Shorter TB regimens What is in de pipeline?

Martin Boeree, Associate Professor Radboudumc, Nijmegen, the Netherlands Tuesday, 23 September, 2014

Disclosures

• Clinical trials and studies funded by EDCTP, BMG, NWO, NACCAP, KNCV

• Advisory board Janssen Cilag

• Clinical trial drugs donated by Sanofi

Outline

• Introduction, why shorter treatment?

• Resistance

• What is in the pipeline? • Repurposed drugs • New drugs • Combinations, trials and expectations

• Conclusion

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 40-45 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 Ma et al., Lancet, 2010 • 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 Who are performing clinical trials in TB?

• Largest institution to coordinate: GATB = Global Alliance for TB drug Development

• www.tballiance.org

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

Dakar, October 2013 African PanACEA Partners:

Albert-Schweitzer- Makarere University Hospital Tuberculosis Unit NTLP Medical Research Unit

IHRDC Bagamoyo - Ifakara KCMC Health Research and Kibong’oto National Developement Centre Tuberculosis Hospital

MMRP Mbeya Medical Research Programme

UNZA University of Zambia College of Medicine Medical School Blantyre

WITS University of Witwatersrand INS AURUM Instituto National de Aurum Institute for Health Saute Research

UCT + Stellenbosch University of Cape Town / Stellenbosch See also: • Working Group on New TB Drugs:

www.newtbdrugs.org

• Treatment Action Group (TAG) pipeline report www.pipelinereport.org 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 8 + 12 months, but in many patients even longer

• Therefore: some promising shorter treatment developments

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. 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 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 Treatment shortening in drug sensitive TB Compounds under investigation

• Established drugs: H, Rifamycins, Z, E ….. • Repurposed drugs: thioridazine, amoxycilline + clavulanic acid, cotrimoxazole, clofazimine, ertapenem, etc. • Novel compounds • TMC207 (bedaquiline) • OPC-67683 (delamanid) • PA-824 • SQ109 • PNU-100480 (sutezolid) • AZT-5847 • Very large number of combinations to test • Must develop regimens not single drugs

Rifamycines

• Rifampicin HR1, HR2, HIRIF, RIFATOX

• Rifapentine study 29, 29 X, plans for phase III

HIGHRIF 1 (HR1) study design 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 CFU (colony forming units) Time

CFU

EBA: Rate of fall of logCFU per ml of sputum per day

Days CFU

Fitted estimates of mean baseline log10(CFU)/ml by treatment 1.0 0.5 0.0 -0.5 -1.0 -1.5 -2.0 -2.5 -3.0 -3.5 -4.0 -4.5

-5.0 log10(cfu)/ml,change fitted frombaseline 0 2 4 6 8 10 12 14 Visit

Control (10 mg/kg) 20 mg/kg 25 mg/kg 30 mg/kg 35 mg/kg

Fitted estimates of difference from mean baseline

log10(CFU)/ml by visit and treatment arm from linear fixed effects model with 95% confidence intervals.

CFU EBA 0-14 days PK

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 Cmax (nonlinear PK) without ceiling

HR2 – study design Time to culture conversion on MGIT

Kaplan-Meier survival estimates

1.00

0.75

0.50

0.25 0.00 0 14 28 42 56 70 84 98 112 126 140 154 analysis time Number at risk dose = 600 48 47 46 39 28 22 14 8 8 8 8 dose = 900 47 46 41 31 23 19 13 7 7 7 7 dose = 1200 47 46 40 28 18 15 12 6 6 6 6 dose = 600 dose = 900 dose = 1200

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

PanACEA-MAMS-TB-01

Study arms, duration of treatment 3 months:

• Control: HRZE INH, rifampicin standard, pyrazinamide, EMB

• Arm 1 (R35): HR35ZE INH, rifampicin 35 mg/kg, pyrazinamide, EMB

• Arm 2 (Q): HRZQ INH, rifampicin standard, pyrazinamide, SQ109 300 mg

• Arm 3 (R20Q): HR20ZQ INH, rifampicin 20 mg/kg, pyrazinamide, SQ109 300 mg

• Arm 4 (R20M): HR20ZM INH, rifampicin 20 mg/kg, pyrazinamide, moxifloxacin

N= 382 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 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 • Double-blind for RPT arms • 5/7 + DOTS • 7/7 + DOTS on week days • Fasting • Fed • Primary endpoint: Efficacy & Safety • Primary endpoint: Safety 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) The quinolones

4

• NIRT (Moxifloxacin or Gatifloxacin)

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

REMox favorable outcome REMox unfavorable outcome 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

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

NIRT, Chennai and Madurai, India

• Three times a week gatifloxacin or moxifloxacin, N= 416 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!

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!! Surrogate markers for sterilizing capacity (for relapse), are they there? What else?

Old compounds

• Pyrazinamide: dose probably too low

• Isoniazide: high doses show efficacy in MDRTB

• Clofazimine

• Thioridazine

• Cotrimoxazol, amoxycilline/clavulanic acid, etcetera H37Rv H37Rv Infection Control Plus infection Thioridazine (B) In contrast, less (A) Extensive lung consolidation pneumonia (arrow) (arrows) is visible in is seen in the lung of control animals after Mice treated with 120 days of infection Thioridazine 32 mg/kg by drug-sensitive daily by intragastric cannula. control Strain H37Rv.

MDR MDR Infection Control Plus Infection Thioridazine (C) Control mice after 120 In comparison, less lung days of infection consolidation (arrow) is seen with MDR strain in the lung of mice infected by show extensive the MDR-TB strain and pneumonic areas treated daily during two (arrow) months with 70 mg/kg of thioridazine 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

New compounds

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 The nitroimidazoles

PA 824 (Chiron, now Novartis) OPC 67683 (Otsuka): delamanid

• Derivatives from metronidazol

21 November EMA approved the drug: Deltyba 50 mg

Source: EMA/CHMP/713909/2013 Committee for Medicinal Products for Human Use (CHMP) logCFU Dose PA - 824 ranging: PA

4.5 5.5 4 5 6 0 Bi-linear regression of vs logCFU day of treatment over regression Bi-linear - 2 824 200mg, 824 200mg, 150mg, 100mg, 50mg Rifafour e275 e275 Rifafour 150mg PA-824 50mg PA-824 4 6 Day 8 PA-824 200mg PA-824 100mg PA-824 AAC56:3027 2012; 10 12

14

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 Oxazolidinones: inhibit protein synthesis

• Linezolid: many side effects, use now in MDR/XDR TB

• PNU 100480 : sutezolid (now Sequella). More potent than linezolid in in vitro, ex vivo and murine models.

• AZD5847 (AstraZeneca): BID 1200 mg. Phase II study planned

SQ 109 (Sequella)

In PanACEA, no EBA in liquid media

2.2 2.2 2.0 2.0 1.8 1.8 1.6 1.6 1.5 1.4 1.4 1.3 1.2 1.2 1.0 1.1

1.0 0.8 DTP, percentage change from baseline from change DTP,percentage DTP, percentage change from baseline from change DTP,percentage 0.9 0 2 4 6 8 10 12 14 0 2 4 6 8 10 12 14 Day of administration of drug Day of administration of drug 75mg SQ109 150mg SQ109 75mg SQ109 150mg SQ109 300mg SQ109 150mg SQ109 + RIF 300mg SQ109 150mg SQ109 + RIF 300mg SQ109 + RIF RIF Monotherapy 300mg SQ109 + RIF RIF Monotherapy Lower 95% limit Upper 95% limit

Fitted estimates of change from baseline of DTP by visit and Fitted estimates of percentage change from baseline of DTP by visit treatment allocation from mixed effects model (PP) and treatment allocation from mixed effects model assuming linear decline with 95% confidence intervals (PP) SQ109

• In first interim analyis in MAMS

• Both SQ109 arms were not superior

• Both arms were therefore stopped 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 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 Thank you