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Advancing Host Directed Therapy for Tuberculosis

April 15-16, 2014

Advancing Host Directed Therapy for Tuberculosis

Developing a Research Roadmap to Drive Through the Translational Barriers

Global TB Drug Pipeline1

Lead Development Lead Optimization Late Pre-clinical Phase I Phase II* Phase III

•Delamanid

•Moxifloxacin

•Bedaquiline•SQ 109•PA 824•AZD 5847•Sutezolid•Linezolid•Levofloxacin•HD Rifamycins•*Clofazimine*

•PBTZ 196

•TBD 354

Preclinical DevelopmentDiscovery Clinical Development

•CPZEN‐45•DC‐159a•Q203•SQ609•SQ641•TBI‐166

•Diarylquinolones•Gyrase Inhibitors•Cyclopeptides•Benzimidazoles•DprE Inhibitors•ihnA Inhibitors•LeuRS Inhibitors•Macrolides•Ruthenium (II) Complexes•Spectinamides•Translocase‐1 Inhibitors

1 Projects that have not identified a lead compound series are considered to be in the screening phase of development and are not included.  As of publication, there are 11 screening projects in progress as described on http://www.newtbdrugs.org/pipeline.php.*Initiation of drug combination studies                                                   New Drugs in Clinic

New Drugs for Combination Studies 

Some new agents for DS/DR combos ‐• Bedaquiline

– Black Box warning– Q‐T interval prolongation– Drug interactions

• Oxazolidinones (sutezolid, AZD‐5847, etc.)– Possibly serious toxicities with prolonged (> 8 wks) use

• Nitroimidazoles (delamanid and PA‐824)– Q‐T interval prolongation– Drug interaction potential with inducers– Low resistance barrier (2 in 100,000)

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Lead Identification Lead Optimization Preclinical Development Phase I Phase II* Phase III

Still a Far Way to Go

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Pipeline still not sufficient to assure at least one entirely  novel combination with increased potency and tolerance

•Only one of ten candidates entering trials advance to approval

•“Generating 5 new or repurposed drugs and at least one 1‐3 month regimen by 2020 will require an estimated 21 additional new drugs to be in clinical development by 2015.”

Rationale for Specific, Small Molecule Adjunctive Immunomodulators in TB Rx

Improving TB-induced immune defects – Particularly macrophages/innate immunity/autophagyDecreasing tissue pathology/sanctuaries(less inflammation, necrosis, caseation, granulomas…Better blood flow/O2, more permeable local environment, fewer inhibitory molecules)

• Improved immune cell access/function• Improved anti-TB drug delivery to bacilli TB may reactivate or change gene expression

to be killed by anti-TB drugs Improved TB clearance occurs in animal models Several candidate agents also being evaluated for

improved HIV therapeutic outcomes

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PZA Workshop September 2012 

PrecedentPZA and Clofazimine as HDT

Empowering Macrophagesand Maintaining BALANCE

• Activation – M1 polarization (IL‐12, TNF‐β…)• Regulatory signaling pathways – wnt/β‐catenin • Balanced with regulatory/inhibitory mechanisms –Tregs, IL‐10, TGF, eicosanoids 

• ROS and NO/anti‐oxidant mechanism balance• Lipid metabolism/storage – a foamy macroφ is a haven and incubator for Mtb

• PRR’s – TLRs, C‐lectins, NOD2,NLRs,STING, RIG‐1….• Support – Neutrophils, T‐cells, NKs, iNKT’s/MAIT, Bcells Killing and autophagy 

Autophagy’s Role in TB

PNAS | Published online October 23, 2012 | E3169

…. Here we show that autophagy plays a dual role against tuberculosis:antibacterial and anti-inflammatory.

Thus, autophagy acts in vivo by suppressing both M. tuberculosis growth and damaging inflammation.

Autophagy

Multidisciplinary ResearchLeverage the greater research resources, exploding basic discoveries, and rich drug pipelines• Oncology ‐ Cell signaling and regulation pathways

o Innate (wnt/ϐ‐caternin) macrophage polarization/function o Adaptive – PD‐1, TEM3 (immune checkpoint inhibition)

• Neurology/Degenerative Diseases o Autophagy – removal toxic intracellular molecules and bacteria (PARKED – key molecule in Parkinson’s and TB) 

• Pulmonary/Autoimmune diseases o Inflammator effectors/control pathways – cytokines (Th1/Th2), PG’s, leukotrienes

• Genomics and Epigenetics – cross‐cutting for all

HDT CAVEATS• May not work 

– PK/PD issues  ‐ delivery to site of action in active form– Extrapolation from different disease models/states – In vitro and animal model (rodent) data not translating– Complexity of regulation/signaling – counter‐reactions

• Could cause harm– Worsen TB disease course– Impact on HIV co‐infection– Increase lung damage

Pulmonary function monitoring is a necessaryevaluation for both efficacy and safety of HDT agents

Future HDT Approaches

• Dose/schedule optimization for TB use• Timing of HDT initiation• Individual “Inflammatory Profiling”

o Hyperinflammatory/High lung damage Anti‐inflammatory agent

o Hypoinflammatory/Low lung damage Immunorestorative agent

o Neither??   None or agent that stimulates autophagy

HDT Research ‐ Path Forward

• Prioritize drugs now in clinical use for TB potential at different stages of development for TB use

• Develop consensus on models/measures of effect• Evaluate most promising agents in the  most appropriate models to generate sufficient pre‐clinical data for optimal clinical evaluation 

• For some – Use models more similar to human for infection pathology and immune reactions (NHPs)

• Develop HDT Research ROADMAP

More support of translational research

HDT Research – ROADMAP Forward

Support translational research projects to • Drive through the translational barrier• Move efficiently to small POC clinical trials –faster for agents with very minimal toxicity risk

• Then ‐ Phase II/trials to shorten therapy• Coordinate planning of studies and funding 

for efficiency and synergy

Thank You

Session 1

TARGETS and MECHANISMS

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BACK-UPS

Innate Immunity Regulation

Wnt/frizzled signalingEffects on macrophages• Wnt3a + fzd1  anti‐inflammatory (M2)Via β‐catenin (and Notch‐1) signaling pathways

– Also causes NK cell anergy

• Wnt5a + fzd4  pro‐inflammatory (M1)Via activation of NF‐κB and MAPK’s

Approved Agents for HDT StudyBOTH enhance immunity/decrease inflammationprimarily by enhancing AUTOPHAGY• Verapamil (+may enhance BDQ, CFZ, PZA, RIF)• Statins• Abl/cKIT TKIs – imatinib, etc.• ? MetforminDecrease inflammation (and IRIS)• NSAIDsIbuprofen#• Leukotriene inhibitors• Phosphodiesterase inhibitors• Corticosteroids