Remestemcel-L Reduces Mortality in Some Patients With COVID-19-Related ARDS

Silviu Itescu, MBBS

The cellular therapy remestemcel-L reduced mortality through 60 days in a prespecified group of ventilator-dependent patients below the age of 65 with COVID-19 and moderate or severe acute respiratory distress syndrome (ARDS); however, those aged over 65 years did not see a statistically significant improvement, according to a statement from Mesoblast, the company developing the therapy.

Enrollment in the study was halted in December 2020, based on a recommendation from a data safety monitoring board at a third interim analysis. At this point, a projected efficacy analysis did not support remestemcel-L. Despite halting enrollment, the board did advise that the study should continue follow up as planned.

At the updated analysis, for patients under the age of 65 (n = 123), there was a 46% reduction in the risk of mortality with remestemcel-L plus standard of care compared with standard of care alone (HR, 0.54; 95% CI, 0.286-1.005; P = .0485). The rate of mortality with remestemcel-L was 26% compared with 42% for those treated with standard of care alone. The reduction in mortality when looking specifically at moderate and severe ARDS was similar (HR, 0.56 for each); however, these measures did not reach statistical significance when examined individually (P = .98).

“Reduction in mortality in mechanically ventilated patients under 65 years old remains a critical unmet need, since as many as 72% of currently hospitalized patients across the US with COVID-19 are in this age category,” Silviu Itescu, MBBS, chief executive officer and managing director of Mesoblast, said in a statement. “This is similar to other causes of viral ARDS such as influenza where 70-80% of patients in intensive care units are under 65. The reduction in mortality seen with remestemcel-L in this age group highlights the potential to make a meaningful difference in the treatment of diseases of excessive inflammation.”

Remestemcel-L consists of allogeneic, expanded, and cultured mesenchymal stromal cells derived from the bone marrow. In December, the FDA granted a fast track designation to remestemcel-L as a potential treatment for ARDS associated with COVID-19 infection. Based on findings from the updated analysis, Mesoblast announced plans to meet with the FDA to discuss next steps.

The study enrolled 222 mechanically ventilated patients with COVID-19 and moderate or severe ARDS, with 217 going on to be randomized 1:1 to receive standard of care alone or with 2 infusions of remestemcel-L. The cell therapy was administered at 2 x 10^6 cells/kg 3 to 5 days apart. Throughout the course of the study, the standard of care evolved, with the later incorporation of dexamethasone. In the first 50 patients enrolled, only 2% received dexamethasone compared with 84% in the subsequent 172 patients. Additionally, the age of patients enrolled increased throughout recruitment, starting with a mean age of 59 and advancing to an age of 67. Mesoblast theorized this shift may have led to the early halt in enrollment, since mortality improvement is only seen in patients younger than 65.

In those who received dexamethasone, the benefits seen with remestemcel-L were significantly more pronounced. In those under the age of 65 who received the corticosteroid, there was a 75% reduction in the risk of mortality with remestemcel-L compared with standard of care alone (HR, 0.25; 95% CI, 0.085-0.727; P = .0065). The mortality rate with standard of care in this group was 45% compared with 14% with remestemcel-L. In this same group, there was also a reduction in the time to discharge from initial hospitalization (P = .005) and for those alive off ventilators within 60 days (P = .01) with remestemcel-L versus control.

“The mortality benefit observed with remestemcel-L in ventilator-dependent patients younger than 65, particularly in combination with dexamethasone, has the potential to change the treatment regimen in this critical patient population,” Fred Grossman, DO, chief medical officer of Mesoblast, said in a statement. “As cases continue to surge in younger patients across the US, we plan to meet with the FDA to discuss next steps in the regulatory process.”

In addition to ARDS, remestemcel-L is also being explored as a potential treatment for patients with heart failure and chronic low back pain, with phase 3 studies recently completed. The cell therapy is also being explored in children with inflammatory disease and for adults with steroid refractory acute graft versus host disease (GVHD), an application for which was submitted to the FDA in 2020. In August 2020, the FDA’s Oncologic Drugs Advisory Committee board voted 9 to 1 in favor of its approval for GVHD; however, in early October, the FDA issued a complete response letter requiring additional data. The company has yet to submit a new application.