PT150 · program

PT150 (Org 34517) for Major depressive disorder

DiscontinuedDiscontinuedPop Test Oncology LLC (dba Palisades Therapeutics)

Indications for PT150: Post-traumatic stress disorder · Phase 2 Major depressive disorder · Discontinued Alcohol use disorder · Phase 1

Org 34517 (now PT150), a glucocorticoid receptor antagonist, as adjunctive treatment for psychotic major depression, developed by Organon N.V. In the Phase 2 dose-finding trial (Protocol 28130, October 2004 to July 2006; 274 patients dosed in Belgium, Czech Republic, Germany, India, the UK and the US), 300 mg or 900 mg once daily for 2 weeks on top of usual treatment failed to beat placebo on the primary endpoint of sustained 50% response on the PANSS positive scale (900 mg vs placebo p=0.14), and missed the key secondary HAMD-17 and 300 mg comparisons. The 900 mg dose was numerically better than placebo on PANSS total and positive scores, reaching significance only at some visits. It was well tolerated and raised salivary cortisol dose-dependently. A Phase 2 re-exposure safety study (28133) and a Weill Cornell Phase 2 safety study also completed by 2006. No later depression trial has been registered, and the molecule's current developer is pursuing PTSD and alcohol use disorder instead.

Data current as of

Development timeline

DiscontinuedJan 2008
  1. missedOrganon Phase 2 trial of Org 34517 (PT150) as adjunctive therapy in psychotic major depression missed its primary endpoint (900 mg vs placebo, PANSS positive sustained response, p=0.14).↗
Phase 2Jul 2004 – Jul 2006
  1. Protocol 28130 completed (last patient out July 2006).
  2. Trial (portion) completedOrganon Phase 2 trial of Org 34517 in psychotic major depression completes
  3. Organon Phase 2 dose-finding trial in psychotic major depression (NCT00212797, Protocol 28130) started (registry start 2004-07; the CSR gives first patient in as October 2004).

Readouts

  • 2008-01-24ReportedFull resultsmissedNCT00212797

    Organon Phase 2 trial of Org 34517 (PT150) as adjunctive therapy in psychotic major depression missed its primary endpoint (900 mg vs placebo, PANSS positive sustained response, p=0.14). ↗

Clinical trials in Major depressive disorder

NCT00844922P05842Phase 2Completedn=16

Safety of Org 34517 900 mg in Patients Who Received Org 34517 in a Previous Trial (Study 28133/P05842)

Started Sept 2005· Primary completion Jun 2006

NCT0022627828130Phase 2Completedn=25

Safety Study of ORG 34517 for Major Depression With Psychotic Features

Started Sept 2004· Primary completion Nov 2005· 📍 1 site across 1 country (United States)

NCT0021279728130Phase 2Completedn=273

A Study to Determine the Efficacy and Safety of 2 Doses of Org 34517 as Adjunctive Therapy in Subjects With Psychotic Major Depression (28130)(P05845)

Started Jul 2004· Primary completion Jul 2006

missedprimarySustained response on PANSS positive symptoms scale (>=50% improvement from baseline at both Day 8 and Day 43), 900 mg vs placebo (0.14)

900 mg Org 34517 adjunctive to usual treatment failed to show a statistically significant difference from placebo; key secondary endpoints (HAMD-17 response at 900 mg; PANSS positive and HAMD-17 at 300 mg) also not significant. 900 mg was numerically superior on PANSS total, PANSS-derived BPRS and PANSS positive, reaching significance on Day 8 (BPRS) and Day 22 (BPRS, PANSS positive). AE rates similar to placebo; no deaths. 274 subjects dosed (300 mg n=88, 900 mg n=92, placebo n=94).

Formulations

FormulationRouteRegimenPharmacokinetics
PT150 oral (150 mg capsules)
Organon Phase 2 (Protocol 28130): 150 mg capsules, 300 mg or 900 mg once daily in the evening with dinner for 2 weeks (900 mg arm titrated 300 -> 600 -> 900 mg over Days 1-3). Ethanol-interaction Phase 1: 900 mg/day. AUD human laboratory study NCT06712602: 225 mg then 450 mg twice daily for 5 days before each session. PTSD Phase 2 NCT07187011: 150-900 mg titrated over 7 days, 900 mg target dose.
Oral——

Mechanism of action (compound-wide)

Competitive antagonist of the glucocorticoid receptor (GR, NR3C1), a ligand-activated nuclear receptor. In AtT20 pituitary cells Org 34517 blocked corticosterone-induced GR nuclear translocation without inducing translocation itself (unlike mifepristone), and was described as a true competitive GR antagonist without partial agonist activity. In rats it occupied GR in the anterior pituitary and brain without occupying the mineralocorticoid receptor, and did not cause episodic HPA-axis activation on chronic dosing. The current sponsor describes PT150 as a modulator of both GR and the androgen receptor (AR): predominantly systemic GR antagonism in vivo, with direct AR down-regulation and minor GR agonism at the cellular level. In patients with psychotic depression it produced a dose-dependent rise in salivary cortisol, consistent with central GR blockade. The clinical hypothesis in PTSD and alcohol use disorder is that blocking GR signalling normalizes stress (HPA-axis) responses that drive symptoms, craving and stress-induced drinking.

TargetActionAffinity
Glucocorticoid receptorprimaryNR3C1Antagonist—ⓘ
Androgen receptorARModulator—ⓘ

← Full PT150 compound page (identity, identifiers, all indications)

Sources

  1. Differential effects of the new glucocorticoid receptor antagonist ORG 34517 and RU486 (mifepristone) on glucocorticoid receptor nuclear translocation in the AtT20 cell line. Ann N Y Acad Sci. 2008. doi:10.1196/annals.1410.072 — Annals of the New York Academy of Sciences / PubMed
  2. NCT00212797 (28130 / P05845) — Efficacy and Safety of 2 Doses of Org 34517 as Adjunctive Therapy in Psychotic Major Depression (Phase 2, completed) — ClinicalTrials.gov (U.S. National Library of Medicine)
  3. NCT00226278 (28130 site study) — Safety Study of ORG 34517 for Major Depression With Psychotic Features, Weill Cornell (Phase 2, completed) — ClinicalTrials.gov (U.S. National Library of Medicine)
  4. NCT00844922 (28133 / P05842) — Safety of Org 34517 900 mg re-exposure in psychotic major depression (Phase 2, completed) — ClinicalTrials.gov (U.S. National Library of Medicine)
  5. Organon N.V. Clinical Trial Report synopsis, Protocol 28130 — dose-finding study of Org 34517 (300 mg / 900 mg) as adjunctive therapy in psychotic major depression (EudraCT results attachment; copyright Merck Sharp & Dohme) — EU Clinical Trials Register (EMA) / Merck Sharp & Dohme
  6. Theise ND, Arment AR, Chakravarty D, et al. Clinical stage molecule PT150 is a modulator of glucocorticoid and androgen receptors with antiviral activity against SARS-CoV-2. Cell Cycle. 2020. doi:10.1080/15384101.2020.1859752 — Cell Cycle (Taylor & Francis) / PubMed