Advancing Host Directed Therapy for Tuberculosis April 15-16, 2014

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2 Welcome and Thanks! Advancing Host Directed Therapy for Tuberculosis April 15-16, 2014

3 Advancing Host Directed Therapy for Tuberculosis Developing a Research Roadmap to Drive Through the Translational Barriers

4 Global TB Drug Pipeline 1 Discovery Preclinical Development Clinical Development Lead Development Lead Optimization Late Pre-clinical Phase I Phase II* Phase III Diarylquinolones Gyrase Inhibitors Cyclopeptides Benzimidazoles DprE Inhibitors ihna Inhibitors LeuRS Inhibitors Macrolides Ruthenium (II) Complexes Spectinamides Translocase 1 Inhibitors CPZEN 45 DC 159a Q203 SQ609 SQ641 TBI 166 PBTZ 196 TBD 354 Bedaquiline SQ 109 PA 824 AZD 5847 Sutezolid Linezolid Levofloxacin HD Rifamycins *Clofazimine* Delamanid Moxifloxacin 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 *Initiation of drug combination studies New Drugs in Clinic

5 New Drugs for Combination Studies Lead Identification Lead Optimization Preclinical Development Phase I Phase II* Phase III 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) 5

6 Still a Far Way to Go 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

7 Rationale for Specific, Small Molecule Adjunctive Immunomodulators in TB Rx Improving TB-induced immune defects Particularly macrophages/innate immunity/autophagy Decreasing tissue pathology/sanctuaries (less inflammation, necrosis, caseation, granulomas Better blood flow/o 2, 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

8 Precedent PZA and Clofazimine as HDT PZA Workshop September

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10 Empowering Macrophages and 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

11 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.

12 Autophagy

13 Multidisciplinary Research Leverage 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

14 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 necessary evaluation for both efficacy and safety of HDT agents

15 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

16 HDT Research Path Forward More support of translational research 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 preclinical data for optimal clinical evaluation For some Use models more similar to human for infection pathology and immune reactions (NHPs) Develop HDT Research ROADMAP

17 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

18 Thank You

19 Session 1 TARGETS and MECHANISMS

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21 Innate Immunity Regulation Wnt/frizzled signaling Effects 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

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23 Approved Agents for HDT Study BOTH enhance immunity/decrease inflammation primarily by enhancing AUTOPHAGY Verapamil (+may enhance BDQ, CFZ, PZA, RIF) Statins Abl/cKIT TKIs imatinib, etc.? Metformin Decrease inflammation (and IRIS) NSAIDsIbuprofen# Leukotriene inhibitors Phosphodiesterase inhibitors Corticosteroids