Highlights

Israel’s Bonus BioGroup has become the first pharmaceutical company in the world to develop a drug that is incredibly effective in treating severe COVID-19 infection caused by the SARS-CoV-2 coronavirus.

MesenCure’s estimated efficacy, which significantly reduces the risk of death and significantly shortens hospital stay, is approximately four times greater than that of all other drugs against severe COVID-19.

The administration of MesenCure to patients hospitalized with severe coronavirus infection has been so successful that it is a breakthrough achievement for the pharmaceutical industry at the forefront of the fight against the COVID-19 pandemic.

In January 2022, Bonus BioGroup submitted MesenCure clinical data to the Israeli regulator for approval of this drug.

MesenCure will organically complement the gradually growing armamentarium of antiviral drugs for the treatment and prevention of COVID-19, such as monoclonal antibodies, Veklury (remdesivir), Paxlovid (nirmatrelvir + ritonavir), Lagevrio (molnupiravir), favipiravir, and MIR 19.

 

MesenCure: Clinical Trial Details

The NCT04716998 phase 2 (randomized, open-label, placebo-controlled, multicenter) clinical trial enrolled adult patients hospitalized with severe COVID-19 infection, characterized by diffuse pneumonia, acute inflammation, oxygen saturation ≤ 93%, and life-threatening respiratory distress.

Participants were given MesenCure (intravenous up to three doses) on top of standard COVID-19 therapy or the latter alone.

 

Interim results

According to an interim analysis of the data, the 30-day survival rate was 94.0% (n=47/50) in the MesenCure group — versus 23.3% (n=14/60) in the standard therapy group. Thus, the addition of MesenCure to standard COVID-19 treatment resulted in a 75.2% reduction in the probability of dying.

Use of MesenCure nearly halved the hospital stay, from an average of 17.2 days in the standard therapy group to 9.4 days in the experimental treatment group. At the same time, one-third of severe COVID-19 patients who received the Israeli drug were discharged from the hospital the day treatment ended, while two-thirds were discharged within the following two days.

MesenCure’s safety profile was characterized by acceptable tolerability and the absence of serious adverse reactions.

 

Final Results

According to the final data analysis, which covered the clinical outcomes of 50 patients in the MesenCure group and 150 patients in the control group, the results of the experimental treatment of severe COVID-19 were as follows.

Adding MesenCure to standard COVID-19 therapy provided a 68% relative reduction in mortality and a 57% reduction in the need for invasive ventilation.

The addition of MesenCure shortened the length of hospital stay: over 50% of patients were discharged in two days after treatment, nearly a quarter (25%) were discharged on the day treatment was completed, and two-fifths (40%) were discharged a day later.

MesenCure administration was not accompanied by any adverse events in terms of treatment safety.

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MesenCure: Mechanism of Action

MesenCure is an allogeneic mesenchymal stem cell (MSC) product derived from the adipose tissue of healthy donors.

The cells in MesenCure, which are primed to enhance their immunomodulatory and anti-inflammatory properties and which target inflammation suppression, regeneration of damaged lung tissue, and suppression of cytokine storm, contribute to the healing process of the respiratory system and other internal organs affected by the progression of the coronavirus infection.

The immunomodulatory and anti-inflammatory effects of MesenCure are realized through modulation of immune cell proliferation and activation mediated by the secretion of immunosuppressive factors. After intravenous injection, MesenCure cells accumulate predominantly in the damaged lung tissue. Secreting by mesenchymal cells growth factors of keratinocytes, endothelium and hepatocytes promote regeneration of lung epithelial cells, prevent endothelial cell apoptosis, restore alveolar-epithelial barrier damaged by cytokine storm. Systemically injected mesenchymal cells also save COVID-19 patients from acute myocardial and renal damage, arrhythmia, shock, and death from multiple organ failure.

In general, MesenCure is well suited to treat acute respiratory distress syndrome (ARDS) and pneumonia caused not only by SARS-CoV-2 but also by other pathogens of viral or bacterial nature or by exposure to contaminants.

It should be understood that Bonus BioGroup did a lot of preclinical work on MesenCure to make sure that it was therapeutic. So, in the pre-COVID-19 era, MSCs attracted a considerable amount of attention, but researchers failed to demonstrate their effectiveness in the treatment of ARDS; there were also concerns about hemocompatibility (depending on the original tissue from which MSCs are derived) and the method of administration into the body (relevant in the case of concomitant coagulopathies). Bonus BioGroup has perfected its variant of MSCs derived from adipose stromal cells (ASCs) and then primed.

In animal models of acute lung injury, MesenCure has been shown to reduce edema by 60% and reduce lymphocyte counts in lung fluid by 40%. Three intravenous doses of MesenCure saved animals from death. In vitro, the drug inhibited the proliferation of activated T cells by 83%. When refrigerated, MesenCure retained its immunomodulatory ability longer than unprimed ASCs, i.e., it was a more stable product suitable for long-term storage. The hemocompatibility of MesenCure cells was similar to that of bone marrow MSCs, which are considered safe for intravenous administration. This was evidenced by 50% reduced levels of coagulation factor 3 (F3), its mRNA, protein, and activity, as well as a more than two-fold increase in tissue factor pathway inhibitor (TFPI) levels expressed on MesenCure cells.

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According to clinical studies, MesenCure’s efficacy in treating COVID-19 infection may be related to de novo cellular expression of the gene encoding the interleukin 6 receptor (IL6R), making these cells more susceptible to inflammation compared to non-professionalized naïve mesenchymal stromal cells (NA-MSCs), as well as a more than 8-fold upregulation of the EDIL3 gene encoding an endogenous immune infiltration inhibitor.

The corresponding immunosuppressive effect of MesenCure, demonstrated in vitro, has been shown to suppress CD4 and CD8 T cells activation twice as effectively as NA-MSCs. In addition, MesenCure very rapidly suppressed ROS production by primary neutrophils.

In addition to the local immunosuppressive effects observed in severe COVID-19 patients treated with MesenCure, there was a significant increase in neutrophils and lymphocytes in the blood, associated with the number of doses of the drug administered and mirrored by an increase in peripheral immunity necessary for successful viremia.

 

MesenCure: Expert Comments

MesenCure’s stunning clinical successes have far-reaching implications for patients and health systems.

First, the significant reduction in hospital stays will relieve pressure on an already overheated health care system, free up resources for better care for other patients, and ease the economic burden. Using MesenCure will reduce the cost of hospital treatment for severe COVID-19 by about 40%.

Bonus BioGroup itself estimates that the reduction in hospital stays in real-world MesenCure use could be even greater, as many of the participants in the clinical trial should have been sent home after the first or second of three doses of the drug, but they stayed in the hospital longer, following the study protocol.

Second, the clinical trial compared MesenCure treatment with standard COVID-19 therapy, which in Israel uses perhaps the most advanced methods than the global average. In other words, on a global scale, MesenCure should be expected to reduce mortality and the length of hospitalization even more dramatically.

To underscore the impressive efficacy of MesenCure, it is appropriate to compare it to that of the anti-inflammatory drug Actemra/RoActemra (tocilizumab), an interleukin 6 (IL-6) blocker developed by Roche, which, when used together with glucocorticosteroids, only marginally reduces the mortality of patients hospitalized with COVID-19, from 25.8% to 21.8%, according to meta-analysis.

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Notably, 77% of patients who received MesenCure were at high risk for poor prognosis and/or death from COVID-19 because they were characterized by the presence of any of the risk factors (hypertension, hyperlipidemia, obesity, type 2 diabetes mellitus). Again, MesenCure treatment was administered during the fourth wave of COVID-19 in Israel, which was dominated by the Delta variant of SARS-CoV-2, which is associated with increased mortality.

Since MesenCure does not work against the coronavirus itself but treats its negative effects, it is not necessary to start therapy as early as possible after the manifestation of COVID-19 symptoms. This is fundamentally different from the approaches taken by all antiviral drugs, including monoclonal antibodies, remdesivir, molnupiravir, nirmatrelvir, favipiravir, whose effectiveness is directly related to the timing of COVID-19 development.

Bonus BioGroup is confident that the emergence of new SARS-CoV-2 strains, including the aggressively spreading Omicron (B.1.1.529), will not affect MesenCure’s claimed efficacy. And this is obvious, because MesenCure, unlike antiviral drugs, is not aimed at fighting the coronavirus directly, but the acute inflammation and pneumonia provoked by the cytokine storm.

Bonus BioGroup, which continues to analyze data collected in phase 2 clinical trial, intends to obtain approval for MesenCure in Israel, the United States, and Europe. Regulators will likely require large-scale phase 3 clinical trials. However, due to the unrelenting COVID-19 pandemic, regulatory requirements will probably be relaxed.

Expanding production and availability of MesenCure is not a problem, since a minimum of 45,000 doses of the drug can be obtained from a single donor lipoaspirate after expansion and modification of MSC.

 

Extras

Bonus BioGroup. Focus on MesenCure. Business presentation, April 2022. [PDF]

Mesencure—an enhanced cell therapy explicitly developed for treating acute respiratory distress in Covid-19: from benchtop to bedside. Cytotherapy. 2021 May; 23(5): S21–S22. [source]

Possible divergent local and peripheral immunological effects of low-dose Mesencure, an enhanced mesenchymal cell therapy, may contribute to its success in treating severe Covid-19 patients. ASH 2021. [source]

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