Volume 90, Issue 1 p. 321-335
ORIGINAL ARTICLE

Administration of oxathridine, a first-in-class histamine-3 receptor partial agonist in healthy male volunteers: Central nervous system depression and pseudo-hallucinations

Francis M. Dijkstra

Corresponding Author

Francis M. Dijkstra

Centre for Human Drug Research, Leiden, the Netherlands

Leiden University Medical Center, Leiden, ZA, the Netherlands

Correspondence

Francis M. Dijkstra, MD, Centre for Human Drug Research, Zernikedreef 8, 2333CL Leiden, the Netherlands.

Email: [email protected]

Search for more papers by this author
Rob G. J. A. Zuiker

Rob G. J. A. Zuiker

Centre for Human Drug Research, Leiden, the Netherlands

Leiden University Medical Center, Leiden, ZA, the Netherlands

Search for more papers by this author
Jules A. A. C. Heuberger

Jules A. A. C. Heuberger

Centre for Human Drug Research, Leiden, the Netherlands

Search for more papers by this author
Kawita M. S. Kanhai

Kawita M. S. Kanhai

Centre for Human Drug Research, Leiden, the Netherlands

Leiden University Medical Center, Leiden, ZA, the Netherlands

Search for more papers by this author
Marieke De Kam

Marieke De Kam

Centre for Human Drug Research, Leiden, the Netherlands

Search for more papers by this author
Thierry Duvauchelle

Thierry Duvauchelle

Bioprojet Pharma, Paris, France

Search for more papers by this author
Jeanne-Marie Lecomte

Jeanne-Marie Lecomte

Bioprojet Pharma, Paris, France

Search for more papers by this author
Olivier Labeeuw

Olivier Labeeuw

Bioprojet Biotech, Saint Gregoire, France

Search for more papers by this author
Laurent Landais

Laurent Landais

Bioprojet Biotech, Saint Gregoire, France

Search for more papers by this author
Xavier Ligneau

Xavier Ligneau

Bioprojet Biotech, Saint Gregoire, France

Search for more papers by this author
Philippe Robert

Philippe Robert

Bioprojet Biotech, Saint Gregoire, France

Search for more papers by this author
Marc Capet

Marc Capet

Bioprojet Biotech, Saint Gregoire, France

Search for more papers by this author
Jean-Charles Schwartz

Jean-Charles Schwartz

Bioprojet Pharma, Paris, France

Search for more papers by this author
Joop M. A. van Gerven

Joop M. A. van Gerven

Centre for Human Drug Research, Leiden, the Netherlands

Leiden University Medical Center, Leiden, ZA, the Netherlands

Search for more papers by this author
First published: 19 September 2023

Funding information: This study was sponsored by Bioprojet Pharma. Bioprojet Pharma is not further pursuing development activities for the oxathridine programme.

The authors confirm that the Principal Investigator for this paper is J.M.A. van Gerven and that he had direct clinical responsibility for research subjects.

Abstract

Aims

To characterise the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of single ascending doses of oxathridine, a first-in-class histamine-3 receptor partialagonist, in healthy male volunteers.

Methods

A randomised, double-blind, placebo-controlled study including the NeuroCart, consisting of a battery of drug sensitive neurophysiological tests, was performed. Oxathridine was administered orally as an aqueous solution. After dosing, safety and NeuroCart tests (adaptive tracking [AT], body sway [BS], saccadic peak velocity [SPV], smooth pursuit [SP] eye movements, VAS according to Bond and Lader, VAS according to Bowdle [VAS B&L, Bowdle], pharmaco-electroencephalogram [pEEG], Sustained Attention to Response Task [SART]) were performed at set times.

Results

  Forty volunteers completed the study. Given doses were: 0.5, 2.5, 5, 0.25 and 1.5 mg. At 5 mg, unacceptable and unanticipated adverse events (AEs) of (orthostatic) hypotension and pseudo-hallucinations were reported. Statistically significant effects ([CI]; p-value) of 2.5 mg and 5 mg oxathridine were observed on AT ([−8.28, −1.60]; p = 0.0048), ([−8.10, −1.51]; p = 0.00530), BS ([0.6, 80.2]; p = 0.0455), ([5.9, 93.1]; p = 0.0205) and SPV ([−59.0, −15.9]; p = 0.0011), ([−43.9, −1.09]; p = 0.0399), respectively. Oxathridine 5 mg significantly increased all three VAS Bowdle subscale scores; VAS external ([0.183, 0.476]; p = <.0001), VAS internal ([0.127, 0.370]; p = 0.0001) and VAS feeling high ([0.263, 0.887]; p = 0.0006).

Conclusion

NeuroCart tests indicated central nervous system (CNS) depressant effects. Oxathridine also unexpectedly caused pseudohallucinations. Although this led to the decision to stop further development of oxathridine, these observations suggest that the H3R system could be an interesting new target for the development of novel antipsychotics.

CONFLICT OF INTEREST STATEMENT

T.D., J.L., O.L., L.L., X.L., P.R., M.C. and J.S. are current or former employees of Bioprojet Pharma and may own stock or stock options. The other authors have nothing to declare.

DATA AVAILABILITY STATEMENT

The data collected in this study are proprietary to Bioprojet Pharma. Bioprojet Pharma is committed to public sharing of data in accordance with applicable regulations and laws.