Exposure-response relationship of fedratinib in patients with intermediate-2 or high-risk myelofibrosis.

Abstract

Aims: Fedratinib is a potent, oral, Janus kinase inhibitor for the treatment of myelofibrosis (MF). This report describes exposure-response (E-R) analyses of fedratinib based on pooled data from phase 2/3 studies in patients with intermediate-2 or high-risk MF, with or without prior ruxolitinib exposure.

Methods: Pharmacokinetic (PK) exposures were derived from the population PK analysis. Efficacy endpoints included spleen volume reduction ≥35% (SVR35) and total symptom score reduction ≥50% (TSS response). Safety endpoints included grade ≥3 anaemia or thrombocytopenia, any-grade nausea/vomiting and diarrhoea. The E-R models were developed using logistic regression analyses.

Results: Fedratinib exposure was positively associated with SVR35 (odds ratio [OR], 38.2; 95% confidence interval [CI], 12.4-118; P < 0.001) and TSS response (OR, 20.8; 95% CI, 6.27-69.2; P < 0.001), after adjusting for covariates. Baseline spleen volume was inversely associated with SVR35 (P = 0.029). Prior ruxolitinib exposure was not associated with SVR35 (P = 0.090) or TSS response (P = 0.326). Although numerically higher incidence of adverse events was observed in patients with higher fedratinib exposure, there was no statistically significant association between fedratinib exposure and any safety related endpoints. Prior ruxolitinib exposure was associated with experiencing grade ≥3 thrombocytopenia (P = 0.004). Lower baseline haemoglobin level (<10 g/dL) and platelet count (<100 × 10⁹/L) were associated with experiencing grade ≥3 anaemia (P < 0.001) and thrombocytopenia (P < 0.001), respectively. Antiemetic prophylaxis was associated with lower rates of nausea/vomiting (P < 0.001).

Conclusions: Fedratinib exposure was positively associated with spleen volume reduction and TSS responses, without having significant impact on safety. Fedratinib 400 mg once daily is an appropriate dose for patients with MF regardless of ruxolitinib exposure.