About TB Alliance
Putting science to work for better, faster TB cures

Fighting pandemics
COVID-19 pandemic caused by virus• Caused by SARS-CoV-2, a type of coronavirus•

Primarily affects the respiratory system but other organs as well•An airborne disease•

More than 5 million people dead from COVID-19(likely significant underestimation)

Tuberculosis•

Caused by bacteria Mycobacteria tuberculosis•

Affect mainly the respiratory system but other organs as well•An airborne disease responsible for more than 1.5 million deaths in 2020•

Has been with humanity for millennia

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TB is a Pandemic3Evolution of New TB Therapies

4Cape Town Declaration (Feb 2000)•The Cape Town Declaration was issued to accelerate the development of newdrugs to shorten the treatment of TB and to facilitate its control in the poorestcountries•

Signatories included the Rockefeller Foundation, US NIH, Bill and Melinda Gates
Foundation, the Welcome Trust, Doctors Without Borders, among others•

This provided a road map for Global Alliance for TB Drug Development (TBAlliance)•We are a Product Development Partnership (PDP) and rely heavily on thecollaborations with academic laboratories and the pharmaceutical industry tomaximize the speed and the efficiency of drug discovery and development•We cover the entire drug development process including 1) target selection, 2)
screening, 3) hit-to-lead, 4) lead optimization, 5) preclinical development, 6) Phase Istudies, 7), Phase II studies, 8) Phase III studies, 9) registration, and 10)commercialization•TB Alliance has approximately 60 employees and based in New York City, USA andPretoria, South Africa

5Story of Pretomanid (Pa-824)•The original compound was licensed from Pathogenesis (Chiron)•New chemotype and new mechanism of action•Potent in vitro and in vivo activity•Drug combinations studies at Johns Hopkins University(JHU)
showed promising synergistic activity in animal models
especially in combination with bedaquiline and linezolid – i.e. the “BPaL regimen”

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Nix-TB Phase 3 Clinical Trial
Patients with XDR-TB or who have failed or are intolerant to MDR-TB Treatment

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Nix-TB Results
New England Journal of Medicine, March 2020*--**--**Using definition of XDR-TB prior to 2020**Treatment-intolerant or non-responsive MDR-TB8

U.S. FDA Approves New Treatment for Highly Drug-Resistant Forms of TB
The BPaL regimen (bedaquiline + pretomanid + linezolid) received U.S. approval for people withXDR-TB or treatment-intolerant/non-responsive MDR-TB•

Pretomanid was approved under the LPAD* pathway
for the treatment of XDR-TB or treatmentintolerant/non-responsive MDR-TB in August 2019

•The three-drug, all-oral, six-month regimen wasstudied in the Nix-TB clinical trial•Nix-TB data have demonstrated a successful
outcome in 90 percent of patients after six months oftreatment with BPaL and six months of posttreatment follow-up•This high efficacy was sustained through two-year
follow-up after end of treatment

Please see Full Prescribing Information at:tballiance.org/pretomanid* Limited Population Pathway for Antibacterial and Antifungal Drugs

Michele Spatari/AFP
Source: Conradie et al. Bedaquiline, pretomanid and linezolid for treatment of extensively drug resistant,
intolerant or non-responsive multidrug resistant pulmonary tuberculosis. N Eng J Med 2020;382:893-902.

9About Pretomanid (Pa-824)
Pretomanid is only the third new anti-TB drug approved for use by U.S. FDA in more than 40years, and the first non-conditional approval•Pretomanid is the first anti-TB drug to be developed and registered by a not-for-profit organization•It is a new chemical entity and a member of a class of compounds known as nitroimidazooxazines– Novel compounds are important in pursuing new TB treatments because resistance to many drugs and drugclasses currently used to treat TB is relatively widespread

For more on pretomanid’s unique mechanism of action, visit: tballiance.org/pretomanid*as of Aug 2021

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The Future of TB Treatment
Novel drug combinations enable shorter, simpler and more effective treatment
Available Therapies

Universal Small
Molecule Regimen

Universal Regimen +Novel Approaches

4+≤37-10MonthsMonths

Days

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The Future of TB Treatment
The future, however, is not here yet and we need as many drug hits/leads as possible, not only in quantity because oftheir attrition rates but also in quality (mechanism and target) for fighting drug resistance and for shortening treatment
duration

Drug Leads

Development
Candidates

Successful Launching

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Possible Game Changers in Identifying Hits/Leads
Going from empirical approaches to more target-based approaches
1. CRISPR-interference technology to identify vulnerable genes in Mtb -> J M Rock and D Schappinger, Cell, 2021,184, 4579-4592
2. Metabolomics of Mtb -> K. Planck and K. Rhee, Methods Mol Biol, 2021, 2314, 579-593
3. Caseum: a Niche for Mtb Drug-Tolerant Persisters, J. J. Sarathy and V. Dartois, Clinical Microbiol Rev. 2020, 33(3) e00159-19
4. Mtb: Bacterial fitness within the host macrophage, D. G. Russell, Microbiol Spectr 2019, 7(2)5. Efficient Measurement of Drug Interactions with DiaMOND, B. B. Aldridge, Methods Mol Biol 2021, 2314, 703-713
6. Computational approaches to drug-combination therapies, R. Savic, Eur Respir J., 2021, 57, 2001756
7. Artificial Intelligence, Machine Learning, and Deep Learning in Real-Life Drug Design Cases, C. Mueller, et al.,Artificial Intelligence in Drug Design, 2022, 2390, 383-407
8. Host-directed Therapeutic Strategies for TB, A. Kolloli and S. Subbian, Front. Medicine, 2017, 4: 171

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TB Alliance and GHIT Fund
•GHIT Fund enables Japanese academic and industrial researchers (or any international researchers accessingtargets or compounds originating from Japan) to contribute to global health•

TB Alliance has collaborated with GHIT Fund since its inception. It has enabled us to establish connections withJapanese pharmaceutical companies and research organizations•We have been able to screen unique collections of compounds and to learn diverse approaches toward drugdevelopment•The Japanese organizations we have collaborated under the GHIT sponsorship include: Astellas Pharma, Chugai
Pharmaceutical, Daiichi Sankyo, Daiichi Sankyo RD Novare, Fujifilm Pharmaceuticals, HyphaGenesis, Japan AntiTuberculosis Association (JATA), Mitsubishi Tanabe Pharma, OP Bio Factory, Shionogi Inc, Sumitomo Dainippon
Pharma, and Takeda Pharmaceutical Co.

•Ongoing projects in the Hit-to-Lead Stage with Astellas Pharma, Chugai Pharmaceutical, Daiichi Sankyo RDNovare, and Takeda Pharmaceutical Co.

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TB Alliance and GHIT Fund
There are several stages we can apply for funding, 1) target research, 2) screening, 3) hit-to-lead, and 4) productdevelopment platforms•

Bacterial physiology, genetics → Novel targets for drug discovery•

Screening methodology, unique collection of compounds → Screening•

Repurposing existing compounds → Screening•

Host-directed therapy potential → Novel targets•

AI-Based approaches to drug discovery → Various stages

For the criteria of hits and leads, see
Hit and lead criteria in drug discovery for infectious diseases of the developing world. Katsuno K, Burrows JN, Duncan K,
Hooft van Huijsduijnen R, Kaneko T, Kita K, Mowbray CE, Schmatz D, Warner P, Slingsby BT. Nat Rev Drug Discov. 2015,14(11):751-8.
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TB Alliance and GHIT Fund•

Natural product chemistry is an area of special interest•

Japan has a rich history of natural product development in the areas of antibiotics, anti-cancer agents, and antiparasitic agents, for example;–

Kanamycin, Amikacin-aminoglycosides used against TB, H. Umezawa (Institute of Microbial Chemistry), H. Kawaguchi(Bristol-Banyu),–

Avermectin, S. Omura (Kitasato University)–Mitomycins, H. Hata (Kitasato Institute)•Our co-presenters, Dr. Isshin Tanaka of Daiichi Sankyo RD Novare and Professor Scott Franzblau of University ofIllinois at Chicago both have significant experience and interest in this area•

Dr. Tanaka is Scientist at Daiichi Sankyo RD Novare and we have collaborated in the area of fermentation naturalproducts since 2014. This has been a very productive area•

Professor Franzblau is Director of Institute for Tuberculosis Research at University of Illinois at Chicago and has
been involved in most of the GHIT-funded TB projects since 201316

TB Alliance DonorsIndonesia
Health Fund17

Thank you!

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Back-up slides19

Recent Discovery Progress at TB Alliance
Advancing the pipeline•TBI-223: SAD study completed– MAD study began in January 2021
– 3-month and 6-month animal GLP studies confirmed the lack of bonemarrow toxicity•TBAJ-876: Completed IND enabling studies– Began Phase 1 trials in 2020•

TBAJ-587: Advanced in partnership with Innovative Medicines
Initiative (IMI)– Began clinical-stage testing in 2020
– 3-month safety studies completed; revealed no new findings to the 4week study•MmpL3: Selected 2 preclinical leads– MPL-446 initiated safety studies– MPL-447 endorsed into IMI portfolio; safety studies began Q1 2021

•GHIT-sponsored collaborations with Astellas, Chugai, Daiichi
Sankyo RD Novare, and Takeda21