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A Phase 1 study of S-217622 in healthy adult participants

A Phase 1 study of S-217622

751

Part 1 (SAD part): All participants were Japanese healthy male adults. The median age (range) of each group ranged from 21.5 (20-26) to 31.0 (23-37) years and the mean BMI (SD) ranged from 20.75 (2.01) to 22.55 (2.75). Part 2 (MAD part): The participants were Japanese and White healthy male adults, and Japanese healthy female adults. The median age (range) of each group ranged from 29.0 (20-40) to 34.0 (25-39) years for Japanese healthy male adult participants and 34.5 (26-45) to 38.0 (26-38) years for White healthy adult male participants. The mean BMI (SD) ranged from 21.10 (1.35) to 22.99 (2.54) and 22.83 (2.91) to 24.40 (2.00), respectively. For Japanese healthy female participants, the median age (range) of each group ranged from 25.5 (21-51) to 37.0 (20-52) years and the mean BMI (SD) ranged from 21.52 (3.15) to 22.44 (3.72). Part 3 (DDI with dexamethasone and prednisolone part): All participants were Japanese healthy male adults. The median age (range) of each group ranged from 31.0 (21-39) to 35.5 (27-45) years and the mean BMI (SD) ranged from 21.51 (2.24) to 23.29 (1.82). Part 4 (FE part): All participants were Japanese healthy male adults. The median age (range) of each group ranged from 30.0 (24-34) to 32.0 (23-39) years and the mean BMI (SD) ranged from 21.09 (1.26) to 22.14 (1.56). Part 5 (W-MAD part): All participants were White healthy adults. The median age (range) of each group ranged from 31.0 (25-47) to 37.0 (30-52) years and the mean BMI (SD) ranged from 23.85 (2.87) to 24.74 (1.31). Part 6 (Erderly part): All participants were Japanese healthy elderly male. The median age (range) of each group ranged from 69.0 (65-70) to 73.0 (66-76) years and the mean BMI (SD) ranged from 23.12 (2.91) to 23.68 (2.71). Part 7 (DDI with midazolam part): All participants were Japanese healthy male adults. The median age (range) was 35.5 (23-47) years and the mean BMI (SD) was 22.04 (1.58).

A total of 751 participants enrolled in the study. Of those participants, all 751 signed the ICF, 201 were randomized, and 550 failed the screening. Reasons for the screening failure were protocol deviation for 259 participants, withdrawal by participant for 34 participants, and other for 257 participants. All randomized participants were included in the safety analysis population of each part. All participants who were assigned to the S-217622 groups were included in the PK concentration population and PK parameter population; a total of 38 participants in Part 1, 40 participants in Part 2, 28 participants in Part 3, 14 participants in Part 4, 16 participants in Part 5, 11 participants in Part 6, and 14 participants in Part 7.

No deaths or serious TEAEs were reported. A total of 2 participants (1 in part 2 and 1 in part 4) discontinued from the study due to TEAEs. All TEAEs were mild or moderate in severity, and resolved or were resolving at the time of last follow-up. The most frequent TEAE in the ensitrelvir group was high density lipoprotein decreased (60.2% [97/161]). No clinically significant findings or trends related to ensitrelvir dose were identified in laboratory parameters, vital signs, 12 lead ECG, Columbia-Suicide Severity Rating Scale, or other safety observations, except for the changes reported as TEAEs. No apparent trends related to S-217622 dose were identified over time in laboratory parameters, vital signs, 12 lead ECG, or other safety observations, except for transient changes in lipid parameters including decrease in HDL-C and increase in triglycerides in a dose dependent manner.

Part 1: The exposures to S-217622 increased in an almost dose proportional manner following the single dose administration of S-217622 to Japanese healthy adult male participants at 20 to 2000 mg in the fasted state. Following the single dose administration of S-217622 to Japanese healthy adult male participants at 250 mg, no clinically meaningful difference in exposures were observed between the fasted and fed states. Part 2: The exposures to S-217622 increased in an almost dose proportional manner following the multiple dose administration of S-217622 to Japanese healthy adult participants at 375/125 mg and 750/250 mg for 5 days in the fasted state. Following the multiple dose administration of S-217622 at 375/125 mg for 5 days, the exposure to S-217622 was slightly lower in White healthy adult male participants than in Japanese healthy adult male participants. Part 3: It was suggested that the effect of S-217622 on the PK of dexamethasone was diminished over time, after the last administration of S-217622, and that there was no meaningful effect of S-217622 on the PK of prednisolone. Part 4: Following the single dose administration of the tablet formulation of S-217622 to Japanese healthy adult participants at 375 mg, no clinically meaningful difference in exposures were observed between the fasted and fed states. Part 5: Following the multiple dose administration of the tablet formulation of S-217622 to White healthy adult participants at 375/125 mg for 5 days and at 750/250 mg for 5 days, the exposures to S-217622 increased in a less than dose proportional manner. Part 6: Following the multiple dose administration of the tablet formulation of S-217622 to Japanese healthy elderly particpants at 375/125 mg for 5 days, the exposure was slightly lower than that in healthy Japanese adult female participants, and was comparable to that in White healthy adult participants. Part 7: These results indicated that S-217622 is considered to be a strong CYP3A inhibitor.

No major concerns were shown on the safety and tolerability of S-217622. The exposure to S-217622 increased in an almost dose proportional manner, and it was considered that race, sex, and food conditions had little effect on the exposure of S-217622. There was no meaningful difference in exposure in elderly participants compared to non-elderly particiopants. Regarding the drug-drug interaction, it was shown that S-217622 is a strong CYP3A inhibitor.

Mar. 04, 2025

Sept. 12, 2022

https://journals.asm.org/doi/full/10.1128/aac.00632-22

No

Not applicable

https://jrct.mhlw.go.jp/latest-detail/jRCT2031210202

Nagata Tsutae

Shionogi & Co., Ltd.

1-8, Doshomachi 3-chome, Chuo-ku, Osaka, Osaka

shionogiclintrials-admin@shionogi.co.jp

Corporate Communications Department

Shionogi & Co., Ltd.

1-8, Doshomachi 3-chome, Chuo-ku, Osaka, Osaka

+81-6-6209-7885

shionogiclintrials-admin@shionogi.co.jp

Complete

July. 14, 2021

Interventional

randomized controlled trial

double blind

placebo control

parallel assignment

treatment purpose

Japanese healthy adult male participants (SAD Part, DDI with dexamethasone and prednisolone Part)
Japanese healthy adult male, white healthy adult male or Japanese healthy adult female participants (MAD Part)
Japanese healthy adult male and female participants (FE Part, DDI with midazolam Part)
White healthy adult male and female participants (W-MAD Part)
Participants must be 20 to 55 years of age inclusive, at the time of signing the informed consent form (SAD Part, MAD Part, DDI Part, FE Part, W-MAD Part)
Participants must be 65 years of age or older inclusive, at the time of signing the informed consent form (Elderly Part)

History of cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrinological, hematological, or neurological disorders capable of significantly altering the absorption, metabolism, or elimination of drugs; constituting a risk when taking the study intervention; or interfering with the interpretation of data
Positive SARS-CoV-2 RT-PCR test at admission

Both

COVID-19

Oral administration of S-217622 or placebo

Adverse events, physical examination, laboratory tests, vital signs, 12-lead ECG, holter ECG
Pharmacokinetics (SAD Part, MAD Part, W-MAD Part, Elderly Part)
Dexamethasone, prednisolone, and midazolam: Cmax, Tmax, AUC0-last, AUC0-inf, t1/2,z, lambdaz, MRT, CL/F, Vz/F (DDI Part)
S-217622: Cmax, Tmax, AUC0-last, AUC0-inf, t1/2,z, lambdaz, MRT, CL/F, Vz/F (FE Part)

+81-3-5366-3006

July. 05, 2021

none