The U.S. Food & Drug Administration (FDA) recently removed its Risk Evaluation and Mitigation Strategies (REMS) designation from CAR T immunotherapies. REMS is occasionally applied to drugs with serious potential safety issues, requiring providers to pursue and document more robust mitigation strategies.
The FDA puts these designations in place to ensure patients receive the maximum therapeutic benefits, and providers fully manage severe side effects. While CAR T has been a transformative therapy, redefining what’s possible in oncology, it can also be quite toxic. In this case, the culprits are cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS).
Removing the designation is a routine, and probably warranted, regulatory change. Kymriah was approved eight years ago. It was time. This shift signals that both the regulatory and medical communities are comfortable providers can rely on CAR T’s prescribing information to manage risks and benefits.
But it’s important to remember that removing REMS from CAR T does nothing to reduce the dangers patients face. While this decision does eliminate some administrative hurdles – and that’s a good thing – CRS and ICANS remain serious, potentially life-threatening side effects. To truly protect patients, biopharma must step up and develop safe, effective, accessible drugs to control these toxicities.
CAR T’s promise and pitfalls
Many new treatments claim to be revolutionary – CAR T truly is. This personalized therapy has produced tremendous response rates and, in some cases, durable remissions, particularly in B-cell lymphoma and acute lymphoblastic leukemia While CAR T has only proven effective, so far, in blood cancers, there’s an ongoing race to expand those benefits to solid tumors and other indications. Right now, there are hundreds of CAR T, and other T cell-based, therapies in the pipeline.
Still, more must be done to ameliorate side effects. CRS and ICANS over-activate cytokines to produce T cells, macrophages, and other inflammatory cells. During ICANS, immune cells cross the blood-brain barrier, generating inflammation and potential brain damage. In CRS, massive immune signaling molecule production generates systemic inflammation, not unlike sepsis.
While the REMS discontinuation signals confidence that providers will closely monitor these side effects, their mitigation tools are quite limited. Frontline treatments for CRS include intravenous corticosteroids and tocilizumab, a monoclonal antibody that inhibits the cytokine interleukin-6. Unfortunately, these treatments produce their own serious side effects, putting patients at risk for life-threatening infections, steroid-induced myopathies, and severe cytopenia.
The results are quite stark: 70% to 95% of CAR T patients and 40% to 60% of those receiving T cell engagers develop CRS; as many as 50% of CAR T patients are at risk for ICANS; between 50% to 80% of patients treated with Tocilizumab require high-dose steroids; 33% of patients are eventually transferred to an ICU. The mean length of hospitalization for patients with these severe side effects is 25 days, with costs exceeding $500,000, eating into scarce healthcare resources.
It’s time to refocus on controlling CAR T side effects
As a society, we often focus on a therapy’s benefits but shy away from its limitations. CAR T has produced such tremendous outcomes that the risks have sometimes been minimized. However, CRS and ICANS remain serious problems that endanger patients and limit their access to this groundbreaking therapy.
This access issue is no small thing. No more than 30% of people who could benefit from CAR T actually have access to it. Part of the problem is that the therapy is almost exclusively delivered in academic medical centers, and many patients face geographic barriers. It’s hard on patients and families to travel hundreds of miles for care.
But there’s another problem, and this speaks even more directly to CAR T’s risks and why we need better therapies to control them. Nearly 30% of patients are readmitted because of CRS and ICANS, generating lengthy hospital stays that can limit care for others.
Academic medical center beds are a scarce and defined resource, and this reduced bed availability will only get worse as new agents are approved. If providers cannot guarantee follow-up care, that limits access.
This problem could be greatly alleviated if community hospitals and outpatient centers were better positioned to manage these toxicities. Some of these facilities are working to build that infrastructure, but as noted above, they lack the pharmacological tools to adequately manage CRS and ICANS.
Biopharma is on the hook to eliminate the safety bottleneck
To truly expand CAR T access and prepare for the wave of new T cell-based therapies coming through the pipeline, we must find better ways to manage CRS and ICANS. Ideally, we would develop an orally delivered treatment that reduces or eliminates the need for steroids. This would be quite conducive to outpatient clinics and community hospitals, which would create a ripple effect, alleviating the bed shortage and opening access to many cancer patients.
The REMS decision is a step in the right direction, but we need bigger steps. The biopharma community must comprehensively address the root problem: common and potentially deadly CAR T toxicities. Only then will we be able to fully realize the promise of this revolutionary therapy.
Photo: Main_sail, Getty Images
Teresa Whalen, RPh, is CEO of CytoAgents, a clinical-stage biotech developing novel solutions for Cytokine Release Syndrome (CRS), a life-threatening immune overreaction. With more than 20 years of experience across the healthcare industry, Teresa has served as a biotech innovator, healthcare technology leader, hospital board trustee, life sciences investor, and clinical pharmacist. She has successfully guided healthcare products from concept to market, leveraging her deep expertise in clinical development and commercialization. At CytoAgents, she leads a world-class team of drug development experts and scientific advisors advancing groundbreaking treatments that address systemic inflammation and improve patient outcomes. Teresa also serves on multiple industry boards and is passionate about translating scientific innovation into meaningful therapies that change lives.
This post appears through the MedCity Influencers program. Anyone can publish their perspective on business and innovation in healthcare on MedCity News through MedCity Influencers. Click here to find out how.
