As the dust settled following the FDA’s precedent-setting approval of Kymriah (tisagenlecleucel, previously CTL-019), the chimeric antigen receptor T-cell (CAR T) immunotherapy developed by Novartis AG, analysts and observers began to parse the long-term impact to the players and broader implications for the field.
Kymriah was approved last week to treat patients up to age 25 with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse. (See BioWorld, Aug. 31, 2017.)
Novartis fully intends to stay in the mix.
“We believe this is the beginning of a new wave of treatment options that offer new hope to patients suffering from many different types of cancer,” Bill Hinshaw, the company’s general manager of U.S. Oncology, told BioWorld. “As the first company to invest in CAR T by forging a first-of-its-kind collaboration with the University of Pennsylvania [Penn], we are already working to advance many more therapeutic options in the field of cancer. We remain deeply committed to advancing this field of medicine and to continuing to bring innovative treatment options to patients.”
Kymriah’s approval, coming two days after Gilead Sciences Inc.’s $11.9 billion acquisition of CAR T challenger Kite Pharma Inc., represented a truly transformative moment for the field. (See BioWorld, Aug. 29, 2017.)
But the week didn’t pass without controversy and questions that may beleaguer CAR T developers for years to come. One of the first debates focused on the FDA’s branding of Kymriah as a gene therapy after CTL-019 was advanced consistently as cell therapy. For the most part, experts refused to get spun up about labels.
“It’s both gene and cell therapy,” said Catherine Bollard, president of the International Society of Cellular Therapy and senior scientist in the Center for Cancer and Immunology Research at the Children’s Research Institute, member of the Division of the Blood and Marrow Transplantation and principal investigator and co-director of the Immunology Initiative at the Sheikh Zayed Institute for Pediatric Surgical Innovation, all at Children’s National Health System.
Kymriah’s approval fell under the FDA’s gene therapy regulations, Bollard pointed out, even if it’s not designed to correct a defective or replace a missing gene – actions more often associated with gene therapy. Instead, the treatment is designed to genetically modify a T cell to kill cancer “in a way that’s never been done before,” she said.
The autologous T-cell immunotherapy begins with a patient’s own white blood cells, from which T cells are collected and sent to a manufacturing center where they’re genetically modified to include a gene that contains a CAR that directs the cells to target and kill leukemia cells bearing the CD19 surface antigen. Once the cells are modified, they are infused back into the patient to kill the cancer cells.
Kymriah uses the 4-1BB co-stimulatory domain in its CAR to enhance cellular expansion and persistence. In 2012, Penn partnered with Novartis in a research, development and commercialization pact covering the use of CAR T to treat cancer.
“You can have cell therapy that’s not gene therapy, and you can have gene therapy that’s not cell therapy,” said David Epstein, executive partner at Flagship Pioneering. Epstein, who serves as executive chairman of Flagship-founded Rubius Therapeutics Inc., previously served as CEO of Novartis Pharmaceuticals, a division of the Basel, Switzerland-based pharma, and started and led Novartis’ oncology and molecular diagnostic units.
“In this case, you’re using gene manipulation techniques in order to give a cell back to a patient,” Epstein told BioWorld. “It probably doesn’t really matter what you call it.” (See story in this issue.)
‘Model we should apply for all oncology drugs’
With the start of this week’s CAR-TCR Summit in Boston, which features a Who’s Who of immuno-oncology (I-O) leaders – including multiple members of the Novartis team – more chatter on the historic approval and next steps for the field is expected. Along with the emerging science, initial impressions seemed to fall into three buckets – pricing, production and prospects – for CAR T, engineered T-cell receptor (TCR) development and related technologies.
Not surprisingly, pricing rose to the top. The $475,000 figure that Novartis assigned to Kymriah drew a range of reactions, although most observers thought it reasonable, particularly to treat the gravely ill patients in the targeted population.
“Pediatric ALL is probably the most severe of all cancers,” observed Christiana Bardon, partner of the MPM Oncology Impact Fund and the founder and managing member of Burrage Capital. “These patients have failed all available treatment options. There’s a huge unmet need. These patients are going to die otherwise.”
The single multicenter trial of 63 pediatric and young adult patients with relapsed or refractory (r/r) B-cell precursor ALL that evaluated the safety and efficacy of Kymriah showed an overall remission rate of 83 percent within three months of treatment.
Moreover, the value-based pricing model introduced by Novartis was largely deemed a sensible arrangement. The pharma said it would seek reimbursement only when patients respond to Kymriah by the end of the first month of treatment and would work with the Centers for Medicare & Medicaid Services to enable adoption of the same payment arrangement.
“You have to remember that these are children,” Bardon told BioWorld. “If you can save them, they can have a tremendous and long life span where they can add value to our society.”
In fact, Bardon suggested, introduction of CAR T might have provided the ideal setting to insert value-based pricing into the U.S. drug reimbursement vernacular.
“Value-based pricing is exactly the model we should apply for all oncology drugs, maybe for all drugs,” she said.
As CAR T moves forward, however, treatment applications will move beyond – in some cases many decades beyond – pediatric populations. And differences among technologies mean that some therapies may require multiple hospitalizations and/or infusions. With Kymriah, pricing is based on one-time treatment, and some of the 32 FDA-certified centers that Novartis expects to have in its network by year-end may provide the therapy in outpatient settings.
Some observers wondered aloud whether the value-based pricing model adopted by Novartis will stick. Even if it does, will it be sustainable?
“Price is a concern,” Bollard acknowledged. She added, however, that if CAR T therapies ultimately become the global standard of care for r/r B-cell precursor ALL, replacing allogeneic stem cell transplant, drug manufacturers can argue that the one-time treatment price offers comparable or better value.
No ‘one-size-fits-all pricing model’
But that’s in ALL.
Pricing “is a big question,” said Sadik Kassim, vice president of process and analytical development at Mustang Bio Inc. and a speaker at the CAR-TCR Summit. The Fortress Biotech Inc. subsidiary is advancing a portfolio of CAR T therapies licensed in March 2015 from City of Hope National Medical Center. (See BioWorld Today, March 20, 2015.)
“This discussion has been in the gene therapy field for quite some time, within the context of in vivo gene therapies,” Kassim told BioWorld. “If you have a curative therapy, how do you price that? Do you price it as a value-based model? Do you price it in an annuity model? Do you have a high up-front premium, as in the Strimvelis model? There’s probably not going to be a one-size-fits-all pricing model.”
The Novartis model could open the door for developers of CAR T and similar technologies to negotiate rates for each therapy, by indication, “to get to that magic number,” he said.
Manny Litchman, Mustang’s president and CEO, agreed that pricing “will be highly dependent upon the actual benefit of each CAR T,” suggesting that developers of second- and third-generation therapies that show success in solid tumors and non-oncology indications may push back against a single payment model. Litchman, who served as senior vice president and executive global program head of the Novartis CTL-019 Cell & Gene Therapies Unit, was part of the team that in-licensed the Penn technology.
“Just because Novartis has set out on a certain path doesn’t necessarily mean that others are going to follow,” he maintained. The high response rates shown by Novartis in ALL and Kite in diffuse large B-cell lymphoma aren’t playing out across the board in indications such as non-Hodgkin’s lymphoma and chronic lymphocytic leukemia, he pointed out, and solid tumors will likely be even more problematic.
“As we move to situations where a single infusion is not curative, or does not give the long-term remission we’ve seen in pediatric ALL, I think we’ll see a lot more variation in pricing,” Litchman told BioWorld.
Epstein called the price point for Kymriah “modest,” especially given the company’s value-based initiative, and said the pharma “could have gone higher and chose not to.”
That said, Novartis will likely lose money in the short run with the intention of recouping its investment as it extends the therapy to additional indications and brings other CAR Ts to market, according to Epstein.
“At the beginning of a new era of medicine, you have to invest a lot,” he pointed out. “The payback comes later.”
In terms of sustainability, however, the cost of CAR T therapies won’t move down until allogeneic approaches join the mix, he said.
“It’s hard to predict what each individual company will do,” Epstein said. “But if future generations of cell therapy include allogeneic – where the cost of goods is much lower – and they’re for bigger indications where more patients are being treated, these will increasingly become mainstay therapies. Revenues will be higher, profit margins will be higher and the resulting prices will come down. Of course, the more competition you have, the more likely that’s going to happen, as well.”
Editor’s note: Wednesday in BioWorld: The CAR T supply chain challenge, investment in the space and sustaining R&D.