Chimeric antigen receptor (CAR) T-cell therapy has generated a great deal of excitement in recent months with the approval of Novartis’ Kymriah (tisagenlecleucel) for pediatric acute lymphoblastic leukemia and Kite Pharma’s Yescarta (axicabtagene ciloleucel) for relapsed/refractory large B-cell lymphoma in adults, and experts in the field foresee a wave of approvals for additional indications in the coming months.

“CAR T is coming unbelievably fast,” Richard Maziarz, MD , professor of medicine at Oregon Health and Science University, Portland, said in an interview.

In fact, a search of revealed 120 open CAR T-cell–based therapy trials for cancer and other conditions such as autoimmune diseases, he said.

Price tag pressure

During a plenary session on genetically modified cell therapies at the annual meeting of the Society for Immunotherapy of Cancer, experts and investigators provided a glimpse of what’s in store, including new targets and smarter targeting and combinations that incorporate CAR T-cell therapy to treat solid tumors.

Somewhat lost in the CAR T excitement, however, is the matter of access and affordability. Some estimates put the total cost of CAR T-cell therapy at up to $1.5 million per patient.

The “list price” for tisagenlecleucel is $475,000, and the potential patient pool is in the hundreds. The price for axicabtagene ciloleucel is $373,000, with a potential market in the thousands. Taking this into account, the global CAR T market is estimated at about $72 million and is projected to expand to nearly $3.5 billion in the next decade, said Dr. Maziarz, who is also chair of the Value and Health Economics Interest Group of the American Society for Blood and Marrow Transplantation.

The market for adoptive cell therapy overall – including transplant, CAR T, natural killer cells, and cell vaccines – is projected by some individuals to be worth $30 billion by 2030, he added, noting, for the sake of comparison, that the total estimated U.S. expenditure for all cancer care in the United States in 2010 was $125 billion.

At the heart of the issue of cost is the matter of value, he said.

“You can talk about price, and you can talk about cost, but … what we want to do with our dollars is buy value – and quality and value are very hard to measure,” he said, noting that he expects public and governmental backlash, as was seen with prior high-cost treatments such as Sovaldi for hepatitis C and Glybera for lipoprotein lipase deficiency.

Value-based payment is a recurrent theme in medicine, and these treatments came under intense scrutiny for their high costs. Sovaldi, for example, costs approximately $90,000 for a treatment course. That sounds like a lot of money, but it cures the disease and can prevent long-term complications, Dr. Maziarz said. Still, it received a lot of negative press, and the backlash was severe.

“People do respond to price,” he said, noting that he predicts the same for CAR T-cell therapies.

The costs of CAR T-cell therapy, particularly when taking into consideration the costs that hospitals will incur given the lymphodepletion that patients experience and the after-care required, will likely exceed those of most stem cell transplants and could easily reach the $1 million-plus estimates, Helen Heslop, MD , professor of medicine and pediatrics and director of the Center for Cell and Gene Therapy at Baylor College of Medicine, Houston, said in an interview.

Aside from the research and development costs, these treatments also cost more to make than any others previously made, according to Carl H. June, MD , the Richard W. Vague Professor In Immunotherapy at the University of Pennsylvania, Philadelphia, and a pioneer in CAR T-cell research.

Dr. June predicted that costs will be forced down over time because of process improvements and competition. “What’s unknown is the time span on how long it will take,” he said in an interview.

Groups like the United Kingdom’s National Institute for Health and Care Excellence ( NICE ) are already looking at value-based approaches to providing CAR T-cell therapy, Dr. Heslop said.

“I think there will need to be a lot more comparative effectiveness analyses done,” she said. “I know my institution started to look at the cost in a child with ALL once they relapse, and when you look at all the downstream cost, even though [CAR T-cell therapy] sounds very expensive, as a one-time therapy versus much longer treatment, it may actually be value based,” she said.

For a 70-year-old patient with non-Hodgkin’s lymphoma and a 39% chance of remission at 6 months, payers may be less likely to see the value, she said.

When it comes to improving access, one of the approaches being studied is the use of universal cell banks as opposed to autologous cells for therapy. This “off-the-shelf” approach, much like the approach used in transfusion medicine, would allow for quicker availability of the cells to a greater number of patients, she said.

Dr. June who, along with Dr. Heslop, cochaired the SITC plenary session on genetically modified cell therapy, agreed, saying that if this approach works with T cells, it would radically change the CAR T landscape in terms of availability and, perhaps – eventually – cost.

Preliminary results from phase I studies ( CALM and PALL ) of this approach will be presented at the upcoming annual meeting of the American Society of Hematology. The studies are a joint effort by Servier and Cellectis, which joined forces in the development of UCART19, an allogeneic CAR-T product for the treatment of CD19-expressing B-cell acute lymphoblastic leukemia.

Still, value remains an important consideration. If a therapy is expected to extend a pancreatic cancer patient’s life by a month, it’s probably valid to ask if that is cost effective, but if it is potentially curative for a patient with hematologic malignancy, it’s very hard to say they can’t access it, Dr. Heslop said.

Cost-saving proposals

Efforts to address the cost concerns, including proposals for novel payment strategies, are already emerging. One example involves an offer by Novartis to charge for Kymriah only if treated patients go into remission within 1 month. Details of the plan haven’t been released.

Another approach is being considered in Europe and involves a graduated payment system for an investigational regulatory T cell therapy for autoimmune disease, Dr. Maziarz said. For example, if the drug costs $1 million, the government might pay $200,000 the first year and then $100,000 per year if the patient is cured. “If the patient relapses, they can stop their payment, as cure was not achieved,” he explained.

In many discussions about value, the definition is based on quality-adjusted life years (QALY) gained, he said. A recent statement from the American College of Cardiology and the American Heart Association on cost/value methodology, for example, used $50,000 per QALY gained as the cut-off for a good investment. Costs of $50,000 to less than $150,000 per QALY were considered to be of intermediate value, and costs of $150,000 or greater per QALY gained were considered to be of low value.

“A number of payers are using these guidelines to determine what drugs they will put on their portfolio and make available to enrollees,” Dr. Maziarz said.

In anticipation of cost-related issues with CAR T-cell therapy, the Institute for Clinical and Economic Review ( ICER ) and its California Technology Assessment Forum (CTAP) put out a request for information and input regarding their intent to collaboratively initiate an assessment of CAR T-cell effectiveness and value, he said.

In the meantime, Dr. Maziarz said that most private insurers he’s been in contact with are planning coverage of CAR T-cell therapy but are working out the details of how to do it.

“It’s typically going to involve very, very strict guidelines for the patients who go on therapy – it’s not going to be a liberal use of the product. It will involve strict adherence to the label,” he said.

The real challenge, however, will be in the Medicare and Medicaid programs, because of the current nature of the reimbursement structures and lack of clear procedural codes to define the effort and cost of care associated with the application of these novel cell therapies.

Walid F. Gellad, MD, and Aaron S. Kesselheim, MD, anticipated some of these challenges in light of accelerated approval processes for expensive drugs and proposed in a May 2017 paper that government payers reimburse only the cost of manufacturing and some predetermined mark-up for such drugs until confirmatory trials demonstrate clinical benefit (N Engl J Med. 2017;376[21]:2001-04).

“Both Yescarta and Kymriah are approved with very, very, very limited data – 100 patients, 80 patients. They absolutely look promising. I was part of those studies, so I’m a believer, but the classic approach to determining success in the medical community is a randomized controlled trial,” Dr. Maziarz said.

The proposal by Dr. Gellad and Dr. Kesselheim acknowledged this, and said perhaps full payment isn’t warranted while the drugs remain in development and until they are proven to be a good investment.

Their proposal also calls for an economic impact analysis after 1-2 years on the market for all accelerated-approval pathway drugs that cost over a predetermined amount, timely and optimally designed confirmatory trials following accelerated approval to limit the period of uncertainty about the true clinical effect of the drug, and additional price concessions to public insurance programs for such drugs until the confirmatory trials are completed. Under this proposal, the unpaid portion of drug costs would be held in escrow until the drug’s efficacy is confirmed.

“I think what’s going to happen is that, as prices and costs go up for any therapy, that backlash will occur. These types of proposals to create solutions will come not from individual companies, but from the government,” Dr. Maziarz said. “I’m 100% excited about the work. I’m extremely excited to be part of the explorations. … I just still think we have to at least try to be aware and cognizant of the issues that we’ll be facing.”

Dr. Maziarz has received consulting fees from Novartis, Juno Therapeutics, and Kite Pharma. Dr. Heslop has received consulting fees from Novartis, has conducted research for Cell Medica and holds intellectual property rights/patent from Cell Medica, and has ownership interest in ViraCyte and Marker Therapeutics. Dr. June received royalties from Novartis, has conducted research for Novartis, and has ownership interest in Tmunity Therapeutics.