Manufacturing has constrained Legend Biotech and Johnson & Johnson's supply of their CAR-T therapy Carvykti to heavily pretreated multiple myeloma patients. As the drug targets earlier treatment—and larger markets—the partners have decided to literally double down on production.
J&J and Legend will double investment in their Raritan, New Jersey, manufacturing facility, bringing the total to $500 million, Legend CEO Ying Huang, Ph.D., told investors during a conference Monday. The cell therapy manufacturing site currently makes Carvykti for the U.S.
Together with another factory under construction in Ghent, Belgium, J&J and Legend in the next few years “will be in a position to have a capacity that accommodates the $5 billion-plus peak sales projected by J&J,” Huang said.
With Carvykti, J&J and Legend are in a “supply-constrained environment” that’s driven by two factors, Huang explained. One is an industrywide shortage of lentiviral vectors, which are pricey components used to introduce the CAR construct to patients’ own T cells. That’s why the two companies have decided to bring viral vector production in-house, currently managed by J&J’s Janssen vaccines department. And they expect to come out of the shortage “in the near future,” Huang said.
The other factor, Huang said, is the capacity, or slots, to engineer and culture therapeutic T cells. This involves multiple expansion efforts, including the physical build-out of the New Jersey manufacturing facility, Huang said, and that’s what the new investment is about.
The announcement came weeks after Carvykti’s BCMA-targeted CAR-T rival, Bristol Myers Squibb and 2seventy bio’s Abecma, touted a first-in-class phase 3 win in multiple myeloma patients who had failed two to four prior lines of therapy. The positive KarMMa-3 readout could potentially move Abecma into the third line, while both Abecma and Carvykti are currently only approved as fifth-line treatments.
Abecma’s latest success clearly gives Legend and J&J confidence that Carvykti’s CARTITUDE-4 trial in an even earlier population that has undergone one to three prior lines of therapy could succeed, as well. CARTITUDE-4 finished enrollment in late 2021.
By Legend’s estimate, a second-line multiple myeloma indication based on CARTITUDE-4 represents about 36,000 patients in the U.S., three times that of Carvykti’s current fifth-line opportunity, Steve Gavel, Legend’s vice president of global cell and gene therapy commercial development, said during the conference.
With that potential “major inflection point” in mind, J&J and Legend plan to increase the number of Carvykti’s designated treatment centers to around 70 to 80 from the current 40 with the extra manufacturing capacity in place, Gavel said. Because of limited manufacturing capacity, J&J and Legend have adopted a phased launch strategy to gradually ramp up availability to more treatment sites.
But limited capacity is just one challenge in making Carvykti. During early launch days, J&J and Legend experienced a higher rate of manufacturing failure than they did in the CARTITUDE-1 trial used to support Carvykti’s existing FDA approval, Huang said.
The product release specification for commercial Carvykti that the FDA requires is more stringent than what was used in the clinical study, Huang noted. Besides, investigators screened patients to decide eligibility for the clinical trial, but patient baseline characteristics are more diverse in the real world. And a patient’s baseline health status affects the viability and the number of T cells collected, Huang said.
In the last few months, J&J and Legend have seen an “encouraging trend” in terms of the out-of-specification rate in its manufacturing processing, and the two firms are working hard to fine-tune manufacturing protocol to improve the success rate, Huang added. “I think at this point, we feel very confident that we will be able to overcome this.”
But one team of analysts appears less optimistic. Based on Legend’s comments, SVB Securities analysts in a Tuesday note decided to increase their cost-of-goods-sold estimates for BCMA-targeted CAR-T products over the long term to 35% from the original 15%. Higher costs mean lower profit.
Meanwhile, J&J and Legend have already started clinical trials pushing Carvykti into the front-line setting. Altogether, 64,000 patients are newly diagnosed with multiple myeloma each year across the U.S., the EU and Japan, according to Legend. The CARTITUDE-5 trial is in newly diagnosed myeloma patients who are ineligible for or don’t intend to get stem cell transplant. And CARTITUDE-6 tests Carvykti in transplant-eligible patients and is the only phase 3 registrational trial pitting a BCMA CAR-T against transplant, Legend’s Gavel noted.