A2B530 Receives FDA Orphan Drug Designation in CRC

The novel cell therapy A2B530 has been granted orphan drug designation by the FDA for the treatment of patients with germline heterozygous HLA-A*02–positive, carcinoembryonic antigen (CEA)–expressing colorectal cancer (CRC) that has lost HLA-A*02 expression.¹

A2B530 is the first autologous logic-gated CAR T-cell therapy developed by the A2 Bio proprietary Tmod platform, which uses a dual-receptor design that includes an activator that targets CEA on tumor cells and a blocker that protects normal cells and targets HLA-A*02.^1,2 This novel design aims to selectively kill tumor cells without affecting normal cells, which is a fundamental challenge in the treatment of solid tumors.¹

“The FDA granting orphan drug designation [to A2B530] validates the tremendous unmet need for improved therapies for patients with CRC,” William Go, MD, PhD, chief medical officer of A2 Biotherapeutics, stated in a news release. “This designation supports our commitment to use our novel technology platform to develop new treatment options for patients with difficult-to-treat cancers.”

The phase 1/2 EVEREST-1 trial (NCT05736731) is investigating the safety and efficacy of A2B530 in patients with CRC, pancreatic cancer, non–small cell lung cancer (NSCLC), or other solid tumors that express CEA and have lost HLA-A*02 expression.^1,2 Enrollment in EVEREST-1 is ongoing.¹

To be eligible for enrollment in EVEREST-1, patients 18 years of age and older must have histologically confirmed, recurrent, unresectable, locally advanced, or metastatic CRC, NSCLC, pancreatic cancer, or other solid tumors associated with CEA expression.² Patients must have measurable disease and tissue demonstrating loss of heterozygosity of HLA-A*02 and have been appropriately enrolled and apheresed for potential CAR T-cell manufacturing in the noninterventional, observational BASECAMP-1 trial (NCT04981119), which is identifying patients with solid tumors who would be suitable candidates for treatment with A2B530 in EVEREST-1.^2,3 Approximately 1000 patients will be screened for part 1 of BASECAMP-1, and tumor samples from approximately 500 patients will undergo next-generation sequencing and be followed for a maximum of 2 years.³ Furthermore, approximately 200 patients will be screened for part 2 of the trial. Eligible patients will be enrolled, apheresed and followed for a maximum of 2 years. Patients are permitted to go directly between BASECAMP-1 and EVEREST-1 based on their individual disease course.²

Patients enrolled in EVEREST-1 must have sufficient stored cells available for Tmod CAR T-cell therapy manufacturing and have received prior therapy for the appropriate solid tumor. Patients are also required to have adequate organ function, an ECOG performance status of 0 or 1, and a life expectancy of at least 3 months.

Patients will be excluded from EVEREST-1 if they have disease that is suitable for local therapy or if they can receive standard-of-care therapy that is therapeutic and not palliative; received prior allogeneic stem cell transplant; received prior solid organ transplant; received cancer therapy within 3 weeks or 3 half-lives of A2B530 infusion; have unstable arrythmia, myocardial infarction, angina, or any other significant cardiac disease within the past 6 months; or have any new symptomatic pulmonary embolism or deep vein thrombosis within 3 months of enrollment. Patients will also be excluded if they require supplemental home oxygen.

In EVEREST-1, patients will receive a preconditioning lymphodepletion regimen followed by a single dose of intravenous A2B530 on day 0. Phase 1 of this trial will assess the rate of adverse effects and dose-limiting toxicities by dose level, as well as determine the recommended phase 2 dose of A2B530. Phase 2 will determine the overall response rate per RECIST v1.1 criteria by independent central review. Secondary outcome measures include the persistence of A2B530 Tmod CAR T cells and an analysis of cytokine levels.

In June 2023, the first patient was dosed with A2B530 in EVEREST-1.⁴

References

1. A2 Bio receives FDA orphan drug designation for novel cell therapy program A2B530 in colorectal cancer. News Release. A2 Biotherapeutics, Inc. March 4, 2024. Accessed March 4, 2024. https://www.a2bio.com/a2-bio-receives-fda-orphan-drug-designation-for-novel-cell-therapy-program-a2b530-in-colorectal-cancer/
2. A study to evaluate the safety and efficacy of A2B530, a logic-gated CAR T, in subjects with solid tumors that express CEA and have lost HLA-A*02 expression (EVEREST-1). ClinicalTrials.gov. Updated February 2, 2024. Accessed March 4, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT05736731
3. Solid tumor analysis for HLA loss of heterozygosity (LOH) and apheresis for CAR T-cell manufacturing (BASECAMP-1). ClinicalTrials.gov. Updated February 2, 2024. Accessed March 4, 2024. https://clinicaltrials.gov/study/NCT04981119
4. A2 Bio announces first patient dosed in phase 1 clinical trial of A2B530, a novel cell therapy for the treatment of colorectal, pancreatic, and non-small cell lung cancers. News release. A2 Biotherapeutics, Inc. May 30, 2023. Accessed March 4, 2024. https://www.a2bio.com/a2-bio-announces-first-patient-dosed-in-phase-1-clinical-trial-of-a2b530-a-novel-cell-therapy-for-the-treatment-of-colorectal-pancreatic-and-non-small-cell-lung-cancers/