Early phase evalua*on of SQ109 alone and in combina*on with

Early phase evalua*on of SQ109 alone and in combina*on with

 Early phase evalua-on of SQ109 alone and in combina-on with rifampin in pulmonary tuberculosis pa-ents Berlin, 2014 SQ109, an an--­‐TB drug candidate Tissue distribu3on: concentra3on in lung 3ssue 20-­‐120 fold compared to plasma (mice, rats) Metaboliza3on: hepa3c, CYP 450 2D6 and 2C19. First pass unknown, but probably high Mode of Ac3on: inhibits MMPL 3, a monomycolate transporter involved in cell wall assembly, and other targets Strong Synergy with Rifampicin and other novel drug candidates Phase I Data: 72 subjects dosed. Overall well tolerated, no discon3nua3ons, no SAEs SQ109: efficacy in murine TB LMU-­‐IMPH-­‐SQ109-­‐01: study popula-on Inclusion criteria (selected): -­‐  newly, diagnosed, pulmonary TB, Inclusion
criteria
-­‐  sputum
smear (pselected
osi3ve (): 1+ on IUATLD/WHO scale) -­‐  newly
GeneXpert
, diagnosed, pulmonary TB, -­‐  sputum smear posi3ve (1+ on IUATLD/WHO scale
-­‐  GeneXpert Exclusion criteria
MTB/RIF posi3ve for TB, RIF suscep3ble ) -­‐  HIV posi3ve and
(selected) -­‐  Body weight < 40kg on A
oRT r or less than 250 cd4 cells -­‐  Drug addici3on > 90kg posing
LMU-­‐IMPH-­‐SQ109-­‐01: treatment arms Day 0 Day 2 Day 10 Day 14 Day 17 Day 21 Group 1 N=15 SQ109 75mg alone HRZE Group 2 N=15 SQ109 150mg alone HRZE SQ109 300mg alone HRZE SQ109 150mg/RIF HRZE SQ109 300mg/RIF HRZE RIF alone HRZE Group 3 N=15 Group 4 N=15 Group 5 N=15 Group 6 N=15 H o s p i t a l i z a t i o n
daily sputum collec3on Outpatient
Day 28 Conclusions •  SQ109 is a safe and well tolerated drug
•  No QT increase of regulatory concern o. bserved in the SQ109 groups
• 
SQ109 had no bactericidal effect in humans over 14 days – possible explana3on: -­‐ insufficient concentra3ons in extracellular lesions -­‐ study too short -­‐ mouse model suggests drug ac3vity apparent Outlook Does EBA predict/exclude usefulness of a drug at later 3mepoints? How is the endpoint of 14-­‐day EBA and other endpoints validated against clinically relevant outcome parameters? How well does a mouse study predict 3me course of efficacy in humans? Wallis R., CID, in press Outlook II •  Month 2 culture conversion on solid media (or month 3 in East African trials) is a beler validated surrogate for relevant outcomes •  SQ109 is now given for three months in the PanACEA MAMS TB 01 trial – Interim analysis: will probably not fulfill our preset effect size for improvement over control •  more definite results hopefully to be presented at CROI 2015 Wallis R
ID, O
in ne press Phillips P., PClos 2013 Acknowledgements -­‐ Study team Sponsor: Chief Inves3gator: PI: Co-­‐PI: Microbiology: Sponsor Medical Expert: Project Manager: Trial Sta3s3cian: Chief Medical Officer Sequella Inc.: PanACEA Chief Inves3gators Group: Funding: Medical Center of the University of Munich Michael Hoelscher Andreas Diacon Rodney Dawson Andeas Diacon, Amour Venter Norbert Heinrich Sonja Henne Patrick Phillips Gary Horwith M. Boeree, S. Gillespie, M. Hoelscher EDCTP, BMGF, BMBF, UK-­‐MRC, Sequella Thanks to all par3cipants! Wallis R., CID, in press