During my MSCA, I used a pharmacological model of dopamine over-drive in the meso-striatal pathway consisting of sub-chronic treatment with ketamine for 5 days. On day 7, mice treated with ketamine show enhanced sensitivity to a ketamine challenge as compared to mice treated with vehicle. On day 7, they also present increased dopamine synthesis capacity measured with [18F]-DOPA PET imaging.
I demonstrated that a TAAR1 full agonist (name protected by confidentiality agreement) reduced dopamine synthesis capacity and hypersensitivity to ketamine. These findings confirm the ability of TAAR1 agonists to target the key neurobiology underpinning psychosis with a pre-synaptic mode of action and without D2 blockade. TAAR1 agonists had no effect on baseline dopamine synthesis capacity, which indicates that TAAR1 agonism is unlikely to cause worsening of negative and cognitive symptoms seen with D2 blockers or to cause extrapyramidal side effects and hyperprolactinemia also seen with D2 blockers. I plan to publish these findings in the next 9 months.
I also showed that a TAAR1 partial agonist (name protected by confidentiality agreement) reduced dopamine synthesis capacity when co-administered with cocaine or haloperidol and described these results in two scientific publications (under peer review).
Using [18F]-FDOPA PET, I showed that TAAR1-KO have elevated striatal dopamine synthesis capacity, as seen in patients with schizophrenia. This, thus, suggests that TAAR1 loss of function could contribute to the development of schizophrenia. I plan to publish these findings in the next 6 months.
My preclinical findings support the role of TAAR1 as a promising new target for the treatment of schizophrenia. TAAR1 agonists may provide a real breakthrough, as they would be the first antipsychotic drugs in 70 years acting on the core neurobiological alteration seen in patients with the disorder without D2 blockade.
Several TAAR1 agonists have now progressed to clinical trials. Ulotaront was assessed in a 4-week randomized double-blind Phase 2 trial in people with an acute exacerbation of schizophrenia. It showed efficacy on symptoms relative to placebo, accompanied with very low rates of extra-pyramidal, metabolic and other side effects that are observed with D2 blockers. This drug is currently being assessed in a Phase 3 clinical trial. On the other hand, Ralmitaront, a TAAR1 partial agonist, failed to show superior efficacy relative to placebo in two phase 2 trials.
I have completed recruitment of 19 patients for a single-site, open-label, [18F]-DOPA PET - MRI clinical study evaluating the effect on dopamine synthesis capacity of adjunctive administration of Ulotaront over 14 days in adults with schizophrenia (ClinicalTrials.gov Identifier: NCT04038957). These subjects were male or female patients aged 18 to 50 years diagnostic criteria for a primary diagnosis of schizophrenia. Each participant underwent two [18F]-FDOPA PET – MRI scans, one at baseline and one at the end of the treatment period. The abstract reporting our findings (protected by non-disclosure agreement with industrial partners) will be presented at the ACNP scientific conference in December 2023 and published within the next 6 months. In this clinical study, I also generated a dataset of MRI data, that I will analyze in the next 24 months.
Furthermore, I conducted the analyses of the data collected in a [18F]-DOPA PET Phase 1b clinical study that evaluated whether a TAAR1 partial agonist reduced striatal dopamine synthesis capacity in patients with non-acute schizophrenia. I plan to publish these findings in the next 3 months.
