Background: Talabostat (PT-100) is an orally available small molecule that competitively inhibits dipeptidyl peptidases such as DPP-IV/CD26 and fibroblast activation protein (FAP). In vitro, talabostat promotes proliferation of hematopoietic progenitor cells. In vivo it stimulates expansion of progenitors in both white and red cell lineages and causes tumor regression in mouse models. Talabostat has also been shown to accelerate neutrophil recovery in patients and mice receiving myelosuppressive chemotherapy. Its activity appears to be mediated via rapid upregulation of cytokine and chemokine (e.g., G-CSF, IL-6, IL-8) production.

Methods: This randomized, placebo-controlled, sequential, dose-escalation study was conducted to evaluate the pharmacodynamics and safety of talabostat in healthy male subjects. 48 healthy male subjects aged 19 to 44 years were randomized to receive daily doses of either 25-, 100-, 300-, 600-, 1200-, 1800μg talabostat or placebo for 7 days. Subjects were randomized in cohorts of 8 subjects each in a 6:2 (talabostat: placebo) scheme. Pharmacodynamics were assessed by measurement of plasma DPP-IV activity, plasma G-CSF, IL-6 and IL-11, and white blood cell (WBC), and absolute neutrophil counts (ANC) at specified timepoints intervals during the study. Clinical examinations, laboratories, vitals, ECG, and adverse events (AEs) were evaluated at specified intervals.

Results: At 30 minutes post-dose, talabostat doses ≥ 100μg showed a dose-related, sustained, significant inhibition of DPP-IV activity to 75% to 95% of baseline (p<0.001) in healthy subjects. On Day 1, there was a significant increase in IL-6 at 6 and 12 hours post-dose across all dose cohorts (p<0.01). At 6 and 12 hours, respectively, an average increase in IL-6 of 1426% and 2130% relative to baseline was observed (p<0.05). There was a dose-related increase in G-CSF, with significant increases at doses ≥600μg noted pre-dose on Day 4 (p<0.05). Across all groups on Day 1, an average increase in G-CSF of 132% was noted at 6 hours. Only modest changes in WBC and ANC were noted in these healthy subjects. IL-11 remained unchanged or below the limit of quantitation. The most frequent AEs across all cohorts were (talabostat vs placebo): headache 19/36 (53%) vs 4/12 (33%), myalgia 9/36 (25%) vs 1/12 (8%), nausea 6/36 (17%) vs 0, vomiting 5/36 (14%) vs 1/12 (8%), peripheral edema 5/36 (14%) vs 0, rigors 5/36 (14%) vs 0, sore throat 4/36 (11%) vs 1 (8%)., and arthralgia 4/36 (11%) vs 0. Peripheral edema, myalgia, arthralgia, and rigors were dose-related with all but one event of peripheral edema occurring at talabostat single doses ≥1200μg. There were no serious AEs. The talabostat 1800μg dose cohort was terminated after 2 doses due to adverse events of edema, and talabostat 1200μg was considered the maximum tolerated dose.

Conclusion: Talabostat doses ≥100μg showed significant inhibition of DPP-IV activity. Significant dose-related increases in IL-6 and G-CSF were observed. ANC and WBC counts did not change significantly in healthy subjects over the 7-day study. Multiple doses of talabostat were well-tolerated. These results support conducting additional clinical studies in patients to further evaluate the hematopoietic effects of talabostat.

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