Xiaoli Cheng, PhD, Tien-Yi Lee, PhD, Grace Ledet, BSc, Genet Zemade, MSc, James Tovera, BSc, Robert Campbell, MSc, Nobert Purro, PhD, Thamil Annamalai, MBA, MSc, Mohammad Masjedizadeh, PhD, David Liu, PhD, Roya Nawabi, BSc, Bittoo Kanwar, MD
Protagonist Therapeutics, Newark, CA
Introduction: PTG-200 (JNJ‑67864238) is an oral peptide that acts locally in intestinal tissues to block IL-23 signaling by selectively binding the IL-23 receptor (IL-23R). The gastrointestinal (GI)-restriction of PTG-200 is demonstrated in vivo by marked drug concentrations in GI tissues and feces and limited systemic blood exposure. PTG-200 therapeutic potential was established in a rat model of TNBS-induced colitis, where its threshold concentration in colonic tissue and luminal feces associated with efficacy was determined to inform the human efficacious dose1. The objectives of this Phase 1 study were to assess safety, tolerability, and pharmacokinetics (PK) of PTG-200.
Methods: This first-in-human (FIH) Phase 1 study was a single-center, randomized, double-blind, placebo-controlled trial comprising single and 14-day multiple ascending dose (SAD and MAD) arms in 82 healthy male volunteers. Oral doses ranged from 150 mg to 900 mg once daily (QD, fasted or fed) or twice daily (BID, fed). Subjects were monitored for safety and tolerability. PK in plasma, urine and feces was evaluated.
Results: Oral administration of PTG-200 was well-tolerated. There were no serious adverse events, dose-limiting toxicities, or clinically significant adverse events. PTG-200 plasma exposure was low (Table 1), below that expected to result in systemic biological activity. Following single-dose oral administration under fasted conditions, plasma PTG-200 concentrations exhibited dose-related increases with a median time to maximal concentration (Tmax) at 2 h. Administration of a high-fat meal prolonged the median Tmax to 4 h and had a modest effect on peak concentration (Cmax) and estimated overall exposure. Repeat dosing led to dose-related increases in plasma exposure. Consistent with a terminal half-life of ~1.5 h in plasma, PTG-200 showed no evidence of accumulation except for the 900 mg BID group. Fecal concentrations in several cohorts met or exceeded the targeted threshold concentration associated with efficacy as established using the preclinical colitis model.
Discussion: Orally administered PTG-200 was well-tolerated in this FIH study. Systemic PK was consistent with the GI-restricted design of PTG-200. These safety and PK characteristics, combined with fulfillment of fecal drug threshold concentrations, support further clinical development of PTG-200 for the treatment of IBD. A Phase 2 study in patients with moderate-to-severe Crohn’s disease is planned.
Citation: Xiaoli Cheng, PhD, Tien-Yi Lee, PhD, Grace Ledet, BSc, Genet Zemade, MSc, James Tovera, BSc, Robert Campbell, MSc, Nobert Purro, PhD, Thamil Annamalai, MBA, MSc, Mohammad Masjedizadeh, PhD, David Liu, PhD, Roya Nawabi, BSc, Bittoo Kanwar, MD. P1396 - SAFETY, TOLERABILITY, AND PHARMACOKINETICS OF PTG-200, AN ORAL GI-RESTRICTED PEPTIDE ANTAGONIST OF IL-23 RECEPTOR, IN NORMAL HEALTHY VOLUNTEERS. Program No. P1396. ACG 2019 Annual Scientific Meeting Abstracts. San Antonio, Texas: American College of Gastroenterology.