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Boosting immuno-oncology strategies with innovative immuno-stimulants derived from bacteria, to be administrated in combination with therapeutic monoclonal antibodies

Periodic Reporting for period 1 - ONCO-BOOST (Boosting immuno-oncology strategies with innovative immuno-stimulants derived from bacteria, to be administrated in combination with therapeutic monoclonal antibodies)

Reporting period: 2019-05-01 to 2019-10-31

Immunotherapies have revolutionized cancer treatment and has given a new hope towards cancer cure. However, the average patient response rates to current immunotherapies are still low (25%), and the cure rate without relapse are even lower (10%). In addition, significant differences exist according to patients and tumor types. This gap represents a huge medical and market need.

HEPHAISTOS-Pharma develops ONCO-Boost, a platform of active and non-specific immuno-stimulants able to potentiate commercialized antibodies, by turning cold tumors hot, but also very effective as single agents against cancers with unmet medical needs. Our immunostimulants are based on natural Glycolipids extracted from the outer membrane of bacteria, and chemically detoxified using innovative proprietary process. By stimulating TLR4 receptors of the immune cells, our molecules have the potential to recruit, stimulate and potentiate the anti-tumor immune defenses, offering a great hope to potentiate the efficacy of cancer immunotherapies by turning hidden cold tumors into hot targets for our immune system. Compared to other immuno-stimulant molecules currently in development, including a handful of TLR4 agonists, our immunostimulants are both natural and significantly less toxic (Relevant structure, detoxification process) but also easier to formulate (Highly soluble molecules that can be formulated in Liposomes). This enable their systemic administration, which is unique in this competitive field, and leading to higher efficacy against metastatic cancers.

ONCO-Boost products have been produced and characterized, and their efficacy was validated in vitro on human cells but also in vivo in relevant animal models, first in combination with Rituximab for lymphoma (Raise of complete response rates from 17% to 67%), and then as monotherapy formulated in liposomes for rare and hard-to-treat cancers such as osteosarcoma (50% complete responses). We plan to finalize the pre-clinical development of our product within 2 years, to bring a lead product to the clinic.

The aims of the present project were to strengthen the relevance of our innovative technological and scientific approach and the technical and economic viability of the project by: 1/ Validating the manufacturing feasibility of our products in GMP conditions to demonstrate our capacity to produce GMP batches of our product for regulatory studies and clinical trials, 2/ Validating our regulatory validation plan toward clinical studies, and 3/ Completing economic viability of the project.
All the objectives of the ONCO-Boost project have been achieved and the work carried out allowed:

• To demonstrate the Good Manufacturing Process (GMP) feasibility of ONCO-Boost products
We have validated the GMP transfer feasibility of our technology with an independent consultant and we have identified relevant CMOs with the necessary technologies, infrastructures and capacities for the GMP production of our molecules. All of this demonstrates our capacity to produce GMP batches of our product for regulatory studies and clinical trials. In the meantime, we have scaled up our manufacturing process and have improved our detoxification process enlarging the number of potential bacterial species that we can work with.

• To demonstrate the safety profile and the regulatory feasibility
We have demonstrated the relevance of our detoxification steps to significantly reduce the pyrogenic activity of our products and highlighted their low pyrogenicity compared to competitor products currently in clinical development. With the consultancy of an independent preclinical regulatory expert, we have also validated the feasibility of our preclinical regulatory phase and we drew up the pathway through regulatory assays in order to obtain authorization to go to a first in man clinical trials. In addition, we have further improved our clinical strategy with the help of pre-eminent experts who joined our Scientific Advisory Board. We have chosen to address Osteosarcoma as first indication with our product as monotherapy, and then Non-Hodgkin’s lymphoma in combination with marketed products like Rituximab, modifying somewhat our initial objectives.

• To validate of the economic viability of the project and the commercial exploitation plan
Two (2) market studies were conducted in the frame of the project. The first one on Lymphoma showed that this indication would not thus make an interesting first market because of the number of competitors and the limited access to patients for clinical trials. A second market study on Osteosarcoma showed that this indication would make an interesting first market with possible Fast track to clinical phase and market as 2nd line-treatment due to its orphan disease status and to the absence of efficient treatment today (unmet medical need). We have also identified and entered into discussions/collaboration with 5 big Pharma interested by our products either for human use (ONCO-Boost) in the field of cancer or for veterinary use (VETO-Boost) as vaccine adjuvant. Finally, after confirming the freedom to operate, we have also strengthened our patent portfolio by completing a new patent application protecting notably our composition of matter and the use of molecules for the treatment of cancer.

All these achievements strengthened the technical and economic viability of the project and the relevance of our innovative technological and scientific approach, and thus strongly supports the continuation of the project.
Our strategy aims at developing our products first as stand-alone treatment against hard to treat cancers such as Osteosarcoma, and then as add-on for existing commercialized immunotherapies in order to drastically increase response rates and complete remission. Choosing monotherapy as an approach will make our regulatory validation easier and give us more independence on the development. In addition, as Osteosarcoma is an orphan disease, we expect to get Fast track to bring our product in clinical phase and to market. Our products will also work in synergy with numerous commercialized therapeutic antibodies, enabling strategic deals with the main market leaders. This new strategy will increase our impact on the European market of immuno-oncology and will enlarge the potential number of targeted customers, market, value of the deals, and economic impact inside EU with new potential collaborations and applications of our technology. We thus expect that our immunostimulants will have a significant impact on global health, both at the individual and the public health levels, by both providing effective therapeutic solution for cancers with unmet medical needs and by raising the cure rate of cancer immunotherapies over 50%.
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