FDA Delays BMS's Liso-cel BLA by Three Months, Giving Gilead's KTE-X19 Potential Edge

Bristol-Myers Squibb (BMS) recently announced that the U.S. Food and Drug Administration (FDA) has extended the action date for the Biologics License Application (BLA) of lisocabtagene maraleucel (liso-cel, JCAR017) by three months. Liso-cel is an autologous, CD19-directed chimeric antigen receptor (CAR) T-cell therapy composed of purified CD8+ and CD4+ T cells in a defined 1:1 ratio, indicated for the treatment of adult patients with relapsed or refractory large B-cell lymphoma (R/R LBCL) who have received at least two prior lines of therapy. The FDA has set a new Prescription Drug User Fee Act (PDUFA) target action date of November 16, 2020.

Following the submission and acceptance of the Biologics License Application (BLA), Bristol-Myers Squibb (BMS) submitted additional information to the U.S. Food and Drug Administration (FDA) as requested. This information was deemed a major amendment to the BLA, necessitating additional time for FDA review. BMS stated that it will work closely with the FDA to support the ongoing review of the lisocabtagene maraleucel (liso-cel) BLA and remains committed to making this therapy available to patients.

FDA approval of liso-cel by December 31, 2020, was one of the necessary milestones for the contingent value rights (CVRs) issued at the closing of Bristol-Myers Squibb’s (BMS) acquisition of Celgene in the fourth quarter of 2019. Another required milestone was FDA approval of ide-cel, another BCMA-targeted CAR-T cell therapy, by March 31, 2021. BMS stated that it remains committed to working with the FDA to advance the applications for these two CAR-T cell therapies and achieve the remaining regulatory milestones required by the CVRs.

The BLA for liso-cel is based on the results of the TRANSCEND NHL 001 trial, which is the largest study to date supporting a BLA for a CD19-directed CAR-T cell therapy. The study enrolled a total of 269 patients with relapsed/refractory LBCL (including DLBCL) to evaluate the safety and efficacy of liso-cel.

The study results were presented at the 2019 American Society of Hematology (ASH) Annual Meeting. Data showed that among efficacy-evaluable patients (n=256), the overall response rate (ORR) with liso-cel treatment was 73% (187/256; 95% CI: 67–78), and the complete response (CR) rate was 53% (136/256; 95% CI: 47–59). Responses were similar across all patient subgroups. With a median follow-up of 12 months (95% CI: 11.2–16.7), the median duration of response (DOR) was not reached (95% CI: 8.6–NR). The median progression-free survival (PFS) was 6.8 months (95% CI: 3.3–14.1), and the median overall survival (OS) was 21.1 months (95% CI: 13.3–NR). Among patients who achieved a complete response, the median PFS and OS were not reached; at 12 months, 65.1% of patients remained progression-free and 85.5% were alive.

In the study, 79% (213/269) of all patients experienced treatment-emergent adverse events (TEAEs) of grade ≥3, including neutropenia (60%, 161/269), anemia (38%, 101/269), and thrombocytopenia (27%, 72/269). Cytokine release syndrome (CRS) of any grade occurred in 42% (113/269) of patients, with a median onset of 5 days; CRS of grade 3 or higher occurred in 2% (6/269) of patients. Neurological events (NEs) occurred in 30% (80/269) of patients, with 10% (27/269) experiencing grade 3 or higher NEs. Tocilizumab and corticosteroids were administered in 19% and 21% of patients, respectively.

Liso-cel was developed by Juno, which Bristol-Myers Squibb (BMS) acquired in January 2018 for $9 billion. In early January 2019, BMS announced its acquisition of Celgene for $74 billion. After a series of setbacks, this massive acquisition was successfully completed on November 21, 2019.

Liso-cel is a CAR-T cell therapy targeting the CD19 antigen with 4-1BB as the co-stimulatory domain, in which CD4+ and CD8+ CAR-T cells are maintained at a precise 1:1 ratio. Liso-cel represents a potential best-in-class CD19-directed CAR-T therapy and has previously been granted Breakthrough Therapy Designation by the U.S. FDA.

Liso-cel targets the same antigen as the two commercially available CAR-T cell therapies, Kymriah (Novartis) and Yescarta (Gilead). However, prior to chimeric antigen receptor (CAR) transduction, patients receiving liso-cel undergo pre-separation of CD4+ and CD8+ T cells. These separately transduced cells are then reinfused into the patient at a defined 1:1 ratio. This approach has demonstrated a more favorable safety profile compared with other CAR-T therapies, including a lower incidence of cytokine release syndrome.

Previously, liso-cel was granted Breakthrough Therapy Designation (BTD) and Regenerative Medicine Advanced Therapy (RMAT) designation by the U.S. Food and Drug Administration (FDA) for the treatment of relapsed/refractory aggressive large B-cell non-Hodgkin lymphoma (NHL), including diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), and grade 3B follicular lymphoma (FL). In the European Union, liso-cel was granted Priority Medicines (PRIME) designation by the European Medicines Agency (EMA) for the treatment of relapsed/refractory DLBCL.

Liso-cel was initially poised to become the third CAR-T cell therapy to reach the market. However, due to a three-month extension in its Biologics License Application (BLA) review cycle, KTE-X19, another CAR-T cell therapy from Kite Pharma, a Gilead subsidiary, now has the opportunity to surpass liso-cel and secure FDA approval first. Currently, KTE-X19 is undergoing priority review by the FDA, with a PDUFA target date of August 10, 2020. In late January this year, the European Medicines Agency (EMA) also accepted the Marketing Authorization Application (MAA) for KTE-X19.

KTE-X19 is an autologous, anti-CD19 CAR-T cell therapy submitted for the treatment of adult patients with relapsed or refractory mantle cell lymphoma (R/R MCL). In the United States and the European Union, KTE-X19 was previously granted Breakthrough Therapy Designation (BTD) and Priority Medicines (PRIME) designation, respectively. MCL is a rare type of non-Hodgkin lymphoma (NHL) that originates from cells in the “mantle zone” of lymph nodes and typically affects men over the age of 60.

If approved, KTE-X19 will become the first CAR-T cell therapy for the treatment of mantle cell lymphoma (MCL), and Kite will also become the first biopharmaceutical company with multiple commercialized CAR-T therapies. KTE-X19 utilizes the XLP manufacturing process, which includes T-cell selection and lymphocyte enrichment. For certain B-cell malignancies with evidence of circulating lymphoblasts, lymphocyte enrichment is a necessary step.

Data from the Phase II ZUMA-2 clinical study showed that in adult patients with relapsed or refractory mantle cell lymphoma (MCL), the overall response rate (ORR) was 93% and the complete response rate (CR) was 67% after a single infusion of KTE-X19, with a median follow-up of 12.3 months. Regarding safety, Grade ≥3 cytokine release syndrome (CRS) and neurological events occurred in 15% and 31% of patients, respectively; no Grade 5 CRS or neurological events were reported.

Original Source: Bristol Myers Squibb Provides Update on Biologics License Application (BLA) for Lisocabtagene Maraleucel (liso-cel)

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