Safety and Tolerability of Difelikefalin for the Treatment of Moderate to Severe Pruritus in Hemodialysis Patients: Pooled Analysis From the Phase 3 Clinical Trial Program

Steven Fishbane, Warren Wen, Catherine Munera, Rong Lin, Sukirti Bagal, Kieran McCafferty, Frédérique Menzaghi, Joana Goncalves, Steven Fishbane, Warren Wen, Catherine Munera, Rong Lin, Sukirti Bagal, Kieran McCafferty, Frédérique Menzaghi, Joana Goncalves

Abstract

Rationale & objective: We report a pooled safety analysis of intravenous difelikefalin in participants with moderate to severe chronic kidney disease-associated pruritus (CKD-aP) treated by hemodialysis in 4 phase 3 clinical studies.

Study design: KALM-1 and KALM-2 were randomized, double-blind, placebo-controlled, pivotal phase 3 studies; CLIN3101 (52 weeks) and CLIN3105 (12 weeks) were open-label studies.

Setting & participants: Adults with moderate to severe CKD-aP treated by hemodialysis in North America, Europe, and the Asia-Pacific region.

Intervention: At least 1 intravenous placebo or difelikefalin dose of 0.5 mcg/kg for up to 64 weeks.

Outcomes: Safety.

Results: Safety analyses were conducted with 848 participants in the placebo-controlled cohort (424 participants each in the difelikefalin and placebo groups) and in 1,306 participants in the all-difelikefalin-exposure cohort. In the placebo-controlled cohort, the most commonly reported treatment-emergent adverse events (TEAEs), occurring in ≥2% of participants receiving difelikefalin and with a ≥1% higher incidence than placebo, were diarrhea (9.0% and 5.7%, respectively); dizziness (6.8% and 3.8%, respectively); nausea (6.6% and 4.5%, respectively); gait disturbances, including falls (6.6% and 5.4%, respectively), hyperkalemia (4.7% and 3.5%, respectively); headache (4.5% and 2.6%, respectively); somnolence (4.2% and 2.4%, respectively); and mental status changes (3.3% and 1.4%, respectively). These were mostly mild or moderate, with few leading to discontinuation. Incidence rates of TEAEs, serious TEAEs, and discontinuations because of TEAEs did not increase with long-term exposure. Three participants (0.7%) in the difelikefalin group and 5 participants (1.2%) in the placebo group died during the study.

Limitations: Pooled data from studies with different designs.

Conclusions: Intravenous difelikefalin demonstrated an acceptable safety profile, was generally well tolerated with long-term use, and may address the unmet treatment need for patients with CKD-aP treated by hemodialysis.

Funding: Cara Therapeutics, Inc.

Trial registration: KALM-1 is registered as NCT03422653, KALM-2 as NCT03636269, CLIN3101 as NCT03281538, and CLIN3105 as NCT03998163.

Keywords: Chronic kidney disease; difelikefalin; pruritus; safety; κ-opioid receptor.

© 2022 The Authors.

Figures

Graphical abstract
Graphical abstract

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Source: PubMed

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