TAAR1 Agonism – A Novel Approach To Treating Schizophrenia

Schizophrenia is a chronic, serious and often severely disabling brain disorder that affects more than 20 million people worldwide.¹ The condition is characterized by positive symptoms, such as hallucinations, delusions and disorganized thinking as well as negative symptoms, including lack of emotion, social withdrawal, lack of spontaneity and cognitive impairment which can include problems with memory, attention, and the ability to plan, organize and make decisions.¹ Symptoms typically present in the early to mid-20s, and evidence suggests that treating schizophrenia within the first three years of illness with pharmaceutical, social and psychological interventions can improve outcomes.^2,3

Despite schizophrenia ranking as one of the top 15 leading causes of disability globally, medications to treat it have worked largely the same way since the 1950s.^3,4

Current Schizophrenia Treatment Approaches – Progress, but Unmet Needs Remains

Antipsychotics are the most commonly-prescribed medicines for schizophrenia, belonging to one of two types – typical or atypical. Typical antipsychotic drugs, first introduced in the 1950s, are strong dopamine D₂ receptor antagonists and therefore are often associated with risk for hyperprolactinemia and extrapyramidal symptoms (EPS) such as tremors, muscle contractions, and other involuntary muscle movements that may be debilitating.^5,6

After many years of research, atypical antipsychotics were developed to address some of the challenges of the typical antipsychotics and were introduced to patient care in the early 1990s. Atypical antipsychotics are also antagonists for the dopamine D₂ receptor but with a lower affinity, and added antagonism at serotonin 5-HT_2a receptors.⁷ Though these medications have a lower risk of hyperprolactinemia and EPS than their predecessors, atypical antipsychotics are often associated with an increased risk for cardiometabolic symptoms including weight gain and diabetes.^8,9,10 Additionally, while atypical antipsychotics may effectively treat psychosis and other positive symptoms of schizophrenia, they are less effective at treating negative and cognitive symptoms.¹¹ As these symptoms can have an impact on quality of life for patients and care partners, this remains an important area of unmet need in the management of schizophrenia.

Discovering New Targets – the Potential of TAAR1 Agonism

Although there has been significant interest over the last 60 years to develop novel treatments for schizophrenia that do not block dopamine D₂ receptors, most of these efforts have been unsuccessful in the clinic. However, researchers have recently identified a new promising therapeutic target for the treatment of schizophrenia: trace amine-associated receptor 1 (TAAR1).¹² TAAR1 is a member of a family of G-protein coupled receptors called TAARs, which are activated by trace amines. Trace amines are structurally related to classical neurotransmitters such as dopamine and serotonin, but are present in much lower concentrations in the body.^12,13 TAAR1 is widely expressed throughout the brain and has been found in areas that are associated with the emergence of schizophrenia symptoms, including the ventral tegmental area (VTA) and dorsal raphe nucleus (DRN), which produce dopamine and serotonin, respectively.¹⁴

“We are just beginning to understand the full range of activity of TAAR1 and how we can leverage this knowledge to advance treatment for patients with a variety of neuropsychiatric conditions,” said Andrew J. Cutler, M.D., Clinical Associate Professor of Psychiatry at SUNY Upstate Medical University. “Early research on the role of TAAR1 in the brain is promising, and we are hopeful that a better understanding of TAAR1 may make a real difference in mitigating the array of symptoms of schizophrenia and other brain disorders.”

Understanding the potential of TAAR1 agonism has unlocked new avenues that aim to treat schizophrenia in a new way. Preclinical evidence shows TAAR1 modulates the signaling of several neurotransmitter systems (including dopamine, serotonin, and glutamate) which are often dysregulated in schizophrenia.⁴

Based on TAAR1’s ability to regulate neurotransmitter systems important to mood, psychosis, reward-processing and cognition, researchers believe TAAR1 agonists have potential as a therapeutic target for several neuropsychiatric disorders, including schizophrenia.

Preclinical data demonstrate that TAAR1 agonism produces antipsychotic-like effects without D₂ or 5-HT_2a receptor antagonism. Studies have found that TAAR1 agonists can reduce the firing of dopaminergic and serotoninergic neurons and can also increase transmission through glutamatergic neurons – three concepts important to the treatment of schizophrenia symptoms.¹⁵

A Novel Compound Targeting TAAR1

Ulotaront (SEP-363856) is a TAAR1 agonist with serotonin 1A (5-HT_1A) agonist activity and is the first TAAR1 agonist to enter Phase 3 clinical studies to evaluate the treatment of adults and adolescents (ages 13-17) with schizophrenia.¹⁶ The stem –taront, connotes ulotaront as a member of the TAAR1 agonist class, differentiating itself from suffixes used to denote other pharmacologic substances used among approved antipsychotics (e.g., -done, -pine, -pip).

Results published in The New England Journal of Medicine of the 4-week, double-blind, placebo-controlled pivotal study (SEP361-201) and the 26-week open-label extension study (SEP361-202) showed that treatment with ulotaront significantly reduced both positive and negative symptoms of schizophrenia.¹⁷ The pivotal study met its primary endpoint of change in Positive and Negative Syndrome Scale (PANSS) total score at Week 4, with a statistically significant and clinically meaningful improvement of -17.2 points (ulotaront) vs -9.7 (placebo) points from baseline (p=0.001).^17,18

Ulotaront demonstrated a safety and tolerability profile comparable to placebo.¹⁸ The most common adverse events associated with ulotaront were somnolence, agitation, nausea, diarrhea, and dyspepsia.¹⁸ There were no clinically meaningful changes observed on metabolic parameters (including weight, lipids and glucose) or prolactin levels in either study.¹⁷ Additionally, there were no significant differences observed in potential movement disorders between ulotaront and placebo patients.¹⁸

“Overall, findings from the ulotaront pivotal 4-week trial and 26-week open-label extension suggests that TAAR1 agonism may treat positive and negative symptoms of schizophrenia without significantly increasing weight, elevating prolactin or glucose, or inducing movement disorder adverse effects,” said Dr. Cutler. “The results of the study are promising and demonstrate the potential of ulotaront in the treatment of schizophrenia.”

Ulotaront is currently being evaluated in the global Phase 3 DIAMOND clinical trial program, which includes four studies designed to evaluate the safety, efficacy, and tolerability of ulotaront for the treatment of people with schizophrenia.

To learn more about TAAR1, watch this short video.

References:

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3. National Institute of Mental Health. Schizophrenia. [Internet]. Available from: https://www.nimh.nih.gov/health/statistics/schizophrenia. Accessed October 2021.
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12. Pei Y, Asif-Malik A, Canales JJ. Trace Amines and the Trace Amine-Associated Receptor 1: Pharmacology, Neurochemistry, and Clinical Implications. Front Neurosci. 2016;10:148.
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14. Rutigliano G, Accorroni A, Zucchi R. The Case for TAAR1 as a Modulator of Central Nervous System Function. Front Pharmacol. 2018;8:987
15. Revel FG, Moreau JL, Gainetdinov RR, Bradaia A, Sotnikova TD, Mory R., et al. (2011). TAAR1 activation modulates monoaminergic neurotransmission, preventing hyperdopaminergic and hypoglutamatergic activity. Proc Natl Acad Sci USA 108: 8485–8490.
16. ClinicalTrials.Gov. A Clinical Study to Evaluate the Long-term Safety and Tolerability of an Investigational Drug in People With Schizophrenia. Available from: https://clinicaltrials.gov/ct2/show/NCT04109950?term=sep-363856&recrs=adf&draw=2&rank=2. Accessed October 2021.
17. 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(16):1497-1506.
18. Dworak H, Hopkins SC, Koblan KS, et al. Effects of SEP-363856, a novel TAAR1 agonist, on negative symptoms in schizophrenia: results of a 6-month, open-label treatment study. Paper presented at: 48th Annual Meeting of the American College of Neuropsychopharmacology; December 5, 2019; Orlando, FL