XDR-TB Francesco Blasi Department Pathophysiology and Transplantation, University of Milan, Italy

Disclosures I have accepted grants, speaking and conference invitations from Almirall, Angelini, AstraZeneca, Bayer, Chiesi, GSK, Guidotti-Malesci, Menarini, Novartis, Pfizer, and Zambon I have had recent or ongoing consultancy with Almirall, Angelini, AstraZeneca, GSK, Menarini, Mundipharma and Novartis

92 countries notified at least one case of XDR-TB Ref: Global TB Control Report 2013 GLOBAL TB PROGRAMME Workshop for 18 high-priority countries of the WHO European Region on recording and reporting of drug resistant tuberculosis

Drug Resistant TB: Development and Spread 7

Causes of MDR Patient mismanagement

Definitions TB with any drug resistance MDR TB MDR-TB = Strains resistant to at least INH and RIF (most important 1st-line drugs) XDR-TB = MDR TB strains with additional resistance to any fluoroquinolone and any of the 3 injectable second-line drugs (amikacin, kanamycin, capreomycin) TDR, XXDR = Resistance to all drugs (not standardised defin) TDR/XXDR TB TB with any drug resistance MDR TB XDR TB

Current Therapy and Unmet Needs TB Alliance programs seek to help all TB patient populations Drug Sensitive TB 4 drugs taken for 6 or more months Shorter, simpler therapy M(XDR)-TB Injections and drugs taken for more than 2 years, poorly tolerated More effective, shorter, safer simpler regimens TB/HIV co-infection Drug-drug interactions with ARVs Co-administration with ARVs Latent TB Infection 9 months of isoniazid Shorter, more easily tolerated therapy Pediatric TB No adequate dosing formulations Adequate dosing regimens and formulations Current Therapy Unmet Needs

NIX-TB: “RESCUE” STUDY FOR XDR-TB New Chemical Entities in XDR-TB There is little/no treatment for XDR-/TDR-TB Several new drugs with no pre-existing resistance could have promising data by 2014 Bedaquiline, delamanid, PA-824, sutezolid, SQ109 Proposal: initiate global study of combinations of NCEs in patients with XDR-/TDR-TB at select centers with aim of cure Potential collaborators: Janssen, Otsuka, TB Alliance, Pfizer, Sequella Help patients who would otherwise die Combines a “compassionate use” program with a clinical trial to advance understanding of entirely novel regimens, which can then be applied in DS- and MDR-TB Reactive: Only slated for XDR – not expanding to MDR-TB or DS-TB; this is for patients with no other options. Drugs have not been tested together previously so unethical to attempt to treat patients for which approved cures currently exist, i.e. DS-TB MDR-TB

GLOBAL TB PROGRAMME

Delamanid Delamanid added to a background MDR-TB regimen improves significantly SS-C conversion at month 2 (45.4 vs 29.6%)

Delamanid (ERJ 2014) Results Favourable outcomes were observed in 143/192 patients (74.5%) who receiveddelamanid ≥6 months, compared to 126/229 patients (55.0%) who received delamanid for ≤2 months. Mortality was reduced to 1.0% among those receiving long-term delamanid, versus short-term/no delamanid (8.3%), p<0.001. Treatment benefit was also seen among patients with extensively drug-resistant disease. Conclusion Delamanid for 6 months in combination with an optimized background regimen can improve outcomes and reduce mortality among patients with both MDR- and XDR-TB.

New drugs: Delamanid – a nitroimidazole European Medicines Agency authorized on 21-11-2013

New drugs: Bedaquiline (BDQ) – a diarylquinoline First drug developed for TB in forty years Only data from Phase IIb trials available , further efficacy and safety data needed from rigorously conducted Phase III trials  On December 28, 2012, the U.S. FDA approved BDQ In early 2013, WHO commissioned independent review of data, assessment of validity of surrogate markers for MDR-TB outcome, and cost-effectiveness study In January 2013, WHO held an Expert Committee meeting to get advice In June 2013, after STAG-TB endorsement and through publication of interim guidelines, WHO recommended BDQ use for MDR-TB under five strict conditions WHO has disseminated its guidelines to all Member States and is working on operational manual and other guidance

Bedaquiline: Interim WHO policy guidance BDQ may be added to a WHO-recommended regimen in adult patients with pulmonary MDR-TB, under five specific conditions (conditional recommendation, very low confidence in estimates of effect): Treatment under close monitoring (eg, sound protocols) Proper patient selection (caution: PLHIV and >65; no: children & pregnancy) Patient informed consent required Treatment design based on WHO recommendations (eg, DST, dose, never adding a single drug to a failing regimen) Active pharmacovigilance (esp. cardiac, liver and renal toxicities) Urgent WHO call: acceleration of phase III trial; accurate DST; prospective collection of operational data on BDQ implementation

Bedaquiline (Bq) and PA-824 EBA at 2 w: PA-824+moxi+Z better than: bq, bq+Z, bq+PA-824 Comparable to WHO Cat 1

EBA (Early Bactericidal Activity) studies For reasons of shortening time, improving evaluation efficiency and reducing cost of lengthy evaluation, clinical trials now test new combinations in randomised, 14 day EBA studies involving pulmonary TB patients with drug susceptible disease As judged by two different microbiological endpoints, 2-3 new regimens are compared vs standard regimen on their effectiveness to reduce the number of culturable M. tuberculosis bacilli in sputum

The cost (€) to treat TB and M/XDR is enormous: prevention is cost-effective Cost per case Susceptible MDR-TB XDR-TB Estonia* 2,615 15,344 France 5,691 Germany 7,7,51 55,003 188.466 UK 6,234 62,343 Netherlands 8,340 46,990 148,136 Italy 9,294 Finland 8,243 Spain 9,384 AVERAGE 7,848 54,779 168,310

Interventions over time: old weapons might be useful again to manage XDR First sanatorium Germany, 1857 First Dispensary, Scotland, 1897 BCG vaccination Pneumotorax, Italy, 1907 Drugs, 1945-1962 MMR,1950-1980 Koch, Mtb, 1882 Fox:Ambulatory treatment, 1968 Styblo model, 1978 DOTS, 1991 sanatoria Outbreak Management, Risk Group Management screening drug therapy Socio-economic improvement

Global TB Vaccine Pipeline 2014: good but needs to keep growing Phase II Phase III Phase IIb Phase I Ad5 Ag85A McMaster CanSino VPM 1002 Max Planck, VPM, TBVI MVA85A/AERAS- 485 OETC, Aeras ID93 + GLA-SE IDRI, Aeras Hyvac 4/ AERAS-404 + IC31 SSI, sanofi-pasteur, Aeras, Intercell H56 + IC31 SSI, Aeras, Intercell Hybrid-I + IC31 SSI, TBVI, EDCTP, Intercell AERAS-402/ Crucell Ad35 Crucell, Aeras rBCG Viral vector Protein/adjuvant Attenuated M.tb RUTI Archivel Farma, S.L M72 + AS01 GSK, Aeras M. Vaccae Anhui Longcom, China MTBVAC TBVI, Zaragoza, Biofabri Immunotherapeutic: Mycobacterial – whole cell or extract Hybrid-I + CAF01 SSI, TBVI GLOBAL TB PROGRAMME 21 21

Reality check about vaccines BCG evidence and MVA85A phase 2b trial results BCG: efficacy in disseminated pediatric forms proven. Efficacy against adult contagious forms variable. Revaccination efficacy nihil or dubious MVA85A: Reality check about vaccines Today we do not have a potent pre- and post-exposure vaccine, we have BCG Today we do not have yet clarity about correlates of immunity and bio-markers Today, we do not fully understand pathogenesis and immunity Safe Showing it is feasible to test vaccine candidates in large trials, but… No detectable efficacy GLOBAL TB PROGRAMME

Pneumothorax

Global Policy: MDR-TB and XDR-TB Strengthen basic TB control, to prevent M/XDR-TB Scale-up programmatic management and care of MDR-TB and XDR-TB Strengthen laboratory services for adequate and timely diagnosis of MDR-TB and XDR-TB Ensure availability of quality drugs and their rational use Expand MDR-TB and XDR-TB surveillance Introduce infection control, especially in high HIV prevalence settings Mobilize urgently resources domestically and internationally Promote research and development into new diagnostics, drugs and vaccines

Global Policy: MDR-TB and XDR-TB Strengthen basic TB control, to prevent M/XDR-TB Scale-up programmatic management and care of MDR-TB and XDR-TB Strengthen laboratory services for adequate and timely diagnosis of MDR-TB and XDR-TB Ensure availability of quality drugs and their rational use Expand MDR-TB and XDR-TB surveillance Introduce infection control, especially in high HIV prevalence settings Mobilize urgently resources domestically and internationally Promote research and development into new diagnostics, drugs and vaccines

Global Policy: MDR-TB and XDR-TB Strengthen basic TB control, to prevent M/XDR-TB Scale-up programmatic management and care of MDR-TB and XDR-TB Strengthen laboratory services for adequate and timely diagnosis of MDR-TB and XDR-TB Ensure availability of quality drugs and their rational use Expand MDR-TB and XDR-TB surveillance Introduce infection control, especially in high HIV prevalence settings Mobilize urgently resources domestically and internationally Promote research and development into new diagnostics, drugs and vaccines

Global Policy: MDR-TB and XDR-TB Strengthen basic TB control, to prevent M/XDR-TB Scale-up programmatic management and care of MDR-TB and XDR-TB Strengthen laboratory services for adequate and timely diagnosis of MDR-TB and XDR-TB Ensure availability of quality drugs and their rational use Expand MDR-TB and XDR-TB surveillance Introduce infection control, especially in high HIV prevalence settings Mobilize urgently resources domestically and internationally Promote research and development into new diagnostics, drugs and vaccines

Global Policy: MDR-TB and XDR-TB Strengthen basic TB control, to prevent M/XDR-TB Scale-up programmatic management and care of MDR-TB and XDR-TB Strengthen laboratory services for adequate and timely diagnosis of MDR-TB and XDR-TB Ensure availability of quality drugs and their rational use Expand MDR-TB and XDR-TB surveillance Introduce infection control, especially in high HIV prevalence settings Mobilize urgently resources domestically and internationally Promote research and development into new diagnostics, drugs and vaccines

Conclusion MDRTB and XDRTB are caused by humans, they don’t exist in nature. The most common causes are inappropriate treatment by the practitioner and lack of patient adherence That said, we desperately need newer shorter regimens. The most effective of which will be combination of new molecules The critical path initiative of testing several drugs in combination rather than sequentially is an effective approach New drugs need to be used carefully to preserve their sensitivity and effectiveness

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