Background/Purpose: KPG-818 is a novel CRL4-CRBN E3 ubiquitin ligase modulator that binds to CRBN with high affinity and leads to rapid and effective degradation of Aiolos and Ikaros, the transcription factors that play critical roles in B cell development and proliferation. KPG-818 is currently in development for the treatment of SLE as well as hematological malignancies. This Phase 1b study (NCT04643067) evaluated the safety, tolerability, pharmacokinetics (PK), and potential biomarkers of KPG-818 in patients with mild to moderate SLE.

Methods: The KPG-818 Phase 1b study was an open-label, multicenter, and multiple-dose escalation cohort study. A total of 27 SLE patients were enrolled into four ascending dosing cohorts (6-8 patients in each cohort) to receive KPG-818 orally every day for 14 days in addition to standard of care therapy: A (0.15 mg), B (0.6 mg), C (2.0 mg) and D (5.0 mg). Safety and tolerability assessments included adverse events (AEs), electrocardiograms, laboratory evaluations, and physical examinations. Plasma PK profiles of KPG-818 and biomarkers (Aiolos, Ikaros, CRBN proteins, CD19+ B cells, CD268+ B cells, CD3+ T cells, T regulatory cells (Treg), and plasmacytoid dendritic cells (pDC)) were evaluated.

Results: A total of 27 adult SLE patients were enrolled in the United States; 23 patients were female (85.2%); the mean age was 54.7 years; 44.4% were White and 55.5% were Black or African American. The mean SLE duration was 12.2 years. Of the 27 patients enrolled, 23 completed the study and 4 were discontinued due to an AE or lost to follow-up. 1 Dose-limiting toxicity (urticaria, grade 3) was found in cohort C. The most-reported AEs were rash, local edema, and lymphocytopenia. Most of the adverse events were mild or moderate in severity and assessed as not related to study drug by the investigators. The pharmacokinetic evaluation of KPG-818 demonstrated dose-proportionality among cohorts with a terminal half-life t_1/2 ranging from 8.6 to 10.4 hrs, and the kinetic steady-state was attainted on approximately Day 7. In comparison to baseline, KPG-818 decreased the percentage of B cells in leukocytes, downregulated Aiolos, increased the percentage of Treg, and decreased the percentage of pDC in a dose-dependent manner.

Conclusion: KPG 818 was generally well-tolerated in this SLE population over a 14-day of treatment. The drug-related AEs, mainly skin and hematologic disorders, were clinically manageable. Treatment with KPG-818 resulted in robust and dose-dependent modulatory effects including degradation of Aiolos, B cell depletion, down-regulation of pDC, and up-regulation of Treg. These results strongly support the clinical development of KPG-818 in SLE.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/kpg-818-a-novel-cereblon-crbn-modulator-in-patients-with-sle-results-of-a-phase-ib-multiple-ascending-dose-study/