Data Roundup: December 2024 Features Updates for Cilta-Cel in Multiple Myeloma, mRNA CAR-T in Myasthenia Gravis, and More

Last month, December 2024, the CGTLive® team was diligently tracking the latest data readouts and published literature on cell and gene therapies within oncology, neurology, rare diseases, and more.

As more and more innovative therapies enter the clinical trial field, more data is accrued every month, buoying excitement in the field and sometimes making or breaking the fates of small biotech companies. Last month delivered data updates for Cartesian Therapeutics’ chimeric antigen receptor T-cell (CAR-T) therapy in myasthenia gravis, Johnson & Johnson subsidiary Janssen’s and Legend Biotech's ciltacabtagene autoleucel (cilta-cel; marketed as Carvykti) in multiple myeloma (MM), and more. Our team has highlighted these below.

Click the read more buttons for more details and information about each update.

Cilta-Cel Boosts MRD Negativity Rates Compared to Standard of Care Therapy in New Multiple Myeloma Data

December 11, 2024 - Johnson & Johnson subsidiary Janssen’s and Legend Biotech's ciltacabtagene autoleucel (cilta-cel; marketed as Carvykti) an FDA-approved BCMA-directed autologous CAR-T therapy, has produced higher rates of minimal residual disease (MRD) negativity in comparison to patients treated with standard-of-care (SOC) therapy for lenalomide-refractory MM in newly updated data from the phase 3 CARTITUDE-4 clinical trial (NCT04181827). The findings were presented by study investigator Rakesh Popat, MD, an honorary associate professor at University College London Hospitals, NHS Foundation Trust, at the 66th American Society of Hematology (ASH) Annual Meeting and Exposition, held December 7-10, 2024, in San Diego, California.

The trial randomly assigned participants with relapsed or lenalidomide-refractory MM, who had previously been treated with 1 to 3 prior lines of therapy that included a protesome inhibitor (PI) and an immunomodulatory agent (IMiD), to receive either cilta-cel (n = 208) or SOC (n = 211), which consisted of either pomalidomide, bortezomib, and dexamethasone (PVd) or daratumumab, pomalidomide, and dexamethasone (DPd). For the 145 patients treated with cilta-cel who were evaluable for MRD negativity at a threshold of 10^-5, 89.0% achieved MRD negativity; on the other hand, for the 103 patients treated with SOC evaluable at this threshold, 37.9% achieved MRD negativity (OR: 13.3; P < .0001; median follow-up, approximately 34 months). For the 139 patients treated with cilta-cel who were evaluable for MRD negativity at a threshold of 10^-6, 85.6% achieved MRD negativity; for the 102 patients treated with SOC who were evaluable at this threshold, 18.6% achieved MRD negativity (OR: 28.5; P < .0001). Furthermore, 69% of the patients in the cilta-cel intent to treat (ITT) population evaluable for MRD negativity at the 10^-5 threshold achieved MRD negativity by 56 days posttreatment and 86% of the patients in the cilta-cel ITT population evaluable for MRD negativity at the 10^-5 threshold achieved MRD negativity by 6 months posttreatment.

“Carvykti has established its significant impact on OS and improved PFS compared to standard therapies,” Popat said in a statement.² “The MRD negativity results demonstrate deep responses compared to standard therapies for people living with MM and further underscore the benefit of Carvykti, administered as a single infusion as early as second line.”

Cartesian Therapeutics’ mRNA CAR-T Descartes-08 Produces Durable Responses in Myasthenia Gravis

December 5, 2024 - Cartesian Therapeutics’ Descartes-08, an investigational autologous mRNA-engineered CAR-T therapy for the treatment of autoimmune diseases including myasthenia gravis (MG), has produced durable responses in some patients with MG treated in the phase 2b portion of a clinical trial (NCT04146051).

Cartesian announced efficacy findings for the group of patients in the trial treated with at least 1 dose of Descartes-08 who had at least 3 months of follow-up, which constitutes the primary efficacy dataset. For the 12 patients in this group who had at least 4 months of follow-up, the average MG Activities of Daily Living (MG-ADL) score had reduced by 5.5 (±1.1) at 4 months posttreatment. For the 7 patients within this group who had not previously been treated with biologic therapies the average reduction in MG-ADL score was 6.6 (±1.5). Furthermore, at 6 months posttreatment, an MG-ADL score of 0 or 1 was achieved by 4 of 12 patients (33%) in the primary efficacy dataset and 4 of 7 patients (57%) in the group of patients who had not previously received biologic therapy. For the 5 patients in the primary efficacy dataset who reached 12 months of follow-up, 4 patients (80%) maintained at least a 2 point reduction in MG-ADL score, which was considered a clinically meaningful response. Both of the only 2 patients who had not previously received biologic therapy and reached 12 months of follow-up maintained such a clinically meaningful response, with 1 of these patients maintaining an MG-ADL score in the range for minimum symptom expression (0 to 1).

The safety data set for the trial includes 36 patients, and Cartesian characterized Descartes-08 as “well-tolerated” in this group, with adverse events being “transient and mostly mild.” No cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome occurred in any of the patients, and Descartes-08 was not associated with increased rates of infection or hypogammaglobulinemia. In addition, the CAR-T did not appear to cause vaccine titers for common viruses to decrease.

Bendamustine Is an Effective Alternative to Fludarabine-Based Lymphodepletion in LBCL

December 7, 2024 - Lymphodepletion with bendamustine brought about similar efficacy findings with fewer adverse events (AEs) compared with fludarabine/cyclophosphamide for patients with large B-cell lymphoma (LBCL) being treated with a CD19-directed CAR T-cell therapy, according findings from 5256 patients enrolled in a real-world study presented at the 66th American Society of Hematology (ASH) Annual Meeting, held December 7-10, 2024, in San Diego, California.

In the study, patients received either axicabtagene ciloleucel (axi-cel; Yescarta), tisagenlecleucel (tisa-cel; Kymriah), or lisocabtagene maraleucel (liso-cel; Breyanzi). The objective response rate (ORR) was higher with the fludarabine-based therapy; however, complete response (CR) rates were not significantly different between the groups. Findings were also similar for progression-free survival (PFS) and overall survival (OS). Common AEs associated with CAR T-cell therapies were less common, including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and prolonged cytopenias.

"Bendamustine may be a viable lymphodepletion option for patients at high risk of toxicity; however, longer follow-up is needed to confirm its impact on survival outcomes," lead investigator Alaa Ali, MD, from the Lombardi Comprehensive Cancer Center, Georgetown University, said during a presentation of the results. "There are efficacy trade-offs, as bendamustine shows a lower ORR but maintains similar PFS and OS compared with fludarabine-based lymphodepletion in diffuse large B-cell lymphoma treated with CD19 CAR T cells."

bluebird bio’s Transfusion-Dependent β-Thalassemia Gene Therapy Beti-Cel Continues to Demonstrate Curative Potential in Long-Term Follow-Up Data

December 8, 2024 - bluebird bio’s betibeglogene autotemcel (beti-cel; Zynteglo), a gene therapy approved by the FDA for the treatment of adult and pediatric patients with transfusion-dependent β-thalassemia (TDT) has continued to show curative potential in updated long-term follow-up data from multiple clinical trials.¹ The data were presented at the 66th American Society of Hematology (ASH) Annual Meeting, held December 7-10, 2024, in San Diego, California.

The data come from 63 participants in the long-term follow-up study LTF-303 (NCT02633943), which enrolled patients who were previously treated with beti-cel in phase 1/2 (HGB-204, NCT01745120; HGB-205, NCT02151526) or phase 3 (HGB-207, NCT02906202; HGB-212, NCT03207009) clinical trials for the gene therapy. Of these 63 patients, 2 patients have 10 years of follow-up and 51 patients (81.0%) have at least 5 years of follow-up. It was noted that 1 patient discontinued participation in LTF-303 for personal reasons at 39 months of follow-up.

Notably, protocol-defined transfusion independence (TI) was achieved by 52 of the 63 patients in LTF-303, and all but 1 of these patients had maintained TI through their most recent follow-up. Specifically, TI was achieved by 15 of 22 patients (68.2%) who had received beti-cel in the phase 1/2 trials and 37 of the 41 patients (90.2%) who had received beti-cel in the phase 3 trials. Thompson and colleagues noted that the 1 patient who lost TI status had lost it at 6 years posttreatment after having been diagnosed with HIV complicated by gastrointestinal infection and bleeding and no longer having an Hb level of less than 9 g/dL. Although, it was noted that this patient’s peripheral blood vector copy number maintained stability with continued production of Hb^AT87Q.

Aurion Biotech’s Cell Therapy AURN001 Demonstrates Efficacy and Safety in Phase 1/2 ABA-1, CLARA Clinical Trial

December 22, 2024 - Aurion Biotech’s AURN001 (marketed as Vyznova in Japan), a combination cell therapy and small molecule product that remains investigational in the United States, has demonstrated efficacy and safety in data from the phase 1/2 ABA-1, CLARA clinical trial (NCT06041256) assessing it as an alternative to corneal transplant for corneal edema secondary to corneal endothelial dysfunction.¹

AURN001 consists of allogeneic human corneal endothelial cells, referred to as “neltependocel”, and Y-27632, a small molecule drug that inhibits Rho-associated, coiled-coil containing protein kinase. In ABA-1, CLARA, patients are assigned to receive either a low (2.5x10⁵), medium (5.0x10⁵), or high (1.0x10⁶) dose of neltependocel within the combination product. In an additional arm, participants receive neltependocel alone at a dose equivalent to that used in the high dose AURN001 arm and in yet another arm participants are treated with Y-27632 alone.

Notably, a statistically significant improvement in the proportion of responding patients who achieved at least 15 letters of improvement in best corrected visual acuity (BCVA) compared to the Y-27632-only arm, which constituted the primary end point, was recorded in the high dose arm (50% of responding patients versus 14.3%, P = .02). Furthermore, using the full analysis set population (LOCF, LS mean), the high dose arm showed a statistically significant improvement in change in BCVA at 6 months compared to the Y-27632-only arm (P = .002) and in change in central corneal thickness (CCT) at 6 months compared to the Y-27632-only arm (P = .012). These constituted key secondary end points. The greatest improvement in the Visual Function Questionnaire (VFQ-25) was also observed in the high dose arm.