FDA Approval Sought for Cilta-cel CAR T-cell Therapy

Janssen and Legend Biotech are seeking U.S. approval for their investigational CAR T-cell therapy ciltacabtagene autoleucel  — known as cilta-cel — to treat adults with relapsed or refractory (hard-to-treat) multiple myeloma.

A rolling submission of the biologics license application (BLA) for cilta-cel has been started by Janssen with the U.S. Food and Drug Administration (FDA). Through this process, Janssen will submit individual sections of the application to the FDA as soon as each one is completed, rather than waiting to submit the entire document at once, as is typical.

“Today’s submission marks Janssen’s first cell therapy application, but more importantly, brings cilta-cel one step closer to our goal of making new medical options available to patients with multiple myeloma,” Mathai Mammen, MD, PhD, the global head of Janssen’s research & development, said in a press release.

Peter Lebowitz, MD, PhD, global therapeutic area head of oncology at Janssen’s research & development, called the filing an important “milestone” for the company.

It is “the culmination of a remarkable clinical development effort and collaboration with Legend Biotech,” Lebowitz said.

The two companies entered into a worldwide collaboration and license agreement in December 2017, with plans to jointly develop and commercialize cilta-cel as a treatment for multiple myeloma. According to the terms of the agreement, the BLA submission earned Legend a $75 million milestone payment from Janssen.

In a separate press release, Ying Huang, PhD, Legend’s CEO and chief financial officer, noted that “initiation of the BLA submission is an important milestone in advancing this therapy for patients with multiple myeloma who are heavily pretreated and in need of treatment options.”

“Together with our collaborator Janssen, we look forward to working with the FDA to fulfill this unmet medical need with the goal of making this breakthrough treatment available to patients and healthcare providers in the future,” Huang added.

A type of immunotherapy, cilta-cel involves the collection and genetic modification of a person’s own T-cells — immune cells with the ability to kill cancer cells — to make them better at fighting cancer.

Specifically, the therapy comprises T-cells engineered to recognize and kill cells containing the B-cell maturation antigen (BCMA) — a protein found at high levels on the surface of myeloma cells — while leaving healthy cells unharmed. The modified cells are then expanded and infused back into the patient.

Of note, cilta-cel is also known as LCAR-B38M in China and as JNJ-4528 outside of China.

It received breakthrough therapy designation from regulatory authorities in the U.S. and China, and priority medicines status in the European Union (EU). It also was designated an orphan drug in the U.S., the EU, Japan, and Korea.

These designations are meant to accelerate cilta-cel’s development by providing regulatory support and financial benefits. In addition, they ensure a marketing exclusivity period of seven years in the U.S. and 10 years in the EU upon regulatory approval.

The rolling submission is based on results from the CARTITUDE-1 Phase 1b/2 clinical trial (NCT03548207), sponsored by Janssen, which is evaluating the safety and effectiveness of cilta-cel in adults with relapsed or refractory multiple myeloma.

Participants were required to have received at least three lines of prior treatment — including a proteasome inhibitor (PI), an immunomodulatory agent (IMiD), and a CD38 inhibitor — or failed to respond to treatment with a PI and an IMiD.

The ongoing Phase 2 part of the trial aims to assess the proportion of patients achieving at least partial responses with cilta-cel’s optimal dose, which was determined during the study’s Phase 1b, at a minimum of two years after treatment.

CARTITUDE-1’s latest results, recently presented at the American Society of Hematology 2020 Annual Meeting and Exposition, were derived from one-year data from 97 participants. Among them, 29 were enrolled in Phase 1 and 68 in Phase 2.

The data showed that 97% of treated patients experienced a reduction in cancer burden after a single infusion of cilta-cel, with 67% achieving deep complete responses (no detectable cancer). Most (93%) of the 53 patients with evaluable data were negative for minimum residual disease, meaning they had less than one cancer cell per 10,000 white blood cells.

In responding participants, responses were observed after a median of one month and these tended to improve over time. Notably, 72% of patients had ongoing responses after one year. In addition, most patients were alive (89%) and showed no signs of disease worsening (77%).

Cilta-cel’s safety profile was consistent with that reported in previous trials, with the most common adverse events (side effects) being low levels of blood cells, including neutrophils, platelets, red blood cells, leukocytes, and lymphocytes.

At the time of the analysis, 14 patients had died: six due to treatment-related side effects, five due to disease progression, and three due to side effects unrelated to treatment.

Participants will be followed for at least one more year, after which they may be given the option to enter a 15-year, long-term follow-up study.

“We look forward to working with the FDA in their review of cilta-cel with the goal of bringing a highly-active, dual-binding BCMA CAR-T therapy to patients with relapsed and/or refractory multiple myeloma who are in need of new treatment options,” Lebowitz said.