FDA Approves Cilta-cel as Carvykti for Heavily Treated Myeloma

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by Marta Figueiredo |

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Carvykti formerly cilta-cel | Myeloma Research News | illustration of APPROVED stamp

The U.S. Food and Drug Administration (FDA) has approved the CAR T-cell therapy Carvykti (ciltacabtagene autoleucel) — formerly known as cilta-cel — for certain adults with relapsed or refractory multiple myeloma.

In particular, the approval makes Carvykti available for people who have received at least four prior lines of therapy, including a proteasome inhibitor (PI), an immunomodulatory agent (IMiD), and a CD38 inhibitor.

The decision comes about eight months after the FDA granted priority review to the Carvykti application. The regulatory agency had said it needed more time to review additional data submitted by the therapy’s co-developers Legend Biotech and Janssen.

The two companies entered into a worldwide collaboration and licensing agreement in December 2017, with plans to jointly develop and commercialize Carvykti as a treatment for multiple myeloma.

“Today’s approval of Carvykti is a pivotal moment for Legend Biotech because it is our first-ever marketing approval, but what really excites us is the drug’s potential to become an impactful therapy option for patients in need of long, treatment-free intervals,” Ying Huang, PhD, CEO and chief financial officer of Legend Biotech, said in a press release.

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Similar applications also are being reviewed by health authorities in the European Union (EU) and Japan. The application to the Japanese Ministry of Health, Labour and Welfare specifically covers patients who received at least three prior lines of therapies, including a PI, an IMiD, and a CD38 inhibitor, just one less than specified in the FDA approval.

Notably, in the EU, the application’s initial accelerated assessment was reverted to a standard review timeline to allow health authorities to conduct a good manufacturing practice (GMP) inspection and provide a GMP certificate, which could not be accommodated in the accelerated assessment timetable. A GMP certificate ensures that the manufacturing facility consistently produces high-quality batches of the medication.

The therapy received breakthrough therapy designation in the U.S. and China, and priority medicines status in the EU. It also was designated an orphan drug in the U.S., the EU, Japan, and Korea.

These designations are meant to help accelerate the treatment’s clinical development and regulatory review, in addition to ensuring a marketing exclusivity period of seven years in the U.S. and 10 years in the EU upon regulatory approval.

A type of immunotherapy, Carvykti 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.

The FDA’s approval was based on positive data from the Janssen-sponsored CARTITUDE-1 Phase 1b/2 clinical trial (NCT03548207), which is evaluating the safety and effectiveness of a single Carvykti dose in 113 adults with relapsed or refractory multiple myeloma. After completing a two-year follow-up period, trial participants can choose to enter a 15-year, long-term follow-up study.

Participants had received at least three lines of prior treatment — including a PI, an IMiD, and a CD38 inhibitor — or had failed to respond to treatment with a PI and an IMiD.

The study’s ongoing Phase 2 part aims to assess the proportion of patients who responded to treatment at a minimum of two years after receiving Carvykti’s optimal dose of 0.75 million CAR T-cells per kg. That optimal dose was determined during the study’s Phase 1b.

Interim one-year results, concerning 97 patients treated with the recommended dose, showed that 97% of them experienced a reduction in cancer burden, with 67% achieving stringent complete responses, meaning no detectable cancer.

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Longer follow-up data, after a median of 22 months, showed a similarly high response rate (98%). Notably, a stringent complete response was detected in 83% of participants, suggesting a deepening of clinical response over time. Also, after two years, two-thirds of patients were alive and without signs of disease progression.

Most (92%) of the 61 patients with evaluable data were negative for minimum residual disease, meaning they had less than one cancer cell per 100,000 white blood cells. This status was achieved after a median of one month.

“The treatment journey for the majority of patients living with multiple myeloma is a relentless cycle of remission and relapse with fewer patients achieving a deep response as they progress through later lines of therapy,” said Sundar Jagannath, MD, a professor at Mount Sinai and the principal investigator of the CARTITUDE-1 trial.

“This is why I have been really excited about the results from the CARTITUDE-1 study, which has demonstrated that cilta-cel can provide deep and durable responses and long-term treatment-free intervals, even in this heavily pretreated multiple myeloma patient population,” Jagannath added. “Today’s approval of Carvykti helps address a great unmet need for these patients.”

Carvykti’s safety profile was consistent with that reported in previous trials, with the most common adverse events being low levels of blood cells, including neutrophils (96%), red blood cells (81%), platelets (79%), leukocytes (62%), and lymphocytes (53%).

Cytokine release syndrome — a potentially life-threatening complication of immunotherapies — occurred in 95% of patients, most being mild to moderate in severity and 99% of cases resolving within two weeks of onset.

A total of 20 patients (21%) experienced neurotoxicity, or damage to the brain or nervous system, which was severe or worse in 10 of them (10%).

Because of these side effects, Carvykti will be available in the U.S. through a restricted distribution program called Carvykti REMS. This FDA-required program ensures that eligible patients receive Carvykti only if the medicine’s benefits outweigh its risks. It also ensures that Carvykti is infused at certified facilities and by healthcare providers with proper training to monitor and manage potentially serious side effects.

Carvykti’s prescribing information also carries a “boxed warning,” the FDA’s highest warning level, highlighting that the treatment may cause potentially life-threatening or fatal issues.

In addition to cytokine release syndrome and neurotoxicity, these include parkinsonism and Guillain-Barré syndrome, as well as an increased risk of bleeding and infections due to prolonged decreases in certain blood cells. The treatment also is associated with conditions in which the immune system is overly active, such as hemophagocytic lymphohistiocytosis and macrophage activation syndrome.