On May 1, 2024 SELLAS Life Sciences Group, Inc. (NASDAQ: SLS) ("SELLAS" or the "Company"), a late-stage clinical biopharmaceutical company focused on the development of novel therapies for a broad range of cancer indications, reported the preliminary data from Phase 2a trial of SLS009, a highly selective CDK9 inhibitor, in relapsed/refractory acute myeloid leukemia (r/r AML) and successful filing of a provisional patent application around the ASXL1 mutation and SLS009, including all CDK9 inhibitor drugs (Press release, Sellas Life Sciences, MAY 1, 2024, View Source [SID1234642528]). ASXL1 mutations are associated with poor prognosis in all myeloid diseases, owing to the reduced response to the current treatment options.

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SELLAS has observed a high rate of responses in patients with myelodysplasia-related molecular mutations, as defined by the World Health Organization (WHO). Among all myelodysplasia-related mutations, those in the ASXL1 gene accounted for most responders across all dose cohorts. SELLAS has now expanded the ongoing Phase 2 r/r AML study to include two additional cohorts, one with ASXL1 mutated AML patients and one with patients with myelodysplasia-related molecular abnormalities other than ASXL1.

"These early clinical results are very promising and could open up a new avenue in the treatment of AML and potentially beyond," said Joshua Zeidner, MD, Associate Professor of Medicine, Chief of Leukemia Research, Associate Chief of Research in the Division of Hematology, Director of Clinical Cancer Research Commercial Integration at the University of North Carolina Lineberger Comprehensive Cancer Center and the study’s principal investigator. "ASXL1 is a relatively common mutation in AML which leads to poor outcomes with conventional therapies. There are no known targeted therapies that are effective for these AML patients. I am extremely hopeful that SLS009 will make an impact in the management of patients with ASXL1-mutated AML and potentially other myeloid malignancies with similar disease biology."

Study highlights:

As of April 19, 2024 data cutoff, a 57% overall response rate has been achieved thus far, in the selected optimal dose regimen of 30 mg BIW, far surpassing the targeted 20% rate.
4/4 (100%) r/r AML patients with ASXL1 truncating mutations at the selected dose level achieved an overall response (CR/CRi/MLFS) and are alive.
5/8 (63%) of r/r AML patients, across all dose levels, with ASXL1 truncating mutations treated with SLS009 achieved an overall response.
A review of the mutational status of the patient in the Phase 1 trial with SLS009 monotherapy, who achieved a CR lasting 8+ months, revealed that the patient also harbored an ASXL1 mutation.
The ASXL1 mutation is found in both hematological malignancies as well as solid tumors.
All patients in the study are diagnosed with AML refractory to or relapsed after venetoclax-containing regimens. Enrollment and treatment will be focused on the participants in the expansion cohort receiving 30 mg BIW dose and diagnosed with the ASXL1 mutation.
"The remarkable responses achieved in patients with the ASXL1 mutation underscores the transformative potential of SLS009 in addressing the unmet medical needs of AML but also targeting colorectal cancer, and other tumor types with this alteration," said Angelos Stergiou, MD, ScD h.c., President and Chief Executive Officer of SELLAS. "This is evidenced by strong enthusiasm from the participating investigators reflected in robust enrollment from the clinical sites. These compelling results from the Phase 2a study further reinforce our belief that SLS009 represents a potential breakthrough for relapsed and/or refractory AML patients, and could pave the way for a potential accelerated approval in this defined patient population."

SELLAS intends to initiate discussions with the U.S. Food and Drug Administration (FDA) about the potential for an accelerated approval pathway with SLS009 in the ASXL1 molecularly defined r/r AML population as well as in patients harboring this mutation in other indications.

The Phase 2a clinical trial of SLS009 is an open-label, single-arm, multi-center study designed to evaluate the safety, tolerability, and efficacy of SLS009 in combination with aza/ven at two dose levels, 45 and 60 mg. In the 60 mg dose cohort patients were randomized into either a 60 mg dose once per week or a 30 mg dose two times per week. The target response rate at the optimal dose level is 20% with a target median survival over 3 months. In addition, the study aims to identify biomarkers for the target patient population and enrichment for further trials. For more information on the study, visit clinicaltrial.gov identifier NCT04588922.

About ASXL1
ASXL1 mutations are associated with poor prognosis in all myeloid diseases, owing to the reduced response to the current treatment options. In AML, ASXL1 mutations were an unfavorable prognostic factor as regards survival, with a significantly lower complete response rate. In MDS, ASXL1 mutations are independently associated with worse overall survival, as well as AML transformation. The tables below demonstrate ASXL mutation frequency across hematologic malignancies and solid cancers.

ASXL1 mutations in Hematologic Malignancies with ASXL1m Frequency ≥5%

Condition ASXL1m Frequency US Condition Incidence
AML (Acute Myeloid Leukemia) 20% 20,800
MDS (Myelodysplastic Syndrome) 20% 10,000
MPN (Myeloproliferative Neoplasms) 10% 20,000
CMML (Chronic Myelomonocytic Leukemia) 43% 1,100
Total 51,900

ASXL1 in Solid Cancers with ASXL1m Frequency ≥5%

Condition ASXL1m Frequency US Condition Incidence
CRC MSI-high (Colorectal Cancer with High Microsatellite Instability) 55% 22,500
Cervical Ca. (invasive) 5% 13,800
Liver Ca. 10% 42,400
Total 78,700