ONCOS-102 / Circio Holding - LARVOL DELTA

A Meta-Analysis of First-Line Treatments for Unresectable Pleural Mesothelioma: Indirect Comparisons from Reconstructed Individual Patient Data of Six Randomized Controlled Trials. (PubMed, Cancers (Basel)) - "Our analysis indicates that, in patients with unresectable pleural mesothelioma, three of the five novel treatments provided a significant survival benefit compared with the standard of care. Further research is needed to confirm the OS benefit found in our analysis with some treatments, whereas cisplatin alone and cediranib plus pemetrexed+cisplatin with maintenance with cediranib do not seem to deserve further research."

Journal • Retrospective data • Review • Malignant Pleural Mesothelioma • Mesothelioma • Oncology • Pleural Mesothelioma • Solid Tumor

Inducing expression of ICOS-L by oncolytic adenovirus to enhance tumor-specific bi-specific antibody efficacy. (PubMed, J Transl Med) - "Together, our data suggests that oncolytic adenoviruses encoding ICOSL may enhance functional activity of tumor-specific BsAbs thereby opening a novel avenue for clinical development in immunotherapeutics."

IO biomarker • Journal • Oncolytic virus • Oncology • CD4 • CD8 • CSF2 • ICOS • IFNG

Circio receives waiver of EUR 6.2 million in loans from Business Finland (Circio Press Release) - "Circio Holding ASA...today announces that Business Finland has approved Circio’s application for a waiver in full of three R&D loans totalling EUR 6.2m granted towards the development of ONCOS-102. As a result, Circio’s equity will be increased by a corresponding amount....Business Finland is a public agency that provides funding towards R&D activities for companies in Finland. Targovax Oy, a wholly owned Finnish subsidiary of Circio Holding ASA, received three loans from Business Finland for the development and commercialization of ONCOS-102 in 2010, 2012 and 2013, totalling EUR 6 209 888. The loans were repayable over a ten-year period from 2021-2031 with an interest rate of currently 1.25% p.a."

Financing • Oncology • Solid Tumor

Payload screening identifies enhanced T cell responsiveness aimed for circAde, a circular RNA delivery system, towards treatment of solid tumors (SITC 2023) - "Background We have previously demonstrated successful delivery of a granulocyte-macrophage colony-stimulating factor (GM-CSF) payload to solid tumors through the adenoviral vector ONCOS-102, resulting in robust clinical benefit hallmarked by increased T-cell infiltration and activation of immune-related genetic pathways (e. g. , cytotoxicity and co-stimulatory gene ontologies)...Conclusions Continued screening and characterization of additional immunostimulatory payloads are ongoing, with the aim to further strengthen the results generated using mRNA-encoded constructs by introducing circRNA-encoded payloads to demonstrate the potency of the circAde platform. By deploying a circRNA-based expression system for these payloads, we aim to achieve a more durable payload expression, which is expected to further potentiate and extend the anti-tumor immune response."

Oncology • Solid Tumor • CD4 • CD8 • CSF2

ONCOS-102 plus pemetrexed and platinum chemotherapy in malignant pleural mesothelioma: a randomized phase 2 study investigating clinical outcomes and the tumor microenvironment. (PubMed, J Immunother Cancer) - "ONCOS-102 plus pemetrexed and cisplatin/carboplatin was well tolerated by patients with MPM. In injected tumors, ONCOS-102 promoted a proinflammatory environment, including T-cell infiltration, which showed association with survival at month 18."

Biomarker • Clinical data • Journal • P2 data • Tumor microenvironment • Hematological Disorders • Immunology • Lung Cancer • Malignant Pleural Mesothelioma • Mesothelioma • Neutropenia • Oncology • Solid Tumor

ONCOS-102 plus pemetrexed and platinum chemotherapy in malignant pleural mesothelioma: a randomized phase 2 study investigating clinical outcomes and the tumor microenvironment (J Immunother Cancer) - P1b/2 | N=31 | NCT02879669 | Sponsor: Targovax Oy | "In total, 31 patients (safety lead-in: n=6, randomized: n=25) were enrolled. Anemia (15.0% and 27.3%) and neutropenia (40.0% and 45.5%) were the most frequent grade ≥3 adverse events (AEs) in the ONCOS-102 (n=20) and chemotherapy-alone (n=11) cohorts. No patients discontinued ONCOS-102 due to AEs. No statistically significant difference in efficacy endpoints was observed. There was a numerical improvement in OS (30-month OS rate 34.1% vs 0; median OS 20.3 vs 13.5 months) with ONCOS-102 versus chemotherapy alone in chemotherapy-naïve patients (n=17)."

P2 data • Lung Cancer • Malignant Pleural Mesothelioma • Mesothelioma • Oncology • Solid Tumor • Thoracic Cancer

A Study of ONCOS-102 in Combination With Other Novel Immune-therapies in Advanced Treatment-resistant Melanoma Patients (clinicaltrials.gov) - P2 | N=0 | Withdrawn | Sponsor: Targovax Oy | N=63 ➔ 0 | Not yet recruiting ➔ Withdrawn

Combination therapy • Enrollment change • Metastases • Trial withdrawal • Cutaneous Melanoma • Melanoma • Oncology • Solid Tumor

Granular analysis of individual immune-related gene expression in a randomized phase I/II study of the oncolytic adenovirus, ONCOS-102, in combination with pemetrexed/cisplatin (P/C) in patients (pts) with unresectable malignant pleural mesothelioma (MPM). (ASCO 2023) - P2 | "ONCOS-102 caused increased T-cell infiltration and upregulated immune response-related gene expression in tumor lesions. A trend for prolonged OS was observed in the 1L setting, only. Consistent with observations in PD-1 resistant melanoma, ONCOS-102-induced immune response in the tumor is hallmarked by a high prevalence of cytotoxic T-cells and depolarization of macrophages, which may support addition of checkpoint inhibitors to the combination of ONCOS-102 plus P/C in MPM."

Clinical • Combination therapy • IO biomarker • Oncolytic virus • P1/2 data • Lung Cancer • Malignant Pleural Mesothelioma • Melanoma • Mesothelioma • Oncology • Solid Tumor • CD8 • CSF2 • GZMB

A Study of ONCOS-102 in Combination With Other Novel Immune-therapies in Advanced Treatment-resistant Melanoma Patients (clinicaltrials.gov) - P2 | N=63 | Not yet recruiting | Sponsor: Targovax Oy | Initiation date: Dec 2022 ➔ Jan 2024

Combination therapy • Metastases • Trial initiation date • Cutaneous Melanoma • Melanoma • Oncology • Solid Tumor

Consistent pattern of immune activation induced by oncolytic adenovirus ONCOS-102 across diverse types of solid tumors (SITC 2021) - P1, P2 | "Methods Biopsies were obtained from tumor lesions of patients treated with intra-tumoral injections of ONCOS-102 in combination with chemotherapy or pembrolizumab for MPM and melanoma, respectively. Conclusions ONCOS-102 drives pro-inflammatory modulation of immune TME across tumor types of different origins, anatomical locations and immunological baseline characteristics. Our data support potential of ONCOS-102 to serve as a potent immune sensitizing agent in combination therapies with various classes of immunomodulatory compounds and chemotherapy."

IO biomarker • Oncolytic virus • Lung Cancer • Malignant Pleural Mesothelioma • Melanoma • Mesothelioma • Oncology • Solid Tumor • CD4 • CD8 • CSF2 • GZMB • PD-L1

ONCOS-102 and pemetrexed/cisplatin in patients with unresectable malignant pleural mesothelioma (ESMO 2017) - P2; "Mesothelioma is a rare cancer with poor prognosis and limited treatment options, including surgery, radiotherapy and chemo (pemetrexed + cisplatin/carboplatin). Imaging at baseline, Day 64 and 148. Tumor biopsies from both injected and non-injected lesions at baseline and Day 36."

Oncolytic virus • Mesothelioma

Targovax announces financing of up to NOK 300m over three years to advance its clinical cancer programs & pre-clinical circular RNA platform (Targovax Press Release) - "The financing will enable Targovax to drive long-term shareholder value by supporting progress for its three R&D pillars, including: Dosing the first patients in the ONCOS-102 phase 2 trial in PD-1 resistant melanoma at prestigious cancer centers in the USA and Europe; Generation of in vivo proof-of-concept data in multiple settings for Targovax´s unique circRNA program, an area of rapidly growing interest among big pharma and biotech; Supporting two clinical trials with the enhanced mutant RAS vaccine TG01 led by major academic centers in Norway and the USA."

Financing • Melanoma • Oncology • Skin Cancer • Solid Tumor

Repeat dosing of oncolytic adenovirus ONCOS-102 is associated with enhanced and persistent immune responses and improved systemic activity in anti-PD-1 resistant/refractory (r/r) melanoma (SITC 2022) - P1 | "We recently completed phase 1/2 testing of ONCOS-102, a GM-CSF-encoding oncolytic adenovirus (Ad5/3-D24-GMCSF) in two different dosing schedules in combination with pembrolizumab (pem) in patients (pts) with unresectable, stage III-IV, anti-PD-1 resistant/refractory melanoma ( NCT03003676 ). University of Maryland Institutional Review Board 22 S. Greene Street, Baltimore, Maryland 21201 Name of committee chair: Mark Mishra, MD HP-00078557/17121GCCC and in Norway by 4. REK sør-øst A Gullhaugveien 1-3, 0484 Oslo Name of committee chair.: Knut Engedal All participants gave informed consent before taking part."

IO biomarker • Oncolytic virus • Melanoma • Oncology • Solid Tumor • CSF2

A randomised open-label phase I/II study adding ONCOS-102 to pemetrexed/cisplatin in patients with unresectable malignant pleural mesothelioma – 24 month survival data (SITC 2021) - P2 | "Standard of care (SOC) include pemetrexed/cisplatin and nivolumab/ipilimumab with median overall survival in unresectable disease of 12.1 months and 18.1 months respectively.1 2 ONCOS-102 is a granulocyte-macrophage colony stimulating factor (GM-CSF) expressing oncolytic adenovirus (Ad5/3-D24-GMCSF) with a unique ability to both prime and boost immune responses. Improved survival was associated with ONCOS-102 induced immune activation with a favourable TME modulation providing scientific rationale for combination with check point inhibition. Trial Registration ClinicalTrials.gov NCT02879669"

Clinical • P1/2 data • Lung Cancer • Malignant Pleural Mesothelioma • Mesothelioma • Oncology • Solid Tumor

Modulation of immune gene expression by intra-tumoral oncolytic adenovirus ONCOS-102 is associated with clinical response in anti-PD-1 refractory/resistant melanoma (AACR 2022) - P1 | "We recently completed phase I/II testing of ONCOS-102, a GM-CSF-encoding oncolytic adenovirus (Ad5/3-D24-GMCSF), for therapeutic efficacy and capacity to remodel tumor micro-environment (TME) in combination with pembrolizumab (pem) in patients (pts) with non-resectable, stage III-IV, anti-PD-1 resistant/refractory (R/R) melanoma (NCT03003676). ONCOS-102 drives pro-inflammatory modulation of the TME in PD-1 R/R melanoma tumors. Clinical response ONCOS-102 is associated with efficient viral gene expression and strong, sustained activation of immune-related genes, which may be targets for future combinations of ONCOS-102 and immune-modulators beyond PD-1/PD-L1 inhibitors."

Clinical • IO biomarker • Oncolytic virus • Melanoma • Oncology • Solid Tumor • CSF2 • HAVCR2 • LAG3

Final survival outcomes and immune biomarker analysis of a randomized, open-label, phase I/II study combining oncolytic adenovirus ONCOS-102 with pemetrexed/cisplatin (P/C) in patients with unresectable malignant pleural mesothelioma (MPM). (ASCO 2022) - P2 | "The addition of ONCOS-102 to P/C was well tolerated by MPM patients and resulted in numerically improved 30-month survival rate in the overall population, and improved mOS in chemotherapy-naïve patients, albeit not statistically significant. Substantial immunological activation in tumor associated with ONCOS-102 was demonstrated, correlating with clinical benefit. Further exploration of ONCOS-102 as a treatment option in MPM is warranted"

Biomarker • Clinical • IO biomarker • Oncolytic virus • P1/2 data • Anemia • Hematological Disorders • Immunology • Lung Cancer • Malignant Pleural Mesothelioma • Mesothelioma • Neutropenia • Oncology • Solid Tumor • CD4 • CD8 • CSF2 • GZMB

Study to evaluate intraperitoneal (IP) ONCOS-102 with systemic durvalumab in patients with peritoneal disease who have epithelial ovarian (OC) or metastatic colorectal cancer (CRC): Phase 2 results. (ASCO 2022) - P1/2 | "One dose of cyclophosphamide was given prior to first ONCOS-102 dose. The combination of IP ONCOS-102 and durva was well tolerated. The study did not meet its efficacy endpoint. Evaluation of pre- and on-therapy translational parameters is ongoing."

Clinical • P2 data • Colorectal Cancer • Fatigue • Gastrointestinal Cancer • Immune Modulation • Immunology • Inflammation • Oncology • Ovarian Cancer • Pain • Solid Tumor • CSF2

[VIRTUAL] Phase I/II study to evaluate systemic durvalumab + intraperitoneal (IP) ONCOS-102 in patients with peritoneal disease who have epithelial ovarian (OC) or metastatic colorectal cancer (CRC): Interim phase I clinical and translational results. (ASCO 2020) - P1/2 | " This ongoing Phase 1/2, open-label study (NCT02963831) evaluates safety and antitumor/biologic activity of durvalumab (1500 mg IV, every 4 weeks x 12) + ONCOS-102 (IP, weekly x 6); cyclophosphamide is given pre first ONCOS-102 dose. Combination of durvalumab and IP ONCOS-102 was safe, and no DLTs were observed. Preliminary analyses demonstrate evidence of biologic and clinical activity. Phase 2 enrollment is ongoing."

Clinical • IO Biomarker • P1/2 data • Cardiovascular • Colorectal Cancer • Gastrointestinal Cancer • Hematological Disorders • Immunology • Infectious Disease • Oncology • Ovarian Cancer • Solid Tumor • CD8 • CSF2

[VIRTUAL] A Randomised Open-label Phase I/II Study Adding ONCOS-102 to Pemetrexed/Cisplatin in Patients with Unresectable Malignant Pleural Mesothelioma – 21 Month Analysis (IMIG 2021) - P2 | "ONCOS-102 in combination with SoC chemotherapy was well tolerated. Preliminary survival data show extended survival in ONCOS-102 treated 1st line patients compared to SoC chemotherapy. Changes of immune cells in ONCOS-102 patients were associated with better clinical outcome."

Clinical • P1/2 data • Immunology • Lung Cancer • Malignant Pleural Mesothelioma • Mesothelioma • Oncology • Solid Tumor

ONCOS-102: A Step Forward or Sideways? (PubMed, Clin Cancer Res) - "Intratumoral injection of ONCOS-102, a chimeric oncolytic adenovirus expressing GM-CSF, into anti-PD-1 resistant melanoma with administration of pembrolizumab was safe and effective. Response to therapy was associated with increased lymphocyte infiltration and expression of cytotoxicity and co-stimulatory genes."

IO biomarker • Journal • Melanoma • Oncology • Solid Tumor • CSF2

The ONCOS-102 phase 1b melanoma study is published in the prestigious scientific journal Clinical Cancer Research (Targovax Press Release) - P1b | N=21 | NCT03003676 | Sponsor: Targovax Oy | "Targovax ASA...announces that the completed ONCOS-102 phase 1b study in PD-1 CPI resistant advanced melanoma has been published in the prestigious oncology journal Clinical Cancer Research, published by the American Association for Cancer Research (AACR)....As expected, ONCOS-102 generated strong and durable immune activation in the treated patients, which translated into a promising objective response rate (ORR) of 35%. Importantly, the clinical efficacy was associated with continuous replication of ONCOS-102 within the tumor, statistically significant increase in T-cell infiltration, and broad and persistent upregulation of immunological pathways in responding patients....'We look forward to continuing to work with Targovax in the upcoming phase 2 trial, which will allow us to validate these findings in a larger patient cohort as well as to test ONCOS-102 in interesting new combinations'."

P1 data • Melanoma • Oncology • Skin Cancer • Solid Tumor

Pilot Study of ONCOS-102 and Pembrolizumab: Remodeling of the Tumor Microenvironment and Clinical Outcomes in Anti–PD-1–Resistant Advanced Melanoma (Clin Cancer Res) - P1 | N=21 | NCT03003676 | Sponsor: Targovax Oy | "In 21 patients (Part 1, n = 9; Part 2, n = 12) ONCOS-102 plus pembrolizumab was well tolerated: most adverse events (AE) were mild/moderate in severity....ORR was 35% [response evaluation in solid tumors (RECIST) 1.1, irRECIST]. Reduction in size of ≥1 non-injected lesions observed in 53% patients indicated a systemic effect. In injected tumors, persistent immune-related gene expression and T-cell infiltration were associated with clinical benefit....ONCOS-102 plus pembrolizumab was well tolerated and led to objective responses in patients with anti–PD-1–resistant advanced melanoma."

P1 data • Melanoma • Oncology • Skin Cancer • Solid Tumor

Targovax receives approval to proceed with the ONCOS-102 phase 2 melanoma study from the US FDA (Targovax Press Release) - "The US Food and Drug Administration (FDA) has reviewed and accepted the protocol for the ONCOS-102 phase 2 combination trial in PD-1 checkpoint inhibitor (CPI) refractory advanced melanoma. The study is on track to start in late 2022 or early 2023....Study initiation activities are proceeding according to the communicated timeline, with the aim to start enrolling patients in late 2022 or early 2023....Based on these promising early clinical results, Targovax is planning to conduct a larger, phase 2 multi-cohort study to further explore and validate the benefit of ONCOS-102 in PD-1 CPI refractory melanoma. This phase 2 study will be run in collaboration with Targovax’s partner Agenus, who will provide their Fc-enhanced CTLA-4 (botensilimab) and PD-1 (balstilimab) CPIs for combination with ONCOS-102."

IND • New P2 trial • Melanoma • Oncology • Skin Cancer • Solid Tumor

A Study of ONCOS-102 in Combination With Other Novel Immune-therapies in Advanced Treatment-resistant Melanoma Patients (clinicaltrials.gov) - P2 | N=63 | Not yet recruiting | Sponsor: Targovax Oy

Combination therapy • New P2 trial • Cutaneous Melanoma • Melanoma • Oncology • Solid Tumor

The ONCOS-102 phase 1b melanoma study selected for oral presentation at the SITC 2022 annual meeting (Targovax Press Release) - "Targovax ASA...announces that the SITC abstract review committee has selected the ONCOS-102 phase 1b study in PD-1 resistant advanced melanoma for oral presentation at the annual meeting to be held in November in Boston....At the SITC conference, further translational biomarker analyses and the impact of dosing regimen on systemic activity and immune responses will be presented."

Biomarker • P1 data • Melanoma • Oncology • Skin Cancer • Solid Tumor