J&J, Legend's Carvykti Prolongs Lives in Multiple Myeloma

In a significant development for Johnson & Johnson and Legend Biotech, their CAR-T therapy Carvykti has shown potential to extend the lives of patients with previously treated multiple myeloma. The announcement came after the phase 3 CARTITUDE-4 trial revealed "statistically significant and clinically meaningful" overall survival benefits when Carvykti was compared to standard combination therapies. This trial included myeloma patients who had undergone one to three prior treatment lines. The standard treatments used in the study comprised either Takeda’s Velcade or J&J’s Darzalex combined with Bristol Myers Squibb’s Pomalyst and the corticosteroid dexamethasone.

Previously, Carvykti had already gained FDA approval in April as a second-line therapy for multiple myeloma. This approval was based on CARTITUDE-4 data showing that Carvykti could reduce the risk of disease progression or death by 59% compared to standard therapies. The recent overall survival findings now put Carvykti ahead of Bristol Myers Squibb’s rival CAR-T therapy, Abecma, which is approved as a third-line treatment but lacks evidence of life extension benefits.

In the phase 3 KarMMa-3 study, Abecma showed a 51% improvement in progression-free survival compared to standard combinations in patients who had failed at least two prior lines of therapy. However, there was no indication of an overall survival benefit before adjusting for control patient crossovers. Given the maturity of the data, KarMMa-3 is unlikely to meet statistical significance in overall survival.

Carvykti’s success in overall survival was somewhat anticipated. During an earlier data review in late 2023, Carvykti was associated with a 43% reduction in the risk of death, an improvement from the 22% reduction noted when about a third of deaths had occurred. This expanding effect size provided hope for a statistically significant outcome.

A detailed analysis of the CARTITUDE-4 trial will be presented at an upcoming medical conference and submitted to regulatory authorities globally, according to J&J and Legend. Achieving a definitive overall survival benefit could also help address concerns raised by an early mortality signal noted by the FDA. Before its second-line approval, the FDA observed that in the first 10 months from randomization, patients receiving Carvykti were more likely to die than those in the control group. This concern now appears in the "Warnings and Precautions" section of Carvykti’s label, similar to Abecma's warning.

Despite this, a group of external advisers argued that Carvykti’s long-term benefits outweigh the early mortality risks, a stance the FDA agreed with in granting the approval. Furthermore, in a positive development for Carvykti and other CAR-T therapies, the FDA has recently reduced the reporting requirements under the Risk Evaluation and Mitigation Strategies (REMS) program. CAR-T drugs are available only through REMS due to risks like cytokine release syndrome (CRS) and neurological toxicities. However, the FDA has decided to modify the REMS program to reduce the reporting burden on the healthcare system, removing the need to report adverse events suggestive of CRS or neurological toxicities.

With the second-line approval and an expanded patient population, J&J and Legend are working to enhance the supply of Carvykti, aiming to double its capacity by the end of 2024 compared to 2023. Alongside the second-line approval, the FDA also broadened Carvykti’s manufacturing specifications, potentially improving production success rates. In addition to increasing internal capacity, J&J and Legend have enlisted Novartis to assist in producing Carvykti for both commercial and clinical use.