MesenCure development entrepreneurs (from right): Dr. Dror Ben David, Dr. Shai Meretzky and Dr. Tomer Bronstein.

An interview with Dr. Tomer Bronshtein, Head of Research at Bonus BioGroup

By Sandra Veljković

Haifa, Israel, August 23, 2021. Dr. Tomer Bronshtein, Head of Research at Bonus BioGroup, and his colleagues successfully treated severe patients with COVID-19 with activated Mesenchymal Stromal Cells (MSCs). So far, only three scientific groups have achieved such exciting results: the team of Croatian scientists led by Professor Dragan Primorac from St. Catherine Hospital is among them. The outstanding achievements of Israeli scientists opened doors for further collaboration and expanded use of an innovative COVID-19 treatment.

First of all, congratulation on your recent excellent results in treating patients with severe Covid-19. We learned that you completed Phase I/II at Rambam Medical Center by using MesenCure demonstrating significant improvement on severe Covid-19 patients. Immediately after, the Israeli Health Ministry approved MesenCure for expanded use? What does it mean?

Thank you! The approval means that based on our excellent preliminary efficacy and safety data, the Israel Ministry of Health has approved expanding our ongoing phase 2 study to a multi-center study treating larger numbers of severe Covid-19 patients in additional medical centers nationwide. Simultaneously and building on our established operational capacity to manufacture appropriate amounts of MesenCure under the highest standards, Bonus BioGroup is preparing the regulatory framework and operational landscape for a multi-national phase 3 study, including in Europe, established via strategic collaborations.

Simultaneously, with your clinical work, the group by Prof. Primorac used similar technology and cured the patient with severe COVID-19 and ARDS? It looks like both groups got similar results by using Mesenchymal Stromal Cells. Any comments on it?

To date, Bonus BioGroup used MesenCure to treat only severe Covid-19 patients and prevented them from deteriorating to a critical state and requiring mechanical ventilation while improving their condition and supporting their recovery. The excellent work published by Prof. Primorac's group, being one of the most detailed descriptions of treating Covid-19 with MSCs, complements our work by demonstrating that patients in a critical stage, already mechanically ventilated, may also benefit from MSC-based therapy, as we have long suspected. Simultaneously, our work substantiates that of Prof. Primorac by providing data on more subjects. In addition, we bring forward a product based on professionalized MSCs, as explained below, specifically developed and optimized to treat Covid-19, and that is ready for mass production and wide application.

We realised by reading your reports that the power of Mesenchymal Stromal Cells (MSCs) in reducing lung inflammation, decreasing inflammatory parameters, and increasing blood lymphocytes is tremendous. What is so unique about MSCs?

MSCs are usually referred to as ambulatory cells, from the word ambulance. Normally, they reside outside blood vessels waiting to be called upon to tissue damage or inflammation sites. Upon reaching these sites, the MSCs sense the damage and start working accordingly to regenerate the tissue by secreting an arsenal of bioactive molecules. These molecules attenuate hyper-activated immune cells, such as in Covid-19 cytokine storm and pneumonia, and reduce inflammation as well as promote the regeneration of blood vessels and epithelial and other tissues. Owing to their ability to attenuate the immune system, MSCs can be safely transplanted between individuals without organ matching and without losing potency or causing adverse side effects. This feature and the ability to grow MSCs outside the body to large numbers allow banking MSCs from healthy donors and using them as an off-the-shelf product for treating various conditions, including Covid-19. These natural therapeutic and technological aptitudes of MSCs are reinforced in MesenCure, building on years of MSC-related experience accumulated by Bonus BioGroup, which developed a product optimized to treat acute respiratory distress in Covid-19. 

If we understand correctly, your advanced technology additionally activates Mesenchymal Stromal Cells, making them more stable and potent. Am I right?

Yes, MesenCure consists of professionalized MSCs. In the process of culturing, MesenCure MSCs are subjected to a unique combination of culture conditions involving no genetic editing, making them stronger and more responsive to inflammation. These enhancing conditions were optimized using laboratory and animal models relevant to acute respiratory distress associated with Covid-19. This optimization made MesenCure the first MSC-based product developed explicitly for Covid-19 and tailored for a maximal therapeutic effect. Compared to non-professionalized MSCs, MesenCure MSC demonstrated a significantly improved ability to attenuate immune cells' activation and reduce lung edema and pneumonia while maintaining potency and viability in storage for a much longer duration. Subsequently, when MesenCure MSCs reach the patient, they are more viable and potent than non-professionalized MSC and can elicit a more powerful anti-inflammatory effect. In addition, MesenCure is a fresh product delivered to the patients without being frozen, like most MSC products, guaranteeing they do not lose viability and potency during freezing and thawing, yet with enough shelf-life to support centralized manufacturing and global supply. Lastly, Bonus BioGroup has developed the technological and operational capacity to produce MesenCure doses sufficient for tens of thousands of patients from a single lipoaspirate donor. This amount of MesenCure can be obtained following a relatively short expansion of the cells without losing potency, which is commonly associated with over-expanding the cells.

With the outbreak of Covid-19, it is of the utmost importance to complete the Phase III clinical trial with MSCs treatment of the patients with the severe form of Covid-19. Any plans that you and Prof. Primorac jointly continue with clinical research, more precisely to complete the Clinical Phase III?

We are exploring all possibilities to collaborate with Prof. Primorac's group. Hopefully, we would be able to share with you more information on our collaboration in the near future.

How do you see the future of cell treatment and tissue engineering?

The prospects of biotechnologies, in general, have changed dramatically in the face of Covid-19. While these were largely considered unattainable before the pandemic, now tides have changed, with billions already vaccinated with Pfizer and Moderna's gene-based vaccines. Also, awareness of the potential of biotechnologies to save humanity from all kinds of malaises (present and future) is growing among the general public, policymakers, and healthcare providers, shifting resources into biotechnological developments and facilitating their wider adoption.

This shift and increasing adoption, we are noticing, lately, not only in regard to MesenCure but also regarding BonoFill, Bonus BioGroup's live bone tissue-engineering product based on the patient's cells. BonoFill is positioned to replace the highly burdensome, frequently ineffective, and often risky procedure of bone auto-grafting for treating otherwise non-healing bone defects that persist in about 10% of all fracture patients and additional patients suffering from degenerative bone diseases. Amazingly, despite the tardiness in elective surgeries during Covid-19 lockdowns, the number of medical centers involved in our BonoFill trial has tripled during the pandemic, allowing even more severely disabled patients to return to everyday lives. A similar growing interest in additional fields of tissue engineering was also registered, with bone and cartilage regeneration taking the lead in light of recent successes in treating osteoarthritis by a combination of MSCs and platelet-rich plasma in a study held at Zagreb's St. Catherine Specialty Hospital run by Prof. Primorac.   

Concerning cell therapy and MSC therapy, in particular, there is a growing understanding that despite past disappointments, MSCs could make a real difference in Covid-19, as reflected in our data and the work of Prof. Primorac's group. However, to guarantee this effect, one must treat suitable patients with the right cells. This match can be achieved by combining scientific, technological, and clinical efforts and merging a deep and intimate understanding of the outlook and challenges associated with MSCs and the clinical manifestation and undelaying pathology of Covid-19.

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August 23, 2021.

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