## 5 From PBTZ169 to Macozinone: First Results of the Clinical Studies  
Establishment of a non-profit Innovative Medicines for Tuberculosis Foundation (iM4 TB Foundation) at Ecole Polytechnique Federale de Lausanne (EPFL) in March 2014 was a principal milestone for the further development of PBTZ169 and its transformation from a valuable TB drug candidate to the compound reaching promising results in the pilot clinical studies (Figure 3) [21]. This approach was necessary to overcome the lack of interest from pharmaceutical companies to address the disease primarily affecting low-income countries. The mission of the foundation is \"to develop better and faster-acting medicines to fight tuberculosis and bridge the gap between scientific discovery and the market in order to provide affordable TB treatment to anyone in the world\". In July 2014 the foundation joined in this effort with the Russian pharmaceutical company Nearmedic Plus LLC, which bought a license covering the use of PBTZ169 in most countries of the former Soviet Union, while iM4 TB retained the rights for the rest of the world. Investments of Nearmedic, along with funds raised by iM4 TB, including the generous support of the Bill and Melinda Gates foundation, enabled performing all necessary pre-clinical trials with PBTZ169, such as ADME (absorption, distribution, metabolism, excretion) profiling, toxicology studies, as well as production of clinical supplies of the drug, and preparation of regulatory documents necessary for entering the first clinical trials [21; 22]. Clinical studies were initiated by both iM4 TB and Nearmedic. In the randomized, double-blind, placebo-controlled Phase 1a study performed in Switzerland (NCT03423030) [23] the aim was to assess safety, tolerability and pharmacokinetic profile of PBTZ169 formulated as a spray-dried dispersion versus a native crystal powder. In addition, antitubercular activity of single escalating doses of PBTZ169 ex vivo was evaluated. The study included 32 healthy male volunteers, grouped to 4 panels of 8 subjects, each undergoing 2 investigation periods, during which they received either single doses of PBTZ169 at increasing dose levels up to 320 mg or a matching placebo. Promising results of this study encouraged the iM4 TB team to design of the Phase 1b trial (NCT03776500) [24] aimed at evaluation of the safety, tolerability and pharmacokinetics of PBTZ169 in multiple dosing up to 1200 mg/day in healthy volunteers (32 subjects grouped in 4 consecutive panels) receiving PBTZ169 for 14 consecutive days. An additional goal is to evaluate interactions of PBTZ16 with the human cytochrome P-450 enzyme family [24]. The first Phase 1 clinical trial in Russia (Nearmedic Plus LLC) (NCT03036163, PBTZ169-Z00-C01-1) [25] with an official title \"Open-label Prospective Non-comparative Study of Safety, Tolerability and Pharmacokinetics of PBTZ169 after Single and Multiple Fasting Oral Administration in Increasing Doses in Healthy Volunteers\" was carried out between January and November 2016. The drug was administered in the form of capsules containing 40 mg of the drug. The study included single escalating doses (40, 80, 160, 320, and 640 mg) in fasting conditions, as well as multiple fasting doses (320 and 640 mg) for 14 days. Overall the study included 40 participants [22]. A completed open-label prospective Phase 1b study initiated by Nearmedic Plus LLC (NCT04150224, PBTZ169-Z00-C01-3) [26] was designed to assess the safety, tolerability, pharmacokinetics, and food effects on single, double, and multiple escalating doses in healthy volunteers. During the first part of the study, safety, tolerability, and pharmacokinetics of PBTZ169 in 80 mg capsules were studied in healthy volunteers who received single or double (twice daily) fasting doses, which increased sequentially (640, 960, and 1280 mg once a day and 640 mg twice a day). The food effects were studied for a single 640 mg dose.