Periodic Reporting for period 1 - TACtIK (Trace Amine-Associated Receptor 1 (TAAR1) agonists in a chemogenetic/molecular imaging model of increased dopamine synthesis capacity (Ki))
Berichtszeitraum: 2021-09-01 bis 2023-08-31
Schizophrenia has a worldwide prevalence of 0.2-3.5% and mainly strikes young adults between the ages of 20 and 35, a time when most people are completing their education and establishing themselves as independent adults. This explains the significant burden of schizophrenia to both person and society. Antipsychotic drugs were discovered serendipitously in the 1950s, while their mechanism of action could be elucidated only fifty years later. Using positron emission tomography (PET) imaging, the relationship between dopamine (DA) D2 receptors occupancy and clinical response was demonstrated. Unfortunately, post-synaptic D2 receptor density is not primarily altered in treatment-naïve patients. The major pathophysiological abnormality underlying schizophrenia is pre-synaptic, and consists of increased striatal DA synthesis capacity due to midbrain DA neuron over-activity, as shown by [18F]-FDOPA PET imaging. Prolonged D2 blockade may super-sensitize the system, thus causing tolerance and loss of efficacy, enhancing vulnerability to relapse, and triggering movement disorders. Therefore, in the medical treatment of schizophrenia there is much room for improvement.
A promising, novel target is the trace amine-associated receptor 1 (TAAR1), a recently identified G protein-coupled receptor. TAAR1 is widely expressed across the mammalian brain, including the DAergic ventral tegmental area (VTA) and substantia nigra pars compacta (SNc), the main striatum afferents. Pre-clinical evidence of an interaction between TAAR1 and DA systems has been accumulating at several levels. Different classes of synthetic TAAR1 agonists are currently available. For instance, SEP-363856 (Sunovion Pharmaceuticals) is a TAAR1/5-HT1A agonist that yielded promising results in a phase 2 multisite clinical trial (NCT02969382).
The overall objectives of TACtIK were to demonstrate that drugs targeting TAAR1 reduce dopamine synthesis capacity in a rodent model of meso-striatal dopamine overactivity and in people with a diagnosis of schizophrenia.
A promising, novel target is the trace amine-associated receptor 1 (TAAR1), a recently identified G protein-coupled receptor. TAAR1 is widely expressed across the mammalian brain, including the DAergic ventral tegmental area (VTA) and substantia nigra pars compacta (SNc), the main striatum afferents. Pre-clinical evidence of an interaction between TAAR1 and DA systems has been accumulating at several levels. Different classes of synthetic TAAR1 agonists are currently available. For instance, SEP-363856 (Sunovion Pharmaceuticals) is a TAAR1/5-HT1A agonist that yielded promising results in a phase 2 multisite clinical trial (NCT02969382).
The overall objectives of TACtIK were to demonstrate that drugs targeting TAAR1 reduce dopamine synthesis capacity in a rodent model of meso-striatal dopamine overactivity and in people with a diagnosis of schizophrenia.
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.
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.
TACtIK generated data on new TAAR1 agonists under preclinical development in cooperation with industrial partners. This substantially influenced and shaped industrial decisions on drug development. I co-led a clinical trial sponsored by an industrial partner to test the mechanism of action of Ulotaront, a full TAAR1 agonist in people with schizophrenia, in co-administration with currently available antipsychotic drugs. Ulotaront is currently undergoing phase 3 clinical trial. If successful, these drugs could target the market in the next years and revolutionize the treatment of schizophrenia as drugs with a completely innovative mode of action without D2 blockade. This would allow to overcome the limitations of D2 blockers, consisting of side effects, poor efficacy on negative and cognitive symptoms, and supersensitivity, thus improving the quality of life of people living with schizophrenia and their caregivers.