Frank CobelensTBVI SymposiumLes Diablerets, 29 January 2019

NEW TB REGIMENS AND PROSPECTS FOR THERAPEUTIC VACCINES AND HOST-DIRECTED THERAPY

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Content

New drugs and trials

Host-directed therapies & therapeutic vaccination

Cavities

Needs in TB treatment

Improve outcomes in drug-resistant TB

Shorten TB treatment

Reduce long-term residual lung impairment

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TB drug pipeline

Tiberi et al. Lancet Infect Dis 2018

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Nix-TB Trial

Conradie et al. Union Conference, 2018

Phase III ZeNIX trial

MDR/XDR-TBNix regimen for 26 weeks4 dosing/duration schedules LinezolidFollow-up 78 weeks post-completionN = 180

ClinicalTrials.gov

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NC-005 Trial: Bedaquiline – Pretomanid –Pyrazinamide (BPaZ) w/o Moxifloxacin (BPaMZ)

Dawson et al. CROI 2017

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SimpliciTB trial

www.tballiance.org

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Revised recommendationfor use of 2nd line drugs in treating MDR/XDR-TB

WHO. Rapid communication, 2018

Potential for host-directed therapy

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Strategies for treatment shortening

Drug-susceptible TB or drug-resistant TB

1. New drug combinations

2. Personalized, biomarker-based

◦ Identify those patients who need standard duration/prolonged Tx to achieve relapse-free cure

◦ Treat remaining patients for 2-3 months

3. Combine 1 and/or 2 with host-directed therapeuticsss

Only 2-3 months of standard HREZ treatment results in 70-80% relapse-free cure

Thus far treatment shortening <=4 monthshas proven difficult to achieve

Treatment shortening to >= 4 monthsunlikely to have major public health impact

Agents that can augment host defense mechanisms, modulate excessive inflammation or both, by manipulating the hosts response to a pathogen rather than targeting the pathogen itself

Stek et al. Front Microbiol 2018

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Residual lung damage post-TB treatment

0 20 40 60 80 100

Cavitation

Fibrosis

Bonchiectasis

Pleural thickening

Based on X-ray0 20 40 60 80 100

Cavitation

Fibrosis

Bonchiectasis

Pleural thickening

Nodules

Based on CT scan

Systematic review of 37 radiography studies, minimum/maximum prevalence

Meghji et al. PLoS One 2016

34% – 94% of successfully treated TB patients have residual impaired lung function(obstructive and/or restrictive)

Stek et al. Front Microbiol 2018

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Factors affecting lung damage during TB disease

Stek et al. Front Microbiol 2018

MMPs = Matrix metalloproteinases

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Main types of host-directed therapies

Zumla et al, Lancet Infect Dis 2016

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Host-directed therapies for TB: repurposed drugs and vitamins

Drug/class Mechanism Evidence

Glucocorticoids ↓ INFg, ↓ TNFα, ↓IL-1b Improved outcomes in human TB meningitis, pericarditis, pleurisy; IRIS (HIV)

NSAIDs ↑ LXA4, ↓ COX Improved survival in mice

Selective COX2 inhibitors ↓ COX2, ↑ PGE2 Improved survival in mice, trial ongoing

Statins ↓HMG-CoA reductase Reduce pathology and relapse in mice

Phosphodiesterase inhibitors ↑ Cyclic AMP/ GMP Reduce lung inflammation and promote lung repair in mice

Tyrosine kinase inhibitors ↑ autophagy Reduce pathology and bacterial load in mice

Metformin ↑ autophagy↑ reactive oxygen species

Reduces bacterial burden and lung pathology in miceand humans (but no effect in diabetic TB patients)

Rapamycine, everolimus ↑ autophagy Everolimus being tested in human TB trial

Vitamin D3 (colecalciferol) ↑ autophagy↓ IFN-g, IL-6, IL-10, TNFα↓ MMP-7 and -9

Tiberi et al, Lancer Infect Dis 2018; Palucci & Delogu. Chemotherapy 2018; Stek et al. Front Microbiol 2018

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Vitamin D3 supplementation

Meta-analysis of 8 trials of vit D3 supplementation (1787 patients)

No effect on bacteriological treatment outcomesLimited effect in MDR-TB patientsLimited effect on CXR resolution

Wu et al. BMC Pulm Med 2018

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Host-directed therapies for TB: immunomodulators and therapeutic vaccines

vaccine Composition Trials*

M. vaccae Heat-killed, intradermal Meta-analysis of 13 RCTs (DR/DS-TB): faster culture conversion, no difference in end-of-treatment outcomes.

M. indicus pranii Heat-killed, intradermal Phase III (retreatment TB): faster culture conversion, no difference in end-of-treatment outcomes.

RUTI Liposomal detoxified cellularfragments of M tuberculosis

Safe in Phase I, Phase IIa ongoing

Mesenchymal stromal cells Autologous bone marrow-derivedMSCs

Safe in Phase I, no Phase IIa ongoing

V5 immunitor Inactivated pooled blood, oralcapsule

Improved smear conversion in Phase IIa (MDR-TB), no ongoing trials

Cytokines IL-2, intradermal Meta-analysis of 4 trials (2 DS, 2 MDR-TB): marginallyimproved smear and culture conversion

IFN-γ, aerosolized Well tolerated, inconsistent effectiveness

TNFα inhibitors Etanercept oral Phase II: slightly faster culture conversion

Abate & Hoft. Immuno Targets Ther 2016; Zhang et al. PLoS One 2018

*based on published results and trials listed in ClinicalTrials.gov.

Sharma et al. Sci Rep 2017

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Adjunct M. vaccae immunization

Meta-analysis

13 RCTs (N = 22-1337 patients), Drug resistant ranging from 2-98%

Huang & Hsieh. Human Vaccines Immunother 2017

Effect on relapse?

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Cavities: key target for HDT?

Nachiappan et al. Radiography 2017Ndlovu & Malakalala. Front Immunol 2016

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Highly varied drug penetration in caseum

Dartois. Nat Rev Micriobiol 2014Prideaux et al. Nat Med 2015

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Cavities and bacterial load predict who can be treated for 4 months

Individual patient data meta-analysis of 3 treatment shortening trials (OFLOTUB, REMoxTB, RIFAQUIN)

N = 3405 patients with DR-TB

Comparison = 4 months FQ-based vs 6 months standard

Outcome = relapse-free cure

4M non-inferior to 6M

4M inferior to 6M

Imperial et al. Nat Med 2018

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Cavitation may start well before the diagnosis is made

Esmail et al. Nat Med 2016

PET-CT lesions predict onset of TB disease 6 months in advance

Changes in immune parameters canbe observed from 12-15 months

before onset of clinical TB disease

Scriba et al. Plos Pathogens 2017

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Conclusions

There is a potential role for immunomodulating host-directed therapies/therapeutic vaccination to:

◦ Improve treatment outcomes for drug-resistant tuberculosis

◦ Shorten TB treatment

◦ Reduce post-treatment lung damage

Approaches taken thus far have shown limited success

Preventing/reducing cavity formation is probably a key objective for HDT

Early diagnosis would be important to make effective HDT have (public) health impact

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Thank You

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Percentage of new TB cases with multidrug/rifampin-resistant TB, 2017

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Host-directed therapeutics being evaluated

Palucci & Delogu. Chemotherapy 2018

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Host-directed therapies: small molecule drugs

Drug/class Host target Mechanism Evidence

Glucocorticoids ↓ INFg, ↓ TNFα, ↓IL-1b Improved outcomes in human TB meningitis, pericarditis, pleurisy; IRIS (HIV)

NSAIDs Eicosanoids ↑ LXA4, ↓ COX Improved survival in mice

Selective COX2 inhibitors Eicosanoids ↓ COX2, ↑ PG-E2 Improved survival in mice, trial ongoing

Statins Cholesterol ↓HMG-CoA reductase Reduce pathology and relapse in mice

Phosphodiesteraseinhibitors

Phosphodiesterase ↑ Cyclic AMP/ GMP Reduce lung inflammation and promotelung repair in mice

tyrosine kinase inhibitors Tyrosine kinase ↑ autophagy Reduce pathology and bacterial load in mice

Metformin AMP-activatedprotein kinase

↑ autophagy↑ reactive oxygen species

reduces bacterial burden and lungpathology in mice and humans (but no effect in diabetic TB patients)

Tiberi et al, Lancer Infect Dis 2018; Palucci & Delogu. Chemotherapy 2018

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Potential host-directed therapeutics

Stek et al. Front Microbiol 2018

Inhibiting lung damage and/or promoting lung repair