The main results of clinical trials of the efficacy, safety and pharmacokinetics of the perspective anti-tuberculosis drug makozinone (PBTZ169)

Abstract

Tuberculosis is a chronic infectious disease, usually localized in the respiratory system and representing one of the most important global social and biomedical health problems associated with the spread of therapy-resistant forms (multidrug-resistant and extensively drug-resistant tuberculosis). One of the most promising targets for the development of antimycobacterial drugs is the enzyme DprE1, which is involved in the synthesis of the cell wall of mycobacteria. In the series of DprE1 inhibitor drugs, the most advanced drug is PBTZ169 (INN maсozinone). Clinical trials (CT) of the efficacy and safety of macozinone are conducted by the pharmaceutical company LLC NEARMEDIC PLUS in the Russian Federation, and in other countries (Sponsors: Innovative Medicines for Tuberculosis Foundation, cole polytechnique fdrale de Lausanne and Bill and Melinda Gates Foundation). The publication describes results of completed I, IIa and Ib phases CT, conducted in the Russian Federation.
 Aim. The goal of phase I CT was to assess the safety, tolerability and pharmacokinetics (PK) of PBTZ169, 40 mg capsule, after single and multiple administration under fasting conditions in increasing doses in healthy volunteers. The goal of phase IIa CT was to study the efficacy (in terms of early bactericidal activity EBA), safety and PK of the drug PBTZ169, 80 mg capsules, in various doses, when used as monotherapy in patients with newly diagnosed respiratory tuberculosis with bacterial excretion and retained sensitivity to isoniazid and rifampicin. The purpose of phase Ib CT was to evaluate the safety, tolerability, PK of PBTZ169, 80 mg capsule, after single, double and multiple administration under fasting conditions in increasing doses, as well as the effect of food on its bioavailability in healthy volunteers.
 Materials and methods. The data of 100 healthy volunteers and 15 patients with newly diagnosed pulmonary tuberculosis, who received the study medication PBTZ169, capsules 40 mg and 80 mg, in the dose range 40 mg 1280 mg of PBTZ169, obtained during phase I, IIa and Ib CTs were analyzed. During I phases CTs, safety, tolerability, and PK of the drug after a single and multiple administration under fasting condition and after meals at rising doses were evaluated. The safety assessment included evaluation of AE/SAE, vital signs, ECG results, and laboratory tests results in the safety population. In the course of phase IIa CT, in addition to safety, tolerance, and PK evaluation, the efficacy of the drug (in terms of EBA) using sputum culture on agar with CFU/ml counting (main method) and quantitative PCR method (auxiliary method) was evaluated.
 Results. During all CTs, a high safety and tolerability profile was shown, the main PK parameters of the drug and the efficacy were described. PBTZ169 demonstrated linear PK in the dosage range up to 640 mg after single and multiple administration, a statistically significant of EBA of the drug after monotherapy at the dose of 640 mg/day was demonstrate, and it was concluded that the preferred regimen of the drug PBTZ169 intake is administration after meals. Good tolerability and a favorable safety profile of the drug in the studied doses range were demonstrate during all the CTs.
 Conclusion. One of the most promising and currently studied drugs-inhibitors of DprE1, a new target for the cell wall of mycobacteria, is PBTZ169 or macozinone, which is being develop by the Russian pharmaceutical company NEARMEDIC PLUS ltd.

Development of Macozinone for TB treatment: An Update

“…No adverse effects were considered as definitely related to the drug and, at the study completion, all adverse effects were resolved. There was no increase in adverse effects frequency with growing dose [22].…”

“…There was no increase in the frequency of adverse effects associated with increased dose or with the administration regimen (fasting or in fed conditions), for single or multiple doses. Changes in some mean vital signs, laboratory, instrumental parameters, or physical examination data were not associated with a trend to increase with a growing dose [22].…”

“…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 iM4TB retained the rights for the rest of the world. Investments of Nearmedic, along with funds raised by iM4TB, 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].…”

“…The second part of the study involved the safety, tolerability, and pharmacokinetics of PBTZ169 in 80 mg capsules in healthy volunteers who received 1280 mg daily in fed conditions, for 14 days. In total, 60 healthy volunteers (10 in each cohort) received the investigational drug and completed the study according to the protocol [22].…”

“…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].…”