In a clinical trial involving 13 patients with CLE, participants were randomized to receive either afimetoran (n = 8) or placebo (n = 5). Over the course of 16 weeks, 12 patients completed the treatment, with one patient discontinuing afimetoran due to COVID-19. Afimetoran was found to have a favorable safety profile and was well tolerated compared to placebo, with no serious adverse events reported. Notably, patients treated with afimetoran showed a significant reduction in CLASI-A scores beginning as early as week 4, an improvement that persisted through Week 16 and up to Week 20.

The study also highlighted significant molecular changes associated with afimetoran treatment. There was a rapid and sustained improvement in the molecular disease profile when comparing baseline samples from patients and NHV. This molecular improvement was observed as early as Week 1 and continued throughout the 16-week treatment period, maintaining its effect up to 4 weeks post-treatment. Additionally, the expression of IFN pathway genes in whole blood was significantly reduced at Week 1 compared to baseline (ΔGSVA enrichment score [ES] = 1.57, p < 0.0001) and compared to the placebo group (ΔGSVA ES = 0.56, p < 0.01), with this reduction sustained for the duration of the treatment and at least 4 weeks post-treatment.

Furthermore, afimetoran treatment led to a marked reduction in the expression of the drug target TLR7 and TLR8 pathway genes, as well as key cytokines such as IL-6, TNFα, IL-18, IFNγ, CCL3/MiP1α, and CCL4/MiP1β. This indicates a potent and sustained pharmacodynamic effect. GSVA revealed robust pharmacodynamic activity on immune cell populations, including both immature and activated dendritic cells, macrophages, and IFN and inflammatory pathway signatures, demonstrating afimetoran's significant impact on immune modulation in patients with CLE.

KOL insights

“Over 50 years have passed since the last therapy was approved for CLE. Parenteral (non-oral) administration, use of off-label therapies, or toxicity with long-term use of some existing therapies illustrate a key unmet need to identify novel treatments for CLE. These results provide the first clinical evidence to suggest that afimetoran may offer a benefit to patients. An early and sustained clinical response in patients taking afimetoran was observed vs. placebo as measured by CLASI-A.” – Expert Opinion

Conclusion

In 2023, the total diagnosed prevalent cases of CLE were 477,900 in the US. There is a need to increase awareness of CLE and its pathophysiology and impact on patient quality of life. Hydroxychloroquine and glucocorticoids are the sole US Food and Drug Administration approved medications for CLE, with numerous off-label treatments available. The treatment of CLE is centered upon formulating a regimen of topical and systemic therapies designed to reduce disease activity and minimize cosmetic damage. Approximately half of the patients refractory to antimalarial respond to immunosuppressants; methotrexate is a therapy for CLE if antimalarial does not work. 

TLRs, particularly TLR7 and TLR8, play a significant role in the pathobiology of SLE and have become potential targets for treating CLE. Afimetoran, a first-in-class, orally bioavailable, selective small molecule inhibitor of TLR7 and TLR8, aims to address this. In patients with CLE, afimetoran has shown to be safe and well tolerated compared with placebo. It demonstrated treatment efficacy and potent pharmacodynamic effects early in the treatment period, which persisted throughout and beyond the trial duration. The positive impact of afimetoran on the molecular disease profile, along with its potent pharmacodynamic and clinical effects, suggests that it may offer substantial therapeutic benefits for patients with CLE.

Many potential therapies are being investigated for the management of CLE, and it is safe to predict that the treatment space will experience a significant impact in the coming years owing to the improvement in the rise in the number of healthcare spending across the world