About Generex Biotechnology
Generex Biotechnology Corporation primarily engages in the research and development of drug delivery systems and the use of its proprietary technology for the administration of formulations of large molecule drugs to the oral (buccal) cavity using a hand-held aerosol applicator. All of the company’s Canadian operations are performed by Generex Pharmaceuticals Inc.; Generex Pharmaceuticals Inc. is the 100% owner of 1097346 Ontario Inc., which was also incorporated in Ontario, Canada. The company owns NuGenerex Immuno-Oncology, Inc. (NGIO), a Delaware corporation formerly named Antigen Express, Inc. (NGIO). NGIO engages in the research and development of technologies and immunomedicines for the treatment of malignant, infectious, autoimmune and allergic diseases. NGIO also does business under the name NuGenerex Immuno-Oncology. Buccal Delivery Technology and Products The company’s buccal delivery technology involves the preparation of proprietary formulations in which an active pharmaceutical agent is placed in a solution with a combination of absorption enhancers and other excipients classified ‘generally recognized as safe’ by the U.S. Food and Drug Administration (FDA) when used in accordance with specified quantities and other limitations. The resulting formulations are aerosolized with a pharmaceutical grade chemical propellant and are administered to patients using its proprietary RapidMist brand metered dose inhaler. The device is a small, lightweight, hand-held aerosol applicator comprised of a container for the formulation, a metered dose valve, an actuator and dust cap. Using the device, patients self-administer the formulations by spraying them into the mouth. The device contains multiple applications, the number being dependent, among other things, on the concentration of the formulation. Absorption of the pharmaceutical agent occurs in the buccal cavity, principally through the inner cheek walls. In clinical studies of its primary oral insulin product Generex Oral-lyn, insulin absorption in the buccal cavity has been shown to be efficacious and safe. Buccal Insulin Product – Generex Oral-Lyn In 2005, the company received approval from the Ecuadorian Ministry of Public Health for the commercial marketing and sale of Generex Oral-lyn for the treatment of Type 1 and Type 2 diabetes. The company has completed the delivery and installation of a turnkey Generex Oral-lyn production operation at the facilities of PharmaBrand in Quito, Ecuador. The first commercial production run of Generex Oral-lyn in Ecuador was completed in 2006. The company has reformulated the original Oral-Lyn buccal insulin as a new patentable Oral-Lyn 2 that requires only 2 - 3 pre-prandial (before meal) sprays for the treatment of Type II diabetes. The reformulated Oral-lyn 2 was made possible by new techniques in protein chemistry and pharmaceutical formulation science, that with minimal changes in the production process and content of the components, allow the development of a new and improved, concentrated insulin formulation for improved diabetes management. The company has engaged the University of Toronto’s Center for Molecular Design and Pre-formulations through the University Health Network with the intention of improving the Oral-lyn 2 formulation by increasing the bioavailability of insulin in the product and reducing the number of sprays required to achieve prandial metabolic control for patients with diabetes. NGIO NGIO is developing immunotherapeutic products and vaccines based on the company’s proprietary, patented platform technology, Ii-Key. The Ii-Key is a peptide derived from the major histocompatibility complex (MHC) Class II associated invariant chain that regulates the formation, trafficking, and antigen-presenting functions of MHC class II complexes, essential for the activation of T cells in the immune response. T cells recognize antigenic epitopes when they are 'presented' to them by specific molecules, termed (MHC) on the surface of infected or malignant cells. This interaction activates the T cells, stimulating a multicellular cascade of actions that eliminates the diseased cell and protects against future disease recurrence. When the Ii-Key peptide is linked to an antigenic epitope, it could bind to MHC Class II molecules, displacing resident antigens from the antigen binding groove, essentially 'hijacking' the MHC class II complex to present the Ii-Key epitope to selectively activate T-Cell Th1 responses, thereby increasing the intensity and duration of the immune response. The patented NGIO Ii-Key technology uses synthetic peptides that mimic antigenic protein regions from a virus or tumor biomarker that are chemically linked to the 4-amino acid Ii-Key to ensure immune system activation. In particular, the Ii-Key ensures potent activation of CD4+ T cells, which in turn facilitates antibody production to ward off infection. This Ii-Key modification could be applied to any protein fragment of any pathogen to increase the potency of immune stimulation. The company has developed various Ii-Key Hybrid peptides for the immunotherapeutic targeting of tumor associated antigens in cancer and for vaccines against infectious diseases. Ii-Key hybrid peptides could also be used to selectively activate Th2 responses and thereby induce tolerance to antigens involved in harmful immune reactions, such as autoimmunity, allergy, and transplant rejection. AE37 – Ii-Key/HER2/neu Hybrid Immunotherapeutic Vaccine The company’s immunotherapy vaccine is AE37, an Ii-Key-Hybrid molecule that contains the HER2/neu antigenic peptide linked to the Ii-Key to enhance immune stimulation against HER2, which is expressed in various cancers, including breast, prostate, and bladder cancers. The company has completed a Phase I clinical trial of AE37 in breast cancer: A phase Ib safety and immunology study of AE37 and GM-CSF in 16 breast cancer patients who had completed all first-line therapies and who were disease-free at the time of enrollment to the study (Holmes et al. Results of the first phase I clinical trial of the novel Ii-Key hybrid preventive HER-2/neu peptide (AE37) vaccine. J Clin Oncol 2008;26:3426-33). Furthermore, the company completed a Phase IIb trial of AE37 in the prevention of cancer recurrence in women who were at high risk of recurrence after undergoing successful primary standard of care breast cancer therapies and were disease free at time of enrollment. The final results of the Phase IIb clinical trial of AE37 +/- GM-CSF vaccine for the prevention of recurrence of breast cancer have been published in the peer-reviewed journal, Breast Cancer Research & Treatment. In the AE37 arm of this trial, the investigators found that patients with advanced stage, HER2 under-expression, and TNBC may benefit from AE37 vaccination, and those with both advanced stage and HER2 under expression have a significant clinical benefit to AE37 vaccination, demonstrating earlier DFS plateau that was maintained for up to the ten years of follow-up. Based on the results from this trial, the company has entered into a collaborative agreement with Merck Sharpe & Dohme B.V. and the National Surgical Adjuvant Breast and Prostate Program (NSABP) to conduct a Phase II trial to evaluate the safety and efficacy of AE37 in combination with the anti-PD-1 therapy, KEYTRUDA (pembrolizumab) in patients with metastatic triple-negative breast cancer. The trial is scheduled to begin enrolling patients in the second quarter of 2019. In addition to the breast cancer program, the company has conducted a Phase I clinical trial in prostate cancer, enrolling thirty-two HER-2/neu+, castrate-sensitive, and castrate-resistant prostate cancer patients to demonstrate safety and strong immunological response to AE37. The company is advancing AE37 for the treatment of prostate cancer through a licensing and research agreement with Shenzhen BioScien Pharmaceuticals Co., Ltd. NuGenerex Diagnostics (NGDx) The company’s wholly-owned subsidiary, NGDx is in the business of developing, manufacturing, and distributing rapid point-of-care in-vitro medical diagnostics for infectious diseases. These are commonly referred as rapid diagnostic tests (RDTs). The company manufactures and sells RDTs based upon its own proprietary EXPRESS platforms as well as standard ‘cassette’ devices. NGDx engages in developing and continues to develop an expanding line of RDTs for infectious disease diagnosis. These include products for human immunodeficiency virus, tuberculosis, malaria, hepatitis B, hepatitis C, syphilis, and others. These assays are all qualitative in nature and provide a positive or negative result directly at the clinical site. They could be used for definitive diagnosis, triage or in combination with other assays depending on which disease is being considered. Each device incorporates a test strip containing reagent lines (stripes) that have been impregnated with specific antigens or antibodies that detect the target molecules specific to an infectious disease. The test strips are incorporated into the company’s proprietary EXPRESS platforms. There are two EXPRESS platforms; the EXPRESS and the EXPRESS II. The EXPRESS II is an upgraded version of the original EXPRESS and its use involves fewer operator steps, making it of higher clinical utility value. The Express II platform is designed to be used in a range of clinical and laboratory medical settings and for direct use by consumers in the home. A single drop of blood taken by a finger stick is added directly to the device and the assay is activated by placing a pod of buffer solution onto the device. Results could be read in approximately 5 minutes to 30 minutes. Services and Products NuGenerex Distribution Solutions, LLC (NDC) The company established NDC in 2018 as the foundational piece in the transformation of it into an integrated healthcare holding company that provides solutions for physicians and patients. Part of the NDS model includes a physician-owned management services organization (MSO), which is positioned to procure the company’s new products and services as made available. NDS would also continue to provide inventory selection and management, as well as management services for legal and regulatory compliance, accounting, HR, IT and customer support services through the MSO networks. NDS Expansion The NuGenerex MSO network has operated in five states and is configuring a roll out which would be compliant and reduce healthcare costs through better outcomes. DME-IQ NDS is planning a launch DME-IQ, a novel software as a service (SaaS) solution for physicians to manage in-office distribution of durable medical equipment (DME). DME-IQ supports the development and management of compliant and profitable in-office DME programs. DME-IQ focuses on various key areas, which include negotiating on behalf of the physicians with key vendors to decrease the COGS (Cost of Goods Sold), increasing insurance collections by providing oversight of the coding during the billing process, providing the necessary personnel to manage the appeals processes, and ensuring compliance with state and federal regulations. DME-IQ would automate and provide the orthopedic practices with a proprietary, tablet-based software package that immediately verifies patient benefits and eligibility. This system manages DME inventory, collects patient copays and deductibles, and links patient information with the DME products and necessary patient forms all in one platform. NuGenerex Regenerative Medicine Olaregen Therapeutix, Inc. The company’s majority-owned subsidiary, Olaregen Therapeutix, Inc. is a regenerative medicine company focused on the development, manufacturing and commercialization of products that fill unmet needs in the wound care market. Olaregen’s first product, Excellagen (wound conforming matrix) is a topically applied product for dermal wounds and other indications. Excellagen is a FDA 510(k) cleared device for of an array of dermal wounds, including partial and full thickness wounds, pressure ulcers, venous ulcers, diabetic ulcers, chronic vascular ulcers, tunneled/undermined wounds, surgical wounds (donor sites/ grafts, post-Mohs surgery, post-laser surgery, podiatric, wound dehiscence), trauma wounds (abrasions, lacerations, second-degree burns and skin tears) and draining wounds, enabling Olaregen to market Excellagen in multiple vertical markets. Regentys Extracellular Matrix Hydrogel (ECMH) Regentys’ initial product, ECMH Rectal Solution, is a non-pharmacologic, non-surgical treatment option for millions of patients suffering from mild to moderate ulcerative colitis. Its product candidate is a powder that is reconstituted with saline and delivered as a liquid via enema. As ECMH reaches body temperature, it gels and coats the mucosal lining of the GI tract. The core technology is derived from ECM, an FDA-approved base used for surgical applications and wound treatment. ECMH acts as a bio-scaffold, separating the damaged tissue from waste flow, covering ulcerations to limit the inflammatory response, and facilitating a healing environment using endogenous (the body’s own) stem cells. Intellectual Property Regentys in-licensed patents and co-developed its technology platform with the University of Pittsburgh. It holds patent rights in U.S. and foreign jurisdictions, and has other global filings pending; as well, it has patent applications pending for similar indications predicated on its existing technology in other major global markets. NuGenerex Surgical Products Pantheon Medical and MediSource Partners Pantheon Medical (Pantheon) is a manufacturer of orthopedic foot & ankle surgery kits that offer physician friendly ‘all-in-one’, integrated surgical kits that include plates, screws, and tools required for orthopedic surgeons and podiatrists conducting foot and ankle surgeries. MediSource Partners, LLC (MediSource Partners) is a 10-year old private company that is an FDA registered distributor of surgical, medical, and biologic supplies, with approximately 25 vendor contracts for nationwide distribution of implants and devices for spine, hips, knees, foot, ankle, hand, and wrist surgeries. Additional product lines include biologics (blood, bone, tissue, stem cells), medical equipment, and soft goods. The company maintains partnerships and contracts with hospital systems for ordering, billing and inventory management. The asset acquisitions of Pantheon and MediSource Partners were finalized in 2019. NuGenerex Surgical (aka MediSource) has contracts with approximately 25 vendors (Pantheon Medical) for the distribution of implants and devices, biologics (blood, bone, tissue, and stem cells), medical equipment, soft goods, and kits to process bone marrow aspirates and platelet rich plasma biologics. NuGenerex Health, LLC In addition to its efforts in orthopedic medicine, the company is in the process of setting up NuGenerex Health MSO to provide ancillary health services in partnership with Arizona Endocrinology Center and Paradise Valley Family Medicine. With an initial focus on the management of complex diabetes patients, NuGenerex Health would offer ophthalmology, podiatry, chronic care management services to provide patients with integrated, concierge care to improve outcomes. Strategy The company’s strategy is to revitalize its diabetes program by advancing the reformulated buccal spray Oral-lyn 2 for the treatment of Type II diabetes, and to integrate Oral-Lyn 2 therapy into its end-to-end solution for disease management through its MSO model. Marketing and Distribution NGDx Marketing and Distribution Sales of the NGDx EXPRESS line of diagnostic kits for infectious diseases is dependent on regulatory approvals issued by such agencies as the WHO, FDA and registration with the Global Fund. NGDx EXPRESS II - Syphilis In January 2019, NGDx received CE Marking Certification for its rapid point-of-care Express II Syphilis Treponemal Assay from the European Union. The company is seeking development and distribution partners in international markets for the NGDx product portfolio as it plans for U.S. clinical development of its Express II rapid diagnostic technology for infectious diseases and sepsis. Olaregen Marketing and Distribution Olaregen has established a team of internal sales and marketing professionals who oversee the marketing, sales and distribution for Excellagen. The product might be sold immediately in the United States. Olaregen plans to focus its efforts on selling to specialized ambulatory wound care centers, surgeons, dermatologists, and in phase II nursing homes. In September 2019, Olaregen entered into a national sales and distribution agreement with AvKare Inc. to become the sales and distribution partner for Excellagen’s Wound Conforming Matrix in all Veterans Affairs hospitals along with other government medical facilities throughout the United States. Research and Development Expenditures For the year ended July 31, 2020, the company expended $2,106,364 on research and development activities. Government Regulation The company’s research and development activities and the manufacturing and marketing of its pharmaceutical products are subject to regulation by the FDA in the United States, Health Canada in Canada, and comparable designated regulatory authorities in other countries. Intellectual Property Generex Historical Business Oral-Lyn & RapidMist The company has three issued U.S. patents and one pending U.S. patent application pertaining to various aspects of drug delivery technology, including oral administration of macromolecular formulations (insulin). The company also holds international patents covering its drug delivery technology in jurisdictions other than the U.S., including Canada, Brazil, Argentina, Israel, Australia and Europe. The expiration dates of the U.S. issued patents range from 2020 to 2022, and the international patents are enforceable to 2028. The company intends to submit new patent applications for the reformulated Oral-Lyn II for Type II diabetes upon funding. The company possesses the worldwide manufacturing and marketing rights to its oral insulin product. NGIO Intellectual Property Portfolio Platform Patents The foundational ‘Platform Patents’ for Ii-Key technology focus on methods of increasing the antigen-specific activation of CD4+ T cells. This cell type is a critical component of the immune system, involved both in the recognition of new pathogenic agents as well as in autoimmune syndromes. The first technology platform (Ii-Key hybrid) relates to a means for increasing the vaccine potency of various proteins and while the second (Ii-suppression) relates to generation of a cell-based vaccine (REH-2017-01, REH-2017-02). Oncology Patents This group of patents relate more specifically to the use of the platform technologies for generating anti-cancer vaccines. The company has generated Ii-Key hybrid compounds specifically for patients with breast, prostate, bladder, melanoma and HPV-related cancers (AEX-2001, AEX-2006, AEX-2007). The company holds five U.S. patents and one patent in Japan. The U.S. patent numbers are 7,935,350 (expiring on November 3, 2022), 8,748,130 (expiring on December 10, 2025), 8889143 (expiring on May 18, 2026), 928945 (expiring on September 22, 2027), 8,815,249 (expiring on February 26, 2026). The Japan patent number is 5707326 (expiring on September 1, 2029). These patents cover compositions and methods related to Ii Technology, Ii hybrid peptides used for the enhancement of antigen presentation, constructs for the expression of Ii-Key/antigen epitope fusion peptides, hybrid Ii-Key/antigen epitope fusion peptides, and methods for inhibiting Ii expression. The company also has U.S. patents on the Ii-Key technology have expired, it is in discussions with third parties to extend the patent coverage of the Ii-Key technology for cancer immunotherapy. The expiration dates of the immune-oncology applications of the Ii-Key hybrid technologies extend to 2031. NGDx Intellectual Property NGDx holds a U.S. Patent for its sample delivery system which expires in 2026, US Patent # 7,749,771, titled ‘Device and methods for detecting analyte in a sample’. This is the basis for the company’s EXPRESS system platform. In 2018, the company filed for patent protection for the Express II format with the U.S. Patent and Trade Mark Office. Olaregen Intellectual Property Olaregen has the exclusive license to Excellagen in all regions of the world except Russia, China, and the CIS countries (Armenia, Azerbaijan, Belarus, Georgia, Kazakhstan, Kyrgyzstan, Moldova, Russia, Tajikistan, Turkmenistan, Ukraine, and Uzbekistan). The U.S. patent on Excellagen had been issued as of October 10, 2017 and has 17 years of additional exclusivity. Regentys Intellectual Property Regentys has licensed the exclusive, world-wide intellectual property rights for Regentys ECMH from the University of Pittsburgh in exchange for future royalties. The intellectual property subject to the license is entitled ‘Extracellular Matrix Derived Gels’ and ‘Methods for Preparation of A Terminally Sterilized Hydrogel Derived From Extracellular Matrix’ developed by Stephen Badylak et.al. of University faculty. Additionally, Regentys and the University of Pittsburgh are co-owners by assignment of certain intellectual property rights pertaining to ‘Method and Composition for Treating Inflammatory Bowel Disease Without Colectomy’ developed by Stephen Badylak and Timothy Keane of University and by Marc Ramer of the Regentys. NuGenerex Surgical Supply Subsidiaries Intellectual Property The company pursues strategic alliances and partnerships through intellectual property license agreements, and secure key purchase agreements from suppliers to build upon its portfolio of IP. Competition Alere Inc. is the company’s main competitor. History Generex Biotechnology Corporation was founded in 1983.
