**3. Safety Evaluation in the Phase 1 Clinical Trial as PO**

The greatest advantage associated with delpazolid is its safety. In phase 1a of a phase 1 clinical trial to evaluate its safety, as illustrated in Table 1, 64 subjects were divided into eight groups, six of whom were administered delpazolid and two who were administered the placebo. The study was the first double-blind, randomized human trial of delpazolid. To deliver single-ascending-doses (SADs), delpazolid was administered in a step-wise manner from 50 mg up to 3200 mg. Only mild adverse events were observed up to 2400 mg. At a delpazolid dose of 3200 mg, gastrointestinal (GI) tract-related adverse events were noted. In the 3200 mg dose group, volunteers had to ingest 16 tablets of 200 mg delpazolid tablets at once, resulting in GI tract-related adverse events. Therefore, the maximum tolerated dose of delpazolid was determined to be 2400 mg per day.

**Table 1.** Summary of phase 1a/b and 2a dose-escalation study to assess the safety, tolerability, and pharmacokinetics of delpazolid as a single agent.


Dose-escalation process consisted of a single-ascending-dose phase (SAD) and multiple-ascending-dose phase (MAD). MTD, maximum tolerated dose; QD, quaque die (daily); BID, bis in die (twice per day); SAE, serious adverse event; EBA, early bactericidal activity; HRZE, isoniazid (H), rifampin (R), pyrazinamide (Z), and ethambutol (E). *<sup>a</sup>* Results were not yet published.

A phase 1b study was conducted based on multiple-ascending-doses (MADs) over seven days. Thirty-two subjects were divided into eight groups, six of whom were administered delpazolid and two of whom were administered the placebo. Subjects were given delpazolid in MADs from 400 mg BID (bis in die, twice a day) up to 1600 mg BID over seven days. Doses up to 1200 mg BID for seven days were well-tolerated with no specific adverse events observed. After the 7-day MAD study, a 21-day MAD study was conducted to evaluate bone marrow toxicity, which is one of the most critical side effects of linezolid [8]. Subjects administered 800 mg once a day (QD) to 1200 mg BID delpazolid were monitored for up to three weeks to more accurately assess adverse events such as myelosuppression, as signs such as decreased platelet count may be observed even after two weeks. As illustrated in Table 1, serious adverse events were not observed under the MAD-21-day condition. In summary, no myelosuppression-related adverse events or serious adverse events were observed in phase 1a with SADs up to 2400 mg and in phase 1b with MAD up to 1200 mg BID (2400 mg per day) for 21 days. Therefore, delpazolid does not appear to exhibit adverse events associated with repeated dosing. In addition, delpazolid did not cause CYP-mediated metabolism and cardiac repolarisation issues [6,9–11].
