Bonus BioGroup (TASE: BONS) is a clinical-stage Israeli biotechnology company, engaged in research and development of biomedical tissue-engineered and cell therapy products.

Bonus BioGroup is pleased to announce that on April 26, 2022, data collection and analysis from a preclinical trial have been completed, indicating that its drug product MesenCure may reduce the life-threatening, systemic, hyperinflammatory reaction in patients with Cytokine Release Syndrome (CRS).

Cytokine Release Syndrome is characterized by increased pro-inflammatory cytokines secretion and affects about 41% to 78% of cancer patients treated with immunotherapies[1]. Moreover, this syndrome develops at similar rates in patients treated with hematopoietic stem cell transplantation (HSCT), mainly used to replace abnormal blood cells in leukemia patients. About 13% to 27% of the patients suffering from Cytokine Release Syndrome will develop multi-organ failure resulting in a severe or life-threatening condition.

The efficacy of the MesenCure therapy in the treatment of Cytokine Release Syndrome was demonstrated in a study conducted at the Jackson Laboratory, USA, one of the most respected research institutes in the world. The experiment was performed on animal models with a human immune system afflicted with leukemia from a human source. When these animals are treated for cancer with CAR-T immunotherapy[2], they develop Cytokine Release Syndrome, similar to human cancer patients. The humanized nature of this model makes it highly translational and predictive of the effect of MesenCure on patients suffering from Cytokine Release Syndrome.

As a result of MesenCure therapy for Cytokine Release Syndrome, the levels of multiple cytokines decreased in all experimental group subjects below the median level measured in the control group, indicating a complete, positive response to MesenCure therapy. Furthermore, the decrease in cytokine levels in the experimental group was statistically significant (p<0.05) compared with their levels in the control group.

The cytokines whose levels significantly decreased as a result of treatment with MesenCure for Cytokine Release Syndrome are: IL-4, IL-10, INF-ϒ, TNF-α, and IL-2, which are prevalent in this syndrome, and their decrease rates are similar to those of different cytokines measured in severe COVID patients treated with MesenCure.

Furthermore, it was shown that during the treatment with MesenCure, the efficacy of immunotherapy against the cancerous tumor was maintained, and the safety of MesenCure therapy for Cytokine Release Syndrome was demonstrated.

Immunotherapies designed to activate the immune system against cancerous cells utilize T cells collected from the patient and activated outside the body. Upon their reintroduction to the patient, these activated T cells detect and destroy cancer cells. In addition, patients' immune systems can also be activated using bispecific T-cell engagers (BiTEs) designed to bind cancer cells to immune cells, thereby directing the immune system to act against the cancer cells. However, immunotherapies and hematopoietic stem cell transplantation often lead to immune system hyperactivity, resulting in Cytokine Release Syndrome, similar to the cytokine storm in severe COVID patients that also results from a hyperinflammatory immune response.

The Company estimates that as of 2027, in the US alone, more than 18 thousand patients will suffer each year from Cytokine Release Syndrome following current therapies, including engineered T cells (CAR-T), bispecific T-cell engagers (BiTEs), and hematopoietic stem cell transplantation (HSCT)[3].

Based on the currently available therapies that cause Cytokine Release Syndrome, the addressable market for MesenCure for the treatment of this syndrome is expected to grow at an average annual rate of about 13%, reaching a total of about US$ 200 million in the US alone by 2027. This amount is based on the Company's estimate of achieving an average saving of about 40% in the hospitalization costs of moderate-to-severe Cytokine Release Syndrome patients due to combining MesenCure treatment with current cancer therapies, compared to the hospitalization costs of such patients without the additional MesenCure treatment.

In contrast to general chemotherapy, targeted immunotherapies are designed to attack only the cancer cells, and therefore, their development is currently leading the research of cancer therapies. This fact is reflected in an average annual increase, in the last decade, of about 38% in the number of new clinical trials with products based on CAR-T or BiTEs alone[4].

As a result of the industry's efforts to develop immunotherapies for additional indications, some of which are expected to be approved and applied in the coming years, the addresable market for MesenCure therapy for Cytokine Release Syndrome may grow substantially.

Moreover, the availability of MesenCure therapy may accelerate the development and expand the availability of additional new immunotherapies, more than half of which are likely to fail the clinical study safety phase[5], in most cases due to Cytokine Release Syndrome, therefore not receiving marketing approval and losing investments each year of approximately US$ 100 million in the US alone[6].

In contrast, combining MesenCure into the clinical development of new immunotherapies and consequently reducing possible incidences and / or severity of Cytokine Release Syndrome, thereby improving their safety, may aid the approval of new immunotherapies and significantly reduce the losses and risks to companies developing such modalities.

Dr. Shai Meretzki, CEO of Bonus BioGroup, said that "Demonstrating the success of the drug product MesenCure to integrate with cancer therapies, is an important milestone for the Company in realizing its vision to become a world leader in cellular therapy for the treatment of various diseases and medical conditions. In light of these results, we expect MesenCure, which was shown to be highly effective in treating severe COVID patients suffering from Cytokine Release Syndrome due to SARS-CoV-2 infection (Cytokine Storm), to be highly effective also demonstrate high efficacy in the treatment of cancer patients. These indications will present to the Company further financial opportunities amounting to about US$ 300 million each year in the US alone and double that amount worldwide and will position Bonus BioGroup as an essential player in the field of Oncology, in addition to regenerative medicine and tissue engineering."

Given the estimates that even in the post-epidemic world, when COVID becomes an endemic disease, hundreds of thousands of severe patients[7] are expected each year to be hospitalized in the US alone, Bonus BioGroup continues the clinical development of MesenCure for severe COVID patients.

The Company also intends to continue its efforts toward marketing approval for MesenCure by, including, submitting an application for the approval of a phase III clinical trial with MesenCure for severe COVID patients suffering from life-threatening pneumonia and respiratory distress in Israel and additional territories.

It should be noted that the best currently available treatment for patients suffering from severe Cytokine Release Syndrome is based on the anti-inflammatory drug Acterma^®[8], which is administered in combination with steroids, similar to the treatment for severe COVID patients. Studies have shown that in more than 30% of the patients suffering from severe Cytokine Release Syndrome, Acterma^® is not beneficial[9]. Moreover, Acterma^® does not alleviate the neurological symptoms of the syndrome, which are common in many patients, and may even exacerbate them[10]. In addition, the use of Actemra® may cause serious side effects, including an increased risk for severe infections[11]. Such side effects were not observed in severe COVID patients treated with MesenCure, which was also shown to be at least 4 times more effective than the standard of care in severe COVID patients, which includes the drug Actemra®, as reported by the Company in an immediate report dated January 10, 2022[12].

About Bonus BioGroup and MesenCure therapy

Since its inception, Bonus BioGroup has been involved in cell therapy and tissue engineering to achieve bone tissue regeneration and reconstruction. The main building block utilized to produce the viable bone graft is mesenchymal cells extracted from the patient's adipose tissue. With the outbreak of the global Coronavirus epidemic, the Company began experimenting with the very same mesenchymal cells, isolated from adipose tissue of healthy donors, and their activation to enhance their ability to reduce inflammatory processes, including respiratory infections and others. These efforts led to the development of the cell therapy product, MesenCure.

The efficacy of MesenCure therapy, as demonstrated in the clinical trial for the treatment of severe COVID patients suffering from cytokine storm (also known as Cytokine Release Syndrome), is due to the activation of the mesenchymal cells that comprise MesenCure. This activation enhances the cells' natural ability to ameliorate the inflammation and Cytokine Storm, which without MesenCure therapy can lead to life-threatening, multi-organ damage.

Furthermore, the cells comprising the drug product MesenCure affect inflammation and cytokine storm through various mechanisms. Therefore, MesenCure may have a broader and more robust effect on diverse populations of patients suffering from cytokine storms for various reasons than drugs acting via a single mechanism.

In light of the above and the Company's achievements in demonstrating the efficacy of MesenCure in severe COVID, the Company has expanded its efforts to examine the potential of MesenCure and its derivatives to treat other indications involving systemic inflammations and multi-organ injuries, including Cytokine Release Syndrome due to biological therapies.

In developing the drug product MesenCure, Bonus BioGroup uses various unique technologies and knowledge developed by the Company. The Company's rich intellectual property, including seven families of patents and patent applications, encompasses twenty-seven approved patents and eighteen patent applications in many countries worldwide.

Company estimations regarding forward-looking statements

Bonus BioGroup's assessments regarding the volume of patients suffering from Cytokine Release Syndrome and / or the extent of clinical trials expected in various immunotherapies, as well as regarding the medical effect and / or commercial potential of the drug MesenCure and / or the resulting economic opportunities, and the Company's ability to continue the process of drug development, conducting studies, and arriving at a product that can be medically applied in humans, for the time and expected dates to perform any stage in any experiment and publish its results and obtain regulatory approvals for marketing the product, are forward-looking statements, as defined by the Securities Law of 1968, which are based on the Company's estimates and on the information in its possession at the time of reporting.  

There is no certainty that these estimates will materialize, in whole or in part, among others, due to dependence on the actions of third parties, which are not under the Company's control, on the development of future cancer therapies, on future studies results, if any, due to the possibility of delay in obtaining an approval from relevant authorities and / or change in the relevant conditions and / or feasibility tests that the Company may conduct and / or delay in performing studies and / or need to perform further experiments and / or failure of experiments and / or technological changes and / or the development and / or marketing of similar and / or more efficient competing products and / or the lack of resources and / or the realization of any of the risk factors associated with the research and / or studies and / or its results.

Sincerely,

Bonus BioGroup Ltd.

By: Yossi Rauch (Chairman of the Board) and Dr. Shai Meretzki (CEO and Director)

[1] Mean prevalence of cytokine release syndrome in oncological patients (suffering from: MM, MCL, FL, DLBCL, ALL, and NSCLC) following immunotherapy treatments with engineered T cell (CAR-T) and bispecific T-cell engagers (BiTEs) or patients treated by hematopoietic stem cells trsnaplantion (HSCT), calculated based on 37 reviewed scientific articles.

[2] https://www.jax.org/jax-mice-and-services/in-vivo-pharmacology/safety-and-efficacy-assessment

[3] Calculated based on the prevalence of cytokine release syndrome (for each type of cancer and / or therapy that may lead to this syndrome), the number of patients likely to develop different types of cancer (as detailed in footnote number 1) and which may be treated with immunotherapy, as reflected in market research of Clarivate - DRG - Decision Resources Group, multitplied by the proportion of patients treated by immunotherapy, among them, and the number of patients treated with HSCT, as reflected in the HRSA - Transplant Activity Report.

[4] Based on data collected from www.clinicaltrails.gov on phase I clinical trials between the years 2012-2021.

[5] CAR-T failure rate in Phase I clinical trials according to Clinical Development Success Rates and Contributing Factors 2011–2020. Biotechnology Innovation Organization (BIO).

[6] Estimated based on the number of phase I clinical trials with CAR-T and BiTEs technologies expected to begin in 2027, in the US alone (110 clinical trials, according to a regression model of historical data from www.clinicaltrials.gov), multiplied by the average patient number for a phase I clinical trial (48 patients, according to historical data), multiplied by the treatment cost of each patient in such a clinical trial (40 to 50 thousand dollars), multiplied by the percentage of failure in a phase I clinical trial (56%, see footnote number 5 ), multiplied by the average incidences of cytokine release syndrome, out of the total side effects in phase I clinical trial with CAR-T and BiTEs technologies (78%).

[7] See reports dating January 10, 2022 and April 11, 2022 (references 2022-01-005083 and 2022-01-038652, respectively).

[8] Trade name of a drug manufactured by F. Hoffmann-La Roche AG.

[9] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8585070/

[10] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6746032/

[11] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7414980/