Shorter TB regimens What is in de pipeline? Martin Boeree, Associate Professor Radboudumc, Nijmegen, the Netherlands Tuesday, 23 September, 2014

Transcription

1 Shorter TB regimens What is in de pipeline? Martin Boeree, Associate Professor Radboudumc, Nijmegen, the Netherlands Tuesday, 23 September, 2014

2 Disclosures Clinical trials and studies funded by EDCTP, BMG, NWO, NACCAP, KNCV Advisory board Janssen Cilag Clinical trial drugs donated by Sanofi

3 Outline Introduction, why shorter treatment? Resistance What is in the pipeline? Repurposed drugs New drugs Combinations, trials and expectations Conclusion

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5 Introduction Shorter treatment is top priority in research Increases adherence Decreases emergence of drug resistance Decrease costs and logistical challenges For the first time in years new drugs are introduced A clinical pathway is defined (CPTR) : Preclinical studies. Animal models (mainly murine), Phase I, incl MTD studies Phase II with early bactericidal activity, and 2-3 months to evaluate bacterial response Finally phase III

6 Ma et al., Lancet, 2010

7 The coming years will bring us many phase II and III trials In this talk an update until today Problem is the lack of surrogate markers: Predictors for outcome Treatment failure Relapse Current phase III trials will bring us more knowledge

8 Who are performing clinical trials in TB? Largest institution to coordinate: GATB = Global Alliance for TB drug Development

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10 Other consortia PanACEA (Pan African Consortium for the Evaluation of AntiTB Antibiotics) ->Europe/Africa TBTC (TB Trial Consortium) -> USA ACTG (AIDS Clinical Trial Group) -> USA InterTB -> UK MRC CTU -> UK IUATLD (the Union) -> Global NIRT(National Institute for TB research) -> India

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12 Dakar, October 2013

13 African PanACEA Partners: Albert-Schweitzer- Hospital Medical Research Unit Makarere University Tuberculosis Unit NTLP KCMC Kibong oto National Tuberculosis Hospital IHRDC Bagamoyo - Ifakara Health Research and Developement Centre MMRP Mbeya Medical Research Programme UNZA University of Zambia Medical School College of Medicine Blantyre WITS University of Witwatersrand AURUM Aurum Institute for Health Research INS Instituto National de Saute UCT + Stellenbosch University of Cape Town / Stellenbosch

14 See also: Working Group on New TB Drugs: Treatment Action Group (TAG) pipeline report

15 Resistance Not the focus of this talk In general: a new regimen with new compounds in the future will be as a short as for drug sensitive TB However, current treatment is far too long now : at least months, but in many patients even longer Therefore: some promising shorter treatment developments

16 Developments in shorter MDR treatment regimen Bangla Desh regimen STREAM trial (the Standardised Treatment REgimen of Anti-tuberculosis drugs for patients with MDR-TB) = Bangla Desh with high dose moxifloxacin instead of gatifloxacin Phase III trials Bedaquiline (in STREAM two extra arms, 28 and 40 weeks, levo instead of moxi because of QT), PA 824 (Global Alliance) Delamanid (Otsuka) More clinical cohort studies: linezolid, thioridazine, cotrimoxazol, ertapenem, etc.

17 Bangla Desh regimen First 200 patients published in blue journal 2010 Update on 515 patients. Observational, not a RCT 84.4 % bacteriologically favorable outcome Risk factors for unfavorable outcome Quinolone resistance PZA resistance

18 STREAM Randomization to control (WHO guidelines) and experimental regimen (=modified Bangla Desh regimen) for 9 months Extension to 10 or 11 months depending on smear status at 4 and 5 months XDR and pre-xdr excluded Primary outcome microbiological status at 27 months N=400

19 Treatment shortening in drug sensitive TB

20 Compounds under investigation Established drugs: H, Rifamycins, Z, E.. Repurposed drugs: thioridazine, amoxycilline + clavulanic acid, cotrimoxazole, clofazimine, ertapenem, etc. Novel compounds TMC207 (bedaquiline) OPC (delamanid) PA-824 SQ109 PNU (sutezolid) AZT-5847 Very large number of combinations to test Must develop regimens not single drugs

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22 Rifamycines Rifampicin HR1, HR2, HIRIF, RIFATOX Rifapentine study 29, 29 X, plans for phase III

23 HIGHRIF 1 (HR1) study design

24 HR1 study One control group with standard 10 mg/kg RIF (N=8) 4 consecutive arms of each 15 patients: 20 mg RIF/kg 25 mg RIF/kg 30 mg RIF/kg 35 mg RIF/kg

25 CFU (colony forming units)

26 Time CFU EBA: Rate of fall of logcfu per ml of sputum per day Days

27 CFU Fitted estimates of mean baseline log10(cfu)/ml by treatment Visit Control (10 mg/kg) 20 mg/kg 25 mg/kg 30 mg/kg 35 mg/kg Fitted estimates of difference from mean baseline log 10 (CFU)/ml by visit and treatment arm from linear fixed effects model with 95% confidence intervals. CFU EBA 0-14 days

28 PK

29 Conclusions RIF up to 35 mg/kg is safe and tolerated There is a suggestion of an increasing EBA, especially for 30 and 35 mg/kg PK: superproportional increase in AUC and C max (nonlinear PK) without ceiling

30 HR2 study design

31 Time to culture conversion on MGIT Number at risk dose = 600 dose = 900 dose = 1200 Kaplan-Meier survival estimates analysis time dose = 600 dose = 900 dose = 1200

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33 Conclusions HR2 Doses of 900 and 1200 mg of RIF combined with standard TB drugs for 2 months are safe and equally well tolerated as the standard dose RIF. PK shows again a nonlinear, superproportional increase in AUC and Cmax, though less outspoken as in HR1 Efficacy: modest non-significant difference Conclusions RIFATOX (InterTB and MSF) 900 and 1200 mg safe and tolerated in 300 patients

34 PanACEA-MAMS-TB-01 Study arms, duration of treatment 3 months: Control: HRZE INH, rifampicin standard, pyrazinamide, EMB Arm 1 (R 35 ): HR 35 ZE INH, rifampicin 35 mg/kg, pyrazinamide, EMB Arm 2 (Q): HRZQ INH, rifampicin standard, pyrazinamide, SQ mg Arm 3 (R 20 Q): HR 20 ZQ INH, rifampicin 20 mg/kg, pyrazinamide, SQ mg Arm 4 (R 20 M): HR 20 ZM INH, rifampicin 20 mg/kg, pyrazinamide, moxifloxacin N= 382

35 Rifapentine, study 29 and 29X Rifapentine: long half life, low MIC Murine experiments (Nuermberger et al) predict shortening to 3 months Study 29 Phase 2 N=531 2HRZE vs 2 HPZE (5 days a week) Dorman, JID 2013

36 TBTC Study 29X Phase IIb Dose exploration TBTC S29 amendment = TBTC S29 extension Study 29 Study 29X n = 531 n = 320 FPI = July 2011 Open-label 5/7 + DOTS Fasting Primary endpoint: Efficacy & Safety Double-blind for RPT arms 7/7 + DOTS on week days Fed Primary endpoint: Safety

37 Study 29X, not published yet Clear dose related increase of 2 months culture conversion up to 100% in the 20 mg/kg arm Now phase III with high dose rifapentine is planned (study 31)

38 The quinolones

39 4 NIRT (Moxifloxacin or Gatifloxacin)

40 Non-inferiority study N= 1,931 Cost: appr. 70 M$ Took about 10 years

41 REMox

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44 REMox favorable outcome

45 REMox unfavorable outcome

46 Rifaquin N= 827 standard control regimen 2HRZE/4HR 2EMRZ/2 months twice a week moxifloxacin 400 mg, rifapentine 900 mg 2EMRZ/4 months moxifloxacin 400 mg, rifapentine 1200 mg once weekly Conclusion: 4 months inferior, 6 months non-inferior Not published yet

47 Oflotub N=1836 2HRZG/2HRG (G=gatifloxacin) standard control regimen 2HRZE/4HR 2 months culture conversion rates no difference 4 months no non-inferiority demonstrated, large variation by country and HIV status Not published yet

48 NIRT, Chennai and Madurai, India Three times a week gatifloxacin or moxifloxacin, N= 416

49 NIRT High culture conversion rates at the end of treatment in all arms Gati 95% Moxi 98% Control 97% High proportion of culture conversion at two months Gati 83% Moxi 88% Control 78% High relapse rates until 24 months post treatment Gati 16 % Moxi 10% Control 6 % Trial was prematurely stopped by DSMB!

50 Conclusions from the four quinolone phase III trials 4 months is not (yet) acceptable enough though relapse rates are relatively low Murine models have overpredicted sterile capacity of quinolones Bacterial load markers, such as time to culture conversion do not adequately predict long term outcome. We need markers that predict relapse!!

51 Surrogate markers for sterilizing capacity (for relapse), are they there?

52 What else?

53 Old compounds Pyrazinamide: dose probably too low Isoniazide: high doses show efficacy in MDRTB Clofazimine Thioridazine Cotrimoxazol, amoxycilline/clavulanic acid, etcetera

54 H37Rv Control infection (A) Extensive lung consolidation (arrows) is visible in control animals after 120 days of infection by drug-sensitive control Strain H37Rv. H37Rv Infection Plus Thioridazine (B) In contrast, less pneumonia (arrow) is seen in the lung of Mice treated with Thioridazine 32 mg/kg daily by intragastric cannula. MDR Control Infection (C) Control mice after 120 days of infection with MDR strain show extensive pneumonic areas (arrow) MDR Infection Plus Thioridazine In comparison, less lung consolidation (arrow) is seen in the lung of mice infected by the MDR-TB strain and treated daily during two months with 70 mg/kg of thioridazine

55 Clofazimine A riminophenazine derivative, seems to be very bactericidal in mice, used long time for leprosy, side effects skin coloration + gastrointestinal discomfort + QT prolongation EBA 0-14 (Paris october 2013): none Was used in the Bangladesh regimen Evaluated in the STREAM trial

56 New compounds

57 Bedaquiline (TMC207) Mechanism: inhibits F0 subunit of the mycobacterial ATP synthase proton pump Possible use : Shorter treatment (especially in mice together with PZA strong effect) (shorter) treatment of MDR/XDR TB

58 The nitroimidazoles PA 824 (Chiron, now Novartis) OPC (Otsuka): delamanid Derivatives from metronidazol

59 21 November EMA approved the drug: Deltyba 50 mg Source: EMA/CHMP/713909/2013 Committee for Medicinal Products for Human Use (CHMP)

60 4 4.5 logcfu PA-824 Dose ranging: PA mg, 150mg, 100mg, 50mg Bi-linear regression of logcfu vs day over treatment Day PA mg PA mg PA mg PA mg Rifafour e275 AAC 2012; 56:3027

61 PA 824 Evaluated now in phase II trials (NC trials by the alliance) Ready for evaluation in phase III PaMZ or the STAND trial 2HRZE4RH 4PaMZ

62 Oxazolidinones: inhibit protein synthesis Linezolid: many side effects, use now in MDR/XDR TB PNU : sutezolid (now Sequella). More potent than linezolid in in vitro, ex vivo and murine models. AZD5847 (AstraZeneca): BID 1200 mg. Phase II study planned

63 SQ 109 (Sequella)

64 DTP, percentage change from baseline In PanACEA, no EBA in liquid media Day of administration of drug 75mg SQ mg SQ mg SQ109 + RIF 150mg SQ mg SQ109 + RIF RIF Monotherapy Day of administration of drug 75mg SQ mg SQ mg SQ109 + RIF Lower 95% limit 150mg SQ mg SQ109 + RIF RIF Monotherapy Upper 95% limit Fitted estimates of change from baseline of DTP by visit and treatment allocation from mixed effects model (PP) Fitted estimates of percentage change from baseline of DTP by visit and treatment allocation from mixed effects model assuming linear decline with 95% confidence intervals (PP)

65 SQ109 In first interim analyis in MAMS Both SQ109 arms were not superior Both arms were therefore stopped

66 How further in new combinations? Global Alliance: a series of trials, NC (new combinations): NC001 NC 006 STAND trial in 2014: STAND: 4PaMZ vs 2HRZE4HR PanACEA: MAMS ++ = Big Mama in 2015 TBTC: rifapentine

67 Conclusion: what will we see in the future? Shorter treatment both for DS as for DR TB 4 months 3 months 2 weeks when I am retired + individualized treatment With combinations of strongly sterilizing compounds High dose rifamycin, (Higher dose) of pyrazinamide Bedaquiline Moxifloxacine (?) PA824/delamanid Sutezolid Clofazimine New compounds (BTZ, Q208, etc.) We need therefore a good surrogate marker for sterilizing capacity to predict relapse

68 Thank you