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Could TAAR1 agonism unlock innovation in the treatment of schizophrenia?

It was February 1952, when then 25-year-old Elizabeth became Queen of England upon the death of her father King George. Her death in September 2022 ended her unmatched 70-year reign on the throne. Also in 1952, the first dopamine 2 (D2) receptor antagonist was administered to a patient prior to surgery in Paris, to minimize use of anesthesia and patient anxiety. Impressed by the calming effect on his patients, surgeon Henri Laborit encouraged his colleagues in psychiatry to explore its use.

Fast forward nearly 70 years, and while much of the world has seen leaps and bounds in innovation, one area that has not seen much change is in the treatment of schizophrenia.

Complexities exist in the treatment of schizophrenia

Schizophrenia is a chronic, serious, and often severely disabling brain disorder affecting an estimated 24 million people worldwide and more than 2 million people in the U.S.1,2 People living with schizophrenia experience what are commonly known as positive and negative symptoms, as well as cognitive impairment. Positive symptoms of schizophrenia refer to new behaviors and thoughts that aren’t normally present for a person, such as hallucinations, delusions, and disorganized thinking. While negative symptoms refer to the lessening or absence of normal behaviors for a person and can include lack of emotion, social withdrawal, and loss of motivation.3

The medicines used to treat schizophrenia, referred to as typical and atypical antipsychotics, block D2 and/or serotonin 5-HT2A receptors and have largely worked the same way since they were introduced in the 1950s and 1990s, respectively. Typical antipsychotics are associated with a high occurrence of a cluster of movement disorders known as extrapyramidal symptoms (EPS), and although the newer atypical antipsychotics carry a lower risk of EPS, they are often associated with an increased risk for cardiometabolic symptoms including weight gain and diabetes.4,5 There is also low adherence to medication for schizophrenia and high rates of discontinuation, with up to 74% of people stopping their medication commonly citing side effects as the main reason.4,6 Among other unmet needs, 30% of people living with schizophrenia are resistant to current treatments and 60% achieve only partial symptom control.7

Given the challenges presented, there remains an unmet need for innovation as well as differentiated side effect profiles from currently available medications. Unfortunately, although there has been significant interest and investment over the years in developing novel treatments for schizophrenia that do not block D2 receptors, these compounds have not been approved.

A potential new TAARget emerges

In the early 2000s, scientists identified the trace amine-associated receptor (TAAR) family of proteins.8,9 TAAR1 – the first discovered – is prominently expressed in areas of the brain involved in psychiatric disorders, and areas of the body that regulate energy metabolism.10,11 In the decades since, preclinical studies have suggested that TAAR1 plays an important physiological role in the central nervous system and a likely pathological role in mental health disorders, including schizophrenia.12,13 TAAR1 activation may also help to balance dopamine, serotonin, and glutamate neurotransmission in areas of the brain commonly dysregulated in people living with schizophrenia.10–12

Sunovion’s identification of a TAAR1-targeting compound in the laboratory involved a sophisticated computational analysis of mouse behavior, where the behavioral profiles induced by marketed drugs were assembled into drug class categories.14 Researchers at Sunovion then began to look for new compounds that produced a similar behavioral profile to the antipsychotic class that were neither D2 nor 5-HT2A receptor antagonists. This innovative target-agnostic approach led to the discovery of ulotaront, which is now the first TAAR1 agonist to enter Phase 3 clinical studies in individuals living with schizophrenia, with data anticipated this year.

Pivotal study results for investigational TAAR1 agonist, ulotaront

Results published in the New England Journal of Medicine of the 4-week, double-blind, placebo-controlled Phase 2 study showed that once-daily treatment with ulotaront reduced both positive and negative symptoms of schizophrenia.15 The 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).

In this 4-week study, ulotaront demonstrated a safety and tolerability profile comparable to placebo. Furthermore, no significant differences were observed in potential movement disorders between ulotaront and placebo-treated patients.15 The most common adverse events associated with ulotaront in the SEP361-201 study were drowsiness, agitation, nausea, diarrhea, and stomach or abdominal discomfort.15,16 There were no clinically meaningful changes observed on metabolic parameters (including weight, lipids, and glucose) or prolactin levels in the study.15

Ulotaront received Breakthrough Therapy Designation from the U.S. Food and Drug Administration for the treatment of schizophrenia in 2019. It is currently being investigated in the global Phase 3 DIAMOND (Developing Innovative Approaches for Mental Disorders) clinical development program, which includes four studies designed to evaluate the efficacy, safety, and tolerability of ulotaront for the treatment of people living with schizophrenia. In addition, studies are underway to determine ulotaront’s efficacy in other areas of unmet need, including generalized anxiety disorder (GAD) and the adjunctive treatment of major depressive disorder (MDD).

To learn more about ulotaront and Sunovion’s innovative pipeline of compounds to address serious and persistent mental illness, visit Sunovion.com.


References

  1. Schizophrenia and Psychosis Action Alliance. Societal Costs of Schizophrenia & Related Disorders. Schizophrenia & Psychosis Action Alliance; 2021. Accessed June 10, 2022. https://sczaction.org/insight-initiative/societal-costs/
  2. GBD 2019 Mental Disorders Collaborators. Global, regional, and national burden of 12 mental disorders in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet Psychiatry. 2022;9(2):137-150. doi:10.1016/S2215-0366(21)00395-3
  3. Schizophrenia. National Institute of Mental Health (NIMH). Accessed June 2, 2022. https://www.nimh.nih.gov/health/statistics/schizophrenia
  4. Liu-Seifert H, Adams DH, Kinon BJ. Discontinuation of treatment of schizophrenic patients is driven by poor symptom response: a pooled post-hoc analysis of four atypical antipsychotic drugs. BMC Med. 2005;3(1):21. doi:10.1186/1741-7015-3-21
  5. Üçok A, Gaebel W. Side effects of atypical antipsychotics: a brief overview. World Psychiatry. 2008;7(1):58-62. doi:10.1002/j.2051-5545.2008.tb00154.x
  6. Lieberman JA, Stroup TS, McEvoy JP, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med. 2005;353(12):1209-1223. doi:10.1056/NEJMoa051688
  7. Girgis RR, Zoghbi AW, Javitt DC, Lieberman JA. The past and future of novel, non-dopamine-2 receptor therapeutics for schizophrenia: A critical and comprehensive review. J Psychiatr Res. 2019;108:57-83. doi:10.1016/j.jpsychires.2018.07.006
  8. Bunzow JR, Sonders MS, Arttamangkul S, et al. Amphetamine, 3,4-methylenedioxymethamphetamine, lysergic acid diethylamide, and metabolites of the catecholamine neurotransmitters are agonists of a rat trace amine receptor. Mol Pharmacol. 2001;60(6):1181-1188. doi:10.1124/mol.60.6.1181
  9. Borowsky B, Adham N, Jones KA, et al. Trace amines: identification of a family of mammalian G protein-coupled receptors. Proc Natl Acad Sci U S A. 2001;98(16):8966-8971. doi:10.1073/pnas.151105198
  10. Gainetdinov RR, Hoener MC, Berry MD. Trace amines and their receptors. Pharmacol Rev. 2018;70(3):549-620. doi:10.1124/pr.117.015305
  11. Rutigliano G, Accorroni A, Zucchi R. The case for TAAR1 as a modulator of central nervous system function. Front Pharmacol. 2018;8. Accessed October 4, 2022. https://www.frontiersin.org/articles/10.3389/fphar.2017.00987
  12. Berry MD. The potential of trace amines and their receptors for treating neurological and psychiatric diseases. Rev Recent Clin Trials. 2007;2(1):3-19. doi:10.2174/157488707779318107
  13. John J, Kukshal P, Bhatia T, et al. Possible role of rare variants in Trace amine associated receptor 1 in schizophrenia. Schizophr Res. 2017;189:190-195. doi:10.1016/j.schres.2017.02.020
  14. Dedic N, Jones PG, Hopkins SC, et al. SEP-363856, a novel psychotropic agent with a unique, non-D2 receptor mechanism of action. J Pharmacol Exp Ther. 2019;371(1):1-14. doi:10.1124/jpet.119.260281
  15. 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. doi:10.1056/NEJMoa1911772
  16. Correll CU, Koblan KS, Hopkins SC, et al. Safety and effectiveness of ulotaront (SEP-363856) in schizophrenia: results of a 6-month, open-label extension study. NPJ Schizophr. 2021;7(1):63. doi:10.1038/s41537-021-00190-z