The Phase IIa study of KPG-818, involving 37 adult patients with SLE, demonstrated a promising safety and efficacy profile. Among the participants, 35 completed the study, with a majority being female (91.9%) and the mean age being 54 years. The patient demographics included 75.7% White and 24.3% Black or African American individuals, with an average SLE duration of 13.8 years. The study stratified patients into various dose groups (0.15 mg, 0.6 mg, 2 mg, and placebo) and monitored treatment-emergent adverse events (TEAEs). Leukopenia, lymphopenia, and neutropenia were the most common TEAEs, particularly in the higher dose groups (0.6 mg and 2 mg), where incidences were notably higher compared to the 0.15 mg and placebo groups.

Despite the higher occurrence of TEAEs in the 0.6 mg and 2 mg groups, these adverse events were predominantly mild or moderate in severity. The study reported no deaths. One patient in the 0.6 mg group experienced serious adverse events (SAEs) involving a hip fracture and intestinal obstruction, leading to discontinuation from the study. However, these SAEs were deemed unrelated to the study drug. Additionally, TEAEs led to study drug withdrawal in 22.2% of patients in the 0.6 mg group and 10.0% in the 2.0 mg group. TEAEs necessitated drug interruption in 11.1% of the 0.15 mg group, 44.4% of the 0.6 mg group, and 40.0% of the 2.0 mg group. 

On the efficacy front, KPG-818 demonstrated dose-dependent improvements in clinical outcomes. The 0.15 mg group showed significant improvements in the SLE Disease Activity Index (SLEDAI) and Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) scores compared to baseline and placebo. Pharmacokinetic analyses revealed a favorable dose-exposure relationship with a half-life of approximately 10 hours. Biologically, KPG-818 effectively reduced total B cells, Aiolos+ T cells, and Aiolos+ B cells, while increasing regulatory T cells (Treg). These findings underscore the potential of KPG-818 as an effective treatment for SLE, demonstrating both clinical efficacy and a manageable safety profile, particularly at the lower dose.

Conclusion

Currently, the biologics approved by the US FDA as adjunct therapies for SLE patients are BENLYSTA and SAPHNELO. In contrast, the use of RITUXIMAB for treating SLE is considered off-label. The growth of the SLE market is driven by several factors: the rising prevalence of SLE globally, an increasing aged population, higher healthcare expenditure, advancements in R&D for new therapies, improved awareness and diagnosis, and supportive government initiatives. The total diagnosed prevalent cases of SLE in the 7MM were around 1 million cases in 2023.

KPG-818, administered at 0.15 mg and 0.6 mg doses, demonstrated good tolerability in SLE patients over a 12-week treatment period. These proof-of-concept results suggest that KPG-818, with its unique immunomodulatory mechanism, offers a favorable benefit/risk profile in SLE, warranting further clinical development. The findings support the potential of KPG-818 as a promising treatment for SLE, justifying additional studies to further validate its efficacy and safety.