In an interview with PharmaShots, Ying Huang, Ph.D., CEO and CFO of Legend Biotech shed light on the clinical data following the rolling submission of BLA for Cilta-cel. He also shared insight on Legends' collaboration with Janssen.

Shots:

• The submission of BLA was based on results from the P-Ib/II CARTITUDE-1 study of cilta-cel, which were recently presented at the 62nd ASH Meeting
• The data demonstrated a 97% ORR and 67% stringent CRR, as well as a unique, predictable profile for cytokine release syndrome. The mDOR and PFS still have not been reached in the P-Ib/II data, suggesting a significant durable response
• Janssen is developing cilta-cel in partnership with Legend Biotech. The FDA previously granted BTD for cilta-cel and has agreed to a rolling review of the application

Tuba:  Discuss the clinical data that follows the rolling submission of the Biologics License Application to the U.S. FDA for cilta-cel.

Ying Huang: The submission was based on results from the Phase 1b/2 CARTITUDE-1 study, which evaluated the efficacy and safety of cilta-cel in the treatment of patients with relapsed and/or refractory multiple myeloma. The latest data from the study presented at the 62nd ASH annual meeting demonstrated a 97 percent overall response rate and 12-month progression-free survival rate of 77 percent at a median follow-up of 12.4 months with a manageable safety profile.

Tuba:  Can we have a glance at your collaboration with Janssen? Also, discuss the deal terms and milestones achieved to date.

Ying Huang: In December 2017, Legend entered an exclusive worldwide license and collaboration agreement with Janssen Biotech, Inc. (Janssen) to develop and commercialize cilta-cel.

Legend Biotech received $75M as the fifth milestone payment under its collaboration agreement with Janssen in the clinical development of cilta-cel. Also, the Company recently announced the initiation of a BLA submission for cilta-cel to the FDA for the treatment of relapsed/refractory multiple myeloma.

Tuba:  How do you think the approval of ciltacabtagene autoleucel (cilta-cel) will improve the lives of patients with R/R MM?

Ying Huang: Cilta-cel has the potential to be a transformative treatment option for patients living with R/R MM. Patients with R/R MM have received previous lines of treatment and yet their disease has returned, is non-responsive or is still progressing. Patients who have received prior therapies, including proteasome inhibitors (PIs), immunomodulatory agents (IMiDs) and anti-CD38 therapies, have poor prognoses and few treatment options. Data from the CARTITUDE-1 study showed a very high overall response rate (ORR) that deepened over time, with 97 percent of patients achieving a response and 67 percent of patients achieving a stringent complete response (sCR) at a median follow-up of 12.4 months with a manageable safety profile.

Tuba:  Can you discuss the working of cilta-cel?

Ying Huang: Cilta-cel is a structurally differentiated chimeric antigen receptor T-cell (CAR-T) therapy with two BCMA-targeting single domain antibodies. BCMA is a protein that is highly expressed on myeloma cells. Cilta-cel is delivered in a single intravenous infusion at a target dose of 0.75x106 CAR+ viable T cells/kg.  

Tuba:  When can we expect the launch of the therapy in the U.S.?

Ying Huang: The FDA previously granted Breakthrough Therapy Designation (BTD) for cilta-cel and has agreed to a rolling review of the BLA in which completed portions of the application will be submitted and reviewed on an ongoing basis. Initiation of the BLA submission was announced on December 21, 2020.

Tuba:  After the U.S., which would be the targeted countries for seeking approvals?

Ying Huang: Legend and Janssen are also preparing for regulatory submissions for cilta-cel in the European Union and China. In addition to a U.S. Breakthrough Designation granted in December 2019, cilta-cel received a PRIority MEdicines (PRiME) designation from the European Commission in April 2019, and a BTD in China in August 2020.

Tuba:  Briefly discuss Multiple Myeloma. What is the cause and how does it work in the body?

Ying Huang: Multiple myeloma is an incurable blood cancer that starts in the bone marrow and is characterized by an excessive proliferation of plasma cells. Although treatment may result in remission, unfortunately, patients will most likely relapse. Relapsed myeloma is when the disease has returned after a period of initial, partial, or complete remission and does not meet the definition of being refractory. Refractory multiple myeloma is when a patient's disease is non-responsive or progresses within 60 days of their last therapy. While some patients with multiple myeloma have no symptoms until later stages of the disease, most patients are diagnosed due to symptoms that can include bone problems, low blood counts, calcium elevation, kidney problems, or infections. Patients who relapse after treatment with standard therapies, including protease inhibitors and immunomodulatory agents, have poor prognoses and few treatment options.

Tuba:  Are you planning to explore the potential of cilta-cel in other indications?

Ying Huang: Cilta-cel is an investigational CAR-T cell therapy being studied in a comprehensive clinical development program with Janssen for the treatment of patients with relapsed/refractory multiple myeloma and in earlier lines of treatment. We are also evaluating the potential for outpatient administration of cilta-cel.

For additional information:

• CARTITUDE-2: The global, multi-cohort Phase 2 CARTITUDE-2 (MMY2003, NCT04133636) study of cilta-cel is actively recruiting patients with multiple myeloma in various clinical settings. This study is being conducted to evaluate the overall minimal residual disease (MRD) negative rate of participants who receive cilta-cel to further explore efficacy and safety in earlier patient populations.
• CARTITUDE-4: The global, Phase 3 CARTITUDE-4 (MMY3002, NCT04181827) study of cilta-cel is actively recruiting patients with multiple myeloma who have received 1-3 prior lines of therapy including a PI and IMiD and are refractory to lenalidomide. The study is being conducted to evaluate the efficacy of cilta-cel compared to standard therapies including daratumumab, pomalidomide and low-dose dexamethasone (DPd) or pomalidomide, bortezomib, and low-dose dexamethasone (PVd)

Tuba:  What can you tell us about Legend's pipeline beyond cilta-cel?

Ying Huang: Legend Biotech is working to explore the potential of cell therapy to treat diseases with high unmet needs, such as hematologic malignancies and solid tumors. We recently announced the Investigational New Drug Application submission for our anti-CD4 CAR-T cell therapy candidate for T-cell lymphoma and have several other early-stage clinical trials underway investigating potential treatments for AML, NHL, MM, and gastric, pancreatic, and ovarian cancers.

Image Source: WebMD 

About Author:

Dr. Ying Huang was named Chief Executive Officer of Legend Biotech on November 6, 2020.  He also has served as Chief Financial Officer since July 2019. He has over 9 years of experience in research and development at major multi-national pharmaceutical companies and 12 years of experience as a biotechnology analyst on Wall Street.

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