Plasma gastric biomarker evaluation with avatrombopag dosing in patients with chronic immune thrombocytopenia in phase 3 trials.

Avatrombopag, an oral thrombopoietin receptor agonist (TPO-RA), is approved for treatment of both immune thrombocytopenia (ITP) in adults and thrombocytopenia in patients with liver disease requiring a procedure. While the safety of avatrombopag has been demonstrated in clinical studies,1-3 preclinical repeated-dose studies of avatrombopag conducted in rats reported changes in gastric fundic glands, including degeneration, regenerative hyperplasia and atrophy. These changes were dependent on the dose, concentration and duration of avatrombopag treatment (data on file, Sobi, Inc.) and were associated with reduced gastric acid production, hypergastrinaemia and increased intragastric pH. They reversed within 4 weeks after discontinuing avatrombopag. Hypergastrinaemia has also been reported with H2-receptor antagonists (H2-RAs) and proton pump inhibitors (PPIs); this may be secondary to the suppression of gastric acid and has resulted in gastric carcinoids in rodents.4 In 2-year toxicology studies in mice and rats, the no-observed-adverse-effect-level for gastric changes was defined as exposures 9- to 11-fold compared to the human exposure at 40 mg/day in patients with ITP. While hypergastrinaemia-related gastric hyperplasia has been observed in rodents, this pathophysiology is not thought to directly translate to humans.4 To clarify this, we evaluated gastric wellness by monitoring relevant gastric biomarkers during long-term avatrombopag treatment. The gastric biomarkers pepsinogen (PG)-I, PG-II, the PG-I/PG-II ratio and fasting gastrin-17 are useful for screening for atrophic gastritis.5 Specific biomarker patterns can help determine the location of the gastritis: when atrophic gastritis is present in the fundus, plasma levels of fasting gastrin-17 are high and those of PG-I are low and/or the PG-I/PG-II ratio is low.5 To evaluate the implications of the preclinical findings, an analysis was conducted of patients who received long-term avatrombopag dosing in two phase 3 clinical trials2, 3 by screening for atrophic gastritis using gastric biomarker assessments (gastrin, gastrin-17, PG-I, PG-II and PG-I/PG-II ratio). This analysis included 2 multicentre, randomized, controlled phase 3 trials that assessed the clinical safety and efficacy of avatrombopag and included serial gastric hormone evaluation. Study 1 (NCT01433978) evaluated avatrombopag versus eltrombopag3 and Study 2 (NCT01438840) evaluated avatrombopag versus placebo.2 Enrolled patients were adults (≥18 years) with chronic ITP (baseline platelet count <30 × 109/L). In Study 1, patients were randomized 1:1 to receive a starting dose of 20 mg/day avatrombopag or 50 mg/day eltrombopag for 26 weeks followed by an optional open-label extension phase; dose titration (avatrombopag: 5–40 mg/day; eltrombopag: 25–75 mg/day) was permitted. As noted, Study 1 was terminated early due to enrolment challenges.3 In Study 2, patients were randomized 2:1 to 20 mg/day avatrombopag or placebo. Patients were excluded if: (a) they had a baseline gastrin-17 level greater than the upper limit of normal (ULN) or (b) were taking PPIs or H2RAs and were either not on a stable dose or had gastrin-17 levels >1.5 × ULN. Fasting gastric biomarker data were analysed at baseline, study week 12, end of treatment and follow-up to assess gastric safety parameters. End of treatment (planned as study week 26) was defined as the last day the patient received a dose of study drug. Follow-up was scheduled to be 5–8 weeks after the last dose date. Patients would have been discontinued from the trials if they developed two consecutive fasting gastrin-17 levels >2.5 × ULN, low serum PG-I levels or a low PG-I/PG-II ratio (with low fasting gastrin-17). If they had fasting gastrin-17 levels >5 × ULN, they were required to undergo endoscopy for gastric mucosa evaluation to continue the study. Across both trials, 64 patients received avatrombopag (Study 1, n = 17 [5 of which were initially treated with eltrombopag and switched to avatrombopag in the open-label extension phase]; Study 2, n = 47). Most patients were white (92.2%) and female (64.1%) with a mean age of 46.6 years. The median duration of avatrombopag exposure was 35.1 weeks, and doses ranged between 5–40 mg. Fifty-seven patients had daily dose data available (study 1, n = 13; study 2, n = 44) with the mean daily dose 24.6 mg (adjusted from 20 mg daily depending on platelet count). Among avatrombopag-treated patients, there were no significant changes in mean levels of fasting gastrin, gastrin-17, PG-I, PG-II or the PG-I/PG-II ratio from baseline over the course of the trials (Figure 1). The mean (standard deviation) change from baseline to the end of treatment and follow-up was 4.9 (38) and 3.7 (35) pmol/L, respectively, for gastrin (n = 56 and n = 40), 1.4 (8.3) and 2.7 (13) pmol/L for gastrin-17 (n = 58 and n = 42), 1.6 (63) and 23 (91) μg/L for PG-I (n = 57 and n = 42), −0.2 (5.0) and 1.7 (7.4) μg/L for PG-II (n = 56 and n = 41), and 0.7 (3.8) and 1.2 (4.2) for the PG-I/PG-II ratio (n = 56 and n = 41) (Table S1). All mean and median gastric biomarker levels were within the normal range at all timepoints. The proportion of patients with gastric biomarker levels above the ULN at baseline, end of treatment and follow-up was a respective 3.2% (2/63), 8.8% (5/57) and 9.8% (4/41) for gastrin; 4.7% (3/64), 17.2% (10/58) and 21.4% (9/42) for gastrin-17; 12.7% (8/63), 12.1% (7/58) and 23.3% (10/43) for PG-I; 21.0% (13/62), 20.7% (12/58) and 23.3% (10/43) for PG-II; 3.2% (2/62), 3.4% (2/58) and 7.0% (3/43) for PG-I/PG-II. There was no apparent association of either a higher dose of avatrombopag (>30 mg; Figure S1) or a longer duration of treatment (28 weeks; Figure S2) with higher levels of gastric biomarkers. No patient, albeit with only two on treatment measurements, met the gastric biomarker change criteria for discontinuation or endoscopy. Given the very limited amount of data collected for patients on eltrombopag, they could not be evaluated. These data demonstrated that, unlike preclinical studies in rats in whom gastric toxicity was observed with extremely high avatrombopag doses, chronic avatrombopag dosing in humans at approved doses was associated with insignificant increases in gastric biomarkers. No data demonstrating gastric toxicity were observed. These results confirm clinical data that there appears to be a low risk of gastric toxicity with long-term avatrombopag dosing. Michael Tarantino, James B. Bussel and Eun-Ju Lee served as study investigators. Brian Jamieson participated in data analysis. All authors contributed to data interpretation and participated in the preparation of the manuscript. All authors participated in the critical review and revision of this manuscript. All authors approved the manuscript for submission. Editorial support, specifically assistance with manuscript writing and styling, was provided by Sarah S. Bubeck, PhD, of BioCentric, Inc. (Collingswood, NJ) and funded by Sobi Inc., (Durham, NC). This study was funded by Eisai Inc. and medical writing support was funded by Sobi, Inc., Durham, NC. The funder, Eisai Inc., designed the study and was involved in the analysis and interpretation of data. Sobi Inc., Durham, NC, was involved in the analysis and interpretation of data, in the preparation of the manuscript and in the decision to submit the manuscript for publication. Michael Tarantino: Chief Medical and Chief Executive Officer of the Bleeding and Clotting Disorders Institute; owner and president of Michael D. Tarantino, MD SC, a private medical practice; serves on speaker bureaus for Amgen, BioMarin, Genentech, Grifols, Octapharma, Sobi and Takeda; serves as a private consultant for Amgen, BioMarin, Genentech, Octapharma, Principia, Sobi, Takeda and UCB. James B. Bussel: consultant/ad board attendee for Amgen, Novartis, Sobi, Rigel, UCB, Janssen, Argenx, Astra-Zeneca, Pfizer and RallyBio and is on a Data and Safety Monitoring Board at UCB. Eun-Ju Lee: consultant/advisory board member for UCB and Pharmacosmos. Brian D. Jamieson: employee of Sobi, Inc., Durham, NC. Not applicable. Not applicable. Not applicable. Not applicable. Data S1. Supporting Information Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.