Abstract 1420P
Background
ODM-208 is a first-in-class, oral, non-steroidal small molecule that selectively and completely inhibits the mitochondrial cholesterol side-chain cleavage cytochrome P450 (CYP11A1) enzyme, the first and rate limiting step in steroidogenesis, leading to deficiency of endogenous steroid hormones. The pharmacokinetics (PK) of ODM-208 and the pharmacodynamics (PD) of ODM-208 by measuring serum testosterone levels were studied in the Cypides phase 1 trial in males with progressive mCRPC, who had received at least one prior line of both 2nd generation AR pathway inhibitor (ARPI) and taxane chemotherapy.
Methods
ODM-208 was given at 7 dose levels (3 mg to 75 mg b.i.d.) concomitantly with corticosteroid replacement therapy and ADT. For PK evaluation plasma ODM-208 concentrations were measured on day 1 after a single dose and on day 8 after repeated dosing. The effect of ODM-208 dosing on serum testosterone levels was evaluated by measuring the testosterone concentrations on days 1 and 8 at pre-dose and multiple times post-dose. Population pharmacokinetic modelling was applied for estimation of PKPD relationship.
Results
Rapid absorption of ODM-208 was observed after oral dosing. Median time to plasma peak concentration (tmax) was 2 h after a single dose of ODM-208. The exposure (area under the plasma concentration-time curve [AUC]) and Cmax values after 7 days of repeated dosing were similar to the corresponding values after a single dose. The mean elimination t½ of ODM-208 was 3 h and the steady-state was reached within one week. The AUC0-24 of ODM-208 increased almost dose-proportionately. Serum testosterone concentrations decreased rapidly after a single dose of 3, 5, 15, 25, 50 and 75 mg of ODM-208 on day 1. After one week repeated dosing the concentrations were reduced to close or below the lower limit of quantification (LLoQ: 0.2 ng/dL, <0.0069 nmol/L).
Conclusions
ODM-208 exposure increased and decreased again almost dose-proportionately while concentrations of ODM-208 were similar on days 1 and 8. It was shown that ODM-208 can reach systemic plasma levels capable for excessively reducing serum testosterone levels in a wide dose range.
Clinical trial identification
NIH trial protocol number: 2017-002534-23 Release date:15.6.2017.
Editorial acknowledgement
Legal entity responsible for the study
Orion Corporation Orion Pharma.
Funding
Orion Corporation Orion Pharma.
Disclosure
A. Bernard-Tessier: Financial Interests, Personal, Invited Speaker: Astellas; Financial Interests, Personal, Other, travel fees: Orion, Bayer; Financial Interests, Institutional, Advisory Board: Novartis; Non-Financial Interests, Principal Investigator: Amgen. P. Nykanen: Financial Interests, Personal, Full or part-time Employment: Orion Corporation. T. Utriainen: Financial Interests, Personal, Advisory Board: Bayer; Financial Interests, Personal, Invited Speaker: Amgen; Financial Interests, Institutional, Invited Speaker: Orion. N. Cook: Financial Interests, Institutional, Invited Speaker: Roche, Taiho, Roche, AstraZeneca, RedX, Orion, Avacta, Bayer, Eisai, UCB, Starpharma, Boehringer, Stemline, Ergomed; Non-Financial Interests, Advisory Role: Roche. P. Barthelemy: Financial Interests, Personal, Advisory Board: BMS, MSD, Merck, Pfizer, Ipsen, Bayer, Janssen Cilag, Astellas, Novartis, AMGEN; Financial Interests, Personal, Invited Speaker: AstraZeneca, Seagen. C. Baldini: Financial Interests, Institutional, Advisory Board: BMS; Financial Interests, Institutional, Expert Testimony: MSD; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Institutional, Research Grant: BMS; Financial Interests, Institutional, Invited Speaker: iTeos, AZ, Janssen, Amgen, Bicycle Therapeutics, MSD, Seattle Genetics, Tahio; Non-Financial Interests, Member: ASCO, SIOG, SOFOG, AACR. T. Ikonen: Financial Interests, Personal, Full or part-time Employment: Orion. P. Pohjanjousi: Financial Interests, Personal, Full or part-time Employment: Orion. M. Karimaa: Financial Interests, Personal, Full or part-time Employment, Head of Translational PK/PD: Orion Corporation. J. Malkki: Financial Interests, Personal, Full or part-time Employment: Orion Corporation; Financial Interests, Personal, Stocks/Shares: Orion Corporation. P.T. Toivanen: Financial Interests, Personal, Full or part-time Employment, Principal Data Scientist: Orion Corporation Orion Pharma. C. Garratt: Financial Interests, Personal, Full or part-time Employment: Orion Pharma UK Ltd.; Financial Interests, Personal, Stocks/Shares: Orion Corporation. K. Fizazi: Financial Interests, Institutional, Advisory Board: Astellas, Bayer, Janssen, AAA, MSD, AstraZeneca, Novartis/AAA, Pfizer; Financial Interests, Institutional, Invited Speaker: Astellas, Bayer, Janssen, Sanofi, MSD, AstraZeneca, Novartis, Pfizer; Financial Interests, Personal, Advisory Board: Curevac, Orion; Financial Interests, Institutional, Research Grant, Trial chair: Pfizer, Bayer, AstraZeneca, Orion, MSD, BMS, Janssen; Non-Financial Interests, Principal Investigator, Chair of the 7DX phase 3 trial: BMS; Non-Financial Interests, Principal Investigator, Chair of the Docetaxel-pembrolizumab phase 3 trial: Merck; Non-Financial Interests, Principal Investigator, Chair of the Darolutamide BCR phase 3 trial: Bayer; Non-Financial Interests, Principal Investigator, Chair of the PSMAfore phase 3 trial: AAA/Novartis; Non-Financial Interests, Principal Investigator, Chair of the CYPIDES ODM-208 Phase I-II trial: Orion; Non-Financial Interests, Principal Investigator, Chair of the STESIDES ODM-209 Phase I-II trial: Orion. All other authors have declared no conflicts of interest.