A novel antipsychotic drug has shown promising results in phase 2 clinical trials, according to findings published in the New England Journal of Medicine. The antipsychotic, SEP-363856, shows agonist activity at trace amine-associated receptor 1 (TAAR1) and 5-hydroxytryptatime type 1A (5-HT1A) receptors, but does not target dopamine D2 receptors.
In a 4-week randomized controlled trial and an open label 26-week extension study, SEP-363856 significantly reduced positive and negative symptoms and showed an acceptable safety profile, with no indication of the extrapyramidal symptoms (EPS) or metabolic dysregulation common in most D2 antagonist antipsychotics. To learn more about SEP-363856 as a novel treatment for schizophrenia, we spoke with 2 study authors: Kenneth Koblan, PhD, Chief Scientific Officer of Sunovion Pharmaceuticals, Marlborough, Massachusetts, and John Krystal, MD, Co-Director of Yale Center for Clinical Investigation at Yale School of Medicine, New Haven, Connecticut. The interview was edited for clarity, grammar, and readability.
What do you think is the biggest impact of the results from this study?
Dr Krystal: We have wanted a drug with a new mechanism for 50 years and if this drug works, it might be the first to provide us an alternative. This is a drug that seems to be effective treating the broad symptoms of schizophrenia, not just psychosis, and it is extremely safe and well-tolerated so far, which is always welcome.
Dr Koblan: The pathway that we are working on is quite novel and distinct, and it is previously underappreciated as far as neuropsychopharmacology is concerned. The potential exists for additional indications where there are unmet medical needs in diseases like bipolar disorder or major depressive disorder. A big takeaway is that additional work is needed in the field to understand the role that TAAR1 and 5-HT1A may play in other psychiatric conditions.
How do you see this new antipsychotic contributing to the field of schizophrenia treatment?
Dr Krystal: One of the holy grails for medication development for schizophrenia has been to identify treatments that reduce the symptoms of schizophrenia without blocking the dopamine D2 receptor. Although the current antipsychotic medications help many people, patients with schizophrenia experience residual symptoms. The blockade of the dopamine D2 receptor causes a dopamine signaling deficiency state, particularly if the medications are used in doses that are too high, and symptoms in some ways resemble Parkinson disease.
SEP-363856 didn’t produce the motor side effects that we associate with the standard antipsychotic medications or the metabolic changes, with weight gain or increased lipid levels in the blood. It’s exciting because medications that are well tolerated are more likely to be taken by people who need them.
Dr Koblan: From our perspective, we are focused on bringing innovative medicines to patients, and the unmet medical need for the approximately 2.5 million schizophrenic patients in the United States and over 23 million worldwide, who are looking for a novel therapy. We hope to be able to move forward with the first in a new class of medicines to treat the positive and negative symptoms of schizophrenia, as well as deliver a new and differentiated safety profile.
Can you elaborate a little bit more on what you mean by the new safety profile for this classification of medications?
Dr Koblan: Since the discovery of the very first antipsychotic agents over 60 years ago, all of the major antipsychotics act by blocking the dopamine D2 receptor. They are dopamine D2 receptor antagonists, and the second generation atypical antipsychotics add in another 5-HT2A target. While they are effective in treating the positive symptoms, in general they have minimal efficacy on the negative symptoms, such as apathy or reduced emotional expression. They also have some side effects: cardiometabolic effects, weight gain, and EPS. SEP-363856 has been associated with some somnolence and GI effects, but the neurological and the metabolic profile was similar to placebo.
Is there a potential hypothesis that might explain how agonism at TAAR1 and 5-HT1A have an influence on schizophrenia symptoms?
Dr Koblan: SEP-363856 inhibits firing of a subset of neurons in the ventral tegmental area of the midbrain, a site that is known to be dysregulated in schizophrenic patients. We can therefore modulate that output dopamine circuit. SEP-363856 also inhibits firing in the dorsal raphe, an area known to be hyperactive in schizophrenia.
Is there a timeline for phase 3 trials, especially given potential delays in recruitment due to COVID-19?
Dr Koblan: Sunovion has conducted an end of phase 2 meeting with the FDA and about a year ago received a breakthrough therapy designation. We have agreed upon a phase 3 registration program and initiated it under the name developing innovative approaches for mental disorders (DIAMOND). We are committed to the clinical studies that are outlined in that program and are continuing to monitor the impact that COVID-19 might have on that study.
Knowing that Sunovion also produces LATUDA, a D2 antagonist antipsychotic, might there be any future head to head studies?
Dr Koblan: LATUDA has a differentiated profile with respect to EPS and cardiometabolic effects. At this moment, the phase 3 replication program does not include a head to head comparison with LATUDA. Discussion is ongoing around other potential head to head studies that we may work on in the future.
Is there anything else you think clinicians should know?
Dr Koblan: Sunovion has focused on an innovative approach to look at patients’ unmet needs: from our perspective, cardiometabolic safety in terms of lipids and prolactin and EPS. There are other molecules in our pipeline that target other diseases like treatment resistant or bipolar depression. We are encouraged by the initial studies and committed to replication and full registration. It is the first of what we hope to be a pipeline of new medicines to treat serious mental health conditions.
Koblan KS, Kent J, Hopkins SC, et al. A Non–D2-Receptor-Binding Drug for the Treatment of Schizophrenia. N Engl J Med. 2020;382:1497-1506.