Four of six critically ill COVID-19 (coronavirus) patients significantly improved after receiving an experimental therapeutic designed to reduce inflammation, a major cause of death from this disease, according to a case series published by Cedars-Sinai and Capricor Therapeutics. The four patients got well enough to be discharged from the hospital.
The therapeutic, known as CAP-1002, contains cardio-sphere-derived cells (CDCs) that are grown in the laboratory from human heart tissues. Previous pre-clinical and clinical research showed that the CDCs, originally created by a process developed to treat heart failure, can help the whole body.
Investigators emphasised that the patient outcomes, while encouraging, are not sufficient to prove that CAP-1002 is safe and effective for treating COVID-19 because this was not a clinical trial with a control group.
The case series believed to be the first peer-reviewed report on using a cell therapy in critically ill COVID-19 patients, according to Dr Eduardo Marbán, executive director of the Smidt Heart Institute at Cedars-Sinai.
All six patients in the case series suffered from respiratory failure and required supplemental oxygen prior to receiving the cell therapy; five were on ventilators. Within four days after infusion with CAP-1002, four patients were able to breathe without respiratory support, and within less than three weeks, the four were well enough to be discharged from the hospital. As of 28 April, the two other patients remained hospitalized in intensive care.
None of the patients showed adverse effects from the infusions, and none died during the study period. By comparison, six patients died among a group of 34 comparable COVID-19 patients who were treated in Cedars-Sinai's intensive care unit around the same time but who did not receive the cell therapy.
The patients in the case series were treated at Cedars-Sinai under emergency use provisions, which allows use of therapies not yet approved by the US Food and Drug Administration to treat seriously ill patients when no other treatments are available. "Previous studies provided strong evidence that CDCs have intense benefits for the immune system and inflammation in a number of diseases," Marbán explained, "They accomplish this by secreting exosomes- nanoscale vesicles with a variety of active contents that travel widely throughout the body."
Marbán said this anti-inflammatory effect could be a critical boost for coronavirus patients. Current information, he explained, indicates that the body's overreaction to the COVID-19 infection, rather than the virus itself, often delivers the fatal blow, especially in later stages of the disease.
"'Friendly fire' is what's killing many coronavirus patients," said Marbán, professor of Cardiology and co-author. "The immune system unleashes a so-called cytokine storm into the blood-overwhelming the body with infection-fighting proteins that can trigger multiple-organ failure and death."
Dr Raj Makkar, the principal author, said the investigative team is planning a future clinical trial that would involve dividing a larger number of coronavirus patients into two groups: those who receive the therapy and a control who do not. The team would then compare the outcome for the two groups.
Makkar said. "That is because some coronavirus patients get better on their own with standard treatments." Makkar added that if the CDCs counteract immune overreaction in coronavirus patients, the cells potentially could help prevent or treat two other life-threatening conditions that often develop during the course of the disease: acute respiratory distress and inflammation of the heart muscle, known as myocarditis.
The emergency use treatment was conducted in collaboration with the biotechnology company Capricor Therapeutics in Los Angeles, which provided regulatory support and manufactured the experimental agent (CAP-1002).
There are no definitive therapies for patients with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. Therefore, new therapeutic strategies are needed to improve clinical outcomes, particularly in patients with severe disease. This case series explores the safety and effectiveness of intravenous allogeneic cardiosphere-derived cells (CDCs), formulated as CAP-1002, in critically ill patients with confirmed coronavirus disease 2019 (COVID-19). Adverse reactions to CAP-1002, clinical status on the World Health Organization (WHO) ordinal scale, and changes in pro-inflammatory biomarkers and leukocyte counts were analyzed. All patients (n = 6; age range 19–75 years, 1 female) required ventilatory support (invasive mechanical ventilation, n = 5) with PaO2/FiO2 ranging from 69 to 198. No adverse events related to CAP-1002 administration were observed. Four patients (67%) were weaned from respiratory support and discharged from the hospital. One patient remains mechanically ventilated as of April 28th, 2020; all survive. A contemporaneous control group of critically ill COVID-19 patients (n = 34) at our institution showed 18% overall mortality at a similar stage of hospitalization. Ferritin was elevated in all patients at baseline (range of all patients 605.43–2991.52 ng/ml) and decreased in 5/6 patients (range of all patients 252.89–1029.90 ng/ml). Absolute lymphocyte counts were low in 5/6 patients at baseline (range 0.26–0.82 × 103/µl) but had increased in three of these five patients at last follow-up (range 0.23–1.02 × 103/µl). In this series of six critically ill COVID-19 patients, intravenous infusion of CAP-1002 was well tolerated and associated with resolution of critical illness in 4 patients. This series demonstrates the apparent safety of CAP-1002 in COVID-19. While this initial experience is promising, efficacy will need to be further assessed in a randomized controlled trial.
Siddharth Singh, Tarun Chakravarty, Peter Chen, Akbarshakh Akhmerov, Jeremy Falk, Oren Friedman, Tanzira Zaman, Joseph E Ebinger, Mitch Gheorghiu, Linda Marbán, Eduardo Marbán, Raj R Makkar