We had the opportunity to speak with Dr. Angelos M. Stergiou, MD, Sc.D. h.c., about potential advancements in leukemia treatment through Sellas Life Sciences’ lead assets, GPS and SLS009. These innovative therapies are being developed to address significant unmet medical needs in leukemia, offering the potential for improved survival rates and enhanced quality of life for patients. Dr. Stergiou provided an in-depth look at the mechanisms of action, clinical trial progress, and strategic positioning of these candidates within the evolving landscape of acute myeloid leukemia (AML), highlighting their potential to transform patient outcomes.
Moe Alsumidaie: Can you tell me about your lead assets, GPS and SLS009, and what roles they could potentially play in treating leukemia?
Dr. Angelos Stergiou: GPS, or galinpepimut-S, is a promising asset we in-licensed from Memorial Sloan Kettering Cancer Center, currently in a pivotal phase three trial for AML, the REGAL study. It targets the WT1 antigen, which is overexpressed in many tumor types and is designed to be maximally immunogenic, targeting both CD4 and CD8 cells. This multivalent approach involves 25 carefully selected WT1 epitopes, enhancing its immunogenicity and breaking tolerance, allowing for long-term administration. The safety profile of GPS is comparable to that of a standard vaccine, with minimal side effects. This makes it a potentially unique asset among leukemia treatments, offering longer survival without compromising quality of life.
Our other lead asset, SLS009 is a CDK9 inhibitor that blocks the production of cancer-promoting proteins, leading to cancer cell death. Its high selectivity minimizes toxicity, allowing for combination with other drugs. This selectivity is crucial, as previous CDK9 inhibitors faced challenges due to toxicity. SLS009’s exceptional safety profile enables its use in combination therapies without exacerbating toxicities, providing a significant advantage in treating leukemia as well as other hematological and solid cancer types. It’s effective in killing cancer cells while being in the body long enough to avoid severe toxicities, making it a promising candidate for combination therapies in AML.
Moe Alsumidaie: What specific efficacy and safety benchmarks are you aiming to meet in the REGAL trial, and how might these results influence the trial’s continuation or modification?
Dr. Angelos Stergiou: The REGAL trial’s primary endpoint is overall survival, and we’ve recently triggered the 60th event for an interim analysis by the Independent Data Monitoring Committee (IDMC). The IDMC will assess safety, futility, and efficacy, hoping to recommend the trial’s continuation without modification or, ideally, stopping due to exceptional efficacy. The final analysis requires 80 events, aiming for a hazard ratio of approximately 0.636 to declare statistical significance. The IDMC’s role is crucial, as it evaluates the trial’s conduct, validity, and scientific integrity, guiding whether to continue, modify, or discontinue the trial.
If the IDMC recommends discontinuation due to exceptional efficacy, it would be a significant milestone, indicating that GPS has shown a substantial benefit in extending survival for AML patients at this early stage already. If the trial continues to the final analysis, it likely suggests that GPS is on track to meet its efficacy goals, further validating its potential as a maintenance therapy in AML. We’re optimistic about the trial’s outcomes, highlighting the importance of the IDMC’s independent assessment in guiding the trial’s future direction and ensuring the safety and efficacy of GPS for patients.
Moe Alsumidaie: How are you aligning your clinical trials to meet regulatory requirements, and what challenges have you encountered in this process?
Dr. Angelos Stergiou: For GPS, the primary endpoint of overall survival is well-defined and agreed upon with the FDA, ensuring alignment with regulatory expectations and, in addition, we have received fast track and orphan drug designations. SLS009 has received a rare pediatric disease designation for pediatric acute lymphoblastic leukemia, as well as fast track and orphan drug designations in AML by the FDA and we’re focusing on its development in AML. The challenge lies in ensuring trials meet stringent requirements across jurisdictions but encouraging data in overall response rates and survival guides discussions with regulatory bodies. In the ongoing Phase 2a trial with SLS009, we’ve observed a median overall survival exceeding 7.7 months in patients refractory to venetoclax-based regimens, compared to the historical 2.5 months.
This significant improvement emphasizes the potential of SLS009 to transform outcomes for heavily pre-treated AML patients, and we’re preparing to engage with the FDA about a potential accelerated clinical and regulatory approval pathway. Aligning clinical trial designs and endpoints with regulatory requirements is crucial to ensure successful approval processes. The promising results from SLS009 trials provide a strong foundation for regulatory discussions, emphasizing that we’re on the right path to potentially bring this innovative candidate to patients.
Moe Alsumidaie: What are the key considerations in selecting combination partners for SLS009, and how do you assess the potential for synergistic effects versus increased toxicity?
Dr. Angelos Stergiou: We focus on combinations with BCL-2 blockers like venetoclax, as SLS009 shows extraordinary synergy with these agents. Preclinical and clinical data indicate that SLS009 can improve response rates and is well-tolerated, even in combination. For example, preclinical studies developed a model using cancer cell lines resistant to venetoclax, which, when treated with SLS009, showed a strong efficacy effect. This model was validated in mice and most importantly further supported by patient data, demonstrating that SLS009 does not exacerbate venetoclax’s myelosuppressive effects. As almost all AML patients have heterogenous cancer cells, some cells will depend mostly on BCL2 and will be killed by venetoclax, some will depend on MCL1 and will be killed by SLS009, and some will depend on both BCL2 and MCL1 and the two-fold assault by both anti-apoptotic agents at the same time. In our ongoing Phase 2 study, the addition of azacitidine also allows for a NOXA release enhancement, thus increasing pro-apoptotic effect, a triple hit which may potentially increase the response rates in relapse/refractory 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 as we have seen remarkable response and survival data in those patients.
This rigorous approach ensures that the synergistic potential of SLS009 in combination therapies is maximized while minimizing safety risks. Combining SLS009 with other treatments without increasing toxicity is a key differentiator, offering a promising strategy for enhancing treatment outcomes in AML and potentially other cancers.
Moe Alsumidaie: How do you plan to position GPS and SLS009 within the current treatment paradigm for AML, and what differentiates your approach?
Dr. Angelos Stergiou: GPS is positioned as a maintenance therapy in AML, particularly after complete remission, due to its excellent safety profile. GPS works in the maintenance setting, providing a safe and effective option for patients in remission, potentially extending their survival without compromising quality of life. SLS009 currently targets relapse refractory AML, with the potential to move frontline. Our approach is differentiated by the safety and efficacy of the treatments, including differentiated biology and mechanism of action in ASXL1 mutation tumor types, allowing for potential coverage of the entire AML treatment paradigm, from initial treatment with SLS009 to maintenance with GPS.
Together, these assets offer a comprehensive strategy for managing AML, addressing both immediate and long-term treatment needs. We’re enthusiastic about the potential of GPS and SLS009 to impact patients’ lives, either individually or collectively significantly. The strategic positioning of these treatments within the evolving landscape of AML highlights their potential to transform patient outcomes and provide new hope for those affected by this challenging disease.
Moe Alsumidaie is Chief Editor of The Clinical Trial Vanguard. Moe holds decades of experience in the clinical trials industry. Moe also serves as Head of Research at CliniBiz and Chief Data Scientist at Annex Clinical Corporation.
