Can-Fite BioPharma Stock

Can-Fite BioPharma Ltd. operates as a clinical-stage biopharmaceutical company. The company develops orally bioavailable small molecule therapeutic products for the treatment of cancer, liver and inflammatory diseases, and erectile dysfunction. The company is also developing specific formulations of cannabis components for the treatment of cancer, inflammatory, autoimmune, and metabolic diseases. Its platform technology utilizes the Gi protein associated A3 adenosine receptor (A3AR), as a therapeutic target. The company's pipeline of drug candidates are synthetic, highly specific agonists and allosteric modulators targeting the A3AR.

The company's product pipeline is based on the research of Dr. Pnina Fishman, who investigated a clinical observation that tumor metastasis can be found in most body tissues, but are rarely found in muscle tissue, which constitutes approximately 60% of human body weight. The A3AR agonists and allosteric modulators, the company's pipeline of drug candidates, bind with high selectivity, and affinity to the A3ARs and upon binding to the receptor initiate down-stream signal transduction pathways resulting in apoptosis, or programmed cell death, of tumors and inflammatory cells and to the inhibition of inflammatory cytokines.

The company's product candidates, CF101, CF102, and CF602, are being developed to treat cancer, liver, and inflammatory diseases, as well as erectile dysfunction. CF101, also known as Piclidenoson, is in an advance stage of clinical development for the treatment of autoimmune-inflammatory diseases, including psoriasis. During 2021, the company decided to stop developing Piclidenoson for the treatment of COVID-19 to focus on other indications. CF102, also known as Namodenoson, is being developed for the treatment of HCC and has orphan drug designation for the treatment of HCC in the United States (U.S.) and Europe. Namodenoson was granted Fast Track designation by the Food and Drug Administration (FDA) as a second line treatment to improve survival for patients with advanced hepatocellular carcinoma (HCC) who have previously received Nexavar (sorafenib). Namodenoson is also being developed for the treatment of NASH, a disease for which no FDA approved therapies exist. CF602 is the company's second generation allosteric drug candidate for the treatment of erectile dysfunction, which has shown efficacy in the treatment of erectile dysfunction in preclinical studies and it is investigating additional compounds, targeting A3AR, for the treatment of erectile dysfunction. Preclinical studies revealed that the company's drug candidates have potential to treat additional inflammatory diseases, such as Crohn's disease, oncological diseases, viral diseases, such as the JC virus, and obesity.

The company has in-licensed an allosteric modulator of the A3AR, CF602 from Leiden University. In addition, it has out-licensed the following product candidates for indications that it is pursuing:

Piclidenoson for the treatment of psoriasis to Cipher Pharmaceuticals, or Cipher, for Canada; psoriasis to Gebro Holding (Gebro), for Spain, Switzerland and Austria; psoriasis to CMS Medical (CMS), for China (including Hong Kong, Macao and Taiwan); psoriasis to Kyongbo Pharm Co. Ltd. (Kyongbo Pharm), for South Korea; psoriasis to Ewopharma AG (Ewopharma), for Central Eastern Europe; and osteoarthritis in companion animals, including dogs and cats to Vetbiolix.

Namodenoson for the treatment of liver cancer and NASH to Chong Kun Dang Pharmaceuticals (CKD), for South Korea; advanced liver cancer and NAFLD/NASH to CMS for China (including Hong Kong, Macao and Taiwan); and HCC and non-alcoholic steatohepatitis (NASH) to Ewopharma, for Central Eastern Europe and Switzerland.

The company is preparing a registration plan for the FDA protocol for its upcoming Phase III pivotal trial following a recent submission of a registration plan to the European Medicines Agency (EMA) and successful completion of its Phase III trial for Piclidenoson in the treatment of psoriasis; it is conducting a pivotal Phase III trial for Namodenoson in the treatment of advanced liver cancer which is open for enrollment; it is conducting a Phase IIb study of Namodenoson in the treatment of NASH; it is investigating additional compounds, targeting the A3 adenosine receptor (A3AR), for the treatment of erectile dysfunction; and it isconducting pre-clinical studies with formulations of cannabis components for the treatment of diseases in which there is an overexpression of A3AR.

In June 2022, the company announced positive top-line results from its Phase III COMFORT study of Piclidenoson in the treatment of moderate to serious psoriasis in which Piclidenoson met its primary endpoint. The trial was a Phase III randomized, double-blind, placebo- and active-controlled study of the efficacy and safety of daily Piclidenoson (CF101) administered orally in patients with moderate-to-severe plaque psoriasis.

In April 2022, the company announced it is developing a topical psoriasis treatment with Piclidenoson.

In November 2019, the company announced that the U.S. Patent and Trademark Office (PTO), has issued to it Patent #10,265,337 titled 'Use of A3 Adenosine Receptor Agonist in Osteoarthritis Treatment' for Piclidenoson for the treatment of osteoarthritis in mammals. It is evaluating potential partnerships with companies in the animal health pharmaceutical market that may in-license and develop Piclidenoson for the companion animal market, a substantial and rapidly growing global market.

In June 2021, the company signed a development and commercialization agreement with Vetbiolix, a France-based veterinary biotech company, for the development of Piclidenoson for the treatment of osteoarthritis in companion animals, including dogs and cats. During 2022, Vetbiolix completed dose-ranging pharmacokinetic (PK) studies in dogs and determined the optimal efficacy and safety dosage for a planned European multicentric clinical study. Piclidenoson was well tolerated, with the PK data proportional to dose. Pre-clinical studies were also conducted showing Piclidenoson has a very favorable safety profile. Based on these data, Vetbiolix has designed a European Multicentric Clinical study protocol for dogs with osteoarthritis which has been approved by an ethical committee.

In February 2012, the FDA granted an orphan drug status for the active moiety, or the part of the drug that is responsible for the physiological or pharmacological action of the drug substance, of Namodenoson for the treatment of HCC. Subsequently, in October 2015, the EMA granted Namodenoson orphan drug designation for the treatment of HCC.

In September 2015, the FDA granted Fast Track designation to Namodenoson as a second line treatment to improve survival for patients with advanced HCC who have previously received Nexavar (sorafenib).

Israel's Ministry of Health has previously approved Namodenoson for Compassionate Use for HCC.

The company is conducting a Phase IIb study Namodenoson in the treatment of NASH, having announced first patient enrollment in January 2022. The Phase IIb trial is a multicenter, randomized, double-blind, placebo-controlled study in subjects with biopsy-confirmed NASH.

In January 2023, the company announced that in pre-clinical studies, Namodenoson significantly inhibits the growth of pancreatic carcinoma as a stand-alone treatment.

In March 2021, the company announced new data from a preclinical study of CF602 in the treatment of erectile dysfunction (ED), in a diabetes experimental model. The study evaluated the efficacy of topically applied CF602 in a 4-cohort study with diabetic Sprague-Dawley (SD) rats receiving placebo; 100nM CF602; 500nM CF602.

In January 2017, a patent was granted to the company by the United States Patent and Trademark Office (USPTO) covering A3AR ligands for use in the treatment of erectile dysfunction. The patent addresses methods for treating erectile dysfunction with different A3AR ligands, including its erectile dysfunction drug candidate, CF602. With this new broader patent protection, the company made a strategic decision to investigate additional compounds, owned by it, for the most effective and safest profile in this indication and it is seeking to partner development of CF602.

In December 2020, the company received approval from the Medical Cannabis Unit of Israel's Ministry of Health to conduct pre-clinical studies on the effect of nanomolar concentrations of cannabinoid fractions on the proliferation and functionality of cancer, inflammatory and adipocyte cells (fat cells). This regulatory approval allows the company to advance its cannabinoid program by evaluating the effect of cannabis fractions at nanomolar concentrations binding with A3AR.

In February 2021, the company announced the completion of a set of pre-clinical studies demonstrating that cannabis derived compounds bind to A3AR, mediating therapeutic effects.

In April 2021, the company announced the completion of a set of pre-clinical studies demonstrating that a CBD rich T3/C15 cannabis fraction inhibited the growth of liver HEP-3b hepatocellular carcinoma cells via the A3AR by inhibiting Wnt- and NF-kappa B-related regulatory pathways. An A3AR antagonist, MRS1523 reversed this effect demonstrating that the inhibitory effect is mediated via its target, A3AR.

In March 2015, the company completed the development of a commercial predictive biomarker blood test kit for A3AR. The biomarker test can be used at any molecular biology lab, where a small blood sample from a prospective patient would be tested and within just a few hours, results indicate if the patient would benefit from treatment with the company's drugs, which are in clinical trials for rheumatoid arthritis, psoriasis, and liver cancer.

The USPTO previously issued to the company a patent for the utilization of A3AR as a biomarker to predict patient response to its drug Piclidenoson in autoimmune inflammatory indications.

Strategy

The company's strategy is to build a fully integrated biotechnology company that discovers, in-licenses, and develops an innovative and effective small molecule drug portfolio of ligands that bind to a specific therapeutic target for the treatment of cancer, liver, and inflammatory diseases and erectile dysfunction. The company continues to develop and test its existing pipeline, while also testing other indications for its existing drugs and examining, from time to time, the potential of other small molecules that may fit its platform technology of utilizing small molecules to target the A3AR. The company generally focuses on drugs with global market potential and it seeks to create global partnerships to effectively assist it in developing its portfolio and to market its products.

The key elements of the company's strategy are to continue to advance its clinical and preclinical pipeline; test its products for additional indications which fit its molecules' mechanism of action; identify other small molecule drugs or ligands; focus on its product candidates closest to realizing their potential; and avoid dependency on a small number of small molecules and indications.

Using this approach, the company has successfully advanced its product candidates for a number of indications into various stages of clinical development. Specific elements of the company's strategy are to intend to continue to develop its existing portfolio of small molecule orally bioavailable drugs, both for existing targeted diseases, as well as other potential indications; seek attractive product candidates and innovative technologies to in-license or acquire; primarily develop products that target major global markets; and commercialize the company's product candidates throughout-licensing arrangements. The company intends to focus on product candidates that would be synergistic with its A3AR expertise.

Research and Development Expenses

For the year ended December 31, 2022, the company's research and development expenses included $7.76 million.

Intellectual Property

Patents

As of March 30, 2023, the company owned or exclusively licensed (from Leiden University) 18 patent families that, collectively, contain approximately 209 issued patents and pending patent applications in various countries around the world relating to its two clinical candidates, Piclidenoson and Namodenoson, and its preclinical candidate, CF602.

With respect to the company's product candidates, it owns patents and/or have patent applications pending in several countries around the world for the following families of patents:

A3AR Ligands to Treat Viral Diseases: A family of patents which pertain to use of substances that bind to the A3AR for the treatment of viral diseases, such as AIDS and hepatitis, and which inhibit viral replication. Such patents were granted in the United States, in Europe (by the EPO and validated in France, Germany, Italy, Switzerland and the United Kingdom), Australia, China, Israel, Japan, Singapore, Canada, and Hong Kong. These patents have a filing date of January 1, 2002, and a priority date of January 16, 2001, and expired in January 2022, other than the U.S. patent that will expire in 2023.

A3AR Ligands to Treat RA - A patent which pertains to the use of A3AR agonists for the treatment of inflammatory arthritis, in particular rheumatoid arthritis. This patent was granted in the United States and is set to expire in 2023.

A3AR as a Predictive and Follow Up Biomarker: A family of patents and patent applications which pertain to a method of identifying inflammation, determining its severity, and determining and monitoring the efficacy of the anti-inflammatory treatment by determining the level of A3AR expression in white blood cells as a biological marker for inflammation. These patents were granted in the United States, Europe (by the EPO and validated in France, Germany, Italy, Spain, Switzerland and the United Kingdom), Australia, Israel, Japan, China, Mexico, and Canada. The patents are set to expire in 2025. There is a patent application pending in Brazil that was refused and the refusal may be appealed until September 2025. Each of the patents and the patent application has a filing date of November 30, 2005, and a priority date of December 2, 2004.

Specific Dose to Protect from Psoriasis: A family of patents and patent applications which pertains to the use of a specific dose level of Piclidenoson (total daily dose of 4.0 mg) for the treatment of psoriasis. Such a patent was granted in Israel, Japan, the United States, South Korea and Europe (by the EPO and validated in in Austria, Belgium, Denmark, France, Germany, Italy, the Netherlands, Spain, Sweden, Switzerland, and the United Kingdom). The patent is set to expire in 2030, and in 2031 in the U.S. There is a patent application pending in India with a filing date of September 6, 2010, and a priority date of September 6, 2009.

Piclidenoson Method of Synthesis: A family of patents which pertain to the method for producing Piclidenoson. Such patents were granted in the United States, India, China, Japan, Israel, and Europe (by the EPO and validated in Austria, Belgium, Denmark, Finland, France, Germany, Greece, Hungary, Ireland, Italy, Luxembourg, Monaco, the Netherlands, Norway, Poland, Portugal, Spain, Sweden, Switzerland, Turkey, and the United Kingdom). These patents are set to expire in 2028 and in 2031 in the U.S. Each patent has a filing date of March 13, 2008, and a priority date of March 14, 2007.

Osteoarthritis (OA) Indication: A family of patents and patent applications which pertain to the use of A3AR agonists for the treatment of OA. Such patents were granted in Europe (by the EPO and validated in Austria, Belgium, Denmark, France, Germany, Italy, Spain, Sweden, Switzerland, the Netherlands, and the United Kingdom), U.S., Australia, Canada, South Korea, China, Israel, Japan, and Mexico. The patents are set to expire in 2026. A patent application is pending in Brazil. These patents and patent applications have a filing date of November 29, 2006, and a priority date of November 30, 2005.

Liver Protection: A family of patents which pertains to the use of A3AR agonists for increasing liver cell division, intended to induce liver regeneration following injury or surgery. Such patents were granted in China, Israel, Japan, the U.S., and Europe (by the EPO and validated in Austria, Belgium, Denmark, France, Germany, Italy, the Netherlands, Poland, Spain, Sweden, Switzerland, United Kingdom, and Turkey). Each patent in this family has a filing date of October 22, 2008, and a priority date of October 15, 2007.

Erectile Dysfunction: A family of patents and patent applications which pertain to treatment of erectile dysfunction. This family includes granted patents in the United States, Australia, China, Hong Kong, Canada, South Korea, Israel, Mexico, and Japan and patent applications in Brazil and Europe. The patents and patent applications have a filing date of August 8, 2013, with priority dates of August 8, 2012, and November 12, 2012.

CAR T Induced Cytokine Release Syndrome: A family of patent applications which pertains to the use of A3AR ligands for managing cytokine release syndrome. This family includes patent applications in Israel and in the U.S., EP and HK claiming priority from this Israeli application. The U.S., EP, and HK patent applications have a filing date of September 16, 2018, and the Israeli patent application has a filing date of September 17, 2017.

NAFLD/NASH: A family of patents and patent applications which pertain to the use of A3AR ligands for the treatment of ectopic fat accumulation. This family includes granted patents in U.S., Israel, Europe (by the EPO and validated in Austria, Belgium, Bulgaria, Croatia, Czechia, Denmark, Estonia, France, Germany, Greece, Hungary, Ireland, Italy, Latvia, Lithuania, Luxembourg, the Netherlands, North Macedonia, Norway, Poland, Portugal, Romania, Serbia, Slovakia, Slovenia, Spain, Sweden, Switzerland, United Kingdom, and Turkey), South Korea, Hong Kong, China, Japan, and Mexico, and patent applications in Brazil and Canada. The patent applications have a filing date of November 22, 2016.

Obesity: A family of patent applications which pertains to the use of A3AR ligand for reducing level of adipocytes and specifically, for treating obesity. This family includes patent applications in Australia, Brazil, Canada, China, Europe, Israel, Japan, Mexico, Korea, the U.S., and Hong Kong. These patent applications have a filing date of January 6, 2020.

Cannabinoids: A family of patent applications pertaining to the use of cannabinoids for treating conditions and diseases that involve elevated expression of the A3AR. This family includes a patent application in Israel and in Australia, Brazil, Canada, China, Eurasia, Europe, India, Japan, Mexico, Korea, Singapore, South Africa, Thailand, and the U.S. claiming priority from this Israeli application. These patent applications have a filing date of January 14, 2021, while the Israeli patent application has a filing date of January 16, 2020.

PD-1/PD-L1: An Israeli patent application pertaining to the use of PD-1/PD-L1 axis inhibitor in combination with an A3AR. This Israeli patent application has a filing date of January 29, 2020.

Treatment of ADVANCED Cancer: A family of patent applications that makes use of A3AR ligands, particularly Namodenoson, for the treatment of advanced solid cancer, including advanced liver cancer. This family includes patent applications in the U.S., Australia, Brazil, Canada, Turkey, Japan, South Korea, and Mexico. The U.S. application was filed on December 28, 2022, claiming priority from a provisional application that was filed on December 29, 2021.

Treatment of Joint Inflammation: An Israeli patent application that makes use of A3AR ligands for the local treatment of articular arthritis. This patent application was filed on January 9, 2023.

Treatment of Psoriasis: An Israeli patent application that makes use of A3AR ligands for the treatment of psoriasis. This patent application was filed on June 29, 2022.

Treatment of Pancreatic Cancer: An Israeli patent application that makes use of A3AR ligands for the treatment of pancreatic cancer, including advanced forms. This patent application was filed on January 23, 2023.

The company holds an exclusive license from Leiden University of the Netherlands to a family of patents and patent applications that relate to the allosteric modulators of the A3AR, which includes the allosteric modulator CF602. This exclusive license relates to patents that were granted in the United States, China, Japan, South Korea, India and in Europe (validated in, Austria, Belgium, Denmark, France, Germany, Italy, the Netherlands, Spain, Sweden, Switzerland, and United Kingdom). These granted patents are set to expire in 2028.

In-Licensing Agreements

Leiden University Agreements

On November 2, 2009, the company entered into a license agreement, or the Leiden University Agreement, with Leiden University. Leiden University is affiliated with NIH and is the joint owner with NIH of the patents licensed pursuant to the Leiden University Agreement. The Leiden University Agreement grants an exclusive license for the use of the patents of several compounds, including CF602, that comprise certain allosteric compound drugs, and for the use, sale, production, and distribution of products derived from such patents in the territory, i.e., China and certain countries in Europe (Austria, Belgium, Denmark, France, Germany, Italy, Spain, Sweden, Switzerland, Holland, and England). Subject to certain conditions, the company may sublicense the Leiden University Agreement. However, the U.S. government has an irrevocable, royalty-free, paid-up right to practice the patent rights throughout the territory on behalf of itself or any foreign government or international organization pursuant to any existing or future treaty or agreement to which the U.S. government is a signatory and the U.S. government may require the company to grant sublicenses when necessary to fulfill health or safety needs.

Out-Licensing and Distribution Agreements

Cipher Pharmaceuticals Agreement

On March 20, 2015, the company entered into a Distribution and Supply Agreement with Cipher granting Cipher the exclusive right to distribute Piclidenoson in Canada for the treatment of psoriasis and rheumatoid arthritis. In 2020, the company ended its development of Piclidenoson for rheumatoid arthritis.

The company is responsible for supplying Cipher with finished product for distribution and conducting product development activities while Cipher is responsible for distributing, marketing, and obtaining applicable regulatory approvals in Canada. The Distribution and Supply Agreement has an initial term of fifteen years, automatically renewable for additional five-year periods and may be terminated in certain limited circumstances, including certain breaches of the agreement and failure to achieve certain minimum quantities of sales during the contract period.

CKD Agreement

On October 25, 2016, the company entered into an exclusive Distribution Agreement with CKD for the exclusive right to distribute Namodenoson for the treatment of liver cancer in South Korea, upon receipt of regulatory approvals. On February 25, 2019, the Distribution Agreement was amended to expand the exclusive right to distribute Namodenoson for the treatment of NASH in South Korea. The Distribution Agreement further provides that the company will deliver finished product to CKD and grant CKD a right of first refusal to distribute Namodenoson for other indications for which it develops Namodenoson.

Gebro Agreement

On January 8, 2018, the company entered into a Distribution and Supply Agreement with Gebro, granting Gebro the exclusive right to distribute Piclidenoson in Spain, Switzerland, Liechtenstein, and Austria for the treatment of psoriasis and rheumatoid arthritis. In 2020, it ended its development of Piclidenoson for rheumatoid arthritis.

The company is initially responsible for supplying Gebro with finished product for distribution and obtaining EMA and Swissmedic marketing approval while Gebro is responsible for distributing, marketing and obtaining pricing and reimbursement approvals in the territories. The Distribution and Supply Agreement has an initial term of fifteen years, automatically renewable for additional five-year periods and may be terminated in certain limited circumstances including certain breaches of the agreement and failure to achieve certain minimum quantities of sales during the contract period.

CMS Medical Agreement

On August 6, 2018, the company entered into a License, Collaboration and Distribution Agreement with CMS for the exclusive right to develop, manufacture, and commercialize Piclidenoson for the treatment of rheumatoid arthritis and psoriasis and Namodenoson for the treatment of HCC and NAFLD/NASH in China (including Hong Kong, Macau, and Taiwan).

According to the agreement, CMS will be responsible for the development of Piclidenoson and Namodenoson to obtain regulatory approval in China and shall be further responsible for obtaining and maintaining regulatory approval in China for the indications described above. The company may, at the option of CMS, supply finished product to CMS.

Kyongbo Pharm Agreement

In August 2019, the company entered into a License and Distribution Agreement with Kyongbo Pharm.

Ewopharma Agreement

In March 2021, the company signed an exclusive distribution agreement with Switzerland-based Ewopharma for Piclidenoson in the treatment of psoriasis and Namodenoson in the treatment of liver diseases namely, HCC, the most common form of liver cancer, and NASH.

Vetbiolix Agreement

In June 2021, the company signed a development and commercialization agreement with Vetbiolix, a France-based veterinary biotech company, for the development of Piclidenoson for the treatment of osteoarthritis in companion animals including dogs and cats. Vetbiolix will have the exclusive right to Piclidenoson in the veterinary osteoarthritis market for two years, during which time Vetbiolix will conduct proof-of-concept studies and cover all associated costs.

Manufacturing

The relevant suppliers of the company's drug products are compliant with both current Good Manufacturing Practices (cGMP), and current Good Laboratory Practices (cGLP), and allows it to manufacture drug products for its clinical trials.

Marketing and Sales

The company intends to license to, or enter into strategic alliances with, larger companies in the pharmaceutical business, which are equipped to market and/or sell its products, if any, through their well-developed marketing capabilities and distribution networks. It intends to out-license some or all of its worldwide patent rights to more than one party to achieve the fullest development, marketing, and distribution of any products it develops.

Government Regulations

In the United States, the Public Health Service Act and the Federal Food, Drug, and Cosmetic Act (FDCA), as amended, and the regulations promulgated thereunder, and other federal and state statutes and regulations govern, among other things, the safety and effectiveness standards for the company's products and the raw materials and components used in the production of, testing, manufacture, labeling, storage, record keeping, approval, advertising and promotion of its products on a product-by-product basis.

History

The company was founded in 1994. The company was incorporated in 1994. The company was formerly known as Can-Fite Technologies Ltd. and changed its name to Can-Fite BioPharma Ltd. in 2001.