Remestemcel-L Reduces Mortality in Patients Less Than 65 Years Old With Moderate/Severe COVID-19 ARDS: Topline 60-Day Results From Randomized Controlled Trial

On Apr 29, 2021

Mesoblast Limited announced the 60 day results from the randomized controlled trial of remestemcel-L in 222 ventilator-dependent COVID-19 patients with moderate/severe acute respiratory distress syndrome (ARDS) which had been halted after the third interim analysis, as previously announced. Remestemcel-L reduced mortality through day 60 by 46% in the pre-specified group below age 65, but not in patients 65 or older. Remestemcel-L reduced mortality by 75% and increased days alive off mechanical ventilation in patients under age 65 when combined with dexamethasone, in comparison with controls on dexamethasone.

“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,” said Mesoblast Chief Executive, Silviu Itescu. “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.”

The trial enrolled 222 mechanically ventilated COVID-19 patients with moderate/severe ARDS across the US, of whom 217 were randomized 1:1 and received either standard of care alone or standard of care plus 2 intravenous infusions of remestemcel-L at a dose of 2 million cells/kg 3-5 days apart. This was the same remestemcel-L dosing regimen used in the earlier compassionate use program where 11 of 12 patients were younger than 65 and 75% successfully came off ventilatory support.

During the course of the trial, as the pandemic evolved, numerous changes occurred in treatment regimes. As a result, the referral pool of patients into the trial became progressively older with comorbidities and refractory to treatment. The median age in the trial increased from 59 in the first half to 67 in the second half, p<0.0001. This may have impacted the outcome of the third interim analysis which resulted in the trial’s early conclusion. It is possible that to achieve mortality reduction in patients over 65 with comorbidities will require a different dosing regimen than that which may be effective in patients under 65.

Key findings in the trial were:

Remestemcel-L reduced mortality by 46% through day 60 in the pre-specified population of 123 treated patients under age 65, 26% vs 42%, Hazard Ratio (HR) 0.54, 95% CI (0.286, 1.005), p=0.048
Remestemcel-L had similar treatment effects on mortality in these patients with either moderate ARDS (HR 0.56) or severe ARDS (HR 0.56)
Standard of care changed during the course of the trial to incorporate dexamethasone, with only 2% of the first 50 patients enrolled receiving dexamethasone compared with 84% of the subsequent 172 patients; this allowed for additional exploratory analyses of remestemcel-L treatment effects in patients who received dexamethasone as part of their standard of care
Remestemcel-L reduced mortality through day 60 by 75% compared to controls in patients under 65 who received dexamethasone as part of their standard of care, 14% vs 45%, HR 0.25, 95% CI (0.085, 0.727), p=0.006
Remestemcel-L increased days alive off ventilator within 60 days and reduced time to discharge from initial hospitalization compared to controls in patients under 65 who received dexamethasone as part of their standard of care, p=0.01 and p=0.005, respectively

“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,” said Dr Fred Grossman, Chief Medical Officer of Mesoblast. “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.”

Mesoblast entered into a license and collaboration agreement with Novartis for the development, manufacture, and commercialization of remestemcel-L, with an initial focus on the treatment of acute respiratory distress syndrome (ARDS), including that associated with COVID-19. The agreement remains subject to certain closing conditions, including time to analyze the results from this COVID-19 ARDS trial.

Additional secondary endpoints, which include days in intensive care, and cardiac, neurological, and pulmonary organ damage, together with measures of circulating cytokines and inflammatory markers, are being evaluated and will be reported when completed.