is leveraged.

Caption: The Biotech CEO Sisterhood and Breaking 7% gathered with allies for the first time at JPM25.\n Take a look back at the biggest stories of the week with Fierce Biotech’s conference\'s kickoff coverage here and the full lowdown from Day 2 here.Check out all the latest news below... Wednesday 6 p.m. ET Jan. 15Nkarta CEO Paul Hastings, a San Francisco local, attributed the thinner crowds to the unusually beautiful weather the city is having this week. “Every year that we have this conference, it\'s rained. This year it\'s been sunny, so there\'s a lot of people outside,” he explained. “We\'ve had very unique, wonderful weather for this time of year, and I think people have been enjoying the outdoors, and because the city\'s done such a nice job of making it safe and protecting everybody, people are outside and enjoying the sunshine. So, you\'re seeing less people crammed into lobbies and elevator spaces and umbrellas and things—I just did an interview outside on Union Square.”When asked about Nkarta’s shift in focus to autoimmune and priorities for the new year, Hastings said the company is singularly focused on enrolling patients in two clinical trials assessing NKX019, the biotech’s allogeneic, off-the-shelf, engineered natural killer (NK) cell therapy, “in order to get a transformative therapy available to patients as quickly as possible.” Wednesday 5 p.m. ET Jan. 15On the third day of the conference, Alto Neuroscience founder and CEO Amit Etkin, M.D., Ph.D., said there’s “definitely lighter attendance this year.”Etkin highlighted the year’s biggest acquisition thus far—Johnson & Johnson’s $14.6 billion buyout of CNS biotech Intra-Cellular Therapies—which was announced the first day of the conference.“What that says is that these disorders that affect many, many, many people, if you have a drug that\'s approved—and in their case, already selling—there\'s a lot of interest because there\'s a lot of need,” Etkin said.“That begs the question, with all the recent failures across companies, how do we actually go forward in this high-need place?” he continued.This has been top of mind since the Alto\'s phase 2b trial assessing ALTO-100 in major depressive disorder missed its primary and key secondary endpoints. However, Etkin said that after looking over the data, they identified “very high rates of compliance with a medication in the adjunctive arm, which explains the clinical effect, and much lower rates of compliance in the monotherapy arm, and that noncompliance came disproportionately from certain sites.”The problem—deemed to be so-called professional patients—has been a part of the field for a long time and is only getting worse, according to Etkin. Professional patients are people who participate in clinical trials but are exaggerating symptoms, don’t take the drug, or are motivated by money or attention.“Any one of these things leads you to not be an informative patient, and so you\'re not actually testing the drug,” Etkin said. “So, we took that to heart and said this is a problem we really need to fix.”To avoid this problem in another study of a depression drug candidate called ALTO-300, Alto conducted a blinded review of all patients in a separate phase 2b trial, removing 52 patients from the 200-person trial for a variety of reasons that “were indicative of site conduct issues and patient appropriateness,” according to Etkin. “And now we\'re going to be doing an interim analysis of that trial to make sure that we\'re—with these people—on the right track in terms of outcome empowering. And hopefully that gets us beyond this.”Going into 2025, the biotech’s mantra is to “rethink everything,” the CEO said. That includes reimagining how drug development happens, reconsidering challenges in trial execution and conduct that has plagued the field, and rethinking how tech is leveraged.All that rethinking is necessary, “because we just can\'t keep doing what we\'re doing as a field and expecting a different outcome,” Etkin concluded. “There has to be a better way to do this, and that is literally our motto.” Wednesday 3:30 a.m. ET Jan. 15Yesterday, spots of pink could be seen on the streets of San Francisco, and it wasn’t a coincidence. Members of the Biotech CEO Sisterhood urged allies to wear the color to underscore how few women continue to be represented in the throngs of blue suits at the conference.The effort was designed to highlight the need for continued leadership representation and access to opportunity, a spokesperson told Fierce Biotech. Wednesday 3:00 a.m. ET Jan. 15GSK’s Chief Scientific Officer Tony Wood, Ph.D., talks M&A, what the Big Pharma seeks in a partner, and how the company is looking to go beyond the current crop of GLP-1s and obesity. Story.