On June 3, 2024 Ascendis Pharma A/S (Nasdaq: ASND) reported new and updated results from its ongoing Phase 1/2 IL-Believe Trial of TransCon IL-2 β⁄γ in a poster presentation at ASCO (Free ASCO Whitepaper) 2024, the annual meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) being held in Chicago May 31–June 4, 2024 (Press release, Ascendis Pharma, JUN 3, 2024, View Source [SID1234644029]). Data included the first presentation of Phase 2 dose expansion Cohort 4 (TransCon IL-2 β⁄γ in combination with TransCon TLR7/8 Agonist) in post anti-PD-1 melanoma and new analyses of patients from dose escalation cohorts with prior disease progression on checkpoint inhibitors, along with biomarker studies correlating cytotoxic immune cell expansion and clinical benefit.
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As of the April 16, 2024 data cutoff, confirmed clinical responses were observed in 40% (two out of five) of efficacy-evaluable patients from Cohort 4, suggesting potential synergy of Ascendis Pharma’s two novel immunotherapy agents.
Of efficacy-evaluable patients with prior disease progression on checkpoint inhibitors to date in the IL-Believe Trial, confirmed clinical responses (per RECIST v1.1) were observed in 45% (five out of eleven) administered TransCon IL-2 β/γ doses ≥80 μg/kg every 3 weeks, suggesting clinical benefit in treatment-resistant settings.
Monotherapy (n=4): 1 confirmed partial response (PR) in colorectal cancer
Combination with pembrolizumab (n=2): 1 confirmed complete response and 1 confirmed PR in small-cell lung cancer
Combination with TransCon TLR7/8 Agonist (n=5): 2 confirmed PRs in melanoma
Biomarker analysis demonstrated comparable, cytotoxic immune expansion between TransCon IL-2 β/γ monotherapy and combination therapy with pembrolizumab, indicating that administration of TransCon IL-2 β⁄γ expands cytotoxic lymphocytes and elevates levels of cytokines and chemokines in the blood without the corresponding expansion of Tregs or eosinophils (markers of toxicity). A statistically significant correlation of clinical benefit with both CD8+ T cell expansion and activation was observed, directly linking this pharmacodynamic effect to clinical activity.
In this trial, TransCon IL-2 β⁄γ alone or in combination with pembrolizumab or TransCon TLR7/8 Agonist was generally well tolerated with no new safety signals.
"We are very encouraged by the clinical response and safety profile for TransCon IL-2 β⁄γ and are pleased to see it working as designed to recruit and amplify the body’s immune response with sustained immune activation without a corresponding increase in markers of toxicity," said Stina Singel, M.D., Ph.D., Ascendis Pharma’s Executive Vice President and Head of Clinical Development, Oncology. "These new data in a heavily pre-treated population who progressed on or did not benefit from prior checkpoint inhibitors support TransCon IL-2 β⁄γ as the first biased IL-2 cytokine therapy to show not only monotherapy activity in a convenient outpatient setting every 3 weeks but also a direct correlation between clinical benefit and expansion of CD8+ T cells. We look forward to additional data readouts expected later this year from larger, indication-specific cohorts."
TransCon IL-2 β⁄γ is an investigational long-acting prodrug with sustained release of an IL-2Rβ⁄γ-selective analog (IL-2 β⁄γ), designed to address the known limitations of interleukin-2 (IL-2) cancer immunotherapy through prolonged activation of IL-2Rβ⁄γ with low Cmax. The Phase 1/2 IL-Believe Trial is investigating the safety and tolerability of TransCon IL-2 β⁄γ alone or in combination with the checkpoint inhibitor pembrolizumab and/or chemotherapy or TransCon TLR7/8 Agonist in participants with locally advanced or metastatic solid tumors. The recommended Phase 2 dose (RP2D) for TransCon IL-2 β⁄γ in the IL-Believe trial is 120 µg/kg administered intravenously every three weeks in an outpatient setting in both the monotherapy and combination-therapy arms.