TB new treatments and new methodological challenges Dr Corinne Merle

Outline  Current pipeline of new TB drugs  Methodological challenges for designing TB trials (using the OFLOTUB project as an example)  Challenges in TB regimen development

TB drug development: to set the scene 1882 Description of the agent of TB Streptomycine (S) 1952 Isoniazid (H) 1954 Pyrazinamide (Z) 1961 Ethambutol (E) 1963 Rifampicin (R) 1952: 1 st regimen: S/PAS/H months therapy 1970s: short course regimen: S/H/R or S/H/Z -9 months therapy 1980s: modern short- course regimen: E (S) H R Z 6 months of therapy 1946: 1 st drug: S Montotherapy led to S resistance 2010

TB drug development: to set the scene 1882 Description of the agent of TB Streptomycine (S) 1952 Isoniazid (H) 1954 Pyrazinamide (Z) 1961 Ethambutol (E) 1963 Rifampicin (R) 1952: 1 st regimen: S/PAS/H months therapy 1970s: short course regimen: S/H/R or S/H/Z -9 months therapy 1980s: modern short- course regimen: E (S) H R Z 6 months of therapy 1946: 1 st drug: S Montotherapy led to S resistance Effective treatment: 95% of treatment efficacy But...  6 months treatment regimen  problem of treatment adherence  Emergence of MDRTB  8.8 millions new TB cases in

Development pipeline for new TB drugs  Shortening TB treatment recognised as a major target for the improvement of TB control  Since the late 90s: new agents discovered  Significant target diversity and potential for better combinations

Development pipeline for new TB drugs

Drugs at a Phase III stage  Both gatifloxacin and moxifloxacin have emerged as candidates from the 8- methoxyfluoroquinolones drug class and are proposed for shortened treatment of pan-susceptible TB.  Gatifloxacin was chosen based on its bactericidal activity and its generic status flotub  35 years after the East African/British Medical Research Council trials, 3 new drugs currently assessed in large Phase III trials  RIFAQUIN trial (Rifapentine)  REMoxTB trial (Moxifloxacin)  OFLOTUB trial (Gatifloxacin)

Gatifloxacin Product Development Plan  Pre-Clinical Toxicology studies  Phase I Pharmacokinetic study ( J Antimicrob Chemother Dec;60(6): )  Phase II SSCC study ( Int J Tuberc Lung Dis Feb;12(2): ).  Phase III pivotal trial with a nested PK/PD also called OFLOTUB flotub More than 10 years in development

Overview of OFLOTUB project: Phase III/PK  Objective To evaluate the efficacy and safety of 4-month gatifloxacin containing regimen compared to the standard WHO-recommended 6-month regimen  Study design A randomized (1:1), open-label, non-inferiority, multi-centre controlled trial with a nested Pharmacokinetic (PK/PD) study  Patients Newly diagnosed microbiologically confirmed TB sensitive adults patients in 5 countries in Africa flotub

 Follow-up  2 years after completion of TB treatment  Patients seen at 1, 2, 4, 6, 9, 12, 15, 18 and 24 months after treatment  Clinical examination, 2 sputum samples collected for smear & culture  Treatment  Test arm : 2 months GHRZ / 2 months GHR  Control arm: 2 months EHRZ / 4 months RH  Daily DOT during the 1 st 2 months of treatment,  Weekly drug delivery during the continuation phase Overview of OFLOTUB project: Phase III/PK

flotub Trial setting and OFLOTUB partners Institute for Research & Development (Marseille) PNLTB (Dakar, Senegal) St George’s Hospital Medical School, (London) KEMRI (Nairobi, Kenya) Tropical Medical Institute (Antwerp) Hôpital Raymond Poincaré (Paris) PNLTB (Cotonou, Benin) PNLTB (Conakry, Guinea) MRC SA (Durban, South Africa) WHO / TDR (Geneva) LUPIN Pharma (India) Thamassat University (Bangkok) London School of Hygiene and Tropical Medicine (London)

flotub Trial setting and OFLOTUB partners Institute for Research & Development (Marseille) PNLTB (Dakar, Senegal) St George’s Hospital Medical School, (London) KEMRI (Nairobi, Kenya) Tropical Medical Institute (Antwerp) Hôpital Raymond Poincaré (Paris) PNLTB (Cotonou, Benin) PNLTB (Conakry, Guinea) MRC SA (Durban, South Africa) WHO / TDR (Geneva) LUPIN Pharma (India) Thamassat University (Bangkok) London School of Hygiene and Tropical Medicine (London)

flotub Trial setting and OFLOTUB partners Institute for Research & Development (Marseille) PNLTB (Dakar, Senegal) St George’s Hospital Medical School, (London) KEMRI (Nairobi, Kenya) Tropical Medical Institute (Antwerp) Hôpital Raymond Poincaré (Paris) PNLTB (Cotonou, Benin) PNLTB (Conakry, Guinea) MRC SA (Durban, South Africa) WHO / TDR (Geneva) Thamassat University (Bangkok) London School of Hygiene and Tropical Medicine (London) LUPIN Pharma (India)

flotub Trial setting and OFLOTUB partners Institute for Research & Development (Marseille) St George’s Hospital Medical School, (London) KEMRI (Nairobi, Kenya) Tropical Medical Institute (Antwerp) Hôpital Raymond Poincaré (Paris) PNLTB (Cotonou, Benin) PNLTB (Conakry, Guinea) MRC SA (Durban, South Africa) WHO / TDR (Geneva) Thamassat University (Bangkok) PNLTB (Dakar, Senegal) London School of Hygiene and Tropical Medicine (London) LUPIN Pharma (India)

flotub Trial setting and OFLOTUB partners London School of Hygiene and Tropical Medicine (London) Institute for Research & Development (Marseille) St George’s Hospital Medical School, (London) KEMRI (Nairobi, Kenya) Tropical Medical Institute (Antwerp) Hôpital Raymond Poincaré (Paris) PNLTB (Cotonou, Benin) PNLTB (Conakry, Guinea) MRC SA (Durban, South Africa) WHO / TDR (Geneva) Thamassat University (Bangkok) PNLTB (Dakar, Senegal) LUPIN Pharma (India)

 1836 patients recruited  316 in Benin, 452 in Guinea, 200 in Kenya, 358 in Senegal and 510 in South Africa  Last patient completed treatment end of April 2009  Last patient last visit: April 2011 (i.e. 24 months of follow-up following the end of treatment)  Percentage of patients LTFU estimated to be around 10 % First results should be released in November 2012  Progress status Overview of OFLOTUB project: Phase III/PK

Non-inferiority design flotub Rationale for Choice of Non-inferiority design  Highly efficient current TB treatment (95% cure rate)  Unlikely that a new regimen will demonstrate superiority  Interest lies with showing whether a new regimen is not inferior Non-inferiority design is an excellent choice for current TB sensitive drug development (A. Nunn et al, Tuberculosis(2008))

Non-inferiority design flotub Rationale for Choice of Non-inferiority design  Highly efficient current TB treatment (95% cure rate)  Unlikely that a new regimen will demonstrate superiority  Interest lies with showing whether a new regimen is not inferior NI design is an excellent choice for current TB sensitive drug development (A. Nunn et al, Tuberculosis(2008)) Implication of NI design on trial population to be analysed  Intention-To-Treat (ITT) Vs Per-Protocol (PP)  ITT approach tends to minimise differences by including protocol deviations  PP is biased because not including all randomised patients In fact, both are equally important and require similar conclusions in order to support final result (Piaggio G, Elbourne DR, et al. JAMA 2006;295(10): )

Choice & measurement of the endpoints flotub  In 1947, endpoint of BMRC Streptomycin trial: Survival or Chest Xray  Nowadays, bacteriological endpoints  TB recurrence main outcome of interest  But restricted to patients cured at the end of the treatment A composite “unfavourable outcome” endpoint including: - treatment failure - Death - TB recurrences

Choice & measurement of the endpoints  Bacteriological diagnosis: Cultures  Solid Vs liquid media  False-positive cultures results from  Misidentification of the strain  Laboratory cross-contamination  Clerical error reporting  More than 3 % of false positive (Burman et al Clin Infect Dis 2000, 31(6): ) Necessity to take 2 sputum samples per visit, per patient to minimise unavailability or false positive culture results Solid medium is the gold standard

Recurrence, relapse and re-infection flotub  Relapse : Reactivation of the original infection  Re-infection: Infection with a new TB strain  Effective treatment should prevent relapse but have no effect on re- infection  Context of TB and HIV, proportion of re-infection can be high  Non-inferiority design context Necessity to differentiate relapse from re-infection using molecular method (e.g. MIRU-VNTR) Recurrence considered to allow comparison with previous trials

Length of patient follow-up flotub  For a TB regimen to be acceptable: Patient must convert to culture negative by the end of treatment most importantly, it must demonstrate clearance of bacteria by keeping patients relapse-free  How long is long enough?  When to start the clock…after the end of treatment (equal follow-up between arms)? or post randomization (unequal follow-up)?  Conservative approach: 24 months after the end of the treatment  In the light of BMRC trials: 1 year follow-up could be enough (Nunn AJ et al. Int J Tuberc Lung Dis 2010, 14(2): )  Discussion on when to start the clock (even more important for shorter treatment regimen trial)

Blinded design versus Open-label design Options  i) non-blinded design: an arm with 4 months of test regimen vs an arm with 6 months of standard regimen  ii) blinded design : 2-months placebo added to the test arm Discussion  Double blinding design favoured in many trial situations  For a shorter regimen, one of the mechanisms for treatment efficacy might be better adherence to treatment  Aspect not captured in blinded design  Pro and Cons Requirements if Open-label design  Laboratory staff are blinded to the treatment regimen the patient is receiving  Strict & objective endpoint definitions and a blinded endpoint committee

Sample size calculation Sample size calculation for a constant 2.5% 1-sided level of significance and variable values for primary outcome percentage, power and delta ‘Event’ percentage in control group Number per group for given delta and power Delta=3%Delta=5%Delta=6% 80%90%80%90%80%90% 5% % %

Sample size calculation OFLOTUB Major Efficacy Outcome “Unfavourable” events % events in control arm20% 1-sided significance level2.5% Power80% Non-inferiority margin δ6% # of patients overall1,394 (2 arms) Adjustment for non assessable patients15% Grand total 1,640 Importance of being powered for both ITT and PP analysis

TB Drug development challenges  Objective is to get new TB treatment regimen not only new TB drug  Novel 3-drug combinations that have potential to:  Shorten treatment to 2 months or less  Be co-administered with ARVs  Be effective against MDR- and XDR-TB ABFE AB ABCE ABCDGFE E D CF G  Conventional approach would need years to develop a combination that contains ≥ 3 new drugs  Adaptive multi-arm multistage (MAMS) trial design, which has been successfully used in cancer — is under discussion.  Even if MAMS, TB drug trial are long and costly 8-10 years 8-10 Years 8-10 years Years

Gatifloxacin product development Length flotub Dec 2002, Grant approval (P III) Nov 2012, 1 st efficacy results Jan - Mars 2005, initiation visits in the 5 recruitment sites for Phase III & PK/PD Design of the phase III study & set-up, capacity building +++ Phase III: last patient recruited: 31 Oct 2008 Follow-up period Phase III: April 2011, last patient FU In total 10 to 11 years Phase I, Phase II, Phase III & PK/PD July 2004, Phase II SSCC August 2003, Phase I & PK Phase III Recruitment period

Gatifloxacin product development Length flotub Dec 2002, Grant approval (P III) Nov 2012, 1 st efficacy results Jan - Mars 2005, initiation visits in the 5 recruitment sites for Phase III & PK/PD Design of the phase III study & set-up, capacity building +++ Phase III: last patient recruited: 31 Oct 2008 Follow-up period Phase III: April 2011, last patient FU Phase I, Phase II, Phase III & PK/PD July 2004, Phase II SSCC August 2003, Phase I & PK Phase III Recruitment period 2.5 years

Gatifloxacin product development Length flotub Dec 2002, Grant approval (P III) Nov 2012, 1 st efficacy results Jan - Mars 2005, initiation visits in the 5 recruitment sites for Phase III & PK/PD Design of the phase III study & set-up, capacity building +++ Phase III: last patient recruited: 31 Oct 2008 Follow-up period Phase III: April 2011, last patient FU Phase I, Phase II, Phase III & PK/PD July 2004, Phase II SSCC August 2003, Phase I & PK Phase III Recruitment period 2.5 years

Gatifloxacin product development Length flotub Dec 2002, Grant approval (P III) Nov 2012, 1 st efficacy results Jan - Mars 2005, initiation visits in the 5 recruitment sites for Phase III & PK/PD Design of the phase III study & set-up, capacity building +++ Phase III: last patient recruited: 31 Oct 2008 Follow-up period Phase III: April 2011, last patient FU Phase I, Phase II, Phase III & PK/PD July 2004, Phase II SSCC August 2003, Phase I & PK Phase III Recruitment period 3.5 years

Gatifloxacin product development Length flotub Dec 2002, Grant approval (P III) Nov 2012, 1 st efficacy results Jan - Mars 2005, initiation visits in the 5 recruitment sites for Phase III & PK/PD Design of the phase III study & set-up, capacity building +++ Phase III: last patient recruited: 31 Oct 2008 Follow-up period Phase III: April 2011, last patient FU Phase I, Phase II, Phase III & PK/PD July 2004, Phase II SSCC August 2003, Phase I & PK Phase III Recruitment period 2 years ?

Gatifloxacin product development Length flotub Dec 2002, Grant approval (P III) Nov 2012, 1 st efficacy results Jan - Mars 2005, initiation visits in the 5 recruitment sites for Phase III & PK/PD Design of the phase III study & set-up, capacity building +++ Phase III: last patient recruited: 31 Oct 2008 Follow-up period Phase III: April 2011, last patient FU Phase I, Phase II, Phase III & PK/PD July 2004, Phase II SSCC August 2003, Phase I & PK Phase III Recruitment period Data management

To reduce the length of TB drug development Set-up phase  Enhancing local capacity; training & re- training….. Huge capacity building investment, important that it is being capitalised and optimised  Necessity to ensure continuity of the research investments in these sites  Necessity to adopt common guidelines for designing TB treatment trials Recruitment period Patient follow-up & outcome of interest  Reduced to 12 months post treatment  Necessity to validate surrogate markers Datamanagement

Conclusion flotub  Shortening the duration of TB treatment is the major target  There are TB drug development challenges  There are methodological challenges when designing phase III TB sensitive RCT  We are advocating for:  a non-inferiority design,  a non-blinded design,  a composite unfavourable endpoint,  a follow-up of 12 months post treatment completion,  added trial procedures specifically aiming at minimizing unavailability of endpoints,  and distinguishing between relapse and re-infection.

Conclusion 1882 Description of the agent of TB Streptomycine (S) 1952 Isoniazid (H) 1954 Pyrazinamide (Z) 1961 Ethambutol (E) 1963 Rifampicin (R) 1952: 1 st regimen: S/PAS/H months therapy 1970s: short course regimen: S/H/R or S/H/Z -9 months therapy 1980s: modern short- course regimen: E (S) H R Z 6 months of therapy 1946: 1 st drug: S Montotherapy led to S resistance 2010 ?

Conclusion 1882 Description of the agent of TB Streptomycine (S) 1952 Isoniazid (H) 1954 Pyrazinamide (Z) 1961 Ethambutol (E) 1963 Rifampicin (R) 1952: 1 st regimen: S/PAS/H months therapy 1970s: short course regimen: S/H/R or S/H/Z -9 months therapy 1980s: modern short- course regimen: E (S) H R Z 6 months of therapy 1946: 1 st drug: S Montotherapy led to S resistance 2010 ? TB Alliance is instrumental (

Conclusion 1882 Description of the agent of TB Streptomycine (S) 1952 Isoniazid (H) 1954 Pyrazinamide (Z) 1961 Ethambutol (E) 1963 Rifampicin (R) 1952: 1 st regimen: S/PAS/H months therapy 1970s: short course regimen: S/H/R or S/H/Z -9 months therapy 1980s: modern short- course regimen: E (S) H R Z 6 months of therapy 1946: 1 st drug: S Montotherapy led to S resistance 2010 ? Ignoring the vulnerable  Children  TB/HIV co-infected patients