July 29, 2019

Paula Bryant Acting Director, OBRRTR OBRRTR in DMID

Office of the Director

Clinical Research Coordination

Office of Office of Office of Office of Office of Office of , Scientific Clinical Clinical Genomics Regulatory Research Resources, Coordination Research Research and Advanced Affairs and Translational and Program Affairs Resources Technologies Research (OBRRTR) Operations

Parasitology and Enterics & Sexually Bacteriology and Respiratory International Transmitted Virology Branch Mycology Branch Diseases Branch Programs Infections Branch Branch HHS Priority Biological Threats* NIAID Cat A NIAID Cat B NIAID Cat C Bacillus anthracis () Burkholderia mallei () Antimicrobial resistance MDR anthrax Burkholderia pseudomallei Pandemic influenza () Ebola virus Rickettsia prowazekii () Marburg virus (plague) Francisella tularensis () Clostridium botulinum toxin (BoNT) Emerging infectious diseases (EID) – ‘Disease X’

Other VHFs (Junin, Machupo, Alphaviruses (WEE,EEE,VEE) Lassa, RVF) Ricin, , SEB, Q-fever

Additional DoD and/or lower priority *PHEMCE SIP 2017-18 From OBRA to OBRRTR

Broad spectrum MCMs & Narrow-spectrum MCMs Enabling Platform for CatA-BioD Technologies for CatA-C BioD & EID preparedness OBRRTR’s Role

1. ‘PHEMCE’: Address USG’s identified biodefense and public health needs • Execute and represent NIH’s BioD and public health emergency R&D to the PHEMCE 2. Product Development: advance candidate MCMs and Platform Technologies late preclinical, IND/IDE- Phase I clinical testing, enabling testing & mfg with Phase II capabilities • Biothreats = PHEMCE requirements based on DHS assessments • EID’s and other public health threats • Regulatory path - accelerated approval, Animal rule, or EUA • Transition to BARDA, DoD or industry 3. Translational Research: facilitate and manage….. • Pre-Clinical Services • Concept Acceleration Program (CAP) • Partnerships Program and CETRs • Containment Facilities/Infrastructure Preclinical Services: Provides critical data to evaluate candidate MCMs

Therapeutics Vaccines

Interventional In Vitro Biopharmaceutical Testing External Requests: full Assessment Agent Products of Antimicrobial suite of capabilities to Activity address key gaps Outbreak Response: Rapid access to evaluate interventions Leveraged by CAP to Chemistry, Manufacturing Manufacturing, and advance promising ideas Controls (CMC) into development Documentation for IND

Research Resources OBRRTR’s Approach

Adv. promising candidates & tech Gap filling studies for PD efforts

Integrated • Move MCMs along Product Dev Preclinical Services critical path Contracts Modular Gap- • Go-no-go decisions Filling Studies MCM Candidates & • De-risk platforms & Technologies to Ph I/II technologies • Outbreak response

Promising Candidates ext. requestors Evolution of the BioD Centers of Excellence

Regional Centers of Excellence for BioD & EID Centers of Excellence for Translational Research

RCE 1 (FY2003-08) RCE 2 (FY2009-13) CETR 1 (FY2014-18) CETR 2 (FY2019-23) 10 Centers 11 Centers 14 Centers 11 Centers Basic/Applied Research Basic/Applied Research Translational Translational Research Category A Category A-C Research AR Bacteria Emerging Pathogens AR Bacteria Emerging Viruses Emerging Viruses

Erica Saphire Scripps Research Institute Consortium for Immunotherapeutics Against VHFs

• Platform to ID efficacious mAb’s against select emerging viruses OBRRTR Vaccines . Goal: develop vaccines and biologics through Phase 1, facilitate handoff to government or industry partners . Product Product Development: ~14 active contracts: ~13 Development diseases; multiple platform technologies, adjuvants Contracts and delivery technologies BAAs . PCS: ~54 Vx Testing and Manufacturing TOs . Collaborative efforts: FANG, Zika, CEPI, Collaborative CarbX, CIVICs, IPTs, etc. PCS Efforts . Successes: 1 PEP indication, 3 product handoffs Task Orders to BARDA, 1 to Industry, 1 to DoD, Significant assay and animal model development contributions that benefit entire community

9 Evolution of BioD Vaccines in OBRRTR

Hanta Univ. (DNA) MTB Flu (adj) Plague (adj + Lyo) H7N9 rPA RiVax Tuli Filo rPA rPA (adj) MVA (lyo) HPAI E. Histolytica MVA Filo rPA rPA (Ad6) Dengue Filo + rPA Tuli (adj) AV7909 AV7909 Lassa Zika-YF BoNT AV7909 Filo Filo + (lyo) (RNA) Lassa

Platform Vx for Technologies for Vx for BioD Priority BioD/NIAID priority and EID BioD pathogens

= Classical BioD = EID Highlight: Anthrax Vaccine Program

 Goal: Improved Ax Vaccine [PD contracts from 2012/2014 BAAs & Preclinical services (PCS)]*

AVA PEP indication Liquid AV7909 Thermostable AV7909 Enhanced, ≤ 2 Dose (Biothrax) (Nuthrax)

. used rPA GUP NHP data . CpG 7909 adjuvant . *Lyophilized, 2 doses . rPA (E. Coli) + W805EC; to support PEP . 2 doses . equivalency to liquid in GP IN - Pfeiffer Bidose (PBL) . . accepted by 2010 . transitioned to BARDA . cGMP mfg ongoing cGMP mfg complete VRBPAC . 2015 . Phase I trial in 2020 Phase I trial 2019 . PEP approved 2015

1st Gen ‘part B’ 2nd Gen 3rd Gen 4th Gen

 Criteria: *Discontinued: *First dual adj combo to . rAd4-PA oral (PaxVax/Emergent) be co-lyo with Ag  dose sparing - single dose preferred . rPA (plant) + QS21 (Fraunhofer) . rPA (P. fluorescens) ± adj.; ID - glide SDI (Pfenex)  dry formulation/enhanced stability . Lyo. rPA; IM - dual chambered syringe (Pharmathene)  ease of delivery . MVA-PA and MVA-PA+LF+EF with DepoVax; IM (BN, Immunovaccine) FOUO Highlight: Filovirus Vaccine Program

NHP efficacy data to support Ad26/MVA hetero prime boost BN PD contract: MVA-multi-filo

Efficacy testing of Crucell PD contract: Filo Vx’s in NHPs Ad26/Ad35 multi-filo + modified

Dev. of STD Crucell PD contract: Immune Assays Ad26/MVA Ebola Preclinical and Reagents Integrated Product Dev mono- & multi-valent Services Contracts GUP Immuno & challenge studies to identify CoP Ebola Monovalent:  Completed Ph I on monovalent Ferret  Trans. to BARDA 2015 Challenge Control Animal  EMEA sub. Nov 2019 Model (NHP) Meta-  BLA sub. Mar 2021 Analysis Multivalent Filo:  Completed Ph1  - Red indicates outbreak response MARV vialed DP to DoD 12 Additional Vx PD Accomplishments

. 2nd Gen Smallpox vaccine . Quadrivalent Filovirus/Lassa vaccines • Preclinical through Phase I & II • rVSV platform demonstrated 100% protection in NHP • BN MVA-Imvamune transitioned to BARDA 2010 model • In the SNS; approved for use in Europe and Canada • Rabies platform demonstrated immunogenicity in NHP model . Inviragen/Takeda Dengue vaccine . • provided cGMP and non-clinical support for vaccine Hantavirus DNA vaccine • IND preparation completed; Phase 1 in progress • Transitioned to PD for advanced development . • Phase 3 completed Thermostable Tuberculosis vaccine • First oil based adjuvant to be co-lyophilized with . DoD IND Tularemia vaccine antigen • cGMP and clinical support • Phase I clinical trial in progress • Transferred back to DoD for SIP . Entamoeba histolytica vaccine . Thermostable Ricin vaccine • rLecA, GLA, 3M-052, and phospholipid • cGMP manufacture/release in Oct 2019 • optimizing formulation • initiate Phase 1 in Dec 2019 . Pandemic Influenza Vaccine • CpG & Advax (delta inulin) Masterfile and IND submissions • H7N9 + Advax + CpG - screening formulations Judy Hewitt Deputy Director, OBRRTR

14 The Regulatory Leap of Faith, aka Animal Rule

Animal PK or Animal Safety Animal Efficacy Immunogenicity

?? Human PK or Human Safety Human Efficacy Immunogenicity ??

15 14 Animal Rule Approvals to Date

Date Drug Indication 2003 Pyridostigmine Bromide For military personnel exposed to Soman nerve gas 2006 Cyanokit (hydroxycobalamin) * For cyanide poisoning 2012 Levaquin * For treatment of pneumonic plague Raxibacumab For treatment of inhalational anthrax, along with antibiotics 2013 Antitoxin Heptavalent (Equine) For treatment of botulism 2015 Ciprofloxacin * For treatment of pneumonic plague Anthrasil (anthrax immune globulin) For treatment of inhalational anthrax, along with antibiotics Neupogen (filgrastim) * For treatment of Hematopoietic Syndrome of Acute Radiation Syndrome Moxifloxacin * For treatment of pneumonic plague Neulasta (pegfilgrastim) * For treatment of Hematopoietic Syndrome of Acute Radiation Syndrome BioThrax (vaccine) For post-exposure prophylaxis of anthrax, with antibiotics 2016 Obiltoxaximab (Anthim) For treatment of inhalational anthrax, along with antibiotics 2018 Leukine (sargramostim)* For treatment of Hematopoietic Syndrome of Acute Radiation Syndrome TPOXX (Tecovirimat, ST-246) For treatment of smallpox

* Drugs approved with a single animal model (7) italics = new drug (5) NIAID Animal Model Used (7) NIAID Directly Involved (4) 16 Animal Rule Approval Requires:

17 What does it take to turn a research model into a pivotal model?

18 NIH-FDA Working Groups Selected Antibiotics

Criteria: Anthrax Plague Tularemia . Effective against similar disease manifestations (e.g., pneumonia) Levofloxacin Gentamicin Ciprofloxacin Amoxicillin Ciprofloxacin Levofloxacin . Different classes, to combat Augmentin Levofloxacin Doxycycline potential for resistance Azithromycin Doxycycline Tigecycline . Appropriate formulations available Clarithromycin Ceftriaxone Gentamicin . Safety database Rifampin . Special populations

19 Animal Disease is Very Similar to Human Disease

150 Bacteremia ̶ ̶ + + + + 100 Respiratory Rate

50

0

40 190

39 160

38 Heart Rate Temperature 130

37 100

36 70

6/28 6/29 6/30 7/1 7/2

20 Efficacy of 2 Fluoroquinolones

21 sNDA Submission: 400 MB, >250 files

4 NHP natural history 1 NHP efficacy 4 NHP pathology/radiology 3 NHP PK 2 assay validation 2 small animal efficacy 2 in vitro MIC 18 reports

79%: 18 reports, 19%: 1 white 64 refs, datasets paper, 70 refs 22 Timeline – Plague Studies and Approvals

23 Leveraging Approved Antibiotics for Biothreats

Anthrax Plague Tularemia  Levofloxacin  Gentamicin  Ciprofloxacin  Amoxicillin  Ciprofloxacin  Levofloxacin  Augmentin  Levofloxacin  Doxycycline Azithromycin ?? Doxycycline Tigecycline Clarithromycin Ceftriaxone Gentamicin  Clindamycin Rifampin

 approved  pre-EUA/able Not efficacious

24 Tularemia Disease Course in Humans

Operation Whitecoat Studies in the “8 Ball”

Low dose F. tularensis Schu S4 respiratory challenge study – Saslaw, et al., Arch Intern Med. 107:702, 1961 25 Animal Model Qualification: Elements of a Well-Controlled Non-clinical Study

Well-Characterized Well-Characterized Well-Documented Well-Documented + Pathogen + Challenge Process Animal Model = Pathophysiology

• Fever Onset • Bacteremia/Viremia • Strain/isolate Origin • Nebulizer • Species • Clinical pathology • Provenance • Delivery • Origin • Clinical observations • Characterization: • Challenge dose • Age, weight • Survival/Time to death Particle sizes o Morphology • • Health status • Euthanasia Environmental conditions o Growth kinetics • • Inclusion criteria criteria o Genome sequence • Inhaled volume • Exclusion criteria • Gross necropsy • Master/Working banks • Enumeration • Histopathology • Tissue burden

26 Timeline – Drug Testing & Qualification

27 Ann Eakin SSO, Concept Acceleration Program - Therapeutics

28 Drug Development is Lengthy, Risky, and Costly It takes on average 10-12 yrs & hundreds of millions of dollars to deliver a new drug to market DMID Support Reduces Risk for Product Development

Grants (R21, R01, SBIR, etc)

Product Dev Contracts (BAAs)

Preclinical Services

Ph1/VTEU Services Delivery of Drug Candidates to Late-Stage Development Partners BARDA, DoD, Industry Concept Acceleration Program Evolution of Tx Development in OBRRTR

Narrow & Broad- Narrow & Broad- Address spectrum Public Spectrum Public Narrow-spectrum CatA Bottlenecks in Health with BioD Health (BioD Drug Dev Indication optional)

31 Therapeutic Candidates Transitioned to Partners

Contractor Product/Indication Transition Partner/ Milestone reached

SIGA ST-246 (Tecovirimat)/Smallpox antiviral BARDA; NDA in 2018; HHS SNS

NexBio/Ansun DAS181/flu and parainfluenza BARDA/Phase 3 - Breakthrough designation

PharmAthene Valortim / anthrax anti-PA mAb BARDA Elusys Anthim/ anthrax anti-PA mAb BARDA; BLA in 2016; HHS SNS Emergent AVP-21D9/anthrax anti-PA mAb BARDA XOMA/OLOGY Botulism antitoxins DoD for A and B BioCryst Galidesivir/filovirus Ebola and Marburg BARDA CUBRC/ Tetraphase TP-271 / cUTI, IAI, plague, tularemia, anthrax Phase 2 ready VenatoRx VNRX-5133 BLI / cUTI, IAI, H/VAP, melioidosis BARDA/DoD Emory EIDD1931/2801/BS antiviral chik, flu, alphavirus DoD Smallpox Therapeutic: Tecovirimat (ST-246) First licensed antiviral drug for treatment or prophylaxis of smallpox

FDA Approval Basic Research Translational Product Development 2018

Screening/ Procurement for Discovery Strategic National Efficacy Stockpile (BioShield) Manufacturing Preclinical IND-enabling Studies Late Stage Dev Commercial Manufacturing Phase 1a Phase 1 & 2 FUNDING SOURCE NIAID/DMID GLP Reprotox PhasePhase 1 1 & & 2 2 Company SIGA Technologies, Inc. ClinicalClinicalAssay Trials Trials & Animal Model Dev  BARDA ** Monoclonal Antibodies to Treat Botulism Problem: Need safer, more sustainable, and more effective antitoxins against BoNT

Replace horse polyclonal antibody product in SNS with monoclonal antibody alternatives (Serotypes A, B, C*, D*, E)

Screening & Optimization, DoD isolation Characterization, A&B of BoNT Manufacturing & A/B/E/C/D Phase 1 Trials mAbs A/B/E/C/D mAb cocktails BARDA pending

OBRRTR PD Contracts Advanced NIAID Grants DMID Clinical Services Development James Marks, UCSF XOMA/Ology Galidesivir – Broad-spectrum Antiviral for BioD & EID Yellow Fever Hamster Model

. Polymerase inhibitor potent, broad-spectrum activity against >20 RNA viruses . Efficacious in multiple animal models . Safe in Phase 1 clinical trials . Animal Rule against Marburg - ongoing . Yellow fever Phase 1 trial in Brazil (2019) . CMC and Repro-tox ongoing (BARDA) Synthetic Tetracyclines – Broad-spectrum Antibacterial Drugs Problem: Bacteria have developed resistance to tetracycline antibiotics and discovery of novel analogs is hampered by difficult natural product biosynthesis.

TP-434 TP-434 Eravacycline Discovery, Advanced Dev & FDA Approval, cIAI Basic Research Characterization,Translational & Manufacturing Aug 2018 Early Development State-of-the- BARDA Contract Tetraphase art chemistry H C CH F 3 N 3 for fully- H H OH synthetic O NH tetracyclines TP-271 N 2 H OH N OH O OH O O Back-up BioD, CMC, Program IND-Enabling, TP-271 Ph 1 IV/PO Promising Candidate Ph2- NIAID Grants ready Andrew Myers, OBRRTR PD Contracts IV/PO Treatment Harvard Univ. CUBRC/Tetraphase Bacterial Pneumonia, Plague, Anthrax & Tularemia Current OBRRTR Portfolio of Therapeutics PD Contracts

DEVELOPMENT STAGE SPONSOR DRUG PRECLINICAL IND-enabling Studies PHASE I VNRX-5133 IV BL-BLI/cUTI, IAI, H/VAP, melioidosis VenatoRx VNRX-7145 Oral BL-BLI/cUTI, CABP, melioidosis (IND filed) Spero/Cantab SPR206 IV / cUTI, IAI Hawaii BioTech HB-9702 Oral, small-molecule Anthrax Anti-toxin BioCryst Pharma BCX4430 IM & IV / MARV, EBOV, YFV AbViro AV-1 (mAb) IV / Dengue Virus CARB-X Portfolio DMID contributes in-kind support (SMEs & PCS) A global public-private partnership supporting great science to fight drug-resistant bacteria

FUNDING >$550 million 2016-2021

PORTFOLIO of Drugs, Vaccines, and Diagnostics Projects (Hit-to-Lead through Ph1):

NIAID provides up to $50M in in-kind support through preclinical services (PCS) and technical expertise to assist product developers in the CARB-X program Summary of DMID Support for CARB-X Projects

NIAID support prior to 44 CARB-X award: CARB-X CARB-X projects projects 22 Grants, PCS, or (including 4 PD contracts graduates)

PCS support post-award: 28 CARB-X projects >120 studies CAP: New Drug Combo to treat MDR Bacterial Infections Very few treatment options for infections caused by MDR bacteria expressing GAP metallo-beta-lactamases, such as NDM-1

CAP Combo of Avycaz & Aztreonam used in emergency clinical cases (R. Bonomo) Leveraged PCS for mouse PK & efficacy; ARLG supporting PK/PD & Ph1

in vitro potency Mouse thigh infection in vitro HFIM PK/PD

12

11 CAZ ATM 10 9 Ph1 8 /mL 7 PK 6 5 Safety 4 logCFU Mean Log CFU/Thigh CAZ-AVI + ATM CAZ-AVI 3 LOQ 2

1

0 0 24 48 72 96 120 144 168 Time (hours)

40