Medigene Announces Indication Selection for the Clinical Development of its Lead 3rd Generation TCR-T Therapy Program in Solid Tumors

• Gastric cancer, ovarian cancer, myxoid/round cell liposarcoma and synovial sarcoma selected as initial clinical indications for lead program MDG1015
• MDG1015 is a first-in-class, third generation TCR-T therapy targeting NY-ESO-1/ LAGE-1a, armored and enhanced by costimulatory switch protein PD1-41BB
• Clinical development in both orphan and more common cancer indications addresses high unmet medical need in large patient populations

Planegg/Martinsried, February 12, 2024. Medigene AG (Medigene, FSE: MDG1, Prime Standard), an immuno-oncology platform company focusing on the discovery and development of T cell immunotherapies for solid tumors, today announced the selection of gastric cancer, ovarian cancer and two types of soft tissue sarcomas, myxoid/round cell liposarcoma and synovial sarcoma, as the initial clinical indications for its lead candidate MDG1015. MDG1015 is a first-in-class, third generation T cell receptor engineered T cell (TCR-T) therapy targeting NY-ESO-1/LAGE-1a (New York esophageal squamous cell carcinoma 1 / L Antigen Family Member-1a), armored and enhanced by costimulatory switch protein PD1-41BB in the context of HLA-A*02 (HLA, human leukocyte antigen). Preclinical data presented in 2023 at the AACR and ESMO conferences demonstrated the clear potential of MDG1015 to improve clinical outcomes in solid tumors.

“The selection of these cancers as targets for MDG1015 is an important step as we advance towards the first-in-human trial. Following recent positive EU and US preliminary regulatory interactions, we remain on track for an IND/CTA approval in the second half of 2024,” said Dr. Selwyn Ho, Chief Executive Officer at Medigene. “While clinical data for engineered cell therapies still in development has shown benefits in some of the selected indications, we believe there is still significant room for improvement in terms of efficacy and durability of progression-free survival. We are confident that MDG1015 as a first-in-class armored and enhanced TCR-T therapy has the potential to address these challenges and improve the quality of life of patients suffering with cancer.”

The indications were selected predominantly based on target and/or PD-L1 expression, with 34-60%, 35-55% and 75-80% of gastric cancer, ovarian cancer and the two subtypes of soft tissue sarcoma expressing NY-ESO-1/LAGE-1a, respectively.^i,ii,iii Additional MDG1015 preclinical data will be presented at upcoming scientific conferences in 2024. Within the current treatment landscape, high NY‑ESO-1 expression is associated with a worse prognosis^iv and expression increases with advanced disease stage.^iv,v When looking only at the initially selected solid cancer indications, it is estimated that over 100,000 patients in the world’s top eight economies could be eligible for treatment with MDG1015 based on yearly incidence, target expression and HLA-A*02 positivity. These cancers are also marked by a clear need for new treatment modalities, with estimated five-year survivals for advanced gastric cancer, ovarian cancer and the two subtypes of soft tissue sarcoma as low as 5%-31%.^vi

About Gastric Adenocarcinoma
Gastric cancer represents the fifth most common cause of cancer deaths worldwide^vii and 90% of all gastric cancers are gastric adenocarcinomas (GACs).^viii Overall, ∼60% of people with GAC are not eligible for curative treatment owing to late presentation or comorbidities.^viii The 36% of US patients diagnosed with distant metastases have a mere 6.6% 5‑year relative survival rate.^vi

About Ovarian Carcinoma
Ovarian cancer is one of the leading causes of cancer deaths among women, and in 55% of US patients distant metastases are present at the time of diagnosis.^vi Despite advances in treatment, the prognosis remains poor with a 5-year relative survival rate of 31% for US epithelial ovarian cancer patients with advanced disease.^vi

About Myxoid/Round Cell Liposarcoma
Myxoid/round cell liposarcoma is a type of soft tissue sarcoma originating from the fat cells and typically affects younger patients between 30–50 years of age. This disease has an incidence of up to ~1,350 patients in the US which makes it an orphan indication.^vi For patients with advanced disease there is an 8% 5-year disease-specific survival rate.^ix

About Synovial sarcoma
Synovial sarcoma is a type of soft tissue sarcoma characterized by its development in cells around joints and tendons and most often affects adolescents and young adults. The disease has an incidence in line with myxoid liposarcoma, of up to ~1,300 patients in the US making it an orphan indication.^vi In 50% of synovial sarcoma cases the disease metastasizes to other areas of the body, most commonly to the lungs. For patients with advanced stage disease, the median overall survival at or after second line therapy is under a year and the 5-year overall survival is 10%.^vi,x

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About Medigene AG

Medigene AG (FSE: MDG1) is an immuno-oncology platform company dedicated to developing differentiated T cell therapies for treatment of solid tumors. Its End-to-End Platform is built on multiple proprietary and exclusive technologies that enable the Company to generate optimal T cell receptors against both cancer testis antigens and neoantigens, armor and enhance these T cell receptor engineered (TCR) -T cells to create best-in-class, differentiated TCR-T therapies, and optimize the drug product composition for safety, efficacy and durability. The End-to-End Platform provides product candidates for both its own therapeutics pipeline and partnering. Medigene’s lead TCR-T program MDG1015 is expected to receive IND/CTA approval in the second half of 2024. For more information please visit https://medigene.com/

About Medigene’s MDG1015 Program

MDG1015 is a first-in-class, 3rd generation T cell receptor engineered T cell (TCR-T) therapy targeting NY-ESO-1/ LAGE-1a, a well-recognized and validated cancer testis antigen, which is expressed in multiple tumor types. MDG1015 contains our optimal affinity 3S (sensitive, specific and safe) NY-ESO-1/LAGE-1a TCR combined with our proprietary PD1-41BB costimulatory switch protein that blocks the PD1/PD-L1 inhibitory axis while simultaneously activating the T cell through the well described -41BB pathway further enhancing the activity and persistence of the TCR-T in the hostile tumor microenvironment. MDG1015 is currently undergoing IND/CTA enabling studies with IND/CTA approval expected in the second half of 2024.

About Medigene’s PD1-41BB Costimulatory Switch Protein

Checkpoint inhibition via PD-1/PD-L1 pathway:

Cells of solid tumors are sensitive to killing by activated T cells but can escape this killing activity by producing inhibitory molecules known as ‘checkpoint proteins’, such as the Programmed Death Ligand 1 (PD-L1), on their surface. When this occurs, activated T cells which express PD-1, the natural receptor for PD-L1, are inactivated. The expression of PD-L1 is an adaptive immune resistance mechanism for tumors that can help them survive and grow.

The 4-1BB (CD137) costimulatory signaling pathway:

Effective T cell immune responses to antigens typically require both a primary antigenic stimulation via the T cell receptor (TCR) and costimulatory signals. The intracellular signaling domains of the 4-1BB protein offer a well-characterized pathway of costimulation and enhanced T cell responses.

Medigene’s PD1-41BB switch receptor turns the tumor’s attempted self-defense mechanism against the tumor by substituting the inhibitory signaling domain of PD-1 with the activating signaling domain of 4‑1BB. Therefore, instead of inactivating T cells, the switch receptor delivers an activating signal to TCR-T cells. PD1-41BB-modified TCR-T cells proliferate strongly in the presence of PD-L1-positive tumor cells and kill more tumor cells upon repeated exposure. Additionally, switch receptor signals enable TCR-T cells to function better with low levels of glucose or high levels of TGFß, two conditions characteristic of strongly hostile tumor microenvironments.

This press release contains forward-looking statements representing the opinion of Medigene as of the date of this release. The actual results achieved by Medigene may differ significantly from the forward-looking statements made herein. Medigene is not bound to update any of these forward-looking statements. Medigene^® is a registered trademark of Medigene AG. This trademark may be owned or licensed in select locations only.

Medigene

Pamela Keck
Phone: +49 89 2000 3333 01
E-mail: investor@medigene.com

MC Services AG
Raimund Gabriel/Julia von Hummel
Phone: +49 89 210 228-0
E-mail: medigene@mc-services.eu

ⁱ Blouch et al, Annals of Oncology (2021) 32 (suppl_5): S382-S406. 10.1016/annonc/annonc686

ⁱⁱ Odunsi K, et al. Cancer Res. 2003 Sep 15 ;63(18) :6076-83

ⁱⁱⁱ Lai JP, Robbins PF, Raffeld M, et al. NY-ESO-1 expression in synovial sarcoma and other mesenchymal tumors: significance for NY-ESO-1-based targeted therapy and differential diagnosis. Mod Pathol. 2012;25(6):854-858. doi:10.1038/modpathol.2012.31

^iv Raza A, et al. J Transl Med 2020 Mar 27;18(1):140. https://doi.org/10.1186/s12967-020-02306-y

^v Aung PP, et al. Hum. Pathol. 2014 Feb; 45(2): 259–267. https://doi.org/10.1016/j.humpath.2013.05.029

^vi The American Cancer Society, Cancer Statistics Center, SEER database htps://cancerstatisticscenter.cancer.org [accessed 05Feb2024]

^vii Global Cancer Observatory https://gco.iarc.fr/today [accessed 05Feb2024]

^viii Lordick et al. An. of Oncol. volume 33, issue 10, p1005-1020, October 2022 Gastric cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. https://doi.org/10.1016/j.annonc.2022.07.004

^ix Disease-specific survival from Hoffman et al. (2013), Localized and metastatic myxoid/round cell liposarcoma. Cancer, 119: 1868-1877

^x Carroll C, Patel N, Gunsoy NB, Stirnadel-Farrant HA, Pokras S. Meta-analysis of pazopanib and trabectedin effectiveness in previously treated metastatic synovial sarcoma (second-line setting and beyond). Future Oncol. 2022;18(32):3651-3665. doi:10.2217/fon-2022-0348