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Can-Fite Biopharma Ltd. (NYSE:CANF) is a biopharmaceutical company focused on the development of small molecule therapeutics for the treatment of autoimmune, inflammatory, and oncology indications. The company is currently focused on the development of two lead compounds: piclidenoson (formerly CF101), which is currently in a Phase 3 trial for the treatment of psoriasis, and namodenoson (formerly CF102), which is being developed for the treatment of liver cancer and non-alcoholic steatohepatitis (NASH). Can-Fite is also in the discovery phase for cannabinoid-based pharmaceuticals.
The technology underpinning Can-Fite’s technology is based on the observation that malignant tumors almost never metastasize to voluntary striated muscles. Tumor cells grown in vitro with muscle cells exhibit altered morphology (Dialdetti et al., 1996), with this effect shown to be caused by adenosine through the A3 adenosine receptor (A3AR) (Fishman et al., 2000). The A3AR is found in very low levels on normal tissue, however it is often overexpressed in a number of different types of cancer, including skin, colon, breast, renal, ovarian, and liver cancers (Fishman et al., 2007). Muscle cells are resistant to tumor growth through their release of A3AR agonists. Interestingly, the A3AR is also overexpressed in peripheral blood mononuclear cells (PBMCs) of patients with various inflammatory conditions including rheumatoid arthritis (RA), psoriasis, and Crohn’s disease (Ochalon et al., 2009). The fact that the A3AR is expressed in very low levels in healthy tissue and is overexpressed in diseased tissue makes it a compelling target for pharmaceutical intervention.
Overview of Piclidenoson and Namodenoson
Piclidenoson and namodenoson are Can-Fite’s lead development compounds. Both molecules are derivatives of adenosine and are agonists of the A3AR, with little to no affinity for the other adenosine receptors (A1, A2a, A2b).
Both compounds have been tested in multiple preclinical and clinical studies, and importantly there have been no reports of safety or toxicological issues. Below is an overview of the indications for each compound, past clinical results, and where each drug is currently in development.
Piclidenoson for Treating Psoriasis
Psoriasis is a chronic, noncontagious, multisystem inflammatory condition that most commonly presents on the skin of the elbows, knees, scalp, back, and thighs. Plaque psoriasis is the most common, affecting approximately 80-90% of all individuals with psoriasis. It is caused by the hyperproliferation of epidermal keratinocytes that results in red or white, scaly, itchy skin lesions. Approximately 20% of psoriasis patients also suffer from psoriatic arthritis, an inflammatory joint disease (Zacharlae, 2003). There is no cure for psoriasis, thus depending on the severity of the condition and how it responds to treatment, some patients may require therapy for life.
Psoriasis treatments are quantified in clinical testing through the use of the Psoriasis Area and Severity Index (PASI). This is a composite score that takes into account the average redness, thickness, and scaliness of the psoriatic lesions, weighted by the area of involvement (Feldman et al., 2005). While absolute PASI score is often utilized as an inclusion criterion for clinical trials, it is the percent change in PASI score that is important in measuring efficacy. For example, PASI75 means the percentage of patient that achieved a 75% or more reduction in their PASI score from baseline. For patients with severe psoriasis, clinicians typically consider at least 75% improvement in disease (PASI75) to be a clinically meaningful improvement indicative of success.
Can-Fite previously conducted a Phase 2/3 trial of piclidenoson in patients with plaque psoriasis (NCT01265667). It was a randomized, double blind, placebo controlled trial with a primary efficacy endpoint of PASI75 at Week 12 and an open-label extension out to Week 32 (David et al., 2016). While the trial did not meet the primary endpoint of percentage of patients with PASI75 at Week 12 (2mg piclidenoson: 8.5% vs. placebo: 6.9%; P=0.621), at Week 32 PASI mean improvement for 2mg piclidenoson was 57% compared to baseline (P<0.001), with linear improvement in PASI50/75/90/100. These results point to continued improvement for patients treated with piclidenoson out to Week 32, which is contrast to the FDA approved oral psoriasis medication Otezla®, in which efficacy plateaus at approximately Week 16 (Papp et al., 2015).
Can-Fite is currently conducting the Phase 3 Comfort trial to evaluate the safety and efficacy of piclidenoson compared to apremilast (Otezla®) and placebo in patients with moderate-to-severe plaque psoriasis (NCT03168256). The randomized, double blind, placebo controlled trial is anticipated to enroll 407 patients in a 3:3:3:2 ratio between 2 mg piclidenoson twice daily, 3 mg piclidenoson twice daily, 30 mg apremilast twice daily, or placebo. Medication will be administered for 32 weeks with the option to continue through an extension period up to 48 weeks. The primary endpoint of the trial is the percentage of patients who achieve PASI75 at Week 16 comparing piclidenoson and placebo. A key secondary endpoint is an inferiority comparison between piclidenoson and apremilast at Week 16 and Week 32. An overview of the trial is given below.
In December 2019, the company announced that the trial had reached 50% enrollment and in October 2020 the company announced positive results from a pre-planned interim analysis. The independent data monitoring committee (IDMC) recommended that the study continue with the original sample size and to drop one dose group, indicating that the optimal dose has been identified.
Psoriasis Treatments/Market Opportunity
For mild psoriasis, treatment typically consists of topical ointments, including corticosteroids, vitamin D, and moisturizers. Systemic treatments are usually reserved for treating moderate-to-severe psoriasis, with the market dominated by biologic treatments from Novartis (NVS), Johnson and Johnson (JNJ), and Eli Lilly (LLY). The psoriasis market is currently valued at approximately $17 billion and is expected to grow to $29 billion by 2026 (EvaluatePharma). The following table shows the therapies that are forecast to be leading the psoriasis market in 2026.
The advantages for piclidenoson includes the fact it is an oral therapy with an excellent safety profile and could be positioned as a cost-effective therapy. All of the biologics are administered via injection, and the anti-TNFα therapies include a “black-box” warning for increased risk of infection and cancer. The biologics cost approximately $2,000 per month in the E.U. and approximately $5,000 per month in the U.S., while apremilast is approximately $750 per month in the E.U. and approximately $3500 in the U.S. We estimate that piclidenoson would likely be priced comparably to apremilast.
With a projected market size of $29 billion, and oral therapies (apremilast and deucravacitinib) representing approximately $5.7 billion of that, there is an enormous opportunity for piclidenoson in psoriasis. Capturing just 10% of the oral market represents a potential $500 million opportunity.
Piclidenoson for Treating COVID-19
Due to piclidenoson’s anti-inflammatory characteristics shown in the Phase 2 psoriasis trials and from the interim analysis of the ongoing Phase 3 psoriasis trial, Can-Fite will be evaluating its ability to treat patients with moderate Covid-19. The company has filed an IND, which has been approved by the FDA, to initiate a Phase 2 randomized, double blind, placebo controlled clinical trial in approximately 40 patients who will receive standard of care treatment along with either 2 mg piclidenoson or placebo in a 1:1 ratio (NCT04333472). The primary endpoint of the trial is the proportion of trial participants alive and free of respiratory failure at Day 29, with respiratory failure defined as a need for non-invasive or invasive mechanical ventilation, high-flow oxygen, or extracorporeal membrane oxygenation. We anticipate the trial initiating soon.
Namodenoson for Treating Liver Cancer
Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer, with over 700,000 individuals affected worldwide, and is the third leading cause of cancer death in the world (ACS). HCC is relatively rare in the U.S. (approximately 35,000 individuals in the U.S. will be diagnosed with HCC in 2015) and other countries where hepatitis infections are not widespread, as most cases of HCC are due to hepatitis infection (both hepatitis B and C). Most cases of liver cancer in countries with low hepatitis rates are due to metastasis of other primary tumors.
HCC most often occurs in the context of a cirrhotic liver, thus patients with cirrhosis typically undergo ultrasonography every six months such that diagnosis of HCC can be made at an early stage. The most effective treatment option for both HCC and the underlying cirrhosis is a liver transplant, and 5-year survival rates higher than 50% can be achieved with this strategy (Forner et al., 2012). Unfortunately, most cases of HCC are too advanced once identified to qualify for this procedure.
Tumor staging plays an essential role in guiding treatment options; however, prognosis is also determined by the severity of the underlying liver disease. There are a number of staging systems currently in use, with the Barcelona Clinic Liver Cancer (BCLC) the only one to take into account a patient’s performance status and cancer-related symptoms as well as the severity of liver disease.
Along with tumor staging, advanced liver cancer patients with cirrhosis are categorized using the Child-Pugh score, with Child-Pugh A being the least severe and Child-Pugh B and C being progressively worse. Patients with Child-Pugh A are typically treated with Lenvima® or Nexavar®, however there are no approved therapies for Child-Pugh B or C patients. In patients with HCC, Child-Pugh score is correlated with overall survival, as patients with Child-Pugh A consistently show increased survival over those with Child-Pugh B or C (Cabibbo et al., 2012).
In March 2019, Can-Fite announced topline results from a Phase 2 clinical trial of namodenoson in Child-Pugh B patients, specifically in patients with Child-Pugh B7, B8, and B9. While the trial did not achieve the primary endpoint of overall survival in the whole population (n=78), superiority in overall survival was found in the largest study subpopulation of Child-Pugh B7 patients (n=56), with namodenoson-treated patients (n=34) showing median overall survival of 6.8 months compared to 4.3 months in placebo-treated patients (n=22) [HR: 0.77 (95% CI = 0.49 – 1.40)].
To follow up on the Phase 2 results, Can-Fite has designed a Phase 3 clinical trial following consultation with both the FDA and EMA. It will be a placebo controlled, double blind trial that will look to enroll approximately 450 HCC patients with Child Pugh B7 following one or two prior lines of treatment. The primary endpoint of the trial is overall survival with secondary endpoints examining progression free survival, safety, and pharmacokinetics.
Liver Cancer Market Opportunity
Liver cancer represented an approximately $1.6 billion market in 2019 and is anticipated to grow to approximately $4.0 billion by 2025 (EvaluePharma). The leading liver cancer drugs in 2019 were Lenvima®, which is sold by Eisai and generated revenues of $626 million, and Nexavar®, which is sold by Bayer and generated revenues of $548 million. With all liver cancer treatments currently approved for early stage disease, and no approved therapies for Child-Pugh B patients, a drug like namodenoson with a benign side effect profile and encouraging Phase 2 results has the potential to stand out as a therapy for a very hard-to-treat population.
Namodenoson for Treating NASH
Nonalcoholic fatty liver disease (NAFLD) is a type of fatty liver where there is deposition of fat (steatosis) in the liver brought on by something other than alcohol consumption and is often due to obesity. Approximately 10 to 20 percent of individuals in the U.S. have fat in their liver but no indication of inflammation. Nonalcoholic steatohepatitis (NASH) is inflammation and damage in the liver brought on by a buildup of fat and is the most severe form of NAFLD. NASH is an often “silent” liver disease as most people with NASH feel well and are not aware that they have a liver problem. Nevertheless, NASH can be severe and lead to cirrhosis, in which the liver is permanently damaged and scarred and no longer works properly, liver failure, and hepatocellular carcinoma. It is estimated that two to five percent of individuals in the U.S suffer from NASH (NIDDK).
There are currently no treatment options available for those that develop NASH. Physicians typically advise NASH patients to lose weight (if they are overweight or obese), get more exercise, eat healthy, and avoid alcohol and unnecessary medications. While these are simply standard recommendations for maintaining a healthy lifestyle, they can make a difference in patients with NASH. Losing weight typically leads to improved liver tests and may possibly reverse the disease, but usually only to a certain extent. In addition, very few people lose sufficient weight to impact their health (Fildes et al., 2015).
Earlier in 2020, Can-Fite announced positive topline results from an exploratory Phase 2 clinical trial of namodenoson in patients with NAFLD/NASH. The double blind, placebo controlled, dose-finding efficacy and safety study enrolled 60 patients with NAFLD with or without NASH. Patients with evidence of active inflammation received 12.5 mg (n=21) or 25 mg (n=19) of namodenoson or placebo (n=20). Results showed that 36.8% of patients in the 25 mg namodenoson group had ALT normalization compared to 10% in the placebo group (P=0.038). A statistically significant decrease in AST was also seen in the 25 mg group. In addition, patients in the 25 mg cohort had a statistically significant decrease in hepatic fibrosis as measured by Fibrosis-4 (FIB-4) score compared to placebo (P=0.026). The company is currently designing a Phase 2b clinical trial to follow up on these results.
NASH Market Opportunity
As mentioned previously, there are no FDA approved therapies for the treatment of NASH, however there are a large number of compounds under development. Many of the compounds are focused on decreasing liver fat in early stage patients, with fewer focused on decreasing fibrosis in late stage patients. Since namodenoson appears to have a greater impact on decreasing fibrosis than lowering liver fat, the drug could potentially be utilized in patients with later stage disease as an anti-fibrotic therapy. In addition, a number of NASH patients who develop fibrosis are at an increased risk for developing liver cancer, and as namodenoson has shown activity against liver cancer, it could offer multiple therapeutic effects in this population.
Cannabinoid Drug Discovery
Can-Fite has a strategic partnership in place with Univo Pharmaceuticals for the discovery of cannabinoid compounds. The company recently received approval to initiate pre-clinical studies to evaluate the effect of cannabis fractions on the proliferation and functionality of cancer, inflammatory, and adipose cells. Cannabinoids bind to the A3AR, and Can-Fite has filed a patent on cannabinoid-based treatment of disease in which A3AR overexpression is associated. The company has also developed an in vitro assay to identify clinically active cannabis derived compounds for the treatment of specific diseases, which will be marketed on a ‘fee for service’ basis to other pharmaceutical companies. The medical cannabis market is projected to grow to approximately $56.7 billion by 2026 (Adroit Market Research) and represents a ‘call option’ for Can-Fite investors on any future cannabinoid compounds that exhibit activity in inflammatory or oncology indications.
Looking ahead to 2021, Can-Fite will be continuing to enroll patients in the ongoing Phase 3 trial of piclidenoson in psoriasis, initiating a clinical trial of piclidenoson in COVID-19 patients, initiating a Phase 3 clinical trial of namodenoson in liver cancer, and initiating a Phase 2b trial of namodenoson in NASH. Each of these represent large market opportunities, with the cannabinoid research as potential upside to the story, and coupled with the company’s currently very low market cap makes Can-Fite an intriguing investment opportunity. We look forward to updates from the company on each of the development programs in the year ahead.
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