Safer Pipeline Antipsychotics for Driving Vehicles

Background

Around 67% of patients with a psychiatric disease have a driving license; 77% of these patients report regular driving with their vehicles, and 88% use prescribed medication.

The Odds Ratio (OR) for motor vehicle crashes associated with the use of antipsychotics is 2.20 (Range 1.37-3.52 ), P=0.00. (1)

Furthermore, Dr Alexander Brunnauer and colleagues established that under steady-state antipsychotic medication,31%( range 27-42.5%) of schizophrenic or schizoaffective patients showed severe impairment in skills relevant for driving. (2)

However, second-generation antipsychotics showed lower driving impairment than first-generation antipsychotics.?

Twenty-three per cent (15%–27%) of patients showed severe driver impairment compared with 42% (34%–60%) of patients treated with first-generation antipsychotics.

Moreover, there is an increased risk of collision responsibility in drivers prescribed sedating antipsychotics (adjusted odds ratio [aOR] 1·35 [98·75% CI 1·25-1·46]). (3)

Non-sedating or minimally sedating pipeline antipsychotics may reduce future motor vehicle accidents.

Pipeline Antipsychotics with low Incidence of Somnolence or Sedation

1.TV-46000.?The US Food and Drug Administration (FDA) has accepted Teva Pharmaceuticals and MedinCell’s new drug application (NDA) for their drug, TV-46000/mdc-IRM, to treat schizophrenia.?

TV-46000 is an extended-release suspension of risperidone administered as a subcutaneous injection.

The adverse reactions ≥5% and greater than placebo were nasopharyngitis, increased weight, and extrapyramidal disorder. (4,5,6)

2.?Ulotaront.?Sunovion Pharmaceuticals is developing Ulotaront ( SEP-363856) in the United States.

It is in a phase 3 Long-term Safety and Tolerability in Schizophrenia study to be completed by November 2022.

It is also undergoing Phase 3 schizophrenia studies in Japan and China.

This drug activates TAAR1 (trace amine-associated receptor 1) in addition to 5-HT1A (serotonin 1A) receptors.

Ulotaront was examined in phase 2 Parkinson's disease psychosis.

This medication has a somnolence incidence of 4.5%. (7)

3.?KarXT?is being developed by Karuna Therapeutics.

It is an oral modulator of muscarinic receptors found in the central nervous system (CNS) and peripheral tissues.?

KarXT combines xanomeline, a novel muscarinic agonist, with Trospium, an approved muscarinic antagonist.

It preferentially stimulates muscarinic receptors in the CNS.

The medication is in phase 3 studies for schizophrenia.?

Additional research includes Phase 2 studies in adjunctive treatment for psychosis and patients with negative and cognitive symptoms.

KarXT is also undergoing phase 1 evaluation for dementia-related psychosis.

Somnolence incidence was similar in the placebo and KarXT treatment groups. (8)?

4.?Roluperidone?Minerva Neurosciences licensed Roluperidone from Mitsubishi Tanabe Pharma.??

Roluperidone acts as a 5-HT2A and σ2 receptor antagonist under development by Minerva Neurosciences for schizophrenia.

The results for a 40-week Open-Label Extension study of Roluperidone for the treatment of Negative symptoms in schizophrenia were released on May 11, 2021.

Over the 40 week open-label extension period, the investigators found improvement in negative symptoms of 6.8 points in the 32 mg arm and 7.5 points in the 64 mg arm.

Somnolence was below 4% for Roluperidone. (9)

5.?Brilaroxazine?is an agent that acts as a dopamine D2 receptor partial agonist; Dopamine D3 receptor partial agonist; Dopamine D4 receptor partial agonist.

?It also acts as an antagonist for Serotonin 2A receptors, Serotonin 2B receptors, and Serotonin 7 receptors.

The drug is owned and developed by Reviva Pharmaceuticals.

Brilaroxazine has shown efficacy for pulmonary arterial hypertension (PAH), and idiopathic pulmonary fibrosis (IPF) compared to the approved drugs in proven translational models.?

The company obtained an Orphan Drug Designation from the FDA for PAH and IPF.?

Reviva is developing Brilaroxazine as a potential treatment for schizophrenia.???

The company has completed a Phase 2 trial (NCT01490086) in 234 people with acute schizophrenia or schizoaffective disorder.?

The treatment significantly reduced schizophrenia symptoms and was found safe and well-tolerated.

The FDA has reviewed the Phase 3 protocol, Chemistry, Manufacture Controls (CMC), and long-term toxicology package. (10)

Reviva is preparing to launch Phase 3 trials in people with acute schizophrenia.??

6.?AVP-786.Avanir Pharmaceuticals is a subsidiary of Otsuka America, incorporated.????????????

They are examining the efficacy, safety, and tolerability of AVP-786, as compared with placebo, for negative symptoms of schizophrenia. (11)

7.LB-102. LB Pharmaceuticals is a clinical-stage CNS-focused life science company devoted to commercializing novel and improved versions of successful CNS treatments used extensively overseas but never approved in the United States.??????????

LB-102, or N-methyl amisulpride, is their lead clinical asset.???????

The company was founded in 2015 and, based in New York City. LB-102 is a novel lipophilic derivative of amisulpride designed to treat schizophrenia.??

The drug is a more potent version of amisulpride.??????????

LB pharmaceuticals have completed a Receptor Occupancy study of LB-102 Using Positron Emission Tomography (PET) in Healthy Volunteers. (12)

A Phase 2 clinical trial in acute schizophrenia patients should begin in early 2022.

8.?NaBen.?SyneuRx is developing its sodium benzoate (NaBen) treatment in adult schizophrenia.

The company projects that it will produce an interim analysis of its Phase IIb/III (NCT02261519) study in adult schizophrenia in quarter 1, 2022.

The 348-patient Phase IIb/III, the adaptive study has a primary endpoint of a change in the Positive and Negative Syndrome Scale (PANSS that occurs eight weeks after treatment randomization.???

SyneuRx initiates Phase 2b/3 studies (SND12 and SND13) in refractory schizophrenia and adult schizophrenia in Europe.???????????????????????

NaBen is also evaluated in separate Phase II trials in refractory (NCT03094429) and adolescent schizophrenia (NCT01908192). (13)

Summary

Driving studies with minimally sedating pipeline antipsychotics will reduce motor vehicle accidents for those currently taking sedating antipsychotics.?

References

1) Aida A. LeRoy, Pharm.D. and M. Lee Morse. Multiple Medications and Vehicle Crashes Analysis: Final Report NHTSA.US Department of Transportation/National Highway Traffic Safety Administration. APPENDIX VIII. Table 1B Significant Odds Ratios for Driver Impairing Drugs. May 2008.??

2) Alexander Brunnauer, Florian Herpich, Peter Zwanzger, Gerd Laux, Driving Performance Under Treatment of Most Frequently Prescribed Drugs for Mental Disorders: A Systematic Review of Patient Studies,?International Journal of Neuropsychopharmacology, Volume 24, Issue 9, September 2021, Pages 679–693,?https://doi.org/10.1093/ijnp/pyab031

3) Jeffrey R Brubacher, Herbert Chan, Shannon Erdelyi, Peter J Zed, John A Staples, Mahyar Etminan. Medications and risk of motor vehicle collision responsibility in British Columbia, Canada: a population-based case-control study. Lancet Public Health 2021;6: e374–85 Published Online April 19, 2021.https://doi.org/10.1016/S2468-2667(21)00027-X

4) Teva and MedinCell Announce FDA Acceptance of New Drug Application for TV-46000/mdc-IRM as a Treatment for Patients with Schizophrenia. August 31, 2021.https://www.tevapharm.com/news-and-media/latest-news/teva-and-medincell-announce-fda-acceptance-of-new-drug-application-for-tv-46000mdc-irm-as-a-treatment-fo/

5) Teva. New Phase 3 Data Presented at Psych Congress 2021 Showed TV-46000/mdc-IRM Significantly Prolonged Time to Impending Relapse Compared to Placebo in Patients with Schizophrenia. October 30, 2021. https://www.tevapharm.com/news-and-media/latest-news/new-phase-3-data-presented-at-psych-congress-2021-showed-tv-46000mdc-irm-significantly-prolonged-time-to/

6) Phase 3 data of mdc-IRM, first product based on MedinCell’s technology, shows significant improvements in patients with schizophrenia. MedinCell. November 15, 2021. https://www.medincell.com/phase-3-data-of-mdc-irm-first-product-based-on-medincells-technology-shows-significant-improvements-in-patients-with-schizophrenia/

7) Correll CU, Koblan KS, Hopkins SC, Kent J, Cheng H, Goldman R, Loebel A. Safety and Effectiveness of SEP-363856 in Schizophrenia: Results of a 6-Month, Open-Label Extension Study. CNS Spectr. 2021 Apr;26(2):148-149. doi: 10.1017/S1092852920002357. PMID: 34127116.

8) Karuna Therapeutics. Karuna Therapeutics Announces New England Journal of Medicine Publication of Data from EMERGENT-1 Phase 2 Trial Evaluating KarXT in Schizophrenia. February 24, 2021. https://investors.karunatx.com/news-releases/news-release-details/karuna-therapeutics-announces-new-england-journal-medicine

9) Minerva Neurosciences Announces the Results of the Phase 3 Trial of Roluperidone for the Treatment of Negative Symptoms of Schizophrenia Following the Completion of the 40-Week Open-Label Extension. May 11, 2021.https://ir.minervaneurosciences.com/news-releases/news-release-details/minerva-neurosciences-announces-results-phase-3-trial-0

10) Reviva Pharmaceuticals Holdings, Inc. Corporate Presentation July 2021.https://ir.revivapharma.com/static-files/99decd3b-43df-4496-87f9-7bc4bf2f8f07

11) Clinicaltrials.gov. Efficacy, Safety, and Tolerability of AVP-786 for the Treatment of Negative Symptoms of Schizophrenia.?NCT03896945.November 21, 2021. https://www.clinicaltrials.gov/ct2/show/NCT03896945?term=AVp-786&cond=Schizophrenia&draw=2&rank=1

12) Receptor Occupancy of LB-102 Using Positron Emission Tomography (PET) in Healthy Volunteers. (NCT04588129 ). September 24, 2021. https://www.clinicaltrials.gov/ct2/show/NCT04588129?term=LB+102&cond=Schizophrenia&draw=2&rank=1

13) Clinicaltrials.gov. NaBen? | Schizophrenia. September 13, 2021. https://clinicaltrials.gov/ct2/results?cond=Schizophrenia&term=NaBen%C2%AE&cntry=&state=&city=&dist=