With wider approval, J&J and Legend's Carvykti quickly leaps ahead of BMS' rival myeloma CAR-T

Merely hours after Bristol Myers Squibb’s Abecma secured the FDA’s blessing to break into earlier treatment of multiple myeloma, Johnson & Johnson and Legend Biotech’s Carvykti received a similar go-ahead—but in an even earlier setting and with expanded manufacturing specifications.

With an approval Friday, Carvykti has become the first BCMA-directed therapy for multiple myeloma patients who have received at least just one prior line of therapy. To be eligible, a patient’s cancer must be refractory to BMS’ Revlimid, mirroring the population enrolled in the CARTITUDE-4 trial, which supported the recent Carvykti filing.

Moving into the second line represents a key step in J&J’s plan to make Carvykti a $5 billion-plus product at peak sales. Last year, the drug pulled in $500 million in sales.

The second-line approval puts Carvykti one line ahead of BMS’ Abecma, which on Thursday received the FDA’s green light as a third-line option. It’s a remarkable feat for J&J and its partner Legend given that BMS reached the market about a year faster in the fifth-line indication.

Since Abecma’s U.S. approval in 2021 and Carvykti’s a year later, Abecma has gradually ceded market leadership to Carvykti thanks to the latter’s perceived better efficacy. Among U.S. treatment centers that offer both therapies, Carvykti holds about 80% of the late-line market share, a Legend exec said during a conference call last month.

In the CARTITUDE-4 trial, patients randomized to the Carvykti arm were found to have a 59% lower risk of disease progression or death compared with those in the control arm. The comparator group received combination treatment regimens of either Pomalyst-Velcade-dexamethasone or Darzalex-Pomalyst-dexamethasone.

As was the case with BMS, J&J had to defend Carvykti’s earlier-line case in front of an FDA advisory committee after the FDA flagged an early death signal, in which a higher proportion of patients in the Carvykti arm died within the first 10 months of randomization compared with the standard therapy arm. The external expert panel unanimously backed Carvykti because of its stunning progression-free survival results and a seemingly widening overall survival benefit over the longer term.

Still, the FDA’s early-death concern exists on Carvykti’s label in the “warnings and precautions” section—which comes lower than the boxed warning—similar to Abecma’s prescription information.

Also like Abecma, Carvykti’s new label includes a new line in its boxed warning, which describes the risk of post-treatment secondary T-cell malignancies. This addition comes as part of a classwide issue the FDA raised in November with all existing marketed CAR-T cell therapies.

Before the latest update, Carvykti in December got a unique boxed warning item detailing other secondary cancers, including myelodysplastic syndrome and acute myeloid leukemia.

Simultaneously with the earlier-line nod, the FDA has signed off on expanded manufacturing release specifications for Carvykti, a J&J spokesperson confirmed to Fierce Pharma. J&J declined to provide details related to the attributes.

As part of the application, the companies submitted to the FDA “a wealth of what I call the sensitivity analysis by correlating the release spec with the clinical outcome,” Legend CEO Ying Huang, Ph.D., said during the March call. With a wider specification, the companies are expected to improve supply by further reducing the manufacturing failure rate.

Meanwhile, J&J and Legend have been busy increasing their manufacturing capacity as the second-line nod is expected to significantly expand the number of patients who will be eligible for Carvykti. Legend has previously estimated that the market size is about 36,000 patients in the U.S., about three times that of the fifth-line opportunity. Further, Legend believes supply constraints have limited the partners' ability to capture even more market share from BMS in the U.S.

For 2024, the pair aims to make two capacity increases at their New Jersey plant, according to Huang. They also just expanded a contract manufacturing pact with Novartis, which will help make Carvykti for both commercial and clinical supply at its own New Jersey plant through the end of 2029.

External manufacturing contributions are an important pillar of J&J and Legend’s goal to reach an annual capacity of 10,000 doses by the end of 2025, Huang said on the March call.

With the second-line nod in place, attention now turns to the first-line setting. The CARTITUDE-5 trial is testing Carvykti in patients with newly diagnosed multiple myeloma not intended for stem cell transplant, and the CARTITUDE-6 study is trying to replace transplants with Carvykti in transplant-eligible patients.

BMS is taking a different approach. The phase 3 KarMMa-9 trial is not trying to replace transplants but is testing Abecma in patients who have suboptimal response after stem cell transplantation.