POS0057 KPG-818, A NOVEL CEREBLON MODULATOR IN PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS: RESULTS OF A RANDOMIZE, DOUBLE-BLIND, PLACEBO-CONTROLLED, PHASE 2A STUDY

Background:

KPG-818 is a novel CRL4-Cereblon (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 involved in innate and adaptive immune cell development, maturation, and proliferation, and linked to the genetic risk for Systemic Lupus Erythematosus (SLE). KPG-818 is currently in development for the treatment of SLE as well as hematological malignancies. The KPG-818 Phase 2a study (NCT04643067) evaluated the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of KPG-818 in patients with SLE.

Objectives:

To evaluate safety, PK, PD, and preliminary efficacy of KPG-818 in patients with SLE.

Methods:

The KPG-818 Phase 2a study was a multi-center, randomized, double-blind, placebo-controlled study that was conducted in the United States. Adult autoantibody-positive SLE patients with a SLE Disease Activity Index 2000 (SLEDAI 2K) score ≥6 at screening and ≥4 at baseline were randomized (1:1:1:1) to oral KPG-818 (0.15 mg, 0.6 mg, 2 mg) or placebo once daily (QD) for 12 weeks while continuing standard background lupus medications with at least one of the following: oral corticosteroid, anti-malarial, or immunosuppressant. Primary endpoints were safety and tolerability.

Results:

A total of 37 adult SLE patients were randomized, and 35 patients completed the study. 34 patients (91.9%) were female; the mean age was 54.0 years; 28 patients (75.7%) were White, and 9 patients (24.3%) were Black or African American. The mean SLE duration was 13.8 years. The most common (>2 patients in any treatment groups) treatment-emergent adverse events (TEAEs; KPG-818 0.15 mg/0.6 mg/2 mg/placebo groups) were leukopenia (0%/22.2%/40.0%/0%), lymphopenia (0%/11.1%/40.0%/11.1%) and neutropenia (0%/22.2%/30.0%/0%). Most TEAEs were mild or moderate in severity and more common in the highest dose group. No patient in 0.15 mg group experienced these TEAEs. There was no death. 1 patient (0.6 mg group) experienced SAEs of hip fracture and intestinal obstruction and discontinued from the study. The SAEs were considered not to be related to study drug. A total of 3 patients (22.2% in 0.6 mg group and 10.0% in 2.0 mg group) experienced TEAEs leading to study drug withdrawal and 9 patients (11.1% in 0.15 mg group, 44.4% in 0.6 mg group, and 40.0% in the 2.0 mg group) experienced TEAEs leading to study drug interruption. The SLEDAI score and Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) activity scores improved relative to baseline and placebo in KPG-818 0.15 mg group. KPG-818 showed good dose-exposure correlation and T_1/2 of 10 hours; KPG-818 reduced the numbers of total B cells, Aiolos+ T cells and Aiolos+ B cells and increased Treg cells.

Conclusion:

KPG-818 0.15 mg and 0.6 mg were generally well-tolerated in this SLE population over a 12-week of treatment. The proof-of-concept findings suggest a favorable benefit/risk ratio in SLE for KPG-818, a drug with a novel immunomodulatory mechanism of action, supporting further clinical development of KPG-818 in SLE.

REFERENCES:

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Acknowledgements:

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Disclosure of Interests:

None declared.