Dopamine serotonin stabilizer RP5063: A randomized, double-blind, placebo-controlled multicenter trial of safety and efficacy in exacerbation of schizophrenia or schizoaffective disorder

Cantillon, Marc; Prakash, Arul; Alexander, Ajay; Ings, R. M. J.; Sweitzer, Dennis; Bhat, Laxminarayan

doi:10.1016/j.schres.2017.01.043

Cited by 36 publications

(47 citation statements)

References 20 publications

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“…These initial safety observations were clarified further in the phase II evaluation of RP5063 8. In this study, RP5063 dosed between 15 and 50 mg dosed once daily for 28 days had a TEAE rate of 54.8% (similar to positive control of aripiprazole at 55%).…”

Section: Discussionmentioning

confidence: 74%

“…They provided valuable insight that guided dose planning for the phase II clinical study dose range of 15–50 mg 8. Doses in both studies seemed to be safe and generally well tolerated.…”

Section: Discussionmentioning

confidence: 98%

“…However, detecting a significant signal for clinical efficacy is limited by multiple factors: (i) the patient population; (ii) low baseline PANSS for overall analysis; (iii) small size of the treatment groups; and (iv) short duration of treatment. Evaluation of longer‐term effects would have required a longer treatment period, such as in the phase II study over 28 days or the planned phase III study over 42 days 8. Nevertheless, considering the half‐life of RP5063, 10 days of dosing could translate to 2 weeks of exposure, which was not evaluated in this multidose phase 1 study 8, 10…”

Section: Discussionmentioning

confidence: 99%

“…This compound possesses high‐binding affinity with partial agonist activity for D 2/3/4 and 5‐HT 1A/2A , and antagonist activity for 5‐HT 2B/7 receptors, and moderate‐binding affinity for the serotonin transporter (SERT) 8. Rodent models of pharmacologic‐induced behaviors associated with schizophrenia have demonstrated that RP5063 was active in limiting both psychosis and cognitive symptoms 8, 9…”

mentioning

confidence: 99%

“…Preclinical safety pharmacology studies indicated that RP5063 was well tolerated in toxicity evaluations ranging from 1–9 months and produced no metabolic, cardiovascular, pulmonary, or central nervous system adverse effects 8. The no observable effect level for cardiovascular, respiratory, and central nervous system effects in rats were 45, 100, and 10 mg/kg, respectively (human equivalent dose, HED): 24, 16, and 1.6 mg/kg or 1,440, 960, and 96 mg/60 kg patient, respectively).…”

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confidence: 99%

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Initial Clinical Experience of RP5063 Following Single Doses in Normal Healthy Volunteers and Multiple Doses in Patients with Stable Schizophrenia

Cantillon¹,

Ings²,

Bhat³

2018

Clinical Translational Sci

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RP5063 is a multimodal dopamine (D)‐serotonin (5‐HT) stabilizer with a high affinity for D2/3/4 and 5‐HT1A/2A/2B/7 receptors and moderate affinity for the serotonin transporter. Single‐dose (10 and 15 mg fasting, 15 mg fed) safety in healthy volunteers and multiple‐dose (10, 20, 50, and 100 mg fed, 10 days) safety and pharmacodynamics in patients with stable schizophrenia were defined in two phase I studies. In the single‐dose study, 32 treatment‐emergent adverse events (TEAEs) were observed. Orthostatic hypotension (n = 6), nausea (n = 5), and dizziness (n = 4) were the most common. One serious adverse event (SAE), seen in a patient who should not have been in the study due to a history of seizures, involved brief seizure‐like symptoms. In the multiple‐dose study, 75 TEAEs were reported. Akathisia (n = 20) and somnolence (n = 14) were the most frequent. No clinically significant changes were seen in glucose or prolactin levels, lipid profiles, weight, or electrocardiographic recordings. In both studies, all TEAEs resolved and none led to withdrawal from the study or death. A pharmacodynamic evaluation reflected significant improvements with RP5063 (P < 0.05) over placebo in an analysis of patients with a baseline Positive and Negative Syndrome Scale (PANSS) score ≥50 for positive subscale scores. Improvements of the Trail Making A and Trail Making B test results were observed for patients treated in the 50 mg dose group for days 5, 10, and 16. These findings indicate that RP5063 is well‐tolerated up to 100 mg and displays promising preliminary clinical behavioral and cognition activity signals in patients with stable disease over a 10‐day period.

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Section: Discussionmentioning

confidence: 74%

“…They provided valuable insight that guided dose planning for the phase II clinical study dose range of 15–50 mg 8. Doses in both studies seemed to be safe and generally well tolerated.…”

Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Initial Clinical Experience of RP5063 Following Single Doses in Normal Healthy Volunteers and Multiple Doses in Patients with Stable Schizophrenia

Cantillon¹,

Ings²,

Bhat³

2018

Clinical Translational Sci

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Response efficacy and heterogeneity of antipsychotic drugs in schizophrenia: Systemic review and meta‐analysis

Zhang

Tang

Zhang

et al. 2021

Human Psychopharmacology

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BackgroundsThis meta‐analysis aimed to assess antipsychotic and placebo effects in patients with schizophrenia at the level of symptom factors.MethodsA systematic literature search up to June 2020 was undertaken and 62 studies were included, with 23,478 patients with schizophrenia at the study baseline point. We calculated mean differences with 95% confidence intervals. The comparison was made according to the study content using a continuous method with a random‐effects model.ResultsPatients with schizophrenia treated by antipsychotic drugs had a significantly lower psychiatric rating scale total score; lower clinical global impression of severity; lower positive and negative syndrome scale; and lower assessment of negative symptoms total score, when compared to placebo treated patients.ConclusionsPatients with schizophrenia treated with an antipsychotic drug show a much greater improvement and lower inconsistency in the level of symptom factors when compared to the effects of placebo. Our findings evidence for a comparatively homogeneous outcome of the antipsychotic‐treatment in improving schizophrenia symptoms. This opposes the notion of the presence of patient sub‐groups with treatment non‐responsive schizophrenia.

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Current emerging therapeutic targets and clinical investigational agents for schizophrenia: Challenges and opportunities

Ye,

Wang,

et al. 2024

Medicinal Research Reviews

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Since the first discovery of antipsychotics in the 1950s, targeting dopaminergic drugs has manifested to well manage the positive symptoms of schizophrenia with limited efficacy for the negative and cognitive symptoms. In past decades, extensive efforts have been undertaken towards the development of innovative agents that can effectively stabilize the dopamine and serotonin systems or target to nondopaminergic pathways, leading to various promising drug candidates entering into clinical trials. Notably, the sigma‐2, 5‐HT2A, and α1A receptor antagonist roluperidone, as well as a fixed‐dose combination of the M1/4 receptor agonist KarXT, have been submitted for NDA applications. The dual agonist ulotaront, which targets TAAR1 and 5‐HT1A receptors, and the GlyT1 inhibitor iclepertin have advanced into phase 3 clinical trials. Nevertheless, satisfactory therapeutic strategies for schizophrenia remain elusive. This review highlights current clinical endeavors in developing novel chemical small‐molecule entities and fixed‐dose combinations for the treatment of schizophrenia since 2017, thus facilitating the efficient development of the next generation of antipsychotics.

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Dopamine serotonin stabilizer RP5063: A randomized, double-blind, placebo-controlled multicenter trial of safety and efficacy in exacerbation of schizophrenia or schizoaffective disorder

Cited by 36 publications

References 20 publications

Initial Clinical Experience of RP5063 Following Single Doses in Normal Healthy Volunteers and Multiple Doses in Patients with Stable Schizophrenia

Initial Clinical Experience of RP5063 Following Single Doses in Normal Healthy Volunteers and Multiple Doses in Patients with Stable Schizophrenia

Response efficacy and heterogeneity of antipsychotic drugs in schizophrenia: Systemic review and meta‐analysis

Current emerging therapeutic targets and clinical investigational agents for schizophrenia: Challenges and opportunities

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