“New influenza antivirals” Aeron Hurt @hurt_lab @ WHOCCFluMelb “New influenza antivirals” Or more specifically… “Polymerase inhibitors” “Baloxavir” Aeron Hurt @hurt_lab @ WHOCCFluMelb COI declaration • Member of baloxavir publication steering committee organized by Shionogi • Research group has received funding to conduct research studies from the following antiviral companies: • Shionogi • Romark • AusBio Acknowledgments • Thanks to the following people for providing data/information/figures used in the talk: • Dr. Zuzana Dobbie, Roche, Switzerland • Dr. Takeki Uehara, Shionogi, Japan • Dr. Harsha Shetty, Seqirus, Australia Action of the ‘current’ influenza antivirals NA inhibitors Adamantanes (M2 ion channel inhibitors) Figure from Open University : http://www.open.edu/openlearn/ocw/mod/oucontent/view.php?printable=1&id=2675&extra=thumbnail_idp1455600 Action of the ‘current’ influenza antivirals Resistance currently very low, but has been seen in the past. Efficacy is moderate. Resistance across NA inhibitors virtually all Peramivir (Rapivab) circulating strains…no longer • Intravenous NA inhibitor recommended • TGA approved in Mar 2018, available in 2019 • Indicated for the treatment of acute influenza infection in adults and children 2 years and older who have been symptomatic for no more than two days* Not on PBS Adamantanes • (M2 ion channel inhibitors) • Use in hospitalised patients Figure from Open University : http://www.open.edu/openlearn/ocw/mod/oucontent/view.php?printable=1&id=2675&extra=thumbnail_idp1455600 Action of the polymerase inhibitors 3 different polymerase inhibitors that are in late-phase clinical trial or recently approved Transcription of vRNA to mRNA starts with “cap-snatching” NA inhibitors • Cellular capped RNA bound by PB2 → pimodivir • Cleaved by PA → baloxavir • Elongation by PB1 → favipiravir Adamantanes (M2 ion channel inhibitors) Polymerase inhibitors Summary of the polymerase inhibitors Baloxavir Favipiravir Pimodivir Polymerase target PA PB1 PB2 Influenza specificity A & B A, B & C A Can inhibit non-influenza viruses? No Yes No Approved for use in some countries? Yes, in Japan (Feb Yes, Japan. (But limited to No, currently in ‘18) and US (Nov pandemic use under Phase III ‘18). Many countries certain conditions). in 2019. Variable efficacy in US trials Dosing routes Oral Oral Oral Has been tested in combination with No No Yes oseltamivir in clinical trials? Ability to inhibit NAI resistant strains? Yes Yes Yes Antiviral- resistant mutants identified in vitro? Yes Yes Yes Antiviral resistant strains identified in clinical Yes No Yes trials? Efficacy of Baloxavir marboxil - Xofluza Baloxavir Long retention time Baloxavir Marboxil (half-life: 79.1 h) (pro drug) Japan Baloxavir Acid Taiwan (active form) Hydrolysis Rest of the world • Single dose delivery • US approved for uncomplicated influenza in >12 years of age • Japan also approved for use in children <12 years CAPSTONE-1: Phase III study of baloxavir vs. placebo or oseltamivir in OwH influenza patients Study design Treatment period (5 days) Follow-up period (17 days) ▪ Aged 12–64 years 2 Baloxavir 40 or 80 mg§ ▪ Otherwise healthy Aged 2 20–64 ¶ ▪ Fever (≥38°C axillary), Oseltamivir 75 mg BID years 1 ≥1 systemic symptom* and Placebo ≥1 respiratory symptom** Day 6–22 ▪ ≤48 hours from symptom 2 Aged Baloxavir 40 or 80 mg§ onset 12–19 1 N=1436 (ITTI N=1064) years Placebo Key exclusion criteria Study endpoints ▪ Hospitalisation ▪ Primary endpoint: time to alleviation of symptoms ▪ High risk of influenza complications ▪ Key secondary endpoints: virological outcomes, time to fever resolution ▪ Primary safety endpoints: incidence of TEAEs *Headache, feverishness/chills; muscle/joint pain or fatigue of moderate or greater severity. **Cough, sore throat or nasal congestion of moderate or greater severity; §Single dose on Day 1 (40 mg for body weight <80 kg, 80 mg for ≥80 kg); ¶For 5 days. Hayden et al. N Engl J Med 2018 Adapted from slide kindly provided by Zuzana Dobbie, Roche Baloxavir significantly reduced TTAS by >24 hours vs. placebo and was comparable with oseltamivir Proportion of patients with symptoms Proportion of patients with symptoms Baloxavir Baloxavir 1.0 If treatment was <24 hrs post symptom onset: 1.0 32.8 hr improvement in TTAS If treatment was >24 hrsPlacebo post symptom onset: 13.2 hr improvementOseltamivir in TTAS 0.8 Censor 0.8 Censor Baloxavir Placebo Baloxavir Oseltamivir (n=455) (n=230) (n=507) (n=514) 0.6 53.7 80.2 0.6 Median (95% CI), hours 53.5 53.8 (49.5, 58.5) (72.6, 87.1) Median (95% CI), hours (48.0, 58.5) (50.2, 56.4) Difference (95% CI), −26.5 (−35.8, −17.8) 0.4 hours 0.4 Difference (95% CI), hours −0.3 (NR) P-value* <0.001 p-value NR 0.2 0.2 Proportion Proportion of patients unalleviated 53.7 80.2 Proportion of unalleviated patients 53.5 53.8 0 0 0 30 60 90 120 150 180 210 240 270 300 330 360 0 30 60 90 120 150 180 210 240 270 300 330 360 Time from start of treatment (hours) Time from start of treatment (hours) Primary endpoint. Intention-to-treat infected patients population *Stratified generalised Wilcoxon test (stratification factors: country and symptoms score at baseline) Patients who did not experience alleviation of symptoms were censored at the last observation time point. Subset of patients whose TTAS was not missing Hayden et al. N Engl J Med 2018 Adapted from slide kindly provided by Zuzana Dobbie, Roche Baloxavir significantly reduced viral titres vs. placebo or oseltamivir from 1 day post dose Viral titre: baloxavir vs placebo Viral titre: baloxavir vs oseltamivir¶ 2 Baloxavir (n=427) 2 Baloxavir (n=352) 1 Placebo (n=210) 1 Oseltamivir (n=359) 0 0 § § re re -1 -1 aseline in aseline in aseline in aseline in -2 -2 b b irus tit irus tit v v -3 -3 -4 -4 -5 * * -5 * nfluenza nfluenza * i i * * Change from Change from -6 -6 -7 -7 -8 -8 1 2 3 4 5 6 7 8 9 1 2 3 4 5 6 7 8 9 Baloxavir 427 412 404 114 403 97 407 Baloxavir 427 412 404 114 403 97 407 Placebo 210 201 191 57 192 48 197 Placebo 210 201 191 57 192 48 197 (n) (n) Study Day Study Day Secondary endpoint. ITTI population § ¶ *p<0.05 vs placebo or oseltamivir; Mean log10 (TCID50/ml); Adults aged 20–64 years Hayden et al. N Engl J Med 2018 Adapted from slide kindly provided by Zuzana Dobbie, Roche The median time to cessation of viral shedding was 24 hours following baloxavir treatment Median time to cessation of viral shedding (infectious virus) Placebo 96 hours n=209 Oseltamivir 72 hours n=357* p<0.0001 Baloxavir baloxavir 24 hours vs placebo n=426** § and oseltamivir *Adults aged 20–64 years; **n=351 for comparison vs oseltamivir (adults aged 20–64 years) §Stratified generalised Wilcoxon test One day was converted into 24 hours Hayden et al. N Engl J Med 2018 Adapted from slide kindly provided by Zuzana Dobbie, Roche Baloxavir was well tolerated, with numerically fewer AEs than oseltamivir Incidence of AEs 100 Placebo (N=309) 90 Oseltamivir (N=513) 80 Baloxavir (N=610) 70 60 50 40 30 24.6 24.8 Proportion of (%) patients Proportion 20.7 20 10 0.0 0.1 0.0 0.0 0.0 0.3 0.4 0.3 0.3 0 † Any AE Death SAEs AEs leading to withdrawal of study drug *No significant differences were noted between the groups except for pre-specified comparison of treatment-related AEs, which were more common with oseltamivir than baloxavir (p=0.009) †Excluding death See slide notes for AEs reported in at least 1% of patients in any treatment group Hayden et al. N Engl J Med 2018 Adapted from slide kindly provided by Zuzana Dobbie, Roche Summary: CAPSTONE 1 and 2 CAPSTONE-1: Phase III study of OwH patients (Hayden et al. N Engl J Med, 2018) • Baloxavir was superior to placebo and comparable with oseltamivir in alleviating influenza symptoms • Baloxavir was superior to both placebo and oseltamivir in reducing viral titres and median time to the cessation of viral shedding • Baloxavir was well tolerated CAPSTONE-2: Phase III study in high-risk influenza patients of baloxavir vs placebo or oseltamivir (unpublished, Ison et al.ID Week, San Fran, 2018) • Confirmed safety in this population • Baloxavir was superior to placebo in improving influenza symptoms (29.1 hr) • For influenza B, baloxavir superior to placebo (by 26.0 hr) and oseltamivir (by 27.1 hr) • Baloxavir associated with significantly fewer influenza-related complications and reduced the requirement for antibiotics compared with placebo Frequency of resistance (or reduced susceptibility) to Baloxavir marboxil Influenza A viral variants with reduced susceptibility to baloxavir have been characterised Cells: MDBK Virus: A/WSN/33 Drug Concentrations: Start at 25xEC50, 5xEC50, 1xEC50, 0.2xEC50, 0.04xEC50. Increase the drug concentrations (x2) in each passage Omoto S et al. Scientific Reports 2018;8:9633 Noshi T. et al. Antiviral Research 2018 (in press) Viral variants conferring reduced susceptibility to baloxavir have been detected in clinical trials PA AA substitution detected and frequency Analysis Predominant Trials Population type/subtype Fold change in susceptibility (n=) <10 fold >10 fold Ph2 OwH in I38T (n=2) 182 A(H1N1)pdm09 E23K (n=1) Japan I38F (n=2) E23G (n=1) I38T (n=33) CAPSTONE-1 370 A(H3N2) E23K (n=1) I38T/M (n=2) OwH A37T (n=1) I38M (n=1) Pediatric study A(H3N2) A37T (n=1) I38T (n=15) 77 in Japan E119G (n=1) I38M (n=3) I38T (n=13) A(H3N2) and B CAPSTONE-2 HR 290 E23K (n=1) I38M (n=1) I38N (n=1) • PA/I38X viral variants not detected in placebo treated patients and occur very rarely among circulating viruses, PA/I38T not detected Hayden FG, et al.