FDA Grants Orphan Drug Designation to CT103A for Relapsed/Refractory Myeloma

The FDA has granted an orphan drug designation (ODD) to the investigational anti-BCMA CAR T-cell therapy CT103A for use as a potential therapeutic option in patients relapsed/refractory multiple myeloma.¹

CT103A utilizes a lentiviral vector containing a CAR structure with a fully human single-chain variable fragment, CD8a hinger, and transmembrane, 4-1BB co-stimulatory and CD3ζ activation domains. By leveraging a proprietary in-house optimization platform, the construct of the BCMA-targeted therapy is hypothesized to be strong and durable.

"FDA approval of ODD to CT103A is of great significance to patients with multiple myeloma and represents the FDA's recognition of CT103A and the clinical data provided by IASO Bio,” Wen Wang, MD, PhD, chief executive officer and chief medical officer of IASO Bio, stated in a press release. "Currently, our team is advancing the clinical development of CT103A to the 4 dimensions of strategy including frontline therapy, combination therapies, indication expansion, and ex-China development. We are looking forward to the launch of CT103A both in China and the United States as soon as possible to offer a living-saving treatment option to more patients."

In February 2021, China’s National Medical Products Administration granted a breakthrough therapy designation to CT103A for the treatment of relapsed/refractory multiple myeloma, based on the results of a phase 1 trial (ChiCTR1800018137), which examined the product in 18 patients with relapsed/refractory multiple myeloma.^2,3

The agent was administered at 1, 3, and 6 x 10⁶ CAR-positive T cells/kg in the dose-escalation phase of the trial, and at 1 x 10⁶ CAR-positive T cells/kg in the expansion cohort.

CT103A elicited an overall response rate of 100%, with 72.2% of patients achieving a complete response (CR) or stringent CR (sCR). Of 4 patients who had prior BCMA CAR T-cell therapy exposure, 3 achieved a sCR with the therapy, and 1 experienced a very good stringent partial response (PR). Additionally, the 1-year progression-free survival (PFS) rate was 58.3% for all cohorts and 79.1% for those without extramedullary myeloma.

Regarding safety, 70.6% of patients experienced grade 1 or 2 cytokine release syndrome (CRS), and no patients experienced immune effector cell–associated neurotoxicity syndrome (ICANS). At data cutoff, CAR transgenes were detectable in 77.8% of patients, and the median CAR transgene persistence was 307.⁵ days. One patient was positive for antidrug antibody, which has been reported to be a high-risk factor for disease relapse or progression following CAR T-cell therapy.

Data from the ongoing phase 1/2 trial (ChiCTR2000033946) further demonstrated the efficacy of CT103A in a cohort of 71 patients with relapsed/refractory multiple myeloma receiving 1 x 10⁶ CAR-positive T cells/kg, which was identified as the recommended phase 2 dose (RP2D).⁴ Following 3 days of lymphodepletion with fludarabine and cyclophosphamide, plus 1 day of rest, patients received CT103A.

All 71 patients were evaluable for efficacy, and data showed that the CAR T-cell therapy produced an ORR of 94.4%; 50.7% of patients achieved a CR or better, 26.8% achieved a very good PR (VGPR), and 16.9% had a PR. The median time to first response was 15 days (range, 11-124). Of the 50 patients who completed follow-up at 3 months, the ORR was 96.0%, with 54.0% achieving a CR or better, 28% having a VGPR, and 14% experiencing a PR.

Among 13 patients who received prior CAR T-cell therapy, the ORR with CT103A was 76.9%, and this included a CR rate or better of 38.5%, a VGPR rate of 15.4%, and a PR rate of 23.1%. Moreover, 92.8% of patients with evaluable bone marrow aspirate achieved minimal residual disease (MRD) negativity, with a median time to negativity of 17 days (range, 13-180). Notably, 75.0% (95% CI, 53.1%-87.6%) of those who achieved MRD negativity had sustained negative status for longer than 6 months.

At 6 months, CT103A was still detectable in 88.5% of patients at 6 months after the infusion; after 12 months, it was detectable in 87.5% of patients. Two of 71 patients were positive for antidrug antibody.

The most common grade 3 or higher treatment-related adverse effects were hematological toxicities. Ninety-three percent of patients experienced CRS, although only 2.8% of cases were grade 3 in severity. The median time to CRS onset was 6 days (range, 1-12), and the median duration of the effect was 4 days (range, 1-27). One patient experienced grade 2 ICANS, and the patient recovered without intervention.

The phase 1/2 FUMANBA-1 trial (NCT05066646) is currently investigating the safety and efficacy of CT103A in patients with relapsed/refractory multiple myeloma who had received at least 3 lines of prior treatment and who had evidence of cell membrane BCMA expression. In these patients, CT103A will be infused at the RP2D of 1.0 x 10⁶ CAR-positive T cells/kg after lymphodepleting chemotherapy.⁵

References

1. U.S. FDA grants orphan drug designation to BCMA CAR-T cell therapy co-developed by IASO Bio and Innovent. News Release. IASO Biotherapeutics and Innovent Biologics, Inc.; February 14, 2022. Accessed February 17, 2022. https://bit.ly/3gXGmT8
2. The BCMA CAR-T Co-developed by IASO Biotherapeutics and Innovent was granted breakthrough therapy designation by the NMPA for the treatment of relapsed/refractory multiple myeloma. IASO Biotherapeutics and Innovent Biologics, Inc.; February 23, 2021. Accessed February 17, 2022. https://bwnews.pr/36gSNaB
3. Wang D, Wang J, Hu G, et al. A phase 1 study of a novel fully human BCMA-targeting CAR (CT103A) in patients with relapsed/refractory multiple myeloma. Blood. 2021;137(21):2890-2901. doi:10.1182/blood.2020008936
4. Li C, Wang D, Song Y, et al. A phase 1/2 study of a novel fully human B-cell maturation antigen-specific CAR T cells (CT103A) in patients with relapsed and/or refractory multiple myeloma. Blood. 2021;138(suppl 1):547. doi:10.1182/blood-2021-152576
5. A phase 1/2 study of a fully human BCMA-targeting CAR (CT103A) in patients with relapsed/refractory multiple myeloma (FUMANBA-1). ClinicalTrials.gov. Updated November 23, 2021. Accessed February 17, 2022. https://clinicaltrials.gov/ct2/show/NCT05066646