New Drugs, New Treatments, Shorter Regimens

Transcription

1 New Drugs, New Treatments, Shorter Regimens Sarah K. Brode, MD MPH FRCP(C) West Park Healthcare Centre, University Health Network, University of Toronto TB Elimination: Back to Basics November 16, 2016

2 TB Elimination: Back To Basics Financial Interest Disclosure (over the past 24 months) Sarah Brode Company Speaker Advisory Research Insmed Astra Zeneca Off label medication use

3 Objectives Following this session, learners will 1. Understand how MDR TB is currently treated 2. Discuss the strengths, weaknesses, and role of the shorter MDR TB treatment regimen 3. Understand the evidence supporting the use of new TB drugs (bedaquiline and delamanid), and their potential role in drug resistant TB treatment New Drugs, New Treatments, Shorter Regimens 16 November

4 Drug resistant TB definitions Multi-drug resistant (MDR): resistant to isoniazid and rifampin +/- other drugs Extensively drug resistant (XDR): MDR TB with additional resistance to a fluoroquinolone and a second-line injectable New Drugs, New Treatments, Shorter Regimens 16 November

5 TB Elimination and MDR TB WHO Priority Action Items for TB Elimination in Low TB Incidence Countries New Drugs, New Treatments, Shorter Regimens 16 November

6 TB Elimination and MDR TB WHO Priority Action Items for TB Elimination in Low TB Incidence Countries New Drugs, New Treatments, Shorter Regimens 16 November

7 Epidemiology of MDR TB: World Notified MDR-TB cases (absolute numbers), % of TB cases (3.5% of new and 20% of previously treated) estimated 450,000 cases every year (8.6 million TB cases per year worldwide) Source: New Drugs, New Treatments, Shorter Regimens 16 November

8 Drug resistant TB in Canada 177 cases of MDR TB (1.1%) 163 (92%) in foreign born 5 (3%) in Cdn born Aboriginal 9 (5%) in Cdn born other Minion et al. PLoS One 2013 New Drugs, New Treatments, Shorter Regimens 16 November

9 Epidemiology of MDR TB Public Health Agency of Canada. Tuberculosis: Drug Resistance in Canada Ottawa (Canada): Minister of Public Works and Government Services Canada; New Drugs, New Treatments, Shorter Regimens 16 November

10 Resources ATS/CDC/IDSA statement being developed New Drugs, New Treatments, Shorter Regimens 16 November

11 Medical treatment of MDR TB Which regimen? Which drugs? How many? How long? New Drugs, New Treatments, Shorter Regimens 16 November

12 Which regimen? Conventional (WHO) regimen At least 18 months Individualized or standardized Most commonly used VERSUS Shorter regimen 9-12 months Standardized Very rarely used Research ongoing New recommendation by WHO in 2016 to provide to select patients N.B. more regimens are under investigation WHO Treatment guidelines for drug resistant tuberculosis; 2016 update New Drugs, New Treatments, Shorter Regimens 16 November

13 Conventional regimen Two phases: Intensive phase, includes second line injectable: 8 months Continuation phase Total duration: at least 20 months if not previously treated for MDR TB; at least 24 months if previously treated for MDR TB Influenced by culture conversion, clinical response, extent of disease, resistance pattern, strength of regimen WHO Treatment guidelines for drug resistant tuberculosis; 2016 update New Drugs, New Treatments, Shorter Regimens 16 November

14 Duration of treatment Ahuja SD et al. Multidrug resistant pulmonary tuberculosis treatment regimens and patient outcomes: an individual patient data meta-analysis of 9,153 patients. PLoS Med 2012; 9: e New Drugs, New Treatments, Shorter Regimens 16 November

15 Management of MDR TB Individualized: Adjust treatment based on drug susceptibility testing How many drugs? At least 5 effective drugs during the intensive phase (pyrazinamide + 4 core second line drugs if possible) Chosen in hierarchical manner Further strengthen the regimen with ethambutol and highdose INH WHO Treatment guidelines for drug resistant tuberculosis; 2016 update New Drugs, New Treatments, Shorter Regimens 16 November

16 The drugs WHO Treatment guidelines for drug resistant tuberculosis; 2016 update New Drugs, New Treatments, Shorter Regimens 16 November

17 MDR TB treatment Drug Resistant TB: A Survival Guide for Clinicians, 3 rd Ed. Curry International Tuberculosis Centre 2016 New Drugs, New Treatments, Shorter Regimens 16 November

18 MDR TB treatment Cure patient Rapidly achieve conversion Prevent emergence of further resistance Prevent relapse Prevent medication side effects Prevent treatment default / non-adherence (Reduce cost) New Drugs, New Treatments, Shorter Regimens 16 November

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20 Drug adverse events in MDR TB Retrospective review of 1027 MDR TB patients in Latvia, % had 1 adverse event Nausea (58%), vomiting (39%), abdo pain (24%), psychiatric episode (13%), hepatitis (9%), renal failure (4%) 20% had a change in drug dose 64% had 1 drug discontinued Bloss et al. IJTLD 2010; 14(3): New Drugs, New Treatments, Shorter Regimens 16 November

21 Short course regimens New Drugs, New Treatments, Shorter Regimens 16 November

22 Short course regimens: Evidence All observational, prospective All included patients never exposed to second line drugs Bangladesh regimen : 9 months Clofazimine, high dose gatifloxacin, EMB, PZA throughout Plus prothionamide, kanamycin, and high-dose INH for minimum of 4 months (intensive phase extended to smear conversion) Relapse free cure of 88% among 206 patients Van Deun et al. AJRCCM 2010 New Drugs, New Treatments, Shorter Regimens 16 November

23 Short course regimens: Evidence Bangladesh regimen : 2014 follow-up included 515 patients 84% treatment success 95% of patients completed treatment within 12 months High-level FQ resistance predictor for unfavorable outcome, especially when also PZA resistant Aung et al. IJTLD 2014 New Drugs, New Treatments, Shorter Regimens 16 November

24 Short course regimens: Evidence 75 patients from Niger 1 and 150 from Cameroon 2 treated for 12 months: success in 89% 1. Piubello et al. IJTLD Kuaban et al. IJTLD 2015 New Drugs, New Treatments, Shorter Regimens 16 November

25 Short course regimens: Evidence WHO analysis: Individual patient data from Bangladesh (N=493), Uzbekistan (N=65), and Swaziland (N=24); as well as aggregated data from Cameroon (N=150), Niger (N=65) and 9 subsaharan African countries (N=408) Total number = 1,205 These were compared with the outcomes of patients without previous exposure to second-line TB drugs who were included in the adult individual patient data (aipd) analysis (N=7,665) WHO Treatment guidelines for drug resistant tuberculosis; 2016 update New Drugs, New Treatments, Shorter Regimens 16 November

26 Short course regimens: Evidence 83.4% vs. 61.7% when compared with treatment failure/relapse/death/loss to follow-up WHO Treatment guidelines for drug resistant tuberculosis; 2016 update New Drugs, New Treatments, Shorter Regimens 16 November

27 Short course regimen WHO 2016 In patients with rifampicin-resistant or multidrug-resistant TB who have not been previously treated with second-line drugs and in whom resistance to fluoroquinolones and second-line injectable agents has been excluded or is considered highly unlikely, a shorter MDR-TB regimen of 9-12 months may be used instead of a conventional regimen conditional recommendation, very low certainty in the evidence WHO Treatment guidelines for drug resistant tuberculosis; 2016 update New Drugs, New Treatments, Shorter Regimens 16 November

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29 STREAM (Evaluation of a Standardised Treatment REgimen of Antituberculosis drugs for patients with Multidrug resistant tuberculosis) trial: non-inferiority multicentre RCT

30 New Drugs, New Treatments, Shorter Regimens 16 November

31 New drugs for MDR TB New Drugs, New Treatments, Shorter Regimens 16 November

32 New Drug: Bedaquiline (TMC207) Brand name: Sirturo Class: Diarylquinoline Mechanism of action: specifically inhibits mycobacterial ATP synthase (unique) Bactericidal with significant in vitro and in vivo activity 3 phase 2b studies have demonstrated efficacy; 2 were RCTs New Drugs, New Treatments, Shorter Regimens 16 November

33 Bedaquiline - Efficacy 160 patients randomized to bedaquiline versus placebo for 24 weeks, plus standard 5 drug background regimen Results: Reduced time to conversion (83 days vs 125 days) Increased rate of conversion at 24 weeks (79% vs 58%) and at 120 weeks Increased cure rate at 120 weeks (58% vs 32%) Diacon NEJM 2014 New Drugs, New Treatments, Shorter Regimens 16 November

34 Bedaquiline - Efficacy Phase 2 open-label single arm trial of 233 patients; culture conversion 72% at 120 weeks Observational data from India (N=5), South Africa (N=91), and France (N=35) have been reported Culture conversion 100%, 76%, 97% Multiple phase 2 and phase 3 trials ongoing Pym European Respiratory Journal 2015 Udwadia International Journal of Tuberculosis and Lung Disease 2014 Ndjeka International Journal of Tuberculosis and Lung Disease 2015 Guglielmetti Clinical Infectious Diseases 2015 New Drugs, New Treatments, Shorter Regimens 16 November

35 Bedaquiline Safety 10 deaths 1 during first 24 weeks, 6 attributable to TB Increased liver enzymes more common in bedaquiline arm (9% versus 1%) QT prolongation more common in bedaquiline arm mean change from baseline 15.4 vs 3.3 msec 1 patient in bedaquiline arm had QTc > 500 msec No reports of clinically significant arrythmias CDC MMWR 2013;62;1-12 New Drugs, New Treatments, Shorter Regimens 16 November

36 Bedaquiline Approved by FDA December 2012 for MDR-TB Not approved in Canada but can obtain via Special Access Program PLUS application to Janssen Dose: 400 mg daily x 2 weeks, then 200 mg TIW x 22 weeks; may be used on a case-by-case basis > 24 weeks (CDC) Positive food effect Monitoring: ECG at baseline and 2, 12, 24 weeks LFTs monthly K, Ca, Mg at baseline New Drugs, New Treatments, Shorter Regimens 16 November

37 New drug: Delamanid Brand name: Deltyba Class: Nitroimidazole (Nitro-dihydro-imidazooxazole) Mechanism of action: inhibition of mycolic acids Bactericidal with significant in vitro and in vivo activity 2 phase 2b studies (1 RCT) demonstrated efficacy New Drugs, New Treatments, Shorter Regimens 16 November

38 Delamanid Efficacy 481 MDR TB patients randomized to delamanid or placebo for 8 weeks plus WHO regimen Results Faster culture conversion Increased proportion achieving culture conversion at 8 weeks 100 mg BID 45.4% 200 mg BID 41.9% Placebo 29.6% Gler NEJM 2012 New Drugs, New Treatments, Shorter Regimens 16 November

39 Delamanid - Efficacy 2 year follow-up data from RCT and open-label 6 month extension Patients receiving 6 months (6 or 8 months) delamanid compared to patients receiving 2 months (0 or 2 months) had A higher proportion with sustained culture conversion; 91% (130/143) vs 71% (112/158) A higher proportion of favorable outcomes; 74.5% (143/192) versus 55% (126/229) Lower mortality; 2.9% (6/205) vs 12.0% (31/259) Skripconoka European Respiratory Journal 2013 Wells European Respiratory Journal 2015 New Drugs, New Treatments, Shorter Regimens 16 November

40 Delamanid - Safety QT only adverse event statistically more common with delamanid (13% vs 4%) Nausea, vomiting, dizziness, headaches are also reported New Drugs, New Treatments, Shorter Regimens 16 November

41 Delamanid Approved for use in Europe, not in the United States Not approved in Canada but can obtain via Special Access Program Dose: 100 mg BID x 6 months Positive food effect Monitoring: ECG at baseline and monthly? K, Ca, Mg at baseline, albumin at baseline New Drugs, New Treatments, Shorter Regimens 16 November

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43 End: Questions? New Drugs, New Treatments, Shorter Regimens 16 November

44 Repurposed drug: Linezolid Variable activity in vitro Modest activity in mouse models Limited early bactericidal activity in humans Observational studies and 2 RCts suggest excellent activity in humans Adverse events common Bone marrow suppression Peripheral neuropathy and optic neuropathy Gastrointestinal, serotonin syndrome and neuroleptic malignant syndrome Dose at 600 mg daily, consider decrease to 300 mg daily if AEs New Drugs, New Treatments, Shorter Regimens 16 November

45 Repurposed drug: Clofazimine Old drug, used to treat leprosy Accumulates in tissues; prolonged half life Delayed bactericidal activity; maybe better for sterilization and preventing relapse (with other drugs)? 4 systematic reviews have evaluated the use of clofazimine for MDR TB Success rates 62-65% One RCT: 105 patients clofazimine vs placebo + background regimen Earlier sputum culture conversion Cavity closure earlier Higher treatment success (74% vs 54%, p = 0.35) O Donnell IJTLD 2016 Tang Clinical Infectious Disease 2015 New Drugs, New Treatments, Shorter Regimens 16 November

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48 Management approach for MDR TB Weak evidence that individualized treatment regimens (based on drug susceptibility testing- DST) better than standardized regimens Individualized regimens preferred 1. Orenstein et al. Lancet Infectious Diseases WHO Guidelines for the programmatic management of drug resistant tuberculosis; 2011 update New Drugs, New Treatments, Shorter Regimens 16 November

49 Lange C et al. Management of patients with multidrugresistant/extensively drug-resistant tuberculosis in Europe: a TBNET consensus statement. ERJ. 2014

50 Why do we need new drugs? Approx. 500,000 new cases of MDR-TB yearly (5% of global TB burden) Lower cure rates and higher mortality with MDR- and XDR-TB We need to be able to cure MDR and XDR-TB, and to prevent emergence of additional resistance Drugs with novel mechanisms of action will ensure activity against drug-resistant M. tuberculosis New Drugs, New Treatments, Shorter Regimens 16 November

51 Bedaquiline - Efficacy In vitro data Inhibits drug-sensitive and drug-resistant TB isolates Bactericidal against dormant (non-replicating) tubercle bacilli Murine model data As active as combination of INH/RIF/PZA (in 1 study) Addition to INH/RIF/PZA results in accelerated clearance of bacilli Synergism with PZA Enhances activity of second line drug combination New Drugs, New Treatments, Shorter Regimens 16 November

52 Bedaquiline - Efficacy 47 patients 23 bedaquiline, 24 placebo 87% HIV negative, 85% cavitary disease Patients converted faster: HR 12 (95%CI 2-61) Proportion achieving conversion at 8 weeks: 48% vs. 9% New Drugs, New Treatments, Shorter Regimens 16 November

53 Bedaquiline - Safety In larger RCT, at week 120, more deaths in bedaquiline group (9/79, 11.4% vs. 2/81, 2.5%) only 1 during 24 wk treatment period 4 deaths in bedaquiline group unexplained Increased QTc 16msec vs 6 msec at 24 wks, none >500 msec, no known associated adverse events In open label study, QT prolongation additive (clofazimine, quinolones, macrolides) New Drugs, New Treatments, Shorter Regimens 16 November

54 Bedaquiline - Efficacy Median time to culture conversion 83 days vs 125 days New Drugs, New Treatments, Shorter Regimens 16 November

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58 Continued efforts to reduce MDR-TB treatment duration, both under observational and trial conditions, is ongoing and is expected to increase the knowledge base for the effectiveness/efficacy and safety of the regimens under different field conditions, patient subgroups, and composition including new drugs. New Drugs, New Treatments, Shorter Regimens 16 November

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60 Short course regimens STREAM (Evaluation of a Standardised Treatment REgimen of Antituberculosis drugs for patients with Multi-drug resistant tuberculosis) trial Non-inferiority multicentre RCT New Drugs, New Treatments, Shorter Regimens 16 November