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6-K – Report of foreign issuer [Rules 13a-16 and 15d-16]

On April 1, 2016 Can-Fite BioPharma Ltd. (NYSE MKT: CANF) (TASE:CFBI), a biotechnology company with a pipeline of proprietary small molecule drugs being developed to treat inflammatory diseases, cancer and sexual dysfunction, reported it has filed its 2015 Annual Report on Form 20-F with the U.S. Securities and Exchange Commission (Filing, Annual, Can-Fite BioPharma, 2015, APR 1, 2016, View Source [SID:1234510288]).

Clinical Development Program and Corporate Highlights Include:

● CF101 – Preparing Phase III Trials in Rheumatoid Arthritis & Psoriasis Scheduled to Commence in 2016

Can-Fite completed its Phase III trial protocol and Registration Plan for CF101 in the treatment of rheumatoid arthritis and submitted it to the European Medicines Agency (EMA) in March 2016. The Company anticipates commencing the trial in the second or third quarter of 2016.

The Phase III trial protocol for CF101 in the treatment of psoriasis is nearing completion, and is planned to be filed with the EMA in the first half of 2016, with study initiation expected in the fourth quarter of 2016.

● CF102 – Conducting Phase II Trial in Liver Cancer & Plans to Commence Phase II Trial in NASH

Can-Fite continues to enroll and dose patients in its global Phase II liver cancer study in the U.S., Europe, and Israel. Completion of enrollment with approximately 78 patients is expected in the second half of 2016. In 2015, the U.S. Food and Drug Administration (FDA) granted Fast Track Designation to CF102 as a second line treatment for hepatocellular carcinoma (HCC) in patients who have previously received Nexavar (sorafenib). HCC is the most common form of liver cancer. CF102 has Orphan Drug Designation in the U.S. for HCC and in 2015 also received Orphan Drug Designation from the EMA for the indication of HCC.

Following compelling preclinical data reported in 2015 on CF102’s efficacy in the treatment of non-alcoholic steatohepatitis (NASH), Can-Fite is preparing to file its Phase II protocol with institutional review boards (IRBs) in the second quarter of 2016. This new indication for CF102 addresses a market estimated to reach $35-$40 billion by 2025 according to Deutsche Bank.

● CF602 – Preparing to Submit IND to FDA for Treatment of Sexual Dysfunction

Can-Fite is currently conducting further preclinical work for CF602 in the treatment of sexual dysfunction in preparation to submit an investigational new drug (IND) application to the FDA in the fourth quarter of 2016. In 2015, Can-Fite reported new findings showing CF602 demonstrated effects on erectile dysfunction superior to that of Viagra in animal studies.

● OphthaliX – Phase II Results for CF101 in Treatment of Glaucoma Expected in Q2 2016

In 2015, Can-Fite’s subsidiary OphthaliX completed patient enrollment in its Phase II trial for CF101 in the treatment glaucoma and related syndromes of ocular hypertension. The Company expects to report data from this study in the second quarter of 2016.

"We believe our portfolio of small molecule drug candidates has strong potential to address unmet needs in today’s treatment markets. Having been tested in over 1,000 patients to date, our drugs have proven safe and shown efficacy in numerous clinical trials," stated Can-Fite CEO Dr. Pnina Fishman. "We are continuing to conduct a very active clinical program designed to move several of these drugs towards regulatory approvals."

Revenues for the twelve months ended December 31, 2015 were NIS 0.64 million ($0.16 million). We did not record any revenues during the year ended December 31, 2014. The increase in revenue was due to the recognition of a portion of the NIS 5.14 million ($1.32 million) upfront payment received in March 2015 under the distribution agreement with Cipher Pharmaceuticals.

Research and development expenses for the twelve months ended December 31, 2015 were NIS 15.05 million (U.S. $3.86 million) compared with NIS 16.2 million (U.S. $4.15 million) for the same period in 2014. Research and development expenses for 2015 comprised primarily of expenses associated with the Phase II study for CF102 as well as expenses for ongoing studies of CF101. The decrease is primarily due to the completion of the Phase II/III psoriasis study during the first quarter of 2015 and a decrease in the scope of the non-clinical expenses during 2015 as compared to the parallel period in 2014.

General and administrative expenses were NIS 10.63 million (U.S. $2.72 million) for the twelve months ended December 31, 2015 compared to NIS 11.57 million (U.S. $2.97 million) for the same period in 2014. The decrease is primarily due to a reduction in salary and investor and public relations expenses.

Financial income, net for the twelve months ended December 31, 2015 aggregated NIS 5.29 million (U.S. $1.36 million) compared to financial income, net of NIS 3.27 million (U.S. $0.84 million) for the same period in 2014. The increase in financial income, net in 2015 was mainly due to a decrease in the fair value of warrants that are accounted as financial liability.

Can-Fite’s net loss for the twelve months ended December 31, 2015 was NIS 19.77 million (U.S. $5.07 million) compared with a net loss of NIS 24.52 million (U.S. $6.28 million) for the same period in 2014. The decrease in net loss for 2015 was primarily attributable to decreases in operating expenses and an increase in financial income, net.

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As of December 31, 2015, Can-Fite had cash and cash equivalents of NIS 66.03 million (U.S. $16.92 million) as compared to NIS 36.09 million (U.S. $9.25 million) at December 31, 2014. The increase in cash during the twelve months ended December 31, 2015 is due to NIS 48.33 million (U.S. $12.39 million) raised from registered direct offerings in September and October 2015 and NIS 5.14 million (U.S. $1.32 million) received from Cipher Pharmaceuticals as upfront payment for entering into the distribution agreement with Cipher offset by operating expenses.

For the convenience of the reader, the reported NIS amounts have been translated into U.S. dollars, at the representative rate of exchange on December 31, 2015 (U.S. $ 1 = NIS 3.902).

The Company’s consolidated financial results for the twelve months ended December 31, 2015 are presented in accordance with International Financial Reporting Standards.

The 2015 Annual Report can be found on the Company’s website at www.canfite.com as well as on the SEC website at www.sec.gov. In addition, security holders may request a hard copy of the Annual Report, which includes the Company’s complete audited financial statements, free of charge. Requests can be made by contacting Can-Fite Investor Relations at 10 Bareket Street, Kiryat Matalon, Petah-Tikva 4951778, Israel or by phone at +972-3-9241114.

CYP1A2 – a novel genetic marker for early aromatase inhibitor response in the treatment of breast cancer patients.

Endocrine resistance is a major obstacle to optimal treatment effect in breast cancer. Some genetic markers have been proposed to predict response to aromatase inhibitors (AIs) but the data is insufficient. The aim of the study was to find new genetic treatment predictive markers of AIs.
The ongoing population-based BC-blood study in Lund, Sweden includes women with primary breast cancer. This paper is based on AI-treated patients with estrogen receptor positive tumors who underwent breast cancer surgery in 2002-2008. First, an exploratory analysis of 1931 SNPs in 227 genes involved in absorption, distribution, metabolism, and elimination of multiple medications, using DMET chips, was conducted in a subset of the cohort with last follow-up in December 31(st) 2011 (13 cases, 11 controls). Second, selected SNPs from the first analysis were re-analyzed concerning risk for early breast cancer events in the extended cohort of 201 AI-treated with last follow-up in June 30(th) 2014. Clinical data were obtained from medical records and population registries.
Only CYP1A2 rs762551 C-allele was significantly associated with increased risk for early events in the 24 patients (P = 0.0007) and in the extended cohort, adjusted Hazard ratio (HR) 2.22 (95 % CI 1.03-4.80). However, the main prognostic impact was found within five years, adjusted HR 7.88 (95 % CI 2.13-29.19). The impact of the CYP1A2 rs762551 C-allele was modified by a functional polymorphism in the regulator gene AhR Arg554Lys (G &gt; A). Compared to patients who were homozygous for the major allele in both genes (CYP1A2 A/A and AhR G/G), a 9-fold risk for early events was found in patients who had at least one minor allele in both genes, adjusted HR 8.95 (95 % CI 2.55-31.35), whereas patients with at least one minor allele in either but not both genes had a 3-fold risk for early events, adjusted HR 2.81 (95 % CI 1.07-7.33). The impact of CYP1A2 rs762551 C-allele was also modified by the CYP19A1 rs4646 C/C, adjusted HR 3.39 (95 % CI 1.60-7.16) for this combination. This association was strongest within the first five years, adjusted HR 10.42 (95 % CI 3.45-31.51).
CYP1A2 rs762551 was identified as a new potential predictive marker for early breast cancer events in AI-treated breast cancer patients. Moreover, combined genotypes of CYP1A2 rs762551 and CYP19A1 rs4646 or AhR Arg554Lys could further improve prediction of early AI-treatment response. If confirmed, these results may provide a way to more personalized medicine.

Identification of a Tumor Specific, Active-Site Mutation in Casein Kinase 1α by Chemical Proteomics.

We describe the identification of a novel, tumor-specific missense mutation in the active site of casein kinase 1α (CSNK1A1) using activity-based proteomics. Matched normal and tumor colon samples were analyzed using an ATP acyl phosphate probe in a kinase-targeted LC-MS2 platform. An anomaly in the active-site peptide from CSNK1A1 was observed in a tumor sample that was consistent with an altered catalytic aspartic acid. Expression and analysis of the suspected mutant verified the presence of asparagine in the probe-labeled, active-site peptide for CSNK1A1. Genomic sequencing of the colon tumor samples confirmed the presence of a missense mutation in the catalytic aspartic acid of CSNK1A1 (GAC→AAC). To our knowledge, the D163N mutation in CSNK1A1 is a newly defined mutation to the conserved, catalytic aspartic acid of a protein kinase and the first missense mutation identified using activity-based proteomics. The tumorigenic potential of this mutation remains to be determined.

A Simple Algorithm for Population Classification.

A single-nucleotide polymorphism (SNP) is a variation in the DNA sequence that occurs when a single nucleotide in the genome differs across members of the same species. Variations in the DNA sequences of humans are associated with human diseases. This makes SNPs as a key to open up the door of personalized medicine. SNP(s) can also be used for human identification and forensic applications. Compared to short tandem repeat (STR) loci, SNPs have much lower statistical testing power for individual recognition due to the fact that there are only 3 possible genotypes for each SNP marker, but it may provide sufficient information to identify the population to which a certain samples may belong. In this report, using eight SNP markers for 641 samples, we performed a standard statistical classification procedure and found that 86% of the samples could be classified accurately under a two-population model. This study suggests the potential use of SNP(s) in population classification with a small number (n ≤ 8) of genetic markers for forensic screening, biodiversity and disaster victim controlling.

Ubiquitination and degradation of ribonucleotide reductase M1 by the polycomb group proteins RNF2 and Bmi1 and cellular response to gemcitabine.

Ribonucleotide reductase M1 (RRM1) is required for mammalian deoxyribonucleotide (dNTP) metabolism. It is the primary target of the antimetabolite drug gemcitabine, which is among the most efficacious and most widely used cancer therapeutics. Gemcitabine directly binds to RRM1 and irreversibly inactivates ribonucleotide reductase. Intra-tumoral RRM1 levels are predictive of gemcitabine’s therapeutic efficacy. The mechanisms that regulate intracellular RRM1 levels are largely unknown. Here, we identified the E3 ubiquitin-protein ligases RNF2 and Bmi1 to associate with RRM1 with subsequent poly-ubiquitination at either position 48 or 63 of ubiquitin. The lysine residues 224 and 548 of RRM1 were identified as major ubiquitination sites. We show that ubiquitinated RRM1 undergoes proteasome-mediated degradation and that targeted post-transcriptional silencing of RNF2 and Bmi1 results in increased RRM1 levels and resistance to gemcitabine. Immunohistochemical analyses of 187 early-stage lung cancer tumor specimens revealed a statistically significant co-expression of RRM1 and Bmi1. We were unable to identify suitable reagents for in situ quantification of RNF2. Our findings suggest that Bmi1 and possibly RNF2 may be attractive biomarkers of gemcitabine resistance in the context of RRM1 expression. They also provide novel information for the rational design of gemcitabine-proteasome inhibitor combination therapies, which so far have been unsuccessful if given to patients without taking the molecular context into account.