Aticaprant

None By Dr. L. Alison McInnes and Jimmy QianWe’re finally moving towards a causality-based nosology for psychiatry: specific symptoms with defined biological underpinnings can now be targeted by new therapies. But how do we bridge clinical development with real-world care? How do we ensure trial endpoints are synchronized with real-world measures, payer requirements, and clinical society guidelines? Below, we dig into the widening gap between research and clinical care. No consensus on how to measure transdiagnostic symptomsExcitingly, researchers have been able to characterize underlying neural circuitry for certain symptoms. The NIMH Fast-Fail Trials initiative, which stipulated that a drug candidate should alter a biomarker in an objectively measurable fashion, accelerated this movement. For anhedonia, investigators identified ventral striatum abnormalities during reward anticipation that normalized in response to kappa opioid receptor (KOR) antagonists. Despite this advancement, there has yet to be consensus on how to measure anhedonia in the clinic. Many clinicians do not practice measurement-based care, and even amongst those who do, measurement of anhedonia is typically confined to the first question of the PHQ-9. Moreover, anhedonia is a transdiagnostic symptom that should be measured across multiple diagnoses, not just depression.Progress has also been made in elucidating the neurocircuitry of cognition in depression. Leanne Williams’ group has identified biotypes with distinct fMRI signatures and associated cognitive abnormalities that may predict differential response to treatment. Meanwhile, Alto Neuroscience is developing cognitive profiling tools to subtype patients for enriched response to its pipeline agents. However, there is no consensus approach to measure cognition in the real-world. Furthermore, tools for characterizing cognitive deficits in depression do not necessarily capture the deficits observed in other disorders. Today, real-world clinicians often miss subtle but disabling cognitive symptoms for lack of appropriate measurement tools.Researchers have made additional advancements in precision measurement spanning EEG, fMRI, digital phenotyping, proteomics, and more. Yet as research progresses, the gap to real-world care widens. New mechanisms of action require more from cliniciansNovel mechanisms of action are also being developed, often enabling precise targeting of pharmacotherapies to specific symptoms. Continuing the anhedonia example, the phase 3 KOR antagonists aticaprant and navacaprant leverage the fact that elevated levels of dynorphin, which activates KORs, are associated with stress, anhedonia, and dysregulation of reward processing.Seltorexant, a selective orexin-2 receptor antagonist, is being studied specifically for depression with insomnia symptoms. Xanomeline-trospium, a dual M1/M4 muscarinic agonist, has shown promise in treating positive, negative, and cognitive symptoms of schizophrenia, with scientists speculating that dual agonism confers broad activity while M1 agonism may be more involved in cognitive improvements.Additional novel mechanisms are being studied or have been recently approved, spanning NMDA and AMPA receptor modulators, dual orexin receptor antagonists, 5HT2a receptor antagonists, GABAA receptor modulators, digital therapeutics, and more. New treatment options coupled with the complexity of treatment pathways and symptom clusters mean clinicians will need to know how to prioritize different mechanisms, measure success, and monitor side effects.Most patients have constellations of symptoms, so how are clinicians to make decisions about which to treat first with these targeted therapies? A hospitalist has objective physiological measures to help prioritize interventions to stabilize an inpatient; similarly, psychiatrists need novel objective measures to select the best treatment pathway for individual patients. Diagnosing and measuring previously untreatable conditions is a challengeIt is wonderful to see therapies for hitherto untreatable indications. Tardive dyskinesia is an example of a historically-neglected condition as there were no effective therapeutics. Why should clinicians and patients spend time measuring symptoms if there is no solution? Though valbenazine and deutetrabenazine have recently been approved for tardive dyskinesia, it is under-diagnosed in the real-world. The symptom measures used in trials are not typically used – or even known – by real-world clinicians. Similar dynamics exist for negative symptoms of schizophrenia, cognitive impairment, and other conditions. Our solution: a Learning Health SystemWe appreciate an analogy by one of the leaders of precision psychiatry, “You wouldn't want to launch electric vehicles without building an EV charging network first.” With breakthroughs in drug development comes an increased need for connectivity across biopharma, regulators, clinicians, payers, and clinical societies.At Osmind, our Learning Health System approach lowers barriers between research and patient care. By building consensus around the same precision measurements, we align evidence goalposts and generate cohorts of well-characterized patients for research. We deploy these measures directly at the point of care through our technology and EHR. Our collaboration with the American Psychiatric Association is an example of this approach.“As we advance in understanding the biological underpinnings of mental illness, an important challenge – and opportunity – will be to ensure that these insights translate into improvements in patient care,” says Husseini Manji, MD, a Strategic Advisor at Osmind. “We must work collaboratively across sectors to create a seamless integration of precision diagnostics and targeted therapeutics into everyday practice and real-world outcomes.” 

Dive Brief:Sales of Johnson & Johnsons depression drug Spravato accelerated in the second quarter, putting the medicine on pace to eclipse $1 billion in annual revenue this year.Globally, Spravato sales totaled $271 billion between April and June, a 61%increase from the same period one year before and a 20% jump from the first quarter. The numbers, disclosed by J&J alongside second quarter earnings Wednesday, reflected increased physician and patient confidence, Jessica Moore, the companys head of investor relations, said on a conference call.Approved for treatment-resistant depression in 2019, Spravato is a form of ketamine thats given as a nasal spray. Its also cleared to treat depressive symptoms in people with major depressive disorder who show acute suicidal ideation or behavior.Dive Insight:Spravato remains a comparatively small product by sales for J&J, which reported more than $22 billion in revenue during the second quarter. But the pharmaceutical giant has high expectations for its growth, telling investors in December that it anticipates sales will grow to between $1 billion and $5 billion annually.Wednesdays numbers are encouraging evidence in support of that forecast. And they could also bode well for brain drugs like Spravato that work in ways that can also cause dissociation and hallucination.Spravato's strong sales trajectory supports the notion psychedelics can become commercially viable for mental health, wrote Jefferies analyst Andrew Tsai in a client note Wednesday.The field is in particular focus as the Food and Drug Administration decides whether to approve MDMA as part of a psychedelic-assisted therapy tested by biotechnology company Lykos Therapeutics. While two late-stage studies run by Lykos showed the therapy could help people with post-traumatic stress disorder, advisers to the FDA last month recommended the agency hold off on an approval, citing issues with how the trials were conducted and MDMAs safety. The FDA is expected to make its verdict by Aug. 11.Experts viewed the negative vote as having a sobering effect on the psychedelic field, although the FDA could still surprise and grant Lykos an approval in some fashion.Behind Lykos are several other companies, including Compass Pathways, which is developing psilocybin for treatment-resistant depression, and Atai Life Sciences, which is working on a form of dimethyltryptamine in the same setting.Spravato's continued sales acceleration ... provides evidence that psychedelics can generate meaningful sales in hard-to-treat [central nervous system] disorders, even if their ultimate use [is] restricted to hospitals or treatment clinics, wrote Tsai.Due to the risk of dissociation and suicidal thoughts, Spravato is only available for use under the supervision of a healthcare professional in a medical office or clinic.Unlike many of its pharmaceutical peers, J&J has maintained neuroscience as a research focus, and is developing two depression drugs behind Spravato that work in new ways. One, seltorexant, showed positive results in a Phase 3 study J&J read out in late May, while the company is awaiting important data on the other, called aticaprant. '