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What ‘ s Going On with SQ109 ?

What ‘ s Going On with SQ109 ?. L M U. Infectex. TB Alliance Open Forum 2 London, December 2006. “… each drug should be developed according to the specific characteristics of the drug itself, not form-fitted into a one-size-fits-all clinical development program…” [Nacy].

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What ‘ s Going On with SQ109 ?

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  1. What‘s Going On with SQ109 ? LMU Infectex

  2. TB Alliance Open Forum 2London, December 2006 “… each drug should be developed according to the specific characteristics of the drug itself, not form-fitted into a one-size-fits-all clinical development program…” [Nacy]

  3. Timecourse for SQ109 Effects In Vivo SQ109 10 mg/kg; INH 25 mg/kg; RIF 20 mg/kg; EMB 100 mg/kg Nikonenko, et al. 2007. Drug therapy of experimental tuberculosis (TB): improved outcome by combining SQ109, a new diamine antibiotic, with existing TB drugs. Antimicrob. Agents and Chemother 51: 1553.

  4. Modeling EBA in the Mouse

  5. Timecourse for SQ109 Effects In Vivo SQ109 10 mg/kg; RIF 20 mg/kg; SQ109 reduced replication of Mtb and improved RIF activity (1/3 log10 CFU) by day 30

  6. TB Alliance Open Forum 2London, December 2006 “… each drug should be developed according to the specific characteristics of the drug itself, not form-fitted into a one-size-fits-all clinical development program…” [Nacy] [TMC207 shows minimal activity in EBA] “…unfortunately, a right-of-passage in the TB community…” [Tibotec]

  7. Individual Patient Log10 CFU over Time

  8. EBA with 95% confidence intervals

  9. Mixed Effects Model Assuming Linear Decline Fitted estimates of difference from mean baseline log10(CFU) /ml by visit and treatment allocation

  10. Individual Patient Log10 CFU over Time

  11. Safety/Tolerability of SQ109 in TB patients • 82 adverse events, of which 56% were gastrointestinal events • One patient died during the 14 day follow-up period due to massive hemoptysis. This was deemed unrelated to study drug by the investigator. • No other serious adverse events (SAEs) . • There were no ECG-related treatment discontinuations. There was no prolongation of QTcB or QTcF beyond 500ms, or an increase of more than 60ms as compared to baseline.

  12. EBA Conclusions SQ109 is a safe and well tolerated drug. It‘s main side effect is nausea, which is more pronounced in the 300mg dose There were no systematic increases in QT in the SQ109 groups Steady state appears to be reached at ~day 7; the induction of CYP2C19 through Rif can be overcome with 300mg SQ109 SQ109 had no bactericidal effect in humans over 14 days; RIF had a 1-log effect in humans over 14 days. Mouse modeling data suggest that: - EBA data in humans mimics that seen in mouse - SQ109 effects are apparent the longer the drug is taken

  13. EBA Study Team Acknowledgments Sponsor: Medical Center of the University of Munich Chief Investigator: Michael Hoelscher PI: Andreas Diacon Co-PI: Rodney Dawson Microbiology: Andeas Diacon, Amour Venter Sponsor Medical Expert: Norbert Heinrich Trial Statistician (MRC): Patrick Phillips Chief Medical Officer Sequella Inc.: Gary Horwith PanACEA Chief Investigators Group: M. Boeree, S. Gillespie, M. Hoelscher Funding: EDCTP, BMGF, BMBF, UK-MRC, Sequella, NIH

  14. EBA Value-Add in TB Drug Development? Drugs effective in TB treatments that work poorly (or not at all) in EBA: • Rifampicin • Linezolid • Clofazimine • Pyrazinamide • Bedaquiline • SQ109

  15. What‘s Next for SQ109 • Registration trial in Russia for MDR-TB: • OBT ± SQ109 (300 mg) • ICH guidelines • Start: Q4 2012 • MAMS study in Africa in DS-TB: • SQ109 (300 mg) vs EMB in SOC • SQ109 (300 mg) vs EMB in SOC high-dose RIF • Start: Q4 2012 • Thorough QT (TQT) in healthy humans • SQ109 (up to 450 mg) ± moxifloxicin • New Drug Combinations in MDR-TB, ACTG • New Drug Combinations in DS-TB, ACTG Infectex

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