This year, the FDA moved two CAR-T therapies into earlier large B-cell lymphoma (LBCL) and cleared a second cell therapy for multiple myeloma. But despite five years of collective experience making and selling engineered human cell products, the biopharma industry is still struggling to ensure smooth and timely access.
Cell therapy leaders at three top U.S. cancer hospitals—Memorial Sloan Kettering Cancer Center, Moffitt Cancer Center and City of Hope—are not satisfied with CAR-T availability and their manufacturers’ operations. During separate interviews at the recent American Society of Hematology annual meeting, the experts said manufacturing constraints were their top sticking point, especially for the myeloma CAR-Ts from Bristol Myers Squibb and Johnson & Johnson.
But the problems go beyond well-documented manufacturing bottlenecks. And, in the case of J&J and Legend Biotech's Carvykti, having witnessed other drugmakers' struggles didn't guarantee immediate success.
“J&J is company No. 4 to roll into the game," Frederick Locke, M.D., Moffitt’s chair of the department of blood and marrow transplant and cellular immunotherapy, said. "And, boy, you’d expect when you’re the fourth one in to know what you’re doing."
Carvykti in February won an FDA approval as a fifth-line treatment for multiple myeloma, almost a year after Abecma became the first B-cell maturation antigen (BCMA)-targeted CAR-T to launch in the disease. Claiming to have learned from Abecma’s mistakes, J&J and Legend adopted a phased approach to Carvykti’s commercial rollout. Instead of a nationwide launch, they made Carvykti available at just 40 cancer centers. But even among the limited number of treatment centers, supplies are far from adequate, experts said.
Unacceptable wait time
“We talk to [multiple myeloma] patients about CAR-T," said Elizabeth Budde, M.D., Ph.D., who chairs City of Hope’s clinical cellular immunotherapy committee. "You give them hope because those two approvals have very good results. And then you put them on this waiting list. Sometimes the waiting list goes out to six months. That’s not acceptable for patients.”
Patients who are eligible for Abecma and Carvykti have already tried and failed four prior therapies, meaning they are already very sick and simply can’t wait that long for therapy, Budde noted.
FDA-approved CAR-T therapies use a patient's own blood, which is collected by doctors and then modified by the companies to target cancer cells bearing specific protein biomarkers. To get the therapy, a doctor must first secure a manufacturing slot from the pharma company to produce the tailor-made therapy. And those slots can be hard to come by.
Thanks to limited manufacturing slots, doctors at Sloan Kettering can only treat about two to three myeloma patients with commercial CAR-Ts out of the 10 they would like to in a month, Jae Park, M.D., the center’s acting chief of cellular therapy service, told Fierce Pharma.
“That’s a very frustrating part for the patients and for clinicians, too,” Park said. “That has to improve.”
To Sloan Kettering's Park, BMS and J&J/Legend are “equally suboptimal” on the operational side of CAR-T treatment. But City of Hope’s Budde and Moffitt’s Locke have a clearer preference.
“The obvious winner is Abecma by far, and not because the efficacy is better. It’s not. But because the company that’s making it knows what they’re doing,” Locke said of BMS’ track record in CAR-T.
But BMS’ early struggles with Abecma were well publicized. The company launched the therapy nationwide last year and immediately hit a manufacturing bottleneck—both because of a shortage of viral vectors that are used to deliver the cell therapy and because of limited production slots.
In a statement to Fierce Pharma, a BMS spokesperson said the company has doubled the number of patient slots for Abecma since the beginning of 2022. It's also “closely engaged with treatment centers to communicate apheresis and slot availability and to optimize patient treatment scheduling," the spokesperson said.
Locke said he's noticed the progress.
“But I will tell you that that company jumped in, rolled up their sleeves, and did everything they could to fix the problem and get their therapy to patients as rapidly as possible,” Locke said of BMS. “I’m not sure about their competitor, who also sells a bispecific T-cell engager that targets the same thing now.”
On the last point, Locke was referring to J&J's Tecvayli, a BCMAxCD3 bispecific that just won FDA approval—also for fifth-line multiple myeloma. Compared with the CAR-Ts, Tecvayli is an off-the-shelf product that can be produced on a massive scale.
When asked about whether Tecvayli is distracting J&J from Carvykti, Meredith Unger, the company's vice president of marketing and operations for CAR-T at Janssen, said that’s not the case.
“We’re excited Tecvayli’s on the market, and it’s going to be an important treatment option for patients. It’s not going to slow us down,” Unger said. “We want to be a cellular therapy company, [we] want to deliver this transformational therapy, and we can’t take our foot off the gas.”
Expanding while under constraint
J&J and Legend have said they plan to add more centers to their network next year, bringing the total to about 70 to 80. They also plan to double the investment in their cell therapy manufacturing facility in New Jersey to $500 million.
Despite opening additional centers, Unger couldn’t guarantee enough supply for all treatment centers and patients. But she did say J&J expects to have increased allocation for existing sites.
J&J is working hard to improve supply and deal with demand fluctuations, she added. And Unger made an argument for expanding to more centers before J&J has enough bandwidth to cope with existing ones.
“If we continue to put this effort that we’re putting in, we will get to the point of unconstrained [production], and you need a network to be able to support that when it happens,” she said. “If we continue to stay with a narrow network, we don’t think we’re best optimizing and setting ourselves up for success.”
For his part, Locke argued that J&J’s approach—opening many centers and allocating slots based on population needs rather than experience with CAR-T—“dilutes the expertise and the use” of Carvykti.
But production capacity isn’t the only manufacturing problem for Carvykti. City of Hope’s Budde noted that her team has had more discussions with J&J than with BMS about "out-of-specification" orders, or those that don't meet strict manufacturing requirements.
“One of the main reasons is, again, you make a patient wait so long to get the product, and then they notify you the product is out-of-spec. That’s very disappointing and disheartening,” Budde said.
During an investor event in October, Legend CEO Ying Huang, Ph.D., acknowledged that the companies had experienced more manufacturing failures with Carvykti than expected. The commercial product’s out-of-specification rate was higher than the 18% recorded in clinical studies, he said.
An out-of-spec CAR-T is no longer considered a commercial product and can only be given to a patient under special protocols without payer coverage. Sloan Kettering’s Park said he wouldn’t be concerned if the product is slightly below FDA-specified cell standards but probably wouldn’t use a product if the numbers were far off.
When using out-of-spec cell therapies, doctors may consider using more conditioning chemotherapy, which prepares a cancer patient for CAR-T treatment. To make things worse, fludarabine, a popular conditioning chemo, has been in shortage, Park said.
In another recent hiccup, City of Hope’s Budde said J&J informed her team a few weeks ago that some final Carvykti products were mistakenly made with twofold lower levels of interleukin-2 (IL-2) during manufacturing. The products aren’t technically out of spec, but Budde argued that they shouldn’t be considered as commercial product, either.
IL-2 is essential to T-cell activation and vitality. The cytokine is commonly used with other agents to expand CAR-T cells during manufacturing. How well the T cells can proliferate and persist are key factors to achieve complete remission and prevent tumor relapses. So the protocol deviation has made Budde worried about the final product’s potency, especially over the long term, given that CAR-T therapies offer the potential of a cure after a one-time treatment.
J&J has offered to reproduce the CAR-T for the affected patients, Budde said. But the long manufacturing process means the patients will have to wait another month or two. Budde has demanded that J&J give the products for free, but J&J has refused, she said.
J&J’s Unger said she’s “aware of the situation” but declined to comment on specific cases.
Despite the problems, BCMA CAR-T remains a seller’s market where doctors don’t have a choice but to use all available supplies. Elsewhere, the CD19 space is different.
Getting timely treatment
While BMS may deliver better customer service than J&J/Legend in the BCMA realm, the company still has some catching up to do with Gilead’s Kite Pharma in the CD19 biomarker arena.
Both Gilead’s Yescarta and BMS’ Breyanzi won recent approvals to treat second-line LBCL patients. Budde, Locke and Park all said their institutions have been using more Yescarta than Breyanzi, partly because Yescarta has been on the market longer. But there are other factors that tip the balance in Yescarta’s favor, they said.
“In the lymphoma space, Kite is definitely easier to work with, much more flexible, readily responsive,” Park said. “We could tell the difference early on, although BMS has gotten a lot better.”
“If I have a patient in front of me, I want to get their CAR-T cell therapy to them as quickly as possible. It is very clear that one of those two products is much better poised to do that. And it is Yescarta,” Moffitt's Locke said. Locke was the lead researcher in the phase 3 ZUMA-7 trial, which secured Yescarta its first-in-class second-line nod in April.
Kite has touted an average 16-day turnaround time for Yescarta from the point of blood cell withdrawal to product release. Breyanzi takes about a week longer.
More broadly speaking, the overall timeline from the point of a doctor’s treatment decision to infusing an LBCL patient with a CD19-targeted CAR-T has improved, Sloan Kettering’s Park said. But Yescarta is “a little bit better than others” at allowing doctors to kick off the process with patient blood cell collection, he added.
City of Hope's Budde applauded both Kite and BMS for having a streamlined the commercial process for their CD19 products and said her team is beginning to use more Breyanzi because of the second-line nod.
The expert did note that Breyanzi appeared to have higher out-of-spec rates. But she also gave BMS a compliment for an arrangement she called “very refreshing.” For each out-of-spec product, the New York pharma has a medical director talk with the doctor about potential implications on efficacy and safety.
BMS has been ramping up its manufacturing footprint. In a statement to Fierce Pharma, a spokesperson said BMS is “proactively managing supply constraints to best address current demand.” For Breyanzi, BMS expects to increase capacity starting in the first quarter of 2023.
The company is expanding three existing cell therapy facilities in New Jersey and Washington and planning to open new ones in Massachusetts and the Netherlands. Those new sites are expected to come online in 2023 and 2025, respectively.
Kite is not problem-free, either. Locke noted that the company didn’t have a good process in place to give patients out-of-spec products, however few they may be.
Kite used to have a special program to manage those cases, but Locke noted Kite ended the program. For now, the burden is on the doctor to file a single-patient investigational new drug application to give the patient an out-of-spec cell therapy
Frank Neumann, M.D., Kite’s head of clinical development, said out-of-spec events are rare with Yescarta but acknowledged that sometimes they may happen at major cancer centers.
“We are planning for early next year a system where patients can get easier access to the therapy,” Neumann said in an interview.
The companies should understand that CAR-T treatment is a collaborative work, Sloan Kettering's Park said.
“It requires so much communication and coordination," Park said. "So to make it easier … we need to listen to each other.”