1. Issues in development for an MDR TB indication Leonard Sacks MD Division of special pathogens and transplant products FDA

6. Pros and cons in developing drugs for MDR TB Area of pressing medical need Drug effect potentially very obvious (e.g. in patients with positive sputum despite years of MDR therapy) Effectively may resemble monotherapy if other drugs have failed May be faster than demonstrating efficacy in drug sensitive patients (Analogous to EBA) Accelerated approval MDR TB is not a homogeneous disease Definitions of resistance vary- clinically, microbiologically Treatment regimens are complex Monotherapy is not a viable approach Reliability of sputum conversion as a surrogate for clinical outcome is not clear.

7. Traditional efficacy studies ARM A Drugs ABCD 95% Success ARM B Drugs ABCX 96% Success Just to see a failure, we need many patients per arm To compare these small differences with confidence we need a large study In this non-inferiority model, the effect of drug X may be masked by the rest of the regimen

8. MDR study ARM A Optimized background Success 3% ARM B Optimized background + X Success 40% In this study, only a handful of patients are needed to show superiority The drug effect is almost entirely attributable to drug X

9. Past experience with drugs for resistant conditions

10. How have we dealt with resistance in the past? MDRSP VRE MRSA Resistant HIV Cancer resistant to chemotherapy

11. MDR S Pneumoniae Established efficacy for drug sensitive S. pneumoniae in randomized controlled blinded studies. Micro evidence of activity in MDRSP Independent mechanism of action Clinical success in 15 cases of pneumonia due to MDRSP

12. MDR S Pneumoniae Source: product label

13. Vancomycin resistant enterococcus Synercid- for Vancomycin resistant E fecium bacteremia for complicated skin and skin structure infection –two comparative trials in complicated skin infections –no primary efficacy demonstrated in drug-sensitive enterococcal infection –Drug was approved based on subpart H using clearance of bacteremia as a surrogate for clinical outcome. Data from four non-comparative studies in 1222 patients with VRE bacteremia

14. Vancomycin resistant enterococcus Linezolid- Randomized double blind studies for the following: –VRE infections, –pneumonia –skin infections

15. Linezolid- dose ranging study for VRE Source: product label

16. Resistant HIV Tipranavir –For combination ARV use –For highly treatment experienced patients or virus resistant to multiple protease inhibitors Approval based on viral suppression at 24 weeks

17. Tipranavir clinical studies Source: Product label

18. Some points on clinical drug development for resistant infections Generally, initial development for drug sensitive disease Controlled data in resistant infections Dose response in resistant infections Data in resistant infections with historical controls Tipranavir is the closest model addressing the issue of combination therapy

19. Quinolones for MDR TB

20. Quinolones What have we learned about quinolones and resistant TB? In vitro –MIC –Mechanism of action Animals Human (retrospective) –EBA –Non-comparative –Comparative Historical

21. Quinolones MICs In vitro and in vivo activities of Moxifloxacin and clinafloxacin against MTB Ji B. Lounis N, Maslo C, Truffot-Pernot C, Bonnafous P, Grosset J Antimicrob, agents and chemo 1998;42:2066-2069 MICs to 15 drug-sensitive and 5 MDR strains MICs to 18 drug-sensitive strains In vitro and in vivo activities of Levofloxacin against MTB Ji B. Lounis N, Truffot-Pernot C, Grosset J Antimicrob, agents and chemo 1995;39:1341-1344

22. Quinolones animal models Mouse 30 day survival rates after IV infection with H37Rv (Rx day 1-28) In vitro and in vivo activities of Moxifloxacin and clinafloxacin against MTB Ji B. Lounis N, Maslo C, Truffot-Pernot C, Bonnafous P, Grosset J Antimicrob, agents and chemo 1998;42:2066-2069

23. Quinolones Human EBA data The bactericidal activity of moxifloxacin in patients with pulmonary tuberculosis R Gosling, L Ulso, N Sam, E Bongard, E Kanduma, M Nyindo, R Morris, S Gillespie. Am J Respir Crit Care Med 2003;168:1342-1345 5 day EBA

24. Quinolones Human data –Retrospective (historical controls) –MDR cure rate (1973-1983) 56% –MDR cure rate (1984-1998) 75% –Treatment and outcome analysis of 205 patients with multidrug resistant tuberculosis Chan E, Laurel V. Strand M. Chan J. Huynh M, Goble M, Iseman M Am J respir Crit Care Med 2004, 169:1003-9

25. Quinolones Human data Survival (TB related) – quinolones versus no quinolones Retrospective (Not randomized) Confounders- surgery

26. Thoughts on study design for drugs to treat MDR TB

27. Study populations Primary MDR –disease more homogeneous –Very low rates in US- target high risk areas e.g. Estonia Secondary MDR –Typically extensive cavitation and fibrosis –Surgery often needed –Problem of drug entry into fibrotic lesions –Patients usually well known to clinics HIV MDR –Outbreak setting - probably less appropriate Number of drugs to which resistance is documented 2, 3 or 7? Extent of disease- cavitation, fibrosis, extent

28. Entry criteria establishing resistance documenting persistent positive cultures despite prior therapy.

29. Study arms The need for not one but two or more new agents Have we reached the point where we can compare a new MDR drug cocktail with a quinolone cocktail?

30. Traditional approach to a resistance claim Establish microbiological efficacy for resistant organisms Identify independent mechanism of action Demonstrate similar in vitro MICs for drug sensitive and MDR strains of the organism Establish efficacy in drug sensitive infection (randomized controlled trials) Limited treatment experience in MDR cases

31. Beginning of the road model Primary resistance to Rifampin and INH usually determined from baseline culture about 1 month after starting therapy Not always identified as clinical drug failure. Some respond to initial therapy though response may be slower (median 2 months) preferable to enroll those with positive sputum culture after 1 month (at initiation of therapy for resistant infection)

32. Possible schema for studying 2 rifampin and INH resistance Smear positive after 30 days INH and Rifampin resistance determined smear positive New drug + second line drug ?quinolone + second line drug smear negative When 1 month cultures available those with a negative culture are excluded from efficacy analysis

33. End of the road model Patients with 6 or 7 drug resistance and persistent sputum positivity In such individuals, a drug with a novel target, good micro against MDR, MDR animal models, volunteer safety data, limited human data on comparative sputum conversion rates could conceivably lead to a limited approval.

34. Possible schema for studying high grade MDR Known high grade MDR 3 months treatment failure Culture positive Background + New drug Background + placebo Alternatives to placebo include dose ranging, immediate versus delayed dosing, historical control data with predetermined minimal efficacy standard

35. End of the road “Reverse EBA” Drug first Placebo first %Culture positive Days

36. Where the drug is very efficacious, small numbers of patients would be needed to show efficacy

37. Conclusions There are several precedents for development of drugs for resistant infection MDR may provide an opportunity to demonstrate the efficacy of new anti-TB agents in small numbers of patients Several study designs are possible MDR studies may be conducted in parallel with studies in drug sensitive disease