Sky-1214, a Small Molecule Splicing Modulator Targeting FANCL and Fanci, Provides a New Mechanism of Action Targeting Multiple Myeloma and Non-Hodgkin's Lymphoma

Introduction: The increasing number of elderly and fragile patients with relapsed/refractory (R/R) Multiple Myeloma (MM) and Large B-cell Lymphoma (LBCL) after chemotherapy and immunotherapies necessitates new, effective and convenient therapies. Novel mechanisms of action are required to overcome the resistance generated by prior treatments. The median overall survival of ‘penta-refractory’ patients (refractory to anti-CD38 Antibodies (Abs), 2 proteasome inhibitors, and 2 IMiDs) is only 5.6 months. The new immunotherapies (CAR-Ts and bi-specific Abs), while effective in controlling the disease, require infusion, and often hospitalization. The understanding of RNA biology and the capacity to develop oral drugs for “undruggable” protein targets opens a new opportunity to address these treatment needs. FANCL and FANCI are critical components of the Fanconi anemia DNA damage repair pathway, which contributes to maintaining the genomic integrity of MM and NHL tumor cells under high replicative stress. SKY-1214 is a small molecule that modulates splicing of FANCI and FANCL pre-mRNA, causing exon skipping and introduction of premature termination codons leading to the degradation of the FANCL and FANCI mRNAs. Preclinical characterization of SKY-1214 showed high monotherapy activity in multiple MM and NHL cell lines and in cell-derived xenograft (CDX) models, including models of high-risk MM and NHL. We describe here the results of in vitro and in vivo studies of SKY-1214 in combination with agents commonly used for the treatment of R/R MM and R/R NHL. Methods: Cell growth and viability were assessed using CellTiter-Glo2.0 assay. The SynergyFinder Rpackage was used to calculate synergy scores for the combination treatments in vitro. CDX MM and NHL models were used to study combination treatments in which tumor growth and body weight were monitored. Results: Treatment with SKY-1214 in combination with dexamethasone (for MM), vincristine (for NHL) and selinexor (for MM and NHL) resulted in improved inhibition of cell growth and viability in multiple cell lines compared to the effect of SKY-1214 alone. Bliss synergy scores indicative of additivity were obtained for all the combinations and models tested. Combination with selinexor resulted in synergistic effect in specific concentration ranges both in MM (KMS-11, KMS-27) and NHL (OCI-LY3) models. In vivo studies of SKY-1214 in combination with selinexor in the KMS-11 and KMS-28BM CDX models or with vincristine in the JeKo-1 CDX model showed superior activity as compared with monotherapy treatments and demonstrated tumor regressions in most of the combination treated groups. Effects of SKY-1214 plus dexamethasone in the MM.1S CDX model also exceeded single agent activity and showed enhanced durability of effect upon treatment cessation. All in vivo combinations showed acceptable tolerability as determined by stable body weight measurements throughout the studies. Cell lines resistant to dexamethasone and bortezomib (MM.1R and KMS-11/BTZ) remained as responsive to SKY-1214 as the parental non-resistant cell lines. Conclusions : SKY-1214 treatment causes tumor cell growth inhibition and apoptosis in a broad panel of B-cell lines. Tumor regressions were observed in CDX models of high-risk MM and NHL treated with SKY-1214, both as monotherapy and in combination with selinexor or vincristine, respectively. These data, together with the favorable oral bioavailability and pharmacologic characteristics of SKY-1214 with a distinctive mechanism of action, were the basis for an IND submission and a planned FIH study to address the unmet medical need of the growing multi-refractory MM and NHL patient populations.