A phase 1 study of the safety, pharmacokinetics, and pharmacodynamics of intermittent oral PRTX007, an IRF7-biased TLR7 agonist prodrug.

e14606 Background: Systemically active toll-like receptor 7 (TLR7) agonists have demonstrated immune-activating potential but are often limited by inflammatory toxicities. PRTX007 is an orally administered small-molecule TLR7 agonist prodrug designed to selectively activate IRF7-driven interferon responses while minimizing pro-inflammatory cytokine activation. Study PRTX007-002 evaluated an intermittent weekly dosing regimen to increase the magnitude of interferon-pathway engagement following favorable safety and pharmacodynamic findings with every-other-day dosing in a prior Phase 1 study. Methods: PRTX007-002 was a randomized, placebo-controlled Phase 1 study in healthy volunteers. Fifteen subjects received either oral PRTX007 750 mg (n = 12) or placebo (n = 3) on a 3-days-on/4-days-off schedule for two weekly cycles plus one additional dose (seven total doses). Safety, pharmacokinetics (PK), and pharmacodynamic (PD) responses were assessed. Results: PK properties were consistent with prior clinical experience, with no accumulation of PRTX007 or PRX034 upon repeated dosing. Of the 15 subjects enrolled ten (66.7%) subjects experienced TEAEs considered related to study intervention. There were no serious TEAEs. A total of 3 of 15 (20.0%) participants discontinued study drug due to on-target, interferon-like symptoms which resolved within 24 hours with conservative supportive care (2 events each of headache and inflammation, and 1 event of chills, all in the PRTX007 750 mg treatment group). Median peak IFN-alpha levels in PRTX007-treated subjects were 17.1 pg/mL (96.14% CI: 3.0-51.1; p < 0.001 vs baseline), with 92% and 58% exhibiting greater than 10-fold and greater than 100-fold increases, respectively. In all three placebo control subjects IFN-alpha levels remained below the lower limit of quantification. Regarding pro-inflammatory cytokines, IL-6 excursions from baseline were transient and modest in magnitude and the levels of TNF⍺ and IL-1β for all participants remained in the normal range. Interferon-associated PD markers moved in concert in the PRTX007 treatment group, demonstrating interferon-pathway biomarker induction with increasing magnitude over consecutive dosing days and re-induction upon subsequent dosing cycles, consistent with reversible IRF7-biased plasmacytoid dendritic cell activation. Conclusions: Intermittent weekly oral dosing of PRTX007 demonstrated a favorable safety profile with a controlled statistically significant induction of interferon-pathway PD markers in healthy volunteers, with minimal pro-inflammatory cytokine activation. These findings informed dosing regimen selection for a subsequent Phase 2 study PRTX007-003 evaluating PRTX007 in combination with pembrolizumab as neoadjuvant therapy for resectable stage III melanoma. Clinical trial information: 12624000981527.