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Gene therapies have a lot of potential to improve health outcomes for patients with life-threatening diseases but face a number of barriers that restrict access.

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Authors

Will Hinde is a senior director in the West Monroe Partners’ Healthcare Practice and primarily focuses on Health Insurance organizations. He has more than 15 years of business consulting and technology experience and is currently responsible for strategy 

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Binghampton University in New York state will join Mayo Clinic and at least 15 other investigators in developing an implant aimed to treat inflammatory diseases. The project, called Engage Assess SecretE (EASE): A Platform for Treating Chronic Inflammation, is meant to act as a “living pharmacy” triggering cells to produce antibodies that could target inflammatory conditions.

, Ph.D., biochemical engineer at Mayo Clinic, is funded by a $42.8 million grant from the 

Advanced Research Projects Agency for Health (ARPA-H)

, an agency nestled under the Department of Health and Human Services and the National Institutes of Health. ARPA-H funds and supports biomedical and health research with the potential for developing high-impact and transformative treatments.

Mayo Clinic is the primary research site for the EASE project with collaborators from several other sites, including Binghampton University, the University of Minnesota, Case Western Reserve University, the University of Texas, the University of California Davis,and biotechnology companies EnLiSense and Sersense Inc.

“I am very excited that this project has high societal impact and patient relevance. It represents a prime example of convergence science, where clinicians, biologists and engineers come together to produce a sophisticated solution to improve patient care,” Revzin said in a 

, Ph.D., will create electrodes to generate oxygen that will feed the cells that produce the pharmaceutical catalysts.

“Our research group aims to electrochemically generate oxygen to ensure the cells survive during implantation," said Koh. "I'm responsible for developing the 'cafeteria' in the 'factory,' ensuring that they 'eat' properly,” she continued.

Currently, the EASE platform is being developed for the treatment of inflammatory bowel disease, including Crohn’s disease and ulcerative colitis. The researchers hope to eventually use the device to treat autoimmune disorders, such as rheumatoid arthritis and psoriasis.

“This method is intended to treat bowel disease, but the whole platform is structured so that if the antibodies produced by the cells are altered, this might be used as a transformative treatment for other targeted diseases,” Koh commented.

Clinical

Binghamton University, Mayo Clinic and Others Snare NIH Funding for IBD Research 

Seven years ago, when the FDA approved the first-ever chimeric antigen receptor (CAR)-T cell therapy, Novartis’ then-CEO Joseph Jimenez, MBA, said Kymriah (tisagenlecleucel) represented a “paradigm-changing” therapy.

In the years since then, the FDA has approved five more CAR-T therapies, and it is hard to disagree with Jiminez’s assessment. Yet the mainstreaming of CAR-T therapies has changed much more than solely which therapy a physician prescribes. It has also created a unique patient journey, set off a wave of new scientific questions and heightened concerns about the rising cost of care.

Umar Farooq, M.D., a hematologist-oncologist at the University of Iowa (UI) Health Care, has been treating patients with CAR-T cells since 2015, when he began collaborating on a CAR-T clinical trial. His health system now treats between 70 and 80 patients each year with CAR-T cell therapies. “The number of CAR-T cells we’ve been doing every year just continues to increase,” he says.

That’s great news in Farooq’s view because, he says, the therapy has led to dramatic improvements in many of his patients. “With what I’ve seen in the past 10 years, and how drastically it has improved patient outcomes, I’m … very optimistic for the next 10 years.”

As of September 2024, six CAR-T cell therapies covering 16 indications have been approved in the United States, according to the Leukemia & Lymphoma Society. All the therapies have been approved for the treatment of blood cancers, including non-Hodgkin lymphoma, acute lymphoblastic leukemia, multiple myeloma and, as of March 2024, chronic lymphocytic leukemia and small lymphocytic leukemia.

Bethany Lilly, J.D., executive director of public policy at the Leukemia & Lymphoma Society, says the expanding number of indications approved for CAR-T therapy has also increased interest.

“Awareness is growing, so more patients call knowing that they are eligible for the treatment, but [they] often still have questions,” she says.

Farooq says he recommends patients go to an academic medical center once their disease has progressed past one line of treatment.

“If we see you too late and you’re already too frail and the disease has affected your organ function, it would be harder to do,” he says.

Referral speed is important because CAR-T therapy is not a fast process. Farooq says by the time he typically sees a patient, the patient already has insurance authorization for the initial consultation. He and his colleagues will then run tests to ensure the patient’s heart, lungs and other major organs are sufficiently healthy for the therapy. If so, Farooq and colleagues will submit insurance paperwork to get approval for the procedure. Next, they reach out to the cell therapy lab to ensure they are ready to collect the patient’s white blood cells and to the drug manufacturer’s lab to ensure they are ready to receive the cells. It takes a minimum of two weeks from the first patient visit to the time the patient gets the go-ahead, he says.

Then comes the manufacturing itself, which generally takes at least three to four weeks. “Once we know for sure that the cells have been manufactured, meet the quality standards and have arrived at our hospital, it’s only then that we admit the patient to start the low-dose chemotherapy to suppress the immune system,” he says.

In the best-case scenarios, the entire process can take about six weeks in an optimal case, he says, and then the hospitalization is not over. Patients require daily monitoring for adverse events for two to three weeks, usually as an inpatient.

The frequent checkups are necessary because of the significant risk of toxicity from CAR-T therapy, including cytokine release syndrome (CRS) and neurotoxicity.

“And if the patient is … much farther away from the treating center, it would be a very complicated case for a local health facility to deal with,” he says.

Farooq says both CRS and confusion are common, though most of the time the adverse events are not severe.

He sees patients from as far away as Des Moines, which is a little less than two hours from Iowa City, where UI Health Care is based. He says he typically only sees out-of-state patients if it is for a clinical trial.

Still, all that time in the hospital means patients who live far away from their treatment center must plan for things like travel expenses or hotel rooms to undergo the necessary treatment and monitoring. That can create a barrier for many patients, Lilly says.

“It can be thousands of dollars, and not every patient can afford it,” she says. “This is especially the case for low-income patients, who also disproportionately live in rural areas and/or are patients of color.”

Of course, those travel costs are typically just the beginning of the extensive fees associated with CAR-T therapy. Most CAR-T treatments run between $300,000 and $400,000, and sometimes upwards of a half-million dollars, Farooq says. That is why one of the first steps his health system takes is to communicate with a patient’s insurer to verify the procedure will be fully paid for and that the patient will not face financial ruin.

“Considering the treatment is so expensive, if we find out that insurance will cover 80% and the patient is responsible for 20%, it’s usually not practical to move forward,” he says.

Farooq points out one particularly thorny problem he faces is when he treats Medicare patients. When patients have commercial insurance or participate in Iowa’s Medicaid program, he is able to get prior authorization that ensures the cost of the procedure will be covered. That’s not the case for patients on Medicare, he says. The lack of a prior authorization requirement saves time at the beginning, but there’s a big — and potentially costly — caveat. “If for any reason we diverged or did not precisely follow the FDA-approved criteria, Medicare can refuse to cover it later,” he says. What makes matters worse is that that refusal might not come until several months or a year following
the treatment.

“It has happened to me,” Farooq recalls, “and I had to write a few letters to highlight that we exactly followed the approved criteria.”

One place patients can turn to when they encounter barriers is a patient advocacy group like the Leukemia & Lymphoma Society. When patients call for help in getting the therapy covered, Lilly says a typical barrier is the novelty of CAR-T.

“Usually, there is a debate between an insurer and a provider about what the reimbursement for the treatment will be,” she says. “Given the rarity of this treatment, it can often be an issue of first impression for insurers, meaning that they haven’t worked out a specific reimbursement rate.” Even if the therapy is covered, caregivers often have to take unpaid leave or partial pay, depending on their state’s paid leave laws, she notes.

Merith Basey, M.Sc., the executive director of Patients for Affordable Drugs, a group that advocates for lower drug prices, says the high-cost CAR-T therapy — and the ways patients and providers have to scramble to pay for it — shows the need for reframing the debate and discussion swirling around
drug costs.

“The conversation is currently about how we [are] going to pay for them,” she says, “and not how we [are] going to lower the price.”

Even in an American health system that is used to paying multiples of the amount other developed countries pay for the same therapies, Basey says CAR-T prices are an urgent problem. She said there are hundreds of CAR-T products in drug company pipelines and other gene therapies as well. If more than a few are approved, they would dramatically impact the cost of care.

“This is something that needs to be tackled because we know that it would essentially bankrupt health care
systems,” she says.

Farooq says one way to cut costs is by lowering the cost of manufacturing. He notes that UI is collaborating with another academic medical center on a trial to investigate a fast-turnaround manufacturing system. Manufacturing doses of CAR-T therapy in 24 hours could bring the price down to as low as $50,000, he says. There are also efforts to create so-called “off-the-shelf” CAR-T cells, which involve making potentially thousands of CAR-T doses from a single donor. They’re still investigational, he says, but they could significantly change the cost structure.

Basey says the issue is not just how CAR-T therapies are manufactured but where. One of the major reasons for the high price tag of CAR-T is the limited number of manufacturing facilities in the U.S., she says. Tight control of manufacturing by pharmaceutical companies creates a situation where patients must wait for their therapies to travel to sometimes distant manufacturing facilities and back. “Because of that, there’s a bottleneck, and it helps to increase the price,” Basey says.

She points out that countries like Spain and Brazil have developed decentralized manufacturing models for CAR-T, lowering prices by approximately one-tenth.
“They don’t have to be priced so excessively … that they’re not able to treat the people who need them,” she says. She notes that much of the research that goes into developing new medical therapies is funded by taxpayers in the form of grants from the National Institutes of Health, Department of Defense and other agencies. “The government and the taxpayers should be entitled to have a voice in the way that publicly funded medicines are priced so that people can afford them,” she says.

Like Basey, Farooq expects CAR-T to become a more common treatment option, perhaps eventually becoming a first-line treatment for some conditions. He is currently involved with a major multi-institutional study designed to gauge the comparative benefits of first-line CAR-T therapy in certain patients with diseases that are difficult to treat. Current first-line therapies for multiple myeloma and lymphoma have strong safety and efficacy track records. “CAR-T cells will need to prove themselves better,” he says.

Another frontier is CAR-T for diseases other than cancer. Investigators have been evaluating CAR-T as a treatment for autoimmune disease, kidney disease and sickle cell disease.

“If you’re deficient in certain genes or have genetic deficiency disorders, that’s another place for cell therapy,” Farooq says. “You can introduce these cells by introducing the gene in cells."

Yet, introducing genes can also create problems. Last year, amid all the optimism about CAR-T, came one stark note of caution. In November 2023, the FDA published a notice saying it was investigating the risk of T-cell malignancies, including CAR-positive lymphoma, in patients who received BCMA- or CD19-directed CAR-T cells. All six approved CAR-T therapies are directed at either BCMA or CD19.

As of December of last year, the FDA said it had become aware of 22 cases of secondary malignancies following CAR-T therapy, the majority of which occurred during the first two years following treatment.

Stella Bouziana, M.D., Ph.D., of King’s College Hospital NHS Foundation Trust in London, notes that the FDA requires that patients receiving therapies involving genetic manipulation, including CAR-T therapy, be monitored for 15 years “due to a theoretical risk of random insertional mutagenesis caused by the viral vectors, potentially leading to secondary cancers.” After the FDA announcement of secondary T cell malignancies, the follow-up period was changed to a life-long requirement, highlighting the need of prolonged surveillance.

Until last year’s announcement, the risk had remained theoretical. The fact that these secondary malignancies were observed sparked surprise, Bouziana says, especially because in some cases the CAR transgene was identified within the secondary T-cell malignancy.

“This was the first time such cases came to light, and although only a handful of cases have been reported so far, a lot of concern has been raised among clinicians and scientists involved in the CAR-T field regarding the safety of the otherwise very promising CAR-T cell therapies,” she says.

Still, Bouziana says there is no reason to slam the brakes on CAR-T. Rather, she says it’s time to do additional research to better understand the risk, if any.

One idea to consider is whether mRNA technologies can be used in place of viral vectors or gene-editing techniques to introduce the therapy. Doing so, she explains, might avoid random transgene integration into host cells and resulting genotoxicities.

Another question pertains to the optimal dose of infused CAR-T cells. Currently, Bouziana says, CAR-T cells are administered empirically without clear criteria on the optimal cell number and composition. “In classical drug pharmacokinetics and pharmacodynamics, this would seem unimaginable,” she says. The effect of a lack of clear dosing criteria is an unpredictable cell composition and effect
in vivo, she says.

Although patient-advocacy groups such as the Leukemia & Lymphoma Society would like to see further expansion of CAR-T into community hospitals, Bouziana advises caution while research into the secondary malignancy risk is ongoing. “Until data is mature and risks fully elucidated, CAR-T cells should continue to be administered as per current recommendations by expert organizations,” she says.

The good news, she notes, is that clinical and translational research appear to be accelerating in the wake of the FDA’s announcement. Farooq says he is optimistic about the technology and its potential to continue positively impacting patients.

“I wouldn’t say that this is the only technology that would make a difference for cancer patients, but it would be a very important part of those tools,” he says.

But there are some concerns: high costs, extended hospitalizations 
and secondary cancers.

The Mainstreaming of CAR-T

Syndax Pharmaceuticals recently announced the FDA approval of Revuforj (revumenib) for the treatment of relapsed or refractory acute leukemia in adult and pediatric patients one year and older. It is indicated for patients with a lysine methyltransferase 2A gene (KMT2A) translocation, according to a 

Onco360 was chosen as a specialty pharmacy partner by Syndax, a seperate 

“Today marks another major milestone in the leukemia community,” Michael Metzger, CEO and director of Syndax said during the investor call. “With the FDA approval in hand, we look forward to launching Revuforj in the United States this month.”

Revuforj is the first and only menin inhibitor approved by the FDA. It works by preventing rearrangements in KMT2A gene, which can lead to the development of leukemia cells. An estimated 95% ofKMT2Ar acute leukemia patients have KMT2A translocation. This abnormality is seen in about 10% of all leukemias.

Only about 5% of patients with this mutation achieve complete remission with current third-line treatment with a median overall survival rate of less than three months, according to the news release. More than half of patients will relapse after first-line treatment.

Relapsed or refractory acute leukemia with a KMT2A translocation currently has an overall survival rate of less than one year when treated with frontline therapies. 

Will Hinde

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