Based on mounting evidence that tocilizumab improves survival in critically ill patients with COVID-19, the FDA granted it an emergency use authorization for COVID-19 treatment in June. Two months later, the agency added tocilizumab to its list of drug shortages, where it remains despite a slowly increasing supply.
The IL6-blocking drug tocilizumab (Actemra; Genentech) is used for managing rheumatologic diseases and cytokine release syndrome (CRS) in people treated with chimeric antigen receptor (CAR) T-cell therapies. But following mounting evidence that tocilizumab improves survival in critically ill COVID-19 patients, the FDA granted it an emergency use authorization for COVID-19 treatment in June (Lancet 2021;397:1637–45).
In August the FDA added tocilizumab to its shortage list, where it remains.
“I think that Genentech was not prepared for the unprecedented demand; normally tocilizumab is a pretty predictable product,” says Erin Fox, PharmD, of the University of Utah in Salt Lake City. This, combined with a surging Delta variant wave that has led to more hospitalizations than previous variants, and a lower-than-hoped-for uptake of COVID-19 vaccinations, seemingly caught the manufacturer off-guard.
“The shortage is an ongoing area of concern and is impacting both access to CAR T-cell therapies as well as our ability to administer them safely to our patients,” says Navneet Majhail, MD, MS, of the Sarah Cannon Transplant and Cellular Therapy Network in Nashville, TN. CAR T-cell therapies are provided under an FDA Risk Evaluation and Mitigation Strategies program, which due to the acutely life-threatening nature of CRS, requires all institutions administering CAR T cells to have a minimum of two doses of tocilizumab on site for each patient. Several CAR T-cell clinical trials are under way, and they require having tocilizumab on hand to maintain trial protocols and timelines.
Another IL6 inhibitor, siltuximab (Sylvant; EUSA Pharma), and anakinra (Kineret; Sobi), an IL1 inhibitor, are plausible alternatives to treat CRS, but “the majority of data around treatment of CRS following CAR T-cell therapy is with tocilizumab,” notes Majhail, who has worked to boost supplies of siltuximab and anakinra at his institution as a backup option to treat CRS.
The supply of tocilizumab was better in October than in September, but the University of Utah Health academic healthcare system chose to “reserve supply needed for CAR T patients,” only then allocating the remainder for COVID-19 patients. “It was just a balance of trying to make sure that we had enough of everything. When we did not, for COVID-19 patients, we used drugs such as baricitinib [a JAK1/2 inhibitor] to try to conserve the supply,” adds Fox.
The shortage of tocilizumab is “highly unusual,” notes Fox, who says that shortages normally involve low-cost generic drugs, not expensive, brand-name products. In September, Genentech said that replenishment of stock has begun, but warned that “additional intermittent periods of stockouts” are expected in the months ahead, “especially if the pandemic continues at the current pace.”
Majhail agrees: “The situation of tocilizumab shortage is unpredictable and is completely dependent on the prevalence of COVID in our communities.”
Furthermore, a new variant of COVID-19 could stymie Genentech's efforts to restore the supply of tocilizumab, but Fox remains optimistic that future surges in hospitalization rates can be avoided, and that Genentech “has a good plan for continued production and supply,” having learned from the slowly ending shortage. –Victoria Forster