A2 Bio Announces First Patient Dosed in DENALI-1 Phase 1/2 Clinical Study of A2B395, a Novel Allogeneic Precision CAR T Cell Therapy for Patients with Solid Tumors that Express EGFR

First-in-human trial uses the A2 Bio proprietary logic-gated Tmod™ technology platform for precision cell therapies providing selective killing of tumor cells while protecting normal cells

A2 Biotherapeutics, Inc. (A2 Bio), a clinical-stage cell therapy company developing first-in-class logic-gated cell therapies for solid tumors, today announced dosing of the first patient in the DENALI-1 (NCT06682793) clinical study. DENALI-1 is a multicenter phase 1/2 dose-escalation clinical study to evaluate the safety and efficacy of A2B395, an allogeneic logic-gated CAR T cell therapy, in participants with solid tumors that express EGFR and have lost HLA-A*02 expression. A2B395 is the first allogeneic therapy utilizing the A2 Bio Tmod™ technology platform to advance into clinical development.

A2 Bio is advancing A2B395 as a potential new precision cell therapy in participants with solid tumors that express EGFR, including colorectal cancer, non-small cell lung cancer, head and neck squamous cell carcinoma, triple-negative breast cancer, and renal cell carcinoma.

“Dosing of the first patient in DENALI-1 is a key milestone toward providing a precise, novel ‘off the shelf’ CAR T cell therapy for patients with solid tumors that express EGFR. No curative therapies are available for people living with these cancers, and current treatments can be toxic, debilitating, and fatal. All of us at A2 Bio are grateful to the patients, investigators, and clinical care providers participating in DENALI-1,” said John Welch, M.D., Ph.D, interim chief medical officer of A2 Bio.

Significant unmet needs remain for people living with EGFR-positive cancers, despite recent advances that have produced new targeted therapies, antibody-based therapies, and immunotherapies.^1,2 In the recurrent unresectable, locally advanced, or metastatic setting, the intent of standard of care treatment is typically palliative rather than curative, and has not changed significantly in several decades.

Precision medicine enables efficient identification of patients in the A2 Bio clinical studies. Patients are enrolled in DENALI-1 through BASECAMP-1 (NCT04981119), a master prescreening study that identifies patients with HLA loss of heterozygosity (LOH) at any time in the course of their disease via next-generation sequencing. Upon disease progression, the participant may screen for enrollment in DENALI-1. There is no time requirement between the studies, and patients may go directly from BASECAMP-1 to DENALI-1 based on their own disease course. BASECAMP-1 utilizes artificial intelligence (AI)-enabled precision diagnostics as a cost-effective, high-yield approach to identify eligible patients for all A2 Bio clinical studies.^{3, 4}

In addition to A2B395, A2 Bio continues to advance its clinical development of A2B694, the BASECAMP-1 prescreening study, as well as other preclinical programs as the company pursues additional pipeline expansion opportunities using its proprietary Tmod™ technology platform. The Tmod™ platform comprises a suite of technologies that can be used in isolation or in combination, and in both autologous and allogeneic settings, to create novel therapies for various cancers and beyond.

The Tmod™ platform utilizes a dual-receptor design consisting of an activator that targets tumor cells and a blocker that protects normal cells. This dual-receptor design is intended to provide selective killing of tumor tissues that express EGFR and have lost the HLA-A*02 gene permanently. This novel design is aimed at tackling the fundamental challenge in solid tumor cancer medicines – the ability to selectively kill tumor cells and protect normal cells.

About DENALI-1

DENALI-1 (NCT06682793) is a phase 1/2, open-label, nonrandomized study evaluating the safety and efficacy of A2B395 in adults. Patients are enrolled through BASECAMP-1 (NCT04981119), a master prescreening study that identifies patients with HLA LOH at any time in the course of their disease via next-generation sequencing. Upon disease progression the participant may screen for enrollment in DENALI-1.

More information about DENALI-1 and clinical trial sites participating in the study are available on the A2 Bio clinical trials website.

About the Tmod™ Platform

A2 Bio has pioneered a precision-targeting cellular system – the Tmod™ platform – that incorporates two receptors, an activator and a blocker, to aim the powerful armaments of immune cells directly at tumors to unequivocally differentiate tumors from normal tissues. The activator recognizes antigens on tumor cells that trigger their destruction, while the blocker recognizes antigens on normal cells that protect them. This novel blocker technology enables precise, personalized and effective T cell targeting. The blocker component equips Tmod™ cells with the capacity to identify tumors as distinct from normal cells.

About A2 Bio

A2 Biotherapeutics, Inc. (A2 Bio) is a clinical-stage biotech company developing first-in-class logic-gated cell therapies to address the high unmet need in cancers. A2 Bio invented the proprietary Tmod™ cell therapy platform to tackle the fundamental challenge in cancer treatment—the ability of cancer medicines to distinguish between tumor and normal cells. For more information, please visit the company’s website at www.a2bio.com.

References:

¹ Macdonald JB, Macdonald B, Golitz LE, et al. Cutaneous adverse effects of targeted therapies: Part I: Inhibitors of the cellular membrane. J Am Acad Dermatol. 2015;72(2):203-18; quiz 19-20.

² Ganesh K, Massagué J. Targeting metastatic cancer. Nat Med. 2021;27(1):34-44.

³ Smith CJ, Simeone DM, Grierson PM, et al. Improving ethnic and racial diversity in biomarker-driven clinical trials: a proof of concept with the BASECAMP-1 master prescreening study of patients with high-risk solid tumors with human leukocyte antigen-A*02 (HLA-A*02) loss of heterozygosity (LOH). ASCO Annual Meeting 2024. Available at: https://www.a2bio.com/wp-content/uploads/ASCO-2024_Improving-Trial-Diversity.pdf.

⁴ Lozac'hmeur A, Danek T, Yang Q, et al. Detecting HLA loss of heterozygosity within a standard diagnostic sequencing workflow for prognostic and therapeutic opportunities. NPJ Precis Oncol. 2024;8(1):174.

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“Dosing of the first patient in DENALI-1 is a key milestone toward providing a precise, novel ‘off the shelf’ CAR T cell therapy for patients with solid tumors that express EGFR. No curative therapies are available for people living with these cancers."