PBTZ169 (Macozinone) – phase 1a and 1b clinical trials completed
PBTZ169 is a highly potent anti-mycobacterial compound that targets the essential enzyme DprE1. Its new, yet well characterized, mode of action makes this molecule an excellent candidate, notably to treat multidrug-resistant tuberculosis.
PBTZ169 has successfully passed preclinical safety and toxicology assessments, as well as the single (SAD) and multiple ascending doses (MAD) in the Phase Ia and Ib trials, with up to 600 mg, performed at the CHUV Service of Clinical Pharmacology, and one study up to 640 mg performed by Nearmedic Plus in Russia.
PBTZ169 has been investigated in a SAD Phase Ia trial (NCT03423030) in 32 healthy subjects conducted in Switzerland. This study was a mono-centric, prospective, randomized, double-blind, placebo-controlled, single ascending dose study. The Healthy volunteers were grouped in 4 panels of 8 subjects, each undergoing 2 investigation periods, during which they received either single doses of PBTZ169 at increasing dose levels or a matching placebo. Safety and pharmacokinetic parameters were evaluated via control of vital signs and serial blood sampling. This study was completed in March 2018. The SAD trial confirmed the excellent safety and tolerability profile of PBTZ169 up to single doses of 320 mg and produced high quality data to characterize its PK profile.
The results of the Phase Ia SAD trial prompted iM4TB to pursue the clinical development of PBTZ169. Therefore, the MAD Phase Ib trial (NCT03776500) was designed to confirm its safety and tolerability over repeated dosing levels administered orally once (qd) or twice (bid) daily for 14 days, at increasing daily doses up to 1200 mg/day, compared with a placebo. The MAD study started in March 2019 with 32 healthy volunteers grouped in 4 consecutive panels. It was designed to gain further insight into PBTZ169’s PK profile and to collect additional safety data, i.e. by investigating bid regimens. The MAD trial also proved the excellent safety and tolerability profile of PBTZ169. There were no Serious Adverse Events (SAEs), and no subject was withdrawn from the study owing to Adverse Events (AEs). The study was completed in March 2020.
The Phase I trials have shown encouraging preliminary results in terms of pharmacodynamics, with subjects’ plasma samples obtained around the peak of absorption being able to kill ex vivo colonies of M. smegmatis after a suitable dilution (1:32). This is in line with the positive results communicated by Nearmedic after their 14-day Phase IIa trial at 640 mg once daily (qd) in non-resistant TB patients.
These PBTZ169 (Macozinone) Phase I clinical trials under iM4TB leadership were made possible thanks to a generous grant from the Bill and Melinda Gates Foundation.
