onvapegleukin alfa (TransCon IL-2 β/γ) / Ascendis - LARVOL DELTA

IL Believe: A Study to Investigate Safety and Tolerability of TransCon IL-2 β/γ Alone or in Combination With Pembrolizumab and/or TransCon TLR7/8 Agonist or Other Anticancer Therapies in Adult Participants With Locally Advanced or Metastatic Solid Tumor Malignancies (clinicaltrials.gov) - P1/2 | N=320 | Active, not recruiting | Sponsor: Ascendis Pharma Oncology Division A/S | Recruiting ➔ Active, not recruiting

Enrollment closed • First-in-human • Breast Cancer • Cervical Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Small Cell Lung Cancer • Solid Tumor • CTLA4

Anticipated 2026 Milestones:…Oncology Program (onvapegleukin alfa) (GlobeNewswire) - "Expect to report median overall survival (OS) data for a cohort of 70 patients with late-line platinum-resistant ovarian cancer (PROC) from the IL-Believe Trial of TransCon IL-2 β/γ + weekly paclitaxel in the second quarter of this year."

P1/2 data • Platinum resistant • Ovarian Cancer

Select Highlights & Anticipated 2025 Milestones:…TransCon IL-2 β/γ (onvapegleukin alfa) (GlobeNewswire) - "In our IL-Believe trial, 70 patients with late-stage platinum-resistant ovarian cancer (PROC) (median 4 prior lines of therapy; 67% previously treated with at least 2 lines of taxane-containing therapy) have been enrolled. Data continued to suggest that TransCon IL-2 β/γ dosed every three weeks in combination with weekly paclitaxel is generally well-tolerated, with the majority of TransCon IL-2 β/γ-related treatment-emergent adverse events (TEAEs) being Grade 1 or 2 in severity. We expect to provide median overall survival (OS) data for this cohort of 70 patients in the first quarter of next year as the dataset continues to mature."

Enrollment status • P1/2 data • Platinum resistant • Ovarian Cancer

Updated clinical data from TransCon IL-2 β/γ + paclitaxel for platinum resistant ovarian cancer (PROC) in the IL believe trial (ESMO 2025) - P1/2 | "Clinical responses with TransCon IL-2 β/γ (TC IL-2 β/γ; onvapegleukin alfa) in combination with standard of care (SOC) chemotherapy (paclitaxel, docetaxel or pemetrexed) were previously reported showing that TC IL-2 β/γ plus weekly paclitaxel had the best potential for clinical benefit among the chemotherapies evaluated (Yeku et al, ESMO24)...Conclusions Data suggests that TC IL-2 β/γ in combination with paclitaxel for PROC was generally well-tolerated with meaningful clinical responses in heavily pre-treated patients. Sustained and specific expansion of cytotoxic lymphocytes was observed."

Clinical data • IO biomarker • Platinum resistant • Oncology • Ovarian Cancer • Solid Tumor • CD8 • IL2 • PD-1

BelieveIT-201: TransCon (TC) TLR7/8 Agonist, TC IL-2 β/γ, Pembrolizumab Prior to Surgery for Advanced Head and Neck Squamous Cell Carcinoma (clinicaltrials.gov) - P2 | N=27 | Terminated | Sponsor: Ascendis Pharma A/S | Completed ➔ Terminated; The Sponsor made the decision to close enrollment as part of a strategic portfolio review.

Trial termination • Head and Neck Cancer • Oncology • Oropharyngeal Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

BelieveIT-201: TransCon (TC) TLR7/8 Agonist, TC IL-2 β/γ, Pembrolizumab Prior to Surgery for Advanced Head and Neck Squamous Cell Carcinoma (clinicaltrials.gov) - P2 | N=27 | Terminated | Sponsor: Ascendis Pharma A/S | Trial primary completion date: Dec 2024 ➔ Mar 2025

Trial primary completion date • Head and Neck Cancer • Oncology • Oropharyngeal Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

BelieveIT-201: TransCon (TC) TLR7/8 Agonist, TC IL-2 β/γ, Pembrolizumab Prior to Surgery for Advanced Head and Neck Squamous Cell Carcinoma (clinicaltrials.gov) - P2 | N=27 | Completed | Sponsor: Ascendis Pharma A/S | Active, not recruiting ➔ Completed | Trial completion date: Jul 2027 ➔ Mar 2025 | Trial primary completion date: Apr 2025 ➔ Dec 2024

Trial completion • Trial completion date • Trial primary completion date • Head and Neck Cancer • Oncology • Oropharyngeal Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

Ascendis Pharma Reports First Quarter 2025 Financial Results (TradingView) - "Select Highlights & Anticipated 2025 Milestones...Clinical development of TransCon IL-2 β/γ continues, including ongoing investigation of clinical activity in platinum-resistant ovarian cancer...Total revenue for the first quarter of 2025 was €101.0 million, compared to €95.9 million during the same period in 2024."

Clinical • Commercial • Platinum resistant • Ovarian Cancer • Solid Tumor

BelieveIT-201: TransCon (TC) TLR7/8 Agonist, TC IL-2 β/γ, Pembrolizumab Prior to Surgery for Advanced Head and Neck Squamous Cell Carcinoma (clinicaltrials.gov) - P2 | N=27 | Active, not recruiting | Sponsor: Ascendis Pharma A/S | Recruiting ➔ Active, not recruiting | N=92 ➔ 27

Combination therapy • Enrollment change • Enrollment closed • Metastases • Surgery • Head and Neck Cancer • Oncology • Oropharyngeal Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

IL Believe: A Study to Investigate Safety and Tolerability of TransCon IL-2 β/γ Alone or in Combination With Pembrolizumab and/or TransCon TLR7/8 Agonist or Other Anticancer Therapies in Adult Participants With Locally Advanced or Metastatic Solid Tumor Malignancies (clinicaltrials.gov) - P1/2 | N=473 | Recruiting | Sponsor: Ascendis Pharma Oncology Division A/S | Trial completion date: Aug 2027 ➔ Aug 2029 | Trial primary completion date: May 2026 ➔ Aug 2027

Combination therapy • Metastases • Trial completion date • Trial primary completion date • Breast Cancer • Cervical Cancer • HER2 Breast Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Small Cell Lung Cancer • Solid Tumor • IL2

First results from phase II dose expansion cohort of transcon IL-2 β/γ in combination with standard of care chemotherapy for platinum resistant ovarian cancer (PROC) in the IL Believe trial (ESMO 2024) - P1/2 | "Clinical responses with TransCon IL-2 β/γ (TC-IL-2 β/γ, onvapegleukin alfa) +/- pembrolizumab in heavily pre-treated patients with anti-PD-(L)1 relapsed or refractory solid tumors have been reported (Starodub et al, ESMO23). Here, encouraging preliminary results from the PROC cohort are provided. In this PROC cohort (progression within 6 months after completing prior platinum-based therapy), patients received the recommended phase 2 dose of 120 μg/kg TC-IL-2 β/γ IV Q3W plus physician's choice of paclitaxel, docetaxel, or pemetrexed until disease progression or unacceptable toxicity... Initial data suggest that TC-IL-2 β/γ in combination with chemotherapy for PROC is generally well-tolerated with meaningful clinical responses in heavily pre-treated patients. Preliminary evaluation of biomarkers shows a sustained and specific expansion of CLs."

Combination therapy • P2 data • Oncology • Ovarian Cancer • Solid Tumor • IL2

Ascendis to Present First Results from Platinum-Resistant Ovarian Cancer (PROC) Cohort of the Phase 1/2 IL-Believe Trial at ESMO 2024 (GlobeNewswire) - P1/2 | N=393 | IL Believe (NCT05081609) | Sponsor: Ascendis Pharma Oncology Division A/S | "Ascendis Pharma A/S...announced initial data showing signs of clinical activity in heavily pre-treated patients with platinum-resistant ovarian cancer (PROC) treated with TransCon IL-2 β/γ...in its ongoing Phase 1/2 IL-Believe Trial of TransCon IL-2 β/γ. First results will be shared in Poster 762P at ESMO 2024....Of the 18 patients (median age 64 years) included in the initial data, 14 were efficacy evaluable patients who had 1 or more post-baseline tumor assessment(s), plus an additional 4 who discontinued treatment before the first post-baseline tumor assessment due to disease progression or death. Anti-tumor clinical responses were observed in 29% (4/14) of the efficacy evaluable patients (2 confirmed and 2 unconfirmed partial responses in patients who had received three to seven prior lines of treatment...suggesting clinical activity in heavily pre-treated patients."

P1/2 data • Ovarian Cancer

Ascendis Pharma Reports Second Quarter 2024 Financial Results (GlobeNewswire) - "Oncology Programs:...Initial results from the Phase 2 dose expansion cohort of the IL-Believe Trial of TransCon IL-2 β⁄γ in combination with chemotherapy in platinum-resistant ovarian cancer (PROC) will be presented later this month at the European Society for Medical Oncology (ESMO) 2024 Congress in Barcelona, Spain."

P2 data • Ovarian Cancer

TransCon IL-2 β/γ alone or in combination with pembrolizumab, standard of care chemotherapy or TransCon TLR7/8 agonist in advanced/metastatic solid tumors: Updated results of the phase 1/2 IL Believe study. (ASCO 2024) - P1/2 | "TC-IL2 β/γ alone and in combination with P or TransCon TLR7/8 Agonist is generally well-tolerated with meaningful clinical responses in heavily pre-treated patients with anti-PD-(L)1 relapsed or refractory disease. Initial evaluation of biomarkers shows a sustained significant expansion and activation of CLs, elevated levels of cytokines and chemokines in blood without the corresponding expansion of Tregs or eosinophils."

Combination therapy • IO biomarker • Metastases • P1/2 data • Head and Neck Cancer • Lung Cancer • Melanoma • Oncology • Small Cell Lung Cancer • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • CXCL10 • IFNG • IL2 • ISG20

Ascendis Pharma Presents New Data and Updated Results from Phase 1/2 IL-Believe Trial at ASCO 2024 (GlobeNewswire) - P1/2 | N=393 | IL Believe (NCT05081609) | Sponsor: Ascendis Pharma Oncology Division A/S | "Ascendis Pharma...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 2024....Data included the first presentation of Phase 2 dose expansion Cohort 4...in post anti-PD-1 melanoma and new analyses of patients from dose escalation cohorts....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....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."

P1/2 data • Colorectal Cancer • Melanoma • Small Cell Lung Cancer

Ascendis Pharma Reports First Quarter 2024 Financial Results (GlobeNewswire) - "New data from the ongoing Phase 1/2 IL-Believe Trial has been accepted for a poster presentation at the American Society for Clinical Oncology (ASCO) May 31-June 4. The presentation will provide initial data from the combination of TransCon IL-2 β/γ and TransCon TLR7/8 Agonists in patients with melanoma who have progressed on anti-PD1 therapy. During the fourth quarter of 2024, plan to provide a clinical update from the Phase 2 indication-specific, dose expansion cohorts from our TransCon IL-2 β/γ and TransCon TLR7/8 Agonist clinical trials."

P1/2 data • P2 data • Melanoma • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

Ascendis Pharma Reports Fourth Quarter and Full Year 2023 Results (GlobeNewswire) - "Anticipated 2024 Milestones:...(i) TransCon IL-2 β/γ (onvapegleukin alfa): During the fourth quarter of 2024, plan to provide a clinical update from the Phase 2 portion of indication-specific, dose expansion cohorts in the IL Believe trial; (ii) TransCon TLR7/8 Agonist: During the fourth quarter of 2024, plan to provide a clinical update from the Phase 2 portion of indication-specific, dose expansion cohorts in the transcendIT-101 trial."

P2 data • Cervical Cancer • Melanoma • Non Small Cell Lung Cancer • Ovarian Cancer • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

Ascendis Pharma Introduces Vision 2030 (GlobeNewswire) - "Selected Key Updates:...Oncology: (i) During the fourth quarter of 2024, expect to complete enrollment in BelieveIT-201, a Phase 2 trial in advanced head and neck squamous cell carcinoma (HNSCC); (ii) During the fourth quarter of 2024, plan to provide a clinical update from the Phase 2 portion of indication-specific, dose expansion cohorts in the IL-Believe Trial."

Enrollment status • P2 data • Solid Tumor • Squamous Cell Carcinoma of Head and Neck

IL Believe: A Study to Investigate Safety and Tolerability of TransCon IL-2 β/γ Alone or in Combination With Pembrolizumab and/or Chemotherapy or TransCon TLR7/8 Agonist in Adult Participants With Locally Advanced or Metastatic Solid Tumor Malignancies (clinicaltrials.gov) - P1/2 | N=393 | Recruiting | Sponsor: Ascendis Pharma Oncology Division A/S | Trial completion date: May 2025 ➔ Aug 2027 | Trial primary completion date: Jan 2025 ➔ May 2026

Combination therapy • Metastases • Trial completion date • Trial primary completion date • Cervical Cancer • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Small Cell Lung Cancer • Solid Tumor • IL2

Ascendis Pharma Reports Third Quarter 2023 Financial Results (GlobeNewswire) - "Corporate Highlights: (i) TransCon IL-2 β/γ:...Enrollment continues in the Phase 2 portion in indication-specific cohorts; first patient dosed with TransCon IL-2 b/g and TransCon TLR7/8 Agonist in combination. Initial data from indication-specific cohorts expected in the second half of 2024; (ii) TransCon TLR7/8 Agonist: Enrollment continues in Phase 2 portion of transcendIT-101, a Phase 1/2 trial to evaluate TransCon TLR7/8 Agonist as monotherapy or in combination with pembrolizumab in dose escalation and dose expansion. Initial data expected in the second half of 2024."

P1/2 data • Trial status • Solid Tumor

Phase I/II dose escalation and dose expansion study of TransCon IL-2 β/γ alone or in combination with pembrolizumab: Determination of recommended phase II dose (RP2D) for monotherapy (ESMO 2023) - P1/2 | "The RP2D for monotherapy was determined at 120 mcg/kg IV every 3 weeks while dose escalation continues for combination therapy. PK data indicated a half-life of at least 35 hours and PD data confirm durable activation and expansion of cytotoxic immune cells from TransCon IL-2 β/γ."

Combination therapy • Monotherapy • P1/2 data • P2 data • Gastrointestinal Cancer • Microsatellite Instability • Oncology • Pancreatic Cancer • Solid Tumor • IL2 • MSI

Ascendis Presents Updated and New TransCon IL-2 β⁄γ Monotherapy and Combination Therapy Data Confirming Clinical Activity Across Tumor Types at ESMO 2023 (GlobeNewswire) - P1/2 | N=317 | IL Believe (NCT05081609) | Sponsor: Ascendis Pharma | "The data included longer-term follow up of previously presented TransCon IL-2 β⁄γ monotherapy data from the IL-Believe Trial, and was the first presentation of dose escalation data informing recommended Phase 2 dose (RP2D) for TransCon IL-2 β⁄γ in combination with a checkpoint inhibitor....Anti-tumor clinical responses were observed with TransCon IL-2 β⁄γ both as monotherapy (colorectal cancer with confirmed partial response (PR)) and in combination with pembrolizumab (small cell lung cancer (SCLC), 1 with confirmed PR and, subsequent to the August 15, 2023 data cutoff, 1 ongoing with an unconfirmed complete response)....we continue enrolling into indication-specific cohorts and look forward to sharing preliminary data from these cohorts in the second half of 2024.'"

P1/2 data • Colorectal Cancer • Gastrointestinal Cancer • Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor

Ascendis Pharma Reports Second Quarter 2023 Financial Results (GlobeNewswire) - "Enrollment initiated in the Phase 2 portion in indication-specific cohorts, with expected topline/interim analysis from Phase 2 dose-expansion cohorts expected in 2024."

Enrollment status • P2 data • Oncology • Solid Tumor

BelieveIT-201: TransCon (TC) TLR7/8 Agonist, TC IL-2 β/γ, Pembrolizumab Prior to Surgery for Advanced Head and Neck Squamous Cell Carcinoma (clinicaltrials.gov) - P2 | N=92 | Not yet recruiting | Sponsor: Ascendis Pharma Oncology Division A/S

Combination therapy • Metastases • New P2 trial • Surgery • Head and Neck Cancer • Oncology • Oropharyngeal Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

Phase 1/2 dose escalation and dose expansion study of TransCon IL-2 β/γ alone or in combination with pembrolizumab: Initial results from dose escalation. (ASCO 2023) - P1/2 | "TransCon IL-2 β/γ is generally well-tolerated as monotherapy and in combination with pembrolizumab. The pharmacodynamics data confirm a durable activation and expansion of IL-2Rβ/γ+ cytotoxic immune cells over IL-2Rα+ eosinophils and Tregs. Clinical trial information: NCT05081609."

Combination therapy • P1/2 data • Anemia • Fatigue • Gastrointestinal Cancer • Hematological Disorders • Hepatology • Oncology • Pancreatic Cancer • Solid Tumor • Thrombocytopenia • IL2