Slide 1: Results from Ph1 and Ph2a studies of S-217622, a novel 3C-like protease inhibitor
Results from Ph1 and Ph2a studies of S-217622, a novel 3C-like protease inhibitor as once daily oral treatment for SARS-CoV-2 infection Hiroshi Yotsuyanagi1, Norio Ohmagari2, Yohei Doi3,4, Takuhiro Sonoyama5, Ryosuke Shimizu5, Takumi Imamura5, Takao Sanaki5, Keiko Baba5, Genki Ichihashi5, Takahiro F
Slide 2: Transparency declaration
Transparency declaration • I have received consulting fees, honoraria for lectures and chairs in sponsored symposiums, supports for attending meetings and travel from Shionogi & Co., Ltd. • I have received honoraria for lectures and chairs in sponsored symposiums, Support for attending meetings and
Slide 3: 3CLpro is a key enzyme in the viral replication
3CLpro is a key enzyme in the viral replication Viral attachment ACE2 TMPRSS2 Viral entry Exocytosis ERGIC 3CLpro inhibitor Uncoating S-217622 Translation Genome +ss genomic RNA Virion assembly pp1a replication N N pp1ab Transcription Translation S E M Structural proteins N N N sub genomic mRNA O Po
Slide 4: Phase 1 study outline
Phase 1 study outline Multicenter, double-blinded, randomized, placebo-controlled study (jRCT2031210202) PART 1 PART 2 Single ascending dose 2000 mg Multiple dose J N=50 3:1 N=22 H 8:3 (Caucasian E 1000 mg Day 1 Day 2–5 Participants) 3:1 dose dose 375 mg 125 mg D 500 mg 3:1 8:3 F C* 250 mg (Japanese
Slide 5: PK profiles
PK profiles PK profile in Part 1 (fasted state) Geometric mean (%CV) Parameter 20 mg 70 mg 250 mg 500 mg 1000 mg 2000 mg N 6 6 8 6 6 6 Cmax (μg/mL) 1.70 (15.0) 5.20 (18.5) 15.2 (23.6) 32.6 (19.0) 63.8 (39.1) 96.9 (16.5) 2.50 1.50 2.50 2.00 2.75 4.00 Tmax (hr) (1.00, 4.00) (1.00, 4.00) (1.00, 12.00)
Slide 6: PK profile in Part 2: Japanese vs Caucasian participants
PK profile in Part 2: Japanese vs Caucasian participants 40 375/125 mg multiple dose (Japanese) 375/125 mg multiple dose (Caucasian) Cohort F 30 Concentration (µg/mL) (Japanese) Mean (SD) Plasma 20 10 Cohort H (Caucasian) 0 0 24 48 72 96 120 Time (hr)
Slide 7: Safety Ph1
Safety Ph1 S-217622 Placebo Cohort A Cohort B Cohort C fasted Cohort D Cohort E Cohort J (fasted state)b Part 1 20 mg 70 mg 250 mg 500 mg 1000 mg 2000 mg n=6 n=6 n=8 n=6 n=6 n=6 n=12 n (%) events n (%) events n (%) events n (%) events n (%) events n (%) events n (%) events Participants with any 0 0
Slide 8: Phase 2a study outline
Phase 2a study outline Common criteria Multicenter, randomized, placebo-controlled, Study design • Aged 12 to 70 years, at the time of signing the informed double-blinded study consent/assent Study Patients with mild/moderate or population asymptomatic SARS-CoV-2 infection • Diagnosed as SARS-CoV-2
Slide 9: Patient disposition
Patient disposition 70 patients with informed consent screened Screen failure (n=1) • Protocol deviation (n=1) Randomized (n=69) S-217622 125 mg group (n=22) S-217622 250 mg group (n=23) Placebo group (n=24) Received allocated intervention Received the allocated intervention Received the allocated i
Slide 10: Patient demographics and baseline characteristics (ITT)
Patient demographics and baseline characteristics (ITT) S-217622 125 mg S-217622 250 mg Placebo (n=16) (n=14) (n=17) Sex Male, % 50.0 57.1 76.5 Age Years, mean (SD) 38.8 (12.5) 40.4 (10.7) 38.0 (14.2) Symptom severity Asymptomatic 2 (12.5) 2 (14.3) 3 (17.6) Mild/moderate 14 (87.5) 12 (85.7) 14 (82.4
Slide 11: Primary endpoint: change from baseline in viral titer (mITT)
Primary endpoint: change from baseline in viral titer (mITT) 5 Observed value 1 Change from baseline Mean (SD) Mean (SD) 0 4 Log10(TCID50/mL) Log10(TCID50/mL) -1 3 -2 * 2 -3 * 1 ** LLOD = 0.8 -4 0 -5 Number of patients Baseline Day 2 Day 4 Day 6 Day 9 Day 14 Day 21 Number of patients Baseline Day 2
Slide 12: Secondary endpoint: change from baseline in viral RNA (ITT)
Secondary endpoint: change from baseline in viral RNA (ITT) 9 Observed value 1 Change from baseline Mean (SD) Mean (SD) 8 0 Log10(TCID50/mL) Log10(copy/mL) 7 -1 6 -2 ** 5 -3 ** * * 4 LLOQ= 3.398 -4 3 -5 Baseline Day 2 Day 4 Day 6 Day 9 Day 14 Day 21 Baseline Day 2 Day 4 Day 6 Day 9 Day 14 Day 21 Num
Slide 13: Secondary endpoint: time to the first negative viral titer (mITT)
Secondary endpoint: time to the first negative viral titer (mITT) S-217622 S-217622 Proportion of patients with negative 100 Placebo 125 mg 250 mg (n=14) (n=15) (n=13) SARS-CoV-2 viral titer (%) 80 Time to negative 61.3 62.7 111.1 60 viral SARS-CoV-2 (38.0, 68.4) (39.2, 72.3) (23.2, 158.5) 50 titer,
Slide 14: Secondary endpoint: proportion of patients with a positive viral titer (mITT)
Secondary endpoint: proportion of patients with a positive viral titer (mITT) 100 80 60 Placebo S-217622 125 mg Proportion (%) S-217622 250 mg 40 * 20 * * 0 (14/14)(15/15)(14/14) (11/14)(13/15)(10/14) (10/14) (4/15) (2/14) (4/13) (0/15) (2/14) (2/13) (1/14) (0/13) (2/11) (3/15) (1/12) (0/10) (0/15)
Slide 15: Safety Ph2a
Safety Ph2a S-217622 125 mg S-217622 250 mg Placebo (n=21) (n=23) (n=24) n (%) n (%) n (%) Number of participants with any TEAE 11 (52.4) 16 (69.6) 9 (37.5) TEAE leading to discontinuation of study intervention 0 0 0 TEAE reported in ≥5% of patients in any group Nasopharyngitis 2 (9.5) 0 0 Headache
Slide 16: Conclusions
Conclusions • Data presented in Ph1 first-in-human study indicate that S-217622 was well tolerated in healthy individuals, and the pharmacokinetics evaluations highlighted the potential for once-daily administration • In Ph2a, treatment with 5-day oral administration of S-217622 demonstrated a rapid
Slide 17: Appendix
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Slide 18: HDL Cholesterol, Triglycerides in Ph2a
HDL Cholesterol, Triglycerides in Ph2a placebo S-217622 125mg HDL Cholesterol (mmol/L) Triglycerides (mmol/L) S-217622 250mg 3 5 4 Avg (Analysis Value) Avg (Analysis Value) 2 3 2 1 1 0 0 -1 Baseline Day 6 Day 14 Day 28 Baseline Day 6 Day 14 Day 28 Analysis Visit Analysis Visit