Xanomeline Tartrate/Trospium Chloride

Vima Therapeutics debuted on Thursday with a $60-million series A and a goal to develop the first oral treatment for dystonia, a chronic movement disorder characterised by involuntary muscle contractions — with no existing therapeutics that address its root cause.The biotech's lead programme is VIM0423, a muscarinic cholinergic receptor–targeting asset in Phase I testing. The financing, which was led by Atlas Venture and saw participation from Access Industries and Canaan, will fund a Phase II trial of VIM0423 that's slated to launch in the fourth quarter. According to Vima, while therapeutics directed against muscarinic receptors are used today to treat movement disorders, they have unfavourable tolerability profiles, resulting in low efficacy. "With VIM0423, we’ve developed a way to selectively block the specific muscarinic cholinergic receptors in the brain involved in dystonia," Bernard Ravina, Vima's founder and chief executive, told FirstWord. "This targeted approach allows us to address the underlying biology of the disorder while minimising the off-target side effects that have historically made this class of drugs difficult to tolerate. The result is a more precise mechanism designed to deliver efficacy with improved safety and tolerability."Muscarinic receptors have been in the psychiatric spotlight as of late, given that they are the target of Bristol Myers Squibb's novel schizophrenia drug. However, Cobenfy (xanomeline/trospium chloride) agonises the M1/M4 receptors, while VIM0423 is an antagonist. "Dystonia is driven by abnormal signaling in certain brain regions, many of which are also implicated in psychiatric conditions," Ravina said. While psychiatric drugs are designed to enhance signaling, for movement disorders, the goal is to inhibit "activity in the motor networks in the brain to restore balance and reduce involuntary muscle contractions," he explained.Ravina previously served as chief medical officer at Praxis Precision Medicines, and before that, held the same role at Voyager Therapeutics. Prior to those positions, he was the medical director of translational neurology at Biogen.

Syndeio CEO Derek Small, Syndeio With $90 million to start, Syndeio has a lead asset in Phase II clinical trials for major depressive disorder, with plans to soon launch a biomarker trial in Alzheimer’s disease. Founders and executives of Karuna Therapeutics and Naurex are back with a brand-new biotech, aiming to “build the first synapse-targeted company” for the treatment of diseases like depression and Alzheimer’s, according to CEO Derek Small, former chief executive at Naurex. Led by Small—together with former Karuna execs Steve Brannan and Anantha Shekhar and Nobel Laureate Thomas Südhof, among other prominent names—Syndeio Biosciences uncloaked itself Tuesday with $90 million in startup funds. The raise was led by Catalio Capital Management and Innoviva and supported by strategic shareholders AbbVie and Eli Lilly. But $90 million isn’t all the young biotech has behind it, Small told BioSpace in an interview. Syndeio is “built on the investment of hundreds of millions of dollars before that into better understanding” of synaptic plasticity. The Indianapolis-based biotech is building a pipeline of programs focused on optimizing synaptic function to address major depressive disorder (MDD), Alzheimer’s disease, schizophrenia and other synaptopathies. Syndeio aims to “strengthen neural connections through event-driven pharmacology,” according to its announcement . A Personal Mission Syndeio has been in the works for a decade, Small revealed. In 2015, he pivoted his investment firm, Luson Bioventures, to focus solely on neuro, driven by the personal experience of being the primary caregiver to his father, who was suffering from the end stages of early-onset dementia. “The last couple years were really rough for him, but also . . . very clinical for me,” Small said. His father’s dementia led to organ failure, which led to loss of consciousness and ultimately cardiac arrest. In the emergency room, he would be resuscitated, but in that recovery, “pathological hallmarks” of synaptic dysfunction became apparent. “That’s where cognition stops being good [and] a resilient phenotype gets very challenged.” Targeting the synapses has been tried before, Small explained. But the understanding of the pharmacology hasn’t quite been there. Südhof, along with Syndeio Chief Science Officer John Donello, discovered that, in healthy people, synapses operate in a balance. For people who are afflicted with Alzheimer’s, depression, or schizophrenia, that balance can get thrown off, Small said. Much of reestablishing this balance comes down to dosing, he explained. Therefore, Syndeio’s programs are driven by its proprietary Boost synapse pharmacology platform, which combines molecular, functional and behavioral models to predict treatment outcomes and dosing strategies for its synaptogenic agents. In 2013, Südhof won the Nobel Prize for discovering how signals instruct vesicles to release their cargo with precision. Südhof and Syndeio’s other founders have since “uncovered critical nuances in translating the biology of synaptic plasticity into effective therapeutics,” Small said in the company’s press release. Small was the founding CEO of Naurex, an Illinois-based biotech that focused on discovering drugs that enhance synaptic plasticity or strengthen the network for neural cell communication. Naurex was acquired by Allergan in 2015 for $560 million upfront to bolster that company’s mental health profile. Much of the investment in this class of compounds, in fact, came from Allergan, Small said. While Syndeio is targeting a range of neuropsychiatric and cognitive disorders, the biotech is starting with MDD, a particularly intractable disease. At least 30% of people with MDD fail to respond to two or more antidepressants, leaving plenty of unmet need on the table. The company’s lead candidate, zelquistinel, is currently in Phase II trials for MDD, and Syndeio plans to soon begin a first-of-its-kind synaptic function biomarker trial in Alzheimer’s. The company is also looking to bring in more synapse-targeted programs, as Small said Syndeio has “an advantage on how best to develop them, design clinical trials and get them advanced.” Small noted that Syndeio is on a “very similar” path to the wildly successful Karuna, which was acquired by Bristol Myers Squibb for $14 billion in December 2023, nine months before its lead product KarXT (now Cobenfy) won FDA approval for schizophrenia last September. When Karuna went public in 2019, it had a Phase II study of KarXT underway that was designed to be large enough to be registrational, according to Small. Likewise, zelquistinel’s Phase II program is designed to enable moving “right into a Phase III registration strategy.” But Small has a different end goal in mind for Syndeio. “Our goal is not to get taken out,” he said. “Our goal is to actually have a really long-term advantaged synapse modulating–focused company.”