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Piclidenoson - Can-Fite Biopharma

Drug Profile

Piclidenoson - Can-Fite Biopharma

Alternative Names: CF-101; IB-MECA; SI-615

Latest Information Update: 19 May 2020

At a glance

  • Originator Can-Fite BioPharma
  • Developer Can-Fite BioPharma; Lewis Katz School of Medicine
  • Class Amides; Anti-inflammatories; Antineoplastics; Antipsoriatics; Antirheumatics; Antivirals; Eye disorder therapies; Iodobenzenes; Neuroprotectants; Purine nucleosides; Ribonucleosides; Small molecules
  • Mechanism of Action Adenosine A3 receptor agonists
  • Orphan Drug Status

    Orphan designation is assigned by a regulatory body to encourage companies to develop drugs for rare diseases.

    No
  • New Molecular Entity Yes
  • Available For Licensing Yes

Highest Development Phases

  • Phase III Plaque psoriasis; Rheumatoid arthritis
  • Phase II Glaucoma; Ocular hypertension
  • Preclinical COVID 2019 infections
  • No development reported Osteoarthritis; Uveitis
  • Discontinued Colorectal cancer; Dry eyes; Solid tumours

Most Recent Events

  • 18 May 2020 Can-Fite Biopharma files pre-IND application with the US FDA to discuss planned clinical study in COVID-2019 infections
  • 18 May 2020 Can-Fite Biopharma plans a clinical trial in COVID-2019 infections in USA
  • 13 Apr 2020 Can-Fite Biopharma receives approval in Israel for clinical trials for piclidenoson in COVID-2019 infections

Development Overview

Introduction

Piclidenoson is an orally administered, small molecule, adenosine A3 receptor (A3AR) agonist, that is being developed by Can-Fite BioPharma for the treatment of psoriasis, rheumatoid arthritis and osteoarthritis, and ophthalmic indications, including glaucoma, ocular hypertension, COVID-2019 infections and uveitis. Piclidenoson inhibits IL-17 and IL-23 via effect on A3AR which are known to play a major role in the inflammatory process of psoriasis. Clinical development for glaucoma, ocular hypertension, plaque psoriasis, rheumatoid arthritis and uveitis is underway in several countries. Preclinical development for osteoarthritis and COVID-2019 infections is underway in Israel. Development for dry eye syndrome, solid tumours and colorectal cancer was discontinued.

A3AR is over-expressed in various tumour cells and inflammatory cells. Piclidenoson is believed to greatly reduce the inflammatory response, via suppression of TNF-α production, in autoimmune inflammatory diseases. While piclidenoson inhibits growth of cancer cells and induces apoptosis in inflammatory cells, it does not appear to induce such effects in normal proliferating cells such as white blood cells or fibroblasts. Can-Fite considers that the drug may have potential for the treatment of Crohn's disease. In addition, the drug has been shown to prevent retinal ganglion cell loss in vitro and in vivo, indicating its potential in the treatment of glaucoma. The neuroprotective effect in the eye is by inhibition of retinal ganglion cell apoptosis that leads to significantly decreased intraocular pressure.

Piclidenoson was also being developed by Can-Fite for the treatment of cancer. However, the company is focussing the future development of piclidenoson on inflammation, particularly rheumatoid arthritis and psoriasis.

Piclidenoson has emerged from the research programme of Can-Fite BioPharma on A3 adenosine receptor agonists [see Adis Insight drug profile800018692]

Can-Fite and Smart Assays are co-developing a companion diagnostic for identifying patients that may respond to treatment with the company's A3AR agonists, presumably including piclidenoson [see AdisInsight drug profile 800040468] [1] .

Can-Fite is actively seeking partners for the development of piclidenoson for various indication including Coronavirus [2] .

Can-Fite is considering out-licensing agreements with third parties for the commercialisation and development of its therapeutic candidate products.

As at November 2019, no recent reports of development had been identified for phase-I development in rheumatoid-arthritis in Japan, phase-I development in uveitis in the US, preclinical development in osteoarthritis in Israel.

Company Agreements

In March 2020, Can-Fite Biopharma entered into a research and development agreement with the Lewis Katz School of Medicine at Temple University to evaluate the anti-coronavirus effects of piclidenoson. [3]

In August 2019, Can-Fite BioPharma entered into a distribution agreement with Kyongbo Pharm to distribute piclidenoson in South Korea, upon receipt of regulatory approvals. Under the terms of the distribution agreement, Kyongbo Pharm, in exchange for exclusive distribution rights to sell piclidenoson in the treatment of psoriasis in South Korea, made a total upfront payment of $US750 000 to Can-Fite, with additional payments of up to $US3 250 000 upon achievement of certain milestones Can-Fite will also be entitled to a transfer price for delivering finished product to Kyongbo Pharm [4] [5]

In January 2018, Can-Fite BioPharma entered into a distribution agreement with Gebro Pharma, wherein the latter will distribute piclidenoson for the treatment of rheumatoid arthritis and psoriasis in three European countries, including Spain, Switzerland and Austria. Under the terms of the agreement, in late-January 2018, Can-Fite received upfront and milestone payment of $US2 200 000 from Gebro. Can-Fite is eligible to receive additional payments of up to $US7 000 000, upon achievement of certain regulatory, launch and sales-related milestones, and double-digit percentage royalty payments on net sales. In August 2018, Can-Fite initiated the phase III COMFORT trial which will prompt a milestone payment of $US347 264 to Can-Fite from Gebro Holding. [6] [7] [8]

In August 2018, Can-Fite BioPharma entered into a license, collaboration and distribution agreement with CMS Medical Venture Investment Limited for the commercialisation of Can-Fite’s piclidenoson for the treatment of rheumatoid arthritis and psoriasis and namodenoson for the treatment of advanced liver cancer and NAFLD/NASH in China (including Hong Kong, Macao and Taiwan). As per the terms of the agreement, CMS Medical is making an upfront payment of $2 million to Can-Fite, and includes milestone payments of up to $14 million and $58.5 million upon the achievement of certain regulatory and sales milestones, respectively, to Can-Fite. The agreement also offered double-digit royalty payments on net sales. CMS will be responsible to obtain and maintain regulatory approval for the drugs in the indications described above in China. At the option of CMS, Can-Fite may supply finished product to CMS. [9]

In November 2011, Denali Concrete Management Inc announced the closing of the reverse acquisition of Denali by Can-Fite BioPharma Ltd, as a result of which Denali acquired all the outstanding shares of EyeFite Ltd, a private company incorporated in Israel, which has been granted from Can-Fite an exclusive license over piclidenoson for ophthalmic indications. Concurrently, Denali completed a private placement of above $US6 Million from institutional investors (including Can-Fite) at a price of $US1.144 per share. Following the transaction, Can-Fite owns stock of Denali representing approximately 82.3% of the fully diluted share capital of Denali, which consists of approximately 49 million shares. As a result of the closing, Denali became an advanced clinical-stage biopharmaceutical company focused on developing therapeutic products for the treatment of ophthalmic indications. In December 2011, Denali Concrete Management changed its name to OphthaliX Inc. In November 2017, Can-Fite announced that Opthalix successfully completed a merger with Wize Pharma. As a result of the merger, Can-Fite’s ownership of OphthaliX, immediately post-merger, became approximately 8% of the outstanding shares. As part of the merger, Can-Fite cancelled OphthaliX’s prior debts to Can-Fite and terminated an exclusive license to OphthaliX of Can-Fite’s piclidenoson candidate for the treatment of ophthalmic diseases. These rights reverted back to Can-Fite [10] [11]

In March 2015, Can-Fite signed a distribution agreement with Cipher Pharmaceuticals for sales of piclidenoson in Canada. As per the terms of agreement Cipher made an upfront payment of $Can1.65 million to Can-Fite and will make milestone payments of upto $Can2 million plus 16.5% of the net sales of piclidenoson in Canada as royalty payments. Can-Fite will in turn provide finished product to Cipher [12] .

In January 2009, Can-Fite BioPharma granted Kwang Dong Pharmaceutical exclusive rights to develop and commercialise piclidenoson for the treatment of rheumatoid arthritis in South Korea. The agreement includes an upfront payment, as well as milestone payments and royalties on sales [13] [14] .

Can-Fite and the National Institutes of Health (NIH) signed a continuation of a Material Co-operative Research and Development Agreement (M-CRADA) in January 2008, to further investigate piclidenoson for the treatment of uveitis. The agreement was signed based on positive data generated by studies conducted at the National Eye Institute (NEI) of the NIH [15] .

Can-Fite, in September 2006, licensed the rights to piclidenoson (oral and injection) in Japan to Seikagaku Corporation (SKK). Under the terms of the agreement Seikagaku was granted the exclusive licence to develop and market piclidenoson for inflammatory diseases in the Japanese market enabling the company to pursue development for rheumatoid arthritis but not for ophthalmic indications. Can-Fite received a $0.5 million payment from SKK as part of the royalties SKK has agreed to pay under the licensing agreement [16] [17] . Can-Fite was entitled to up to $US20 million in upfront and milestone payments, and up to 12% royalties. By February 2014, Can-Fite had received $US7.5 million under this agreement [18] . However, with effect from August 27, 2015, Seikagaku terminated the licensing agreement and decided to discontinue development of the product, based on the re-assessment of its product strategy for rheumatoid arthritis. Seikagaku decided to focus its efforts towards development of glycosaminoglycan based therapeutics for the treatment of orthopaedic, ophthalmic, and immune and allergic diseases [19] .

In November 2013, Can-Fite executed confidentiality agreements with 10 established pharmaceutical and biotechnology companies with respect to potential negotiations for the commercialisation of piclidenoson for the treatment of autoimmune inflammatory indications [20] .

Key Development Milestones

COVID-19 infections: In May 2020, Can-Fite Biopharma filed a pre-investigational new drug (IND) meeting request with the US FDA to discuss about a planned clinical trial of piclidenoson for treatment of patients with COVID-2019 infections with moderate to severe symptoms. The company intends to submit IND application for clinical trial of piclidenoson which will assess as a potential addition to the current standard of care treatment [21] .

In April 2020, Can-Fite BioPharma received approval in Israel for COVID-2019 trial. In March 2020, Can-Fite BioPharma Ltd. announced that it has submitted piclidenoson for a compassionate use program to treat coronavirus patients to the Institutional Review Board in Israel [22] [23] .

As at March 2020, Can-Fite and Temple University’s Lewis Katz School of Medicine in Philadelphia, are exploring the use of piclidenoson in preclinical studies, for the treatment of COVID-19 infections. Subject to accrual of positive results in these studies, Can-Fite intends to initiate a compassionate use programme in Israel for piclidenoson, for the indication [24] [2] .

Dry eyes

In December 2011, OphthaliX initiated a randomised, double-blind, placebo-controlled phase III trial of two dose levels of piclidenoson (0.1mg or 1.0mg) in patients with dry eye syndrome (NCT01235234; EudraCT 2010-024254-11). The primary efficacy endpoint was the complete clearing of corneal iasisat 24 weeks. The trial enrolled 237 patients in the US, Bulgaria, Romania and Israel. The company reported top-line results in December 2013, showing that the trial did not meet its primary or secondary efficacy endpoints. The treatment was well-tolerated. OphthaliX conducted a retrospective analysis to determine whether there was a correlation between A3 adenosine receptor expression and patients' response to piclidenoson [25] [26] [27] [28] [29] [30] [31] [32] . However, a lack of correlation found between patients' response to the drug and A3 adenosine receptor expression was found, and in June 2014, OphthaliX announced its decision to terminate the development of piclidenoson for dry eye syndrome [33] .

In September 2010, Can-Fite initiated a phase III trial to evaluate two doses of piclidenoson in approximately 240 patients with severe dry eye syndrome. The main clinical endpoints included improvements in corneal fluorescein staining, tear production and dry eye symptom score. This trial was conducted under a US IND, and was to serve as the first of two phase III trials which was to be used to obtain approval in this indication [34] .

Can-Fite completed patient enrolment in a placebo-controlled, phase II trial of oral piclidenoson for the treatment of dry eye syndrome in January 2009, in Israel (NCT00349466). Approximately 80 patients were treated and results were presented in May 2009. Can-Fite initiated this trial in February 2007 after learning that several patients in a phase IIa rheumatoid arthritis trial reported a significant improvement in their dry eye symptoms following treatment with piclidenoson [35] [13] [36] .

Glaucoma and Ocular hypertension

A 16-week, randomised, double-blind, placebo-controlled phase II trial failed to meet its primary endpoint of lowering intraocular pressure in patients with glaucoma or ocular hypertension [37] . The placebo-controlled trial was completed by Can-Fite in April 2017, and assessed the efficacy of piclidenoson 1mg twice-daily in patients with glaucoma or ocular hypertension (NCT01033422; EudraCT2011-002777-27; CF101-231GL) [38] . The trial was initiated in October 2010, and enrolled 89 patients in Israel and Bulgaria. No safety issues were reported [39] [40] [41] [33] . Second cohort studying twice-daily 2mg of piclidenoson was approved by the Bulgarian regulatory authority in December 2014 [42] [43] . In May 2010, Israeli Ministry of Health had approved the trial [44] . The rationale for conducting this trial was based on significant decreases in intraocular pressure observed in a phase II trial of piclidenoson in patients with dry eye syndrome [40] [27] [45] [46] [47] .

Osteoarthritis

In January 2018, Can-Fite withdrew a randomised, double-blind phase II trial of piclidenoson prior to enrolment planned in 188 patients designed to evaluate the efficacy and tolerability osteoarthritis of the knee, in Israel as the company has decided not to conduct the study (NCT00837291; CF101-221OA). Patients were to receive 1mg piclidenoson tablets or placebo every 12 hours, for 12 weeks. The primary outcome measure was to be the proportion of responders, according to the OMERACT-OARSI definition [48] .

In April 2014, Can-Fite BioPharma reported that it had plans to initiate a phase II study in osteoarthritis [1] .

Plaque psoriasis

In August 2018, Can-Fite initiated and dosed first patient in the phase III COMFORT™ trial to evaluate efficacy and safety of piclidenoson patients with moderate to severe plaque psoriasis (NCT03168256; CF101-301PS). The study is designed to have four arms, piclidenoson 2mg, 3mg, matching apremilast 30 mg, or matching placebo in a 3:3:3:2 ratio. The primary end point will evaluate the proportion of patients who achieve a Psoriasis Area and Severity Index (PASI) score response of = 75% (PASI 75) at week 16. The randomised, quadruple masking, parallel assignment trial intends to enroll 407 patients. Enrolment has been initiated in Israel, Bulgaria, Canada, Croatia, Moldova, Bosnia and Herzegovina, Poland and Serbia and anticipated to expand in Canada and Romania. As of December 2019, 50% patient enrollment has been completed in the trial [49] . The trial initiation will prompt a milestone payment of $US348600 to Can-Fite from Gebro Holding [8] [50] . As at September 2018, the first patient has been dosed in Israel [49] [51] .

Can-Fite reported in November 2016, that it reached an agreement with EMA, regarding the finalisation of the phase III COMFORT trial (see above) protocol design. Can-Fite plans to submit its clinical protocol to Institutional Review Boards (IRBs) in the fourth quarter of 2017 [52] . Earlier, in June 2016, Can-Fite had announced the submission of protocol design to the EMA for conducting the trial and a registrational plan for piclidenoson, for the treatment of psoriasis. The trial design is based on efficacy and safety results from a phase II/III study in chronic plaque psoriasis [see below] and patent selection will be based on over expression of the A3AR biomarker. Can-Fite expects that this trial will serve as the first of two phase III trials that will lead to the approval of piclidenoson in this indication in the US [53] [54] [50] .

In August 2017, Can-Fite announced successful completion of the human cardiodynamic safety trial, a regulatory safety requirement of both the US FDA and the EMA prior to the initiation of phase III studies of piclidenoson, in plaque psoriasis and rheumatoid arthritis [see below]. The trial was a placebo-controlled crossover study that used precise methodology to determine the effect of piclidenoson on electrocardiograms of healthy volunteers, at doses 3x higher doses than the planned dose for the phase III trials [55] .

In February 2015, Can-Fite announced the completion of a randomised, double-blind, placebo-controlled phase II/III trial of piclidenoson in patients with psoriasis (NCT01265667; EudraCT2010-024196-83; CF101-202PS) [56] . The trial was initiated in July 2011 and compared two dose levels of piclidenoson (1mg and 2mg) in patients (n=323) with moderate-to-severe chronic plaque psoriasis. The main clinical endpoints were Physician's Global Assessment, Body Surface Area involvement and Psoriasis Activity and Severity Index scores. Top-line results reported in March 2015 indicated that the trial failed to meet its primary endpoint but was found to be safe and well tolerated [57] [58] [59] [60] . The approval of the IND application with the US FDA for a phase II/III trial of piclidenoson in the treatment of psoriasis was announced in June 2010. An interim data analysis of the first 103 patients to complete 24 weeks of treatment was announced in October 2012. The company reported that the drug showed positive clinical effects relative to placebo, plus a favourable safety profile [61] [62] [63] [64] . Interim results were reported in January 2014 [65] [27] . A retrospective analysis of interim data from the trial has indicated that there is correlation between clinical response to piclidenoson and BMI >25 kg/m2. Following the analysis of 103 patients, the 1mg group had been dropped due to futility and additional 220 patients were enrolled in the 2mg group [66] [67] . Enrolment of 326 patients was completed in June 2014, in the US, Bulgaria, Romania and Israel [42] [40] [68] .

A phase II trial of oral piclidenoson in patients with psoriasis was initiated by Can-Fite in June 2007, and was conducted at 10 sites in Israel and Europe (NCT00428974; EudraCT2008-005904-13; CF101-201PS). Enrolment of 75 patients was completed in June 2009 [69] [70] . The psoriasis study protocol was developed by the clinical team at Can-Fite and a psoriasis expert in the US. Patients were treated twice-daily with piclidenoson capsules (1, 2 or 4mg), or placebo capsules, for 12 weeks. The safety and efficacy of the agent was assessed using the Psoriasis Area and Severity Index (PASI) and the Physician Global Assessment [35] [71] . The study has met its primary objectives [72] .

Rheumatoid arthritis (RA)

In October 2017, Can-Fite BioPharma initiated the phase III ACRobat trial to evaluate the efficacy and safety of piclidenoson as a first line treatment compared to methotrexate for the treatment of early rheumatoid arthritis. The primary endpoint of the trial is low disease activity after 12 weeks of treatment. Piclidenoson at 1mg and 2mg, or placebo, will be administered twice daily, and methotrexate or placebo will be administered once weekly. The randomised, double-blind, active and placebo-controlled trial intends to enrol approximately 525 patients (NCT02647762; CF101-301RA). Enrolment is underway in Bosnia and Herzegovina, Canada, Israel, Romania, Serbia and Moldova, and may extend to Poland [73] [74] . In February 2020, Can-Fite Biopharma completed enrolment of 50% patients in the trial [75] .The first patient was dosed in October 2017 [76] [77] . The protocol for a phase III trial in rheumatoid arthritis was agreed upon by European Medicines Agency (EMA). The EMA indicated that piclidenoson should be developed as a first line therapy and an alternative to methotrexate, the standard of care for rheumatoid arthritis [78] [79] [53] [80] . The protocol design and the registration plan for the trial was submitted to the EMA in March 2016, following a pre-submission meeting and was based on positive data from the phase IIb study [see below]. In January 2016, Can-Fite announced that it has submitted its phase III trial protocol to the Institutional Review Board (IRB) of the Barzilai Medical Center in Israel. In August 2015, Can-Fite announced that it planned to submit the protocol for approval in the US. Can-Fite also conducted a successful meeting with the Medical Products Agency (MPA) in Sweden. In May 2017, the company filed a clinical trial application with the Health Canada for piclidenoson [81] [82] [83] [58] [59] . A retrospective analysis of data from a phase II trial of piclidenoson in patients with RA indicated a correlation between clinical response to piclidenoson and BMI >25 kg/m2. These findings were also used to design the planned phase III trial [67] . In April 2017, Can-Fite reported receiving approval from the Institutional Review Board (IRB) of the Barzilai Medical Centre in Israel.

In June 2016, after positive discussions with the EMA on trial protocol, Can-Fite is planning to conduct a phase III trial of piclidenoson in rheumatoid arthritis, which will be the company's second pivotal trial required for its approval for use in rheumatoid arthritis [80] [84] .

Can-Fite completed a phase IIb trial of oral piclidenoson monotherapy in patients with RA and high baseline expression levels of A3 adenosine receptors (NCT01034306). The randomised, double-blind, placebo-controlled, 12-week trial enrolled 79 participants in Israel and Bulgaria [85] . Positive top-line results were presented in December 2013; piclidenoson met all primary efficacy endpoints in the study and was very well tolerated, with no evidence of immunosuppression observed [86] [28] [29] [87] . Additional results were reported in January 2014 [65] .

Can-Fite has conducted two phase IIb trials of piclidenoson added to methotrexate, in patients with RA. The second phase IIb trial of piclidenoson for RA began in April 2008 (NCT00556894; EudraCT2007-006527-13; CF101-203RA). The 12-week trial enrolled 230 patients in Israel, Serbia, the Ukraine, Bulgaria and Poland. Patients received placebo or piclidenoson 0.1 or 1.0mg, once every 12 hours, in addition to weekly methotrexate. In this indication, piclidenoson is being developed in a tablet formulation [88] [89] [90] [91] . In May 2009, when topline results showed that the trial did not meet its primary efficacy endpoint of ACR20 response, Can-Fite stated that it would continue development of piclidenoson only in indications where it is administered as a monotherapy. The results showed no significant difference in ACR20 between the piclidenoson and placebo groups [92] [93] .

Can-Fite reported results from its first phase IIb trial of piclidenoson in patients with RA. The study evaluated the effects of daily oral piclidenoson added to weekly methotrexate (NCT00280917; CF101-202RA). Patients were enrolled in the US, Bulgaria, Poland, Romania, Serbia, the Ukraine and Israel. Results showed an unexpectedly high response in the placebo group, which Can-Fite believed may have resulted from pharmacologically active components among the excipients that reacted with methotrexate to yield the observed response. The placebo formulation included only the excipients of the piclidenoson formulation. Initial laboratory tests showed that the excipients possess biological activity that may explain the marked effect seen in the patients of the placebo group. The company has filed a patent application on the use of these excipients for treating inflammatory diseases [94] [95] [96] .

Results have been reported from a phase IIa trial of piclidenoson in rheumatoid arthritis in Israel [97] [98] [99] .

Seikagaku Corporation has completed a phase I single-dosing trial of piclidenoson for the treatment of RA in Japan [100] . Seikagaku's code is SI 615. Initiation of this trial triggered a payment of $US1 million to Can-Fite [101] . Seikagaku is monitoring the progress of Can-Fite's ongoing phase II trial of piclidenoson monotherapy in RA while it considers its future development strategy for RA in Japan [102] .

Uveitis

OphthaliX's pipeline viewed in July 2013 listed piclidenoson in phase I clinical development for the treatment of uveitis.

In January 2018, OphthaliX withdrew a randomised, double-blind, placebo-controlled phase II trial prior to enrolment designed to investigate the efficacy and tolerability of piclidenoson in patients with active, sight-threatening, noninfectious intermediate or posterior uveitis in Israel, as the company decided not to conduct the study (NCT01905124; CF101-241UV). The company had submitted the trial protocol to regulatory authorities in July 2013. The 6-month trial intended to enrol 45 patients with non-infectious intermediate or posterior uveitis [103] [104] .

In April 2012, OphthaliX announced the completion of preclinical studies of piclidenoson in anterior uveitis. These studies together with previous preclinical studies have shown that piclidenoson was effective in preventing both anterior and posterior uveitis [105] .

Can-Fite has completed a preclinical animal trial of piclidenoson for the treatment of uveitis. The preliminary trial was conducted in the US at the National Eye Institute of the National Institutes of Health (NIH) and demonstrated that piclidenoson significantly reduced ocular disease symptoms via a definitive immunological mechanism of action. Successful collaboration between Can-Fite and the NIH under a Material Co-operative Research and Development Agreement (M-CRADA) is expected to prompt the initiation of a phase II trial in the US, to test the efficacy of piclidenoson in the treatment of uveitis [15] .

Cancer

Piclidenoson was previously in development for the treatment of cancer. However, in light of preclinical data and the results of an interim evaluation of phase II study data, Can-Fite made a decision to focus the further development of piclidenoson on rheumatoid arthritis and other inflammatory indications. Consequently, development for the cancer indication was discontinued.

A multicentre phase II clinical trial in patients with colorectal cancer was conducted in Israel [106] . Interim results showed that piclidenoson appeared to stabilise the disease for at least two months in at least a third of patients [107] .

In May 2004, Can-Fite began a phase I study of piclidenoson in patients with solid tumours. The trial was conducted at three Harvard Medical School hospitals and investigated piclidenoson in combination with three different standard chemotherapeutic regimens. This study followed favourable results from preclinical studies which demonstrated that piclidenoson could potentiate the effects of chemotherapeutic agents and protect white blood cells from the toxic effects of chemotherapy [108] .

Can-Fite BioPharma previously completed two UK-based phase I, placebo-controlled trials of piclidenoson. The drug was safe at therapeutic doses tested, with high oral bioavailability [109] .

Preclinical studies

In December 2014, data presented by the researchers from the National Institutes of Health (NIH) showed the potential of piclidenoson, an adenosine 3 receptor agonist, in the treatment of neuropathic pain. Additionally, earlier presented data showed that piclidenoson prevented chemotherapy-induced neuropathy in preclinical studies [110] .

Long-term preclinical toxicology studies of piclidenoson were completed successfully in 2007. These studies were in full GLP compliance with the requirements of the US FDA and the EMEA, and their successful completion will enable Can-Fite BioPharma to treat patients in phase III trials for prolonged periods [111] .

Financing information

In January 2020, Can-Fite BioPharma raised $2.4 million following exercise certain warrants. The company intends to use the funds for working capital including progression of its phase III trials in psoriasis and the rheumatoid arthritis and for the preparatory work for the phase III liver cancer study [see Adis Insight Drug Profile 800013700] as well as other general corporate purposes [112] .

During the first half of 2014, Can-Fite raised NIS15.9 million ($US4.62 million) for its expenses [113] .

In October 2013, Can-Fite successfully closed a public offering of its common stock for a proceeds of approximately $US6 million. The company intends to use these funds to support its clinical programs, including the ongoing phase II/III psoriasis trial, a phase II glaucoma trial and initiation of phase II development in uveitis. The funds will be also used for general corporate and working capital purposes [114] .

In November 2011, Denali (later OphthaliX) raised more than $US6 million through private placement from investors, including Can-Fite [10] .

Patent Information

In February 2019, Can-Fite BioPharma announced that the U.S. Patent and Trademark Office issued a Notice of Allowance for its application titled "Use of A3 adenosine receptor agonist in the treatment of Osteoarthritis." This patent addresses methods for treating osteoarthritis with A3 adenosine receptor (A3AR) agonists and has been granted in major global markets including North and South America, Europe and Asia [115] .

In October 2017, the Korean Intellectual Property Office issued a patent no 101 741 281 for piclidenoson titled, "Pharmaceutical composition comprising A3 adenosine receptor agonist (IB-MECA/CF-101) for the treatment of psoriasis" [116] .

As at March 2017, piclidenoson is protected by patents, covering its pharmaceutical uses for the treatment of proliferative diseases, including cancer, psoriasis and autoimmune diseases. The patent portfolio includes granted patents in the US, Europe, Australia, Canada, Israel, China, Japan, South Korea, Mexico, Poland, Russia and Hong-Kong. The US patent will expire in 2022, and the ex-US patents will expire in 2020 [117] .

As at March 2017, Can-Fite Biopharma has granted patents, covering the use of a particular dose of piclidenoson (4.0mg daily) for the treatment of psoriasis, in Israel, Japan, the US and Europe, until 2030. Corresponding patent applications were filed on September 6, 2010 in China, Hong Kong, India and South Korea, and the priority date was September 6, 2009 [117] .

As of June 2014, Can-Fite portfolio includes 120 issued and pending patent applications [118] .

Can-Fite reported in November 2016 that it received a Notice of Allowance from the European Patent Office in Q3 2016 indicating that the patent titled, "Pharmaceutical Composition Comprising A3 Adenosine Receptor Agonist (IB-MECA/CF-101) for Treatment of Psoriasis" will be granted [53] .

As at March 2017, Can-Fite Biopharma has granted patents, covering methods of production of piclidenoson, in the US, China, India, Japan and Israel, until 2030. Corresponding patent applications are pending in Europe and India. The patents and patent applications were filed on March 13, 2008, and the priority date was September 6, 2009 [117] .

In June 2015, Can-Fite received a notice of allowance from the US Patent and Trademark Office (USPTO) for a patent covering piclidenoson. The patent, entitled "Process for the synthesis of IB-MECA" covers a method for the chemical synthesis of IB-MECA, an active ingredient of piclidenoson. The patent covers superior methods of manufacturing piclidenoson by reducing the number of synthesis steps which results in reduced drug development costs and potentially increasing margins on any future sales of the product. The patent is set to expire in 2028 [118] .

In February 2015, Can-Fite received a notice of allowance from the USPTO for a patent covering piclidenoson. The patent, entitled "Pharmaceutical Composition Comprising A3 Adenosine Receptor Agonist (IB-MECA/CF-101) For Treatment of Psoriasis" covers daily use of piclidenoson for the treatment of moderate-to-severe psoriasis [119] .

Can-Fite was granted Japanese Patent No. 5467872 in February 2014, titled "Process for the Synthesis of IB-MECA". The patent covers a method for the chemical synthesis of piclidenoson, providing Can-Fite with exclusive manufacturing rights in Japan until 2028 [120] [18] .

The USPTO granted Can-Fite US Patent No. 8 557 790, entitled "A3 Adenosine receptor agonists for the reduction of ocular pressure". The patent relates to use of piclidenoson for the treatment of glaucoma and expires in 2030 [121] . The same patent was granted in Japan in December 2015 [122] .

In September 2013, Can-Fite BioPharma was granted European Patent No. 1 778 236, entitled "Adenosine A3 receptor agonists for the treatment of dry eye disorders including Sjogren's syndrome". This patent relates to piclidenoson, and grants OphthaliX rights in Europe for the use of the agent in Sjogren's syndrome, until 2025 [123] . Also, in September 2013, the company was granted US Patent No. 8 541 182, entitled "A Biological Marker for Inflammation". This patent, which relates to the utilisation of the A3 adenosine receptor as a biomarker to predict patients' response to piclidenoson in autoimmune inflammatory conditions, is due to expire in 2026 [124] .

In February 2012, OphthaliX announced that the Chinese State Intellectual Property Office had issued a Certificate of Patent Invention for Chinese Patent Application No. 200680047569.7, entitled "Adenosine A3 receptor agonists for the treatment of dry eye disorders". This patent grants OphthaliX exclusive rights for the use of piclidenoson in the treatment of dry eye syndrome in China until February 2026 [125] .

In September 2009, Can-Fite was granted a US patent No. US7 589 075B2 covering the use of an adenosine A3 receptor agonist for inhibition of viral replication [126] [2] .

Can-Fite has been granted a patent in the US, Australia, Canada, China, Japan, South Korea and Mexico, and has patents pending in the US, Europe, Brazil and Israel, for use of A3AR agonists in Dry Eye Syndrome (DES) (OpthaliX 2013 Form 10-K). The issued patents are expected to expire in 2025 and the pending patent applications are expected to provide coverage until 2026. Patent applications related to the use of A3AR agonists for the treatment of patients with raised intraocular pressure are pending in the US, Europe, Israel, Japan, China, Hong Kong, Canada, Australia, Mexico and Korea. These pending patent applications will expire in 2030. Patents related to the method of synthesising piclidenoson have been granted in Israel and Japan and is pending in the US, Europe, India, Japan and China; the patents related to synthesis of piclidenoson will expire in 2027.

OphthaliX also acquire patent application under joint ownership of Can-Fite and the NIH, for the use of A3AR agonists for the treatment of patients with uveitis. These patent applications are pending in the United States, Europe, Israel, Japan, China, Canada, Mexico, South Korea and the Russian Federation and will expire in 2031. OphthaliX is in discussion with NIH to obtain additional license to the ownership of NIH in these patents.

A US patent was granted to Can-Fite BioPharma in December 2006 that confers exclusive rights to piclidenoson for the treatment of rheumatoid arthritis. The patent has an expiry date of 2023 [127] .

Can-Fite signed an exclusive licence agreement with the NIH in 2003 for a composition of matter patent that covers piclidenoson. Piclidenoson and the other Can-Fite pipeline A3AR agonists are protected by composition of matter patents licensed from leading medicinal chemistry laboratories in the NIH and Leiden University.

As at March 2017, Can-Fite Biopharma has granted patents, covering the use of A3AR agonists for the treatment of osteoarthritis, in Europe, Australia, Canada, South Korea, China, Israel, Japan and Mexico, until 2026. Corresponding patent applications are pending in the US and Brazil. The patents and the patent applications were filed on November 29, 2006, and the priority date was November 30, 2005 [117] . Can-Fite reported in 2006 that it had filed two patent applications concerning the use of A3AR agonists for the treatment of osteoarthritis and dry eye syndrome [128] .

Drug Properties & Chemical Synopsis

  • Route of administration PO
  • Formulation Tablet, unspecified
  • Class Amides, Anti-inflammatories, Antineoplastics, Antipsoriatics, Antirheumatics, Antivirals, Eye disorder therapies, Iodobenzenes, Neuroprotectants, Purine nucleosides, Ribonucleosides, Small molecules
  • Target Adenosine A3 receptor
  • Mechanism of Action Adenosine A3 receptor agonists
  • WHO ATC code

    D05B (Antipsoriatics for Systemic Use)

    J07B-X (Other viral vaccines)

    L01 (Antineoplastic Agents)

    M01 (Antiinflammatory and Antirheumatic Products)

    S01B-C (Antiinflammatory agents, non-steroidals)

    S01E (Antiglaucoma Preparations and Miotics)

  • EPhMRA code

    D5B (Systemic Antipsoriasis Products)

    J7E9 (All other viral vaccines)

    L1 (Antineoplastics)

    M1 (Anti-Inflammatory and Anti-Rheumatic Products)

    S1E (Miotics and Antiglaucoma Preparations)

    S1R (Ophthalmic Non-steroidal Anti-Inflammatories)

  • Chemical name β-D-Ribofuranuronamide, 1-deoxy-1-[6-[[(3-iodophenyl)methyl]amino]-9H-purin-9-yl]-N-methyl-,
  • Molecular formula C18 H19 I N6 O4
  • SMILES OC(C1C(O)C(O)C(O1)N1C=NC2C(NCC3C=C(C=CC=3)I)=NC=NC1=2)N(C=O)C
  • Chemical Structure
  • CAS Registry Number 152918-18-8

Biomarkers Sourced From Trials

Indication Biomarker Function Biomarker Name Number of Trials

plaque psoriasis

Inclusion

adenosine A3 receptor

1

plaque psoriasis

Outcome Measure

Adenosine

1

rheumatoid arthritis

Exclusion

adenosine A3 receptor

1

rheumatoid arthritis

Inclusion

CRP

adenosine A3 receptor

3

1

rheumatoid arthritis

Outcome Measure

CRP

adenosine A3 receptor

1

1

Biomarker

Drug Name Biomarker Name Biomarker Function
Piclidenoson - Can-Fite Biopharma Adenosine Outcome Measure
adenosine A3 receptor Exclusion, Inclusion, Outcome Measure
CRP Inclusion, Outcome Measure
For more detail, check out BiomarkerBase: the leading source of information about biomarkers used in drug development and diagnostic tests, tracking a comprehensive list of biomarker uses worldwide by over 800 companies

Development Status

Summary Table

Indication Qualifier Patient Segment Phase Countries Route / Formulation Developers Event Date
COVID 2019 infections - - Preclinical Israel unspecified / unspecified Can-Fite BioPharma, Lewis Katz School of Medicine 18 Mar 2020
Colorectal cancer - - Discontinued (II) Israel PO / unspecified Can-Fite BioPharma 29 Apr 2005
Dry eyes - Monotherapy Discontinued (III) Bulgaria, Israel, Romania, USA PO / Tablet Can-Fite BioPharma 09 Jun 2014
Glaucoma - - Phase II Bulgaria, Israel PO / Tablet Can-Fite BioPharma 30 Jun 2010
Ocular hypertension - - Phase II Bulgaria, Israel PO / Tablet Can-Fite BioPharma 01 Oct 2010
Osteoarthritis - - No development reported (Preclinical) Israel PO / unspecified Can-Fite BioPharma 28 Nov 2019
Plaque psoriasis - Monotherapy Phase III Bosnia-Herzegovina, Bulgaria, Canada, Croatia, Israel, Moldova, Poland, Serbia PO / Tablet Can-Fite BioPharma 10 Dec 2019
Plaque psoriasis - Monotherapy Phase II/III Romania, USA PO / Tablet Can-Fite BioPharma 31 Jul 2011
Rheumatoid arthritis - - Phase III Bosnia-Herzegovina, Romania, Serbia PO / Tablet Can-Fite BioPharma 30 Oct 2017
Rheumatoid arthritis MTX-naïve MTX-naïve patients Early-stage disease, In adults, In the elderly Phase III Canada, Israel, Moldova PO / Tablet Can-Fite BioPharma 30 Oct 2017
Rheumatoid arthritis - - Phase II Bulgaria, Czech Republic, Poland, USA, Ukraine PO / Tablet Can-Fite BioPharma 29 Jul 2009
Rheumatoid arthritis - - No development reported (I) Japan PO / Tablet Can-Fite BioPharma 28 Nov 2019
Solid tumours - - Discontinued (I) USA PO / unspecified Can-Fite BioPharma 29 Apr 2005
Uveitis - Monotherapy No development reported (I) USA PO / Tablet Can-Fite BioPharma 28 Nov 2019

Commercial Information

Involved Organisations

Organisation Involvement Countries
Can-Fite BioPharma Originator Israel
Can-Fite BioPharma Owner Israel
Cipher Pharmaceuticals Market Licensee Canada
Kyongbo Pharmaceutical Market Licensee South Korea
Gebro Pharma GmbH Market Licensee Austria, Spain, Switzerland
CMS Medical Licensee China, Hong Kong, Macau, Taiwan
Kwang Dong Pharmaceutical Licensee South Korea
National Institutes of Health (USA) Collaborator USA
Lewis Katz School of Medicine Collaborator USA

Licensing Availability

Licensing Organisation Available Indication Available Phase Region Date
Can-Fite BioPharma - Unspecified - 09 Sep 2013

Scientific Summary

  • Adverse Events Occasional: Dizziness; Flushing; Headache; Nausea; Skin eruptions; Tachycardia; Vomiting

Pharmacokinetics

Clinical studies

in a phase I study in healthy volunteers, the Tmax of an oral dose of piclidenoson was 1-2h after dosing, and t½ was 9h in both single and multidose studies. A single 5mg dose had a Cmax of 81.6 ± 23.6 ng/mL in the single dose study, and 63.6 ± 22.0 ng/mL after the first of the multiple doses. AUCinf was 904.0 ± 221.9 ng.h/mL and 596.1 ± 196.6 ng.h/mL for the single and multiple dose studies respectively. After one week of multiple dosing, AUC0-24h was 601 ± 163.6 ng.h/mL. Pharmacokinetic parameters were linearly proportional to dose [134] .

Preclinical studies

Results investigating the in vivo metabolism and elimination of piclidenoson showed minimal Liver metabolism and intact excretion in the urine. The intact excretion of piclidenoson in the urine is indicative of fewer adverse events [133] .

Adverse Events

Psoriasis

Phase II/III:

Piclidenoson was safe and well tolerated in a phase II/III trial in 323 patients with moderate to severe psoriasis. In the study, patients were randomised to receive piclidenoson (1 or 2mg) or placebo for upto 32 weeks [66] .
[64]

Phase II:

Piclidenoson was safe and tolerated in a phase II trial in 75 patients with moderate to severe psoriasis. In the study, patients were randomised to receive piclidenoson (1, 2 or 4mg) or placebo twice daily for 12 weeks [72] .

Rheumatoid arthritis

Piclidenoson was well tolerated in a phase IIb trial in patients with rheumatoid arthritis. One patient in each of the 0.1 mg, 1 mg and placebo group and 3 patients in the 4 mg group discontinued treatment prematurely. The overall number of adverse events was small with only one "possibly related" serious adverse event [94] .

Results from a phase II trial in 74 patients with active rheumatoid arthritis showed that piclidenoson (0.1-4.0mg bid for 12 weeks) was generally well tolerated with the most common treatment-related adverse events being headache (4.1%), nausea (2.7%), and rash (2.7%) [99] .

Piclidenoson (0.2, 2, and 8 mg/day) monotherapy was well tolerated and no dose-limiting toxicities were reported at dosages of up to 8 mg/day in patients with rheumatoid arthritis. The patients in this phase II trial had active rheumatoid arthritis and had failed 1-4 disease modifying anti-rheumatic drugs. Results were from 66 patients who had completed the full 12 weeks of therapy [98] .

Dry eyes

In a phase II, 12-week trial, piclidenoson was safe and well-tolerated in patients with moderate to severe dry eye syndrome [35] .

Glaucoma:

Piclidenoson was safe and well tolerated in a phase II trial, in patients (n=89) with glaucoma. The trial was conducted with two cohorts; in both the cohorts subjects were randomised in a 3:1 ratio of piclidenoson to placebo where subjects received 1mg and 2mg of piclidenoson in cohort 1 and 2, respectively [37] [38] .

Healthy volunteers

In a phase I study in healthy volunteers, single doses of up to 5mg of piclidenoson was safe and well tolerated. A single dose of 10mg caused flushing, tachycardia, nausea and vomiting which were dose-limiting. Single doses exceeding 5mg and multiple doses of piclidenoson were associated with increased heart rate. Multiple doses up to 4mg every 12h for one week were safe and well tolerated. Above multiple doses of 4mg, patients reported headache, drowsiness, hot flushes and dizziness on standing. These effects declined with dosing duration and were not dose-limiting [134] .

Pharmacodynamics

Summary

Piclidenoson treatment suppressed tumour growth by approximately 52% in mice grafted subcutaneously with HCT-116 colon carcinoma cells. The molecular mechanisms involved in piclidenoson tumour inhibition were shown to be mediated by the modulation of expression levels of the A3 adenosine receptor (A3AR) and glycogen synthase kinase-3β (GSK-3β). Activation of A3AR by piclidenoson caused downregulation of PKAc and PKB/Akt, resulting in a decrease in the level and DNA-binding capacity of NFκB which was demonstrated in vivo and in vitro. A3AR activation also caused decreases in the downstream target genes cyclin D1 and c-Myc. Piclidenoson also caused an upregulation of the active non-phosphorylated form of GSK-3β leading to a decrease in β-catenin expression [136] .

Treatment of mice with IB-MECA reduced carrageenan-induced paw oedema, protected against endotoxin (60 mg/kg, IP) induced lethality, and reduced the severity of joint inflammation in collagen-induced arthritis. IB-MECA inhibited the formation of interleukin-2 and nitric oxide production in the animal paws, and suppressed neutrophil formation [138] .

Clinical

High expression of the A3 adenosine receptor was correlated with a significant response to piclidenoson in a phase IIa trial of the drug in patients with rheumatoid arthritis. In this trial, patients who expressed high levels of the A3 adenosine receptor achieved a significant response to treatment with piclidenoson , compared with a small response in patients with low receptor expression. High expression of the A3 adensoine receptor was found in 70% of patients [97] .

Adenosine A3 receptor expression levels were analysed in 18 patients from a phase II clinical trial in 74 patients with active rheumatoid arthritis. Results showed a highly statistically significant (p < 0.02) correlation between adenosine A3 receptor expression at baseline and ACR50 and ACR70 responses [99] .

Preclinical

In rats with monosodium iodoacetate (MIA)-induced osteoarthritis of the knee, animals that received orally administered piclidenoson 100 µg/kg twice daily (beginning 7 days after MIA injection) showed an improvement in radiographic changes and a marked decrease in knee diameter, cartilage damage, osteoclast/osteophyte formation and bone destruction relative to animals that received vehicle (placebo). Oral administration of the adenosine A3 receptor antagonist MRS 1220 30 minutes prior to administration of piclidenoson negated the effect of the latter drug on knee diameter. Piclidenoson induced deregulation of the NF-κB signalling pathway; this led to down-regulation of tumour necrosis factor-α [132] .

Piclidenoson (10 µg/kg, twice-daily, PO) effectively and specifically inhibited clinical and histological scores as well as pathological manifestations of arthritis in rats with adjuvant-induced arthritis (AIA); these responses were reversible by MRS 1220, a selective A3 adenosine receptor (A3AR) antagonist. PI3K, PKB/Akt, IKK/NF-κB and TNF α expression levels were down-regulated in DLN (drain lymph node) and synovial tissue protein extracts derived from piclidenoson-treated animals. Both PKB/Akt and IKK/NF-κB activation were substantially reduced, which indicated inhibition of transcription activity. In addition, upon PKB/Akt inhibition, GSK-3β and caspase-3 were up-regulated and caused activation of apoptosis; ladder analysis revealed evidence of apoptosis in DLN cells [135] .

Treatment of mice with piclidenoson reduced carrageenan-induced paw oedema, protected against endotoxin (60 mg/kg, IP) induced lethality, and reduced the severity of joint inflammation in collagen-induced arthritis. Piclidenoson inhibited the formation of interleukin-2 and nitric oxide production in the animal paws and suppressed neutrophil formation [138] .

Therapeutic Trials

In a multicentre, double-blind, phase II study, 70 patients with metastatic colorectal cancer received piclidenoson at three different doses. In March 2004, 20 of 56 assessable patients were stable after eight weeks' treatment and continued in the study. Of those stable at eight weeks, six were stable after 16 weeks and two were stable after 24 weeks [107] .

In a phase II study of piclidenoson, patients who received 1mg orally as a monotherapy for 12 weeks experienced a statistically significant improvement in superficial punctate keratitis, reducing ocular surface inflammation, compared with placebo [35] .

No statistically significant differences were found between the piclidenoson treated group and the placebo group in lowering intra ocular pressure (primary endpoint) in a phase II trial in patients (n=89) with glaucoma. The trial was conducted with two cohorts; in both the cohorts subjects were randomised in a 3:1 ratio of piclidenoson to placebo where subjects received 1mg and 2mg of piclidenoson in cohort 1 and 2, respectively [37] [38] .

In a phase IIb study conducted in patients with rheumatoid arthritis (RA) and elevated levels of the A3AR biomarker, piclidenoson produced statistically significant greater reductions in signs and symptoms of RA compared to placebo. ACR20 response rates (percentage of patients exhibiting a 20% improvement in RA symptoms) were 25% and 49% (p = 0.035) for the placebo and piclidenoson treated groups, respectively. The corresponding ACR50 response rates were 9% for placebo and 19% for piclidenoson and the ACR70 response rates were 3% for placebo and 11% for piclidenoson. In total, half of the patients treated with piclidenoson showed clinically meaningful improvements. The patient responses were cumulative over time, suggesting that piclidenoson produced consistent anti-inflammatory effects. In this double-blind study, 79 patients with RA were randomised to receive placebo or oral, twice-daily, 1mg piclidenoson over 12 weeks [86] .

Three doses of piclidenoson in combination with methotrexate were compared with methotrexate alone in a phase IIb trial in 253 patients with rheumatoid arthritis. A total of 239 patients completed 12 weeks of treatment, receiving either 0.1, 1 or 4 mg of piclidenoson, twice daily, or placebo, in combination with weekly methotrexate. The ACR20 response rate showed no difference between patients treated with piclidenoson and the placebo group, all showing about 50%. No significant difference was seen between the piclidenoson treatment groups and placebo. This high rate of placebo response may result from pharmacologically active components among the excipients that reacted with methotrexate. A marked difference between the piclidenoson-treated patients and the placebo group was noted in the ACR50 response in all piclidenoson treatment groups, being 20%, 27% and 19% in the 0.1, 1 and 4 mg groups respectively, as compared with 13% in the placebo group. The difference between the ACR50 response in the group treated with 1 mg of piclidenoson and placebo showed a statistical significance of p = 0.04 and 0.07 by one-side and two-sided analysis, respectively. The ACR70 response was also maximal in the 1 mg treatment group, with 10% of the patients having ACR70 response as compared to 3% in the placebo group. A marked difference between the treatment group and the placebo group was also observed in the EULAR "Good" reponse in all the three piclidenoson treatment groups, with the response rates being 6%, 18% and 11% in the 0.1, 1 and 4 mg groups as compared with 5% of the placebo group. The improvement in the 1 mg group showed a statistical significance of p=0.04 by a two-side analysis [94] .

Interim results of a phase II trial have demonstrated that piclidenoson reduced pain and joint swelling in 80% of the patients in the trial. The activity of the drug was measured using the American College of Rheumatology (ACR) scale. In patients that received piclidenoson 1mg 8% achieved ACR70 (a 70% improvement), 30% achieved ACR50, and 60% achieved ACR20. The trial enrolled 66 patients who received twice daily doses of piclidenoson for 12 weeks [139] .

Piclidenoson (0.2, 2, and 8 mg/day) monotherapy was associated with ACR 20% and 50% response rates of up to 58% and 30%, respectively at 12 weeks (primary endpoint) in patients with rheumatoid arthritis. The maximal response was achieved at a dosage level of 2 mg/day. The patients in this phase II trial had active rheumatoid arthritis and had failed 1-4 disease modifying anti-rheumatic drugs. Results were from 66 patients who had completed the full 12 weeks of therapy [98] .

Updated results from 74 patients showed that maximal responses were achieved with the 1.0mg bid dose of piclidenoson. At 12 weeks, ACR20, ACR50 and ACR70 responses were seen in 55.6%, 33.3%, and 11.5% of patients who received piclidenoson (1mg, bid) [99] .

Phase II/III

At 32 weeks of treatment, 33% of patients achieved Psoriasis Area Sensitivity Index (PASI) 75, with a mean percent of improvement score of 57% (p<0.001), in a phase II/III trial in patients with moderate to severe plaque psoriasis. Piclidenoson was associated with a statistically significant cumulative and linear improvement in PASI 50 (63.5%), PASI 75 (35.5%), PASI 90 (24.7%) and PASI 100 (10.6%) on weeks 20 to 32. Additionally, 20% of patients reached PASI 90 by week 32 of treatment, demonstrating a response rate of 90% clearing of skin lesions. PASI90 subset analysis showed a piclidenoson response rate of 27% in patients previously untreated with systemic psoriasis therapy, compared with 13.5% in patients pretreated with systemic drugs [66] [131] . Previously reported results showed that there was no significant improvement in PASI score in patients treated with piclidenoson compared with placebo. At week 12, PASI 75 score was observed in 8.5% of patients in piclidenoson group, compared with 6.9% in placebo group. Clear or almost clear skin, as measured by Physicians' Global Assessment score, was observed in 6.4% of piclidenoson treated patients versus 3.4% of placebo treated patients. A total of 323 patients with plaque psoriasis were randomised in this double-blinded trial [60] [64] .

Phase II

In a phase II study, patients who received PO piclidenoson at a dose of 2mg showed significant improvement in Psoriasis Activity and Severity Index (PASI) scores, relative to baseline, after 12 weeks of treatment (p < 0.0001). This patient group also showed superior significant improvement over placebo (p = 0.03). In 83% of the 2mg group, disease parameters improved upon treatment with piclidenoson and 35% demonstrated an improvement of >50% (PASI 50). The improvement in disease symptoms was progressive over time and regression analysis suggested that longer treatment will sustain this improvement. In the study, patients were randomised to receive piclidenoson (1, 2 or 4mg) or placebo twice daily for 12 weeks [72] .

Future Events

Expected Date Event Type Description Updated
07 Apr 2020 Trial Update Can-Fite BioPharma plans a phase II for COVID-2019 infections in Israel (PO) (NCT04333472) (700320274) 07 Apr 2020
31 Dec 2018 Trial Update Can-Fite plans to initiate a pivotal, registrational phase III study in Plaque psoriasis in 2018 (NCT03168256) [129] 11 Sep 2018
31 Dec 2017 Trial Update Can-Fite plans to initiate the phase III ACRobat trial for Rheumatoid arthritis in the USA, Europe, Canada and Israel in 2017 (9214096, 9224294, 9163959) (NCT02647762) [130] 01 Nov 2017

Development History

Event Date Update Type Comment
18 May 2020 Regulatory Status Can-Fite Biopharma files pre-IND application with the US FDA to discuss planned clinical study in COVID-2019 infections [21] Updated 19 May 2020
18 May 2020 Trial Update Can-Fite Biopharma plans a clinical trial in COVID-2019 infections in USA [21] Updated 19 May 2020
13 Apr 2020 Regulatory Status Can-Fite Biopharma receives approval in Israel for clinical trials for piclidenoson in COVID-2019 infections [22] Updated 16 Apr 2020
07 Apr 2020 Trial Update Can-Fite BioPharma plans a phase II for COVID-2019 infections in Israel (PO) (NCT04333472) Updated 07 Apr 2020
26 Mar 2020 Trial Update Can-fite submitted a compassionate use treatment for Coronavirus patients in Israel [23] Updated 26 Mar 2020
18 Mar 2020 Phase Change - Preclinical Preclinical trials in COVID-2019 infections in Israel (unspecified route) [24] Updated 20 Mar 2020
18 Mar 2020 Trial Update Can-Fite Biopharma intends to initiate a compassionate use programme in Israel for COVID-2019 infections (subject to positive results from preclinical studies) [24] Updated 20 Mar 2020
15 Mar 2020 Licensing Status Can-Fite Biopharma and Lewiz Katz School of Medical agree to co-develop piclidenoson for COVID-2019 infections [3] Updated 19 Mar 2020
05 Mar 2020 Phase Change Early research in COVID-2019 infections in Israel (unspecified route) [2] Updated 11 Mar 2020
04 Feb 2020 Trial Update Can-Fite Biopharma plans a phase III trial for Rheumatoid arthritis [75] Updated 05 Feb 2020
10 Dec 2019 Phase Change - III Phase-III clinical trials in Plaque psoriasis in Canada (PO) [49] Updated 16 Dec 2019
28 Nov 2019 Phase Change - No development reported No recent reports of development identified for phase-I development in Rheumatoid-arthritis in Japan (PO, Tablet) Updated 28 Nov 2019
28 Nov 2019 Phase Change - No development reported No recent reports of development identified for phase-I development in Uveitis(Monotherapy) in USA (PO, Tablet) Updated 28 Nov 2019
28 Nov 2019 Phase Change - No development reported No recent reports of development identified for preclinical development in Osteoarthritis in Israel (PO) Updated 28 Nov 2019
02 Aug 2019 Licensing Status Can-Fite BioPharma enters into a distribution agreement with Kyongbo Pharm for piclidenoson in South Korea [4] Updated 05 Aug 2019
05 Feb 2019 Patent Information Can-Fite BioPharma receives patent allowance for A3 adenosine receptor (A3AR) agonists in USA [115] Updated 20 Feb 2019
05 Feb 2019 Patent Information Can-Fite BioPharma receives patent allowance for A3 adenosine receptor (A3AR) agonists in North America, South America, Europe and Asia [115] Updated 06 Feb 2019
15 Sep 2018 Phase Change - III Phase-III clinical trials in Plaque psoriasis (Monotherapy) in Bosnia-Herzegovina, Serbia, Poland, Moldova (PO) after September 2018 (NCT03168256) Updated 06 Dec 2019
21 Aug 2018 Phase Change - III Phase-III clinical trials in Plaque psoriasis (Monotherapy) in Croatia, Bulgaria (PO) (NCT03168256) Updated 05 Aug 2019
21 Aug 2018 Phase Change - III Phase-III clinical trials in Plaque psoriasis (Monotherapy) in Israel (PO) [8] Updated 24 Aug 2018
06 Aug 2018 Licensing Status Piclidenoson licensed to CMS Medical in China, Hong Kong, Macao and Taiwan [9] Updated 13 Aug 2018
02 Jul 2018 Trial Update Can-Fite plans to initiate a pivotal, registrational phase III study in Plaque psoriasis in 2018 (NCT03168256) [129] Updated 11 Sep 2018
24 Jun 2018 Biomarker Update Biomarkers information updated Updated 31 Aug 2018
30 Jan 2018 Trial Update Can-Fite BioPharma withdraws a phase II trial prior to enrolment for Osteoarthritis in Israel as the company has decided not to conduct the study (PO) (NCT00837291) Updated 16 Feb 2018
30 Jan 2018 Trial Update Can-Fite BioPharma withdraws a phase II trial prior to enrolment as the company decided not to conduct the study for Uveitis in Israel (PO) (NCT01905124) Updated 16 Feb 2018
08 Jan 2018 Licensing Status Can-Fite Biopharma and Gebro Pharma enters into an exclusive distribution agreement for piclidenoson for Psoriasis and Rheumatoid arthritis in Austria, Spain and Switzerland [6] Updated 12 Jan 2018
17 Nov 2017 Licensing Status Can-Fite BioPharma terminates its licence to OphthaliX for piclidenoson in Opthalmic diseases [11] Updated 23 Nov 2017
01 Nov 2017 Active Status Review Piclidenoson is still in phase II development for Glaucoma (Monotherapy) in Bulgaria and Israel (NCT01033422) Updated 01 Nov 2017
01 Nov 2017 Active Status Review Piclidenoson is still in phase II/III development for Plaque psoriasis (Monotherapy) in USA, Israel, Romania and Bulgaria (NCT01265667) Updated 01 Nov 2017
30 Oct 2017 Phase Change - III Phase-III clinical trials in Rheumatoid arthritis in Bosnia-Herzegovina, Serbia, Romania (PO) after October 2017 (NCT02647762) Updated 06 Dec 2019
30 Oct 2017 Phase Change - III Phase-III clinical trials in Rheumatoid arthritis (Early-stage disease, In adults, In the elderly) in Moldova, Canada (PO) (NCT02647762) Updated 29 Mar 2018
30 Oct 2017 Phase Change - III Phase-III clinical trials in Rheumatoid arthritis (Early-stage disease, In the elderly, In adults) in Israel (PO) (NCT02647762) Updated 01 Nov 2017
17 Oct 2017 Patent Information Can-Fite BioPharma has patent protection for piclidenoson for Psoriasis in South Korea [116] Updated 23 Oct 2017
07 Aug 2017 Trial Update Can-Fite completes Human cardiodynamic safety trial for piclidenoson [55] Updated 09 Aug 2017
07 Aug 2017 Trial Update Can-Fite plans the phase III COMFORT trial in Plaque psoriasis in Europe, Israel and Canada (PO) Updated 09 Aug 2017
30 May 2017 Trial Update Can-Fite plans to initiate the phase III ACRobat trial for Rheumatoid arthritis in the USA, Europe, Canada and Israel in 2017 [52] ,, [120] (NCT02647762) [130] Updated 01 Nov 2017
16 May 2017 Regulatory Status Can-Fite BioPharma files a clinical trial application with the Health Canada in Canada [81] Updated 24 May 2017
01 Apr 2017 Trial Update Can-Fite BioPharma completes a phase II trial in Glaucoma and Ocular hypertension in Bulgaria, Israel (NCT01033422) Updated 27 May 2019
31 Mar 2017 Patent Information Can-Fite Biopharma has patent protection for adenosine A3 receptor agonists for Osteoarthritis in USA, Australia, Canada, South Korea, China, Israel, Japan and Mexico [117] Updated 14 Jun 2017
31 Mar 2017 Patent Information Can-Fite Biopharma has patent protection for methods of production of piclidenoson in USA, China, India, Japan and Israel [117] Updated 14 Jun 2017
31 Mar 2017 Patent Information Can-Fite Biopharma has patent protection for piclidenoson (0.4mg daily) for Psoriasis in Israel, Japan, USA and Europe [117] Updated 14 Jun 2017
31 Mar 2017 Patent Information Can-Fite Biopharma has patent protection for piclidenoson for Cancer, Psoriasis and Autoimmune disorders in USA, Europe, Australia, Canada, Israel, China, Japan, South Korea, Mexico, Poland, Russia and Hong Kong [117] Updated 14 Jun 2017
25 Nov 2016 Patent Information Can-Fite receives patent allowance from European Patent Office for A3 Adenosine Receptor Agonist Piclidenoson (IB-MECA/CF-101) for treatment of Psoriasis [53] Updated 29 Nov 2016
01 Nov 2016 Regulatory Status Can-Fite reaches agreement with EMA regarding protocol design and registration plan for use in Psoriasis Updated 07 Nov 2016
05 Jul 2016 Scientific Update Top-line efficacy and adverse event data from a phase II trial in Glaucoma released by Can-fite Biopharma [37] Updated 08 Jul 2016
01 Jun 2016 Regulatory Status Can-Fite reaches agreement with EMA regarding protocol design and registration plan for use in Rheumatoid arthritis [80] Updated 03 Jun 2016
17 Mar 2016 Regulatory Status Can-Fite BioPharma submits a protocol design and a registration plan with the EMA for Rheumatoid arthritis Updated 23 Mar 2016
04 Mar 2016 Scientific Update Efficacy and adverse events data from a phase II/III trial in Psoriasis presented at the 74th Annual Meeting of the American Academy of Dermatology (AAD-2016) [66] Updated 13 Apr 2016
11 Jan 2016 Regulatory Status Can-Fite intends to file an IND for a phase III trial with the EMA in Europe for psoriasis [54] Updated 14 Jan 2016
17 Dec 2015 Patent Information OphthaliX receives patent protection for piclidenoson in Japan [122] Updated 19 Dec 2015
07 Dec 2015 Trial Update OpthaliX completes enrolment in a phase II trial in Glaucoma in Israel and Bulgaria [39] Updated 08 Dec 2015
28 Aug 2015 Licensing Status Piclidenoson is no longer licensed to Seikagaku Corporation in Japan [19] Updated 31 Aug 2015
15 Jun 2015 Active Status Review CF 101 is still in phase II trials for Glaucoma (Monotherapy) in Israel Updated 15 Jun 2015
15 Jun 2015 Active Status Review CF 101 is still in phase II/III trials for Plaque psoriasis (Monotherapy) in the USA, Bulgaria, Israel and Romania Updated 15 Jun 2015
15 Jun 2015 Active Status Review Phase II development for Rheumatoid arthritis is ongoing Updated 15 Jun 2015
10 Jun 2015 Patent Information Can-Fite receives patent allowance for CF 101 in USA [118] Updated 13 Jun 2015
27 Apr 2015 Scientific Update Updated efficacy data from a phase II/III trial in Psoriasis released by Can-Fite [131] Updated 20 May 2015
30 Mar 2015 Scientific Update Top-line efficacy data from a phase II/III trial in Plaque psoriasis released by Can-Fite [60] Updated 02 Apr 2015
25 Mar 2015 Licensing Status CF 101 market licensed to Cipher Pharmaceuticals in Canada [12] Updated 25 Mar 2015
20 Feb 2015 Patent Information Can-Fite receives patent allowance for CF 101 in USA [119] Updated 20 Feb 2015
04 Feb 2015 Trial Update Can-Fite completes a phase II/III trial in Psoriasis in the US, Europe and Israel [56] Updated 06 Feb 2015
17 Jun 2014 Trial Update Can-Fite completes enrolment in its phase II/III trial for Psoriasis in USA, Bulgaria, Romania & Israel [68] , NCT01265667) Updated 19 Jun 2014
09 Jun 2014 Phase Change - Discontinued(III) Discontinued - Phase-III for Dry eyes in USA, Romania, Israel and Bulgaria (PO) Updated 13 Jun 2014
31 Dec 2013 Trial Update Can-Fite BioPharma completes a phase II trial in Rheumatoid arthritis in Israel and Bulgaria (NCT01034306) Updated 01 Apr 2014
23 Dec 2013 Scientific Update Top-line efficacy data from a phase IIb trial in Rheumatoid arthritis released by Can-Fite (NCT01034306; 9157823) Updated 03 Jan 2014
09 Sep 2013 Licensing Status CF 101 is available for licensing as of 09 Sep 2013. http://www.canfite.com/ Updated 10 Oct 2013
18 Jul 2013 Trial Update Can-Fite BioPharma (OphthaliX) plans a phase II trial for Uveitis in Israel (PO) (NCT01905124) Updated 31 Jul 2013
16 Jul 2013 Regulatory Status OphthaliX submits a phase II trial protocol with European & Israeli authorities for Uveitis [103] Updated 17 Jul 2013
01 Jul 2013 Phase Change - I Phase-I clinical trials in Uveitis in USA (PO) Updated 31 Jul 2013
15 Mar 2013 Trial Update OphthaliX completes enrolment in its phase III trial for Dry eyes in USA, Bulgaria, Romania & Israel in (NCT01235234) Updated 18 Mar 2013
09 Oct 2012 Trial Update Can-Fite BioPharma announces that enrolment will continue in a Phase-II/III trial for Psoriasis in the US, Europe and Israel, following positive results of an interim safety and efficacy analysis [61] Updated 17 Oct 2012
22 Dec 2011 Phase Change - III Phase-III clinical trials in Dry eyes in Bulgaria (PO) Updated 18 Mar 2013
22 Dec 2011 Company Involvement Denali Concrete Management is now called OphthaliX Inc [31] Updated 22 Dec 2011
22 Dec 2011 Phase Change - III Phase-III clinical trials in Dry eyes in Europe (PO) Updated 22 Dec 2011
22 Dec 2011 Phase Change - III Phase-III clinical trials in Dry eyes in Israel (PO) Updated 22 Dec 2011
22 Dec 2011 Trial Update OphthaliX (formerly Denali Concrete Management) initiates enrolment in a phase III trial in Dry eyes in USA, Europe and Israel [31] Updated 22 Dec 2011
22 Nov 2011 Licensing Status Denali Concrete Management acquires EyeFite and all its assets including the licence for CF101 [10] Updated 23 Nov 2011
21 Nov 2011 Company Involvement Denali Concrete Management has been acquired by Can-Fite BioPharma [10] Updated 12 Dec 2011
31 Jul 2011 Phase Change - II/III Phase-II/III clinical trials in Plaque psoriasis in Romania (PO) Updated 19 Jun 2014
31 Jul 2011 Phase Change - II/III Phase-II/III clinical trials in Plaque psoriasis (monotherapy) in Israel, Bulgaria (PO) Updated 17 Oct 2012
31 Jul 2011 Phase Change - II/III Phase-II/III clinical trials in Psoriasis (monotherapy) in Europe (PO) Updated 17 Oct 2012
31 Jul 2011 Phase Change - II/III Phase-II/III clinical trials in Plaque psoriasis (monotherapy) in USA (PO) Updated 02 Aug 2011
31 Jul 2011 Trial Update CanFite BioPharma initiates enrolment in a phase II/III trial for Psoriasis in USA, Europe and Israel (NCT01265667) Updated 02 Aug 2011
31 Oct 2010 Trial Update Can-Fite BioPharma initiates enrolment in a Phase-II trial for Rheumatoid arthritis in Israel (NCT01034306) Updated 17 Oct 2012
01 Oct 2010 Phase Change - II Phase-II clinical trials in Ocular hypertension in Israel, Bulgaria (PO) (NCT01033422) Updated 27 May 2019
08 Sep 2010 Phase Change - III Phase-III clinical trials in Dry eyes in USA (PO) Updated 08 Sep 2010
06 Sep 2010 Patent Information Can-Fite Biopharma files for patent protection for piclidenoson (0.4mg daily) for Psoriasis in China, Hong Kong, India and South Korea [117] Updated 14 Jun 2017
30 Jun 2010 Phase Change - II Phase-II clinical trials in Glaucoma in Bulgaria (PO) Updated 09 Oct 2013
30 Jun 2010 Phase Change - II Phase-II clinical trials in Glaucoma in Israel (PO) Updated 08 Sep 2010
08 Jun 2010 Regulatory Status US FDA approves IND application for CF 101 in Psoriasis [62] Updated 09 Jun 2010
31 Oct 2009 Scientific Update Final pharmacodynamics data from a Preclinical trial in Osteoarthritis released by Can-Fite BioPharma [132] Updated 01 Apr 2010
15 Sep 2009 Patent Information Can-Fite BioPharma has patent protection for adenosine A3 receptor agonist in USA [126] [2] Updated 11 Mar 2020
09 Sep 2009 Scientific Update Efficacy and safety data from a phase II trial in Psoriasis released by Can-Fite BioPharma [72] Updated 11 Sep 2009
04 Jun 2009 Trial Update Can-Fite BioPharma completes enrolment in its phase II trial for Psoriasis in Israel and Europe Updated 04 Jun 2009
02 Jun 2009 Phase Change - II Phase-II clinical trials in Psoriasis in Europe (PO) Updated 04 Jun 2009
19 May 2009 Scientific Update Efficacy and adverse events data from a phase II trial in Dry eyes released by Can-Fite BioPharma [35] Updated 20 May 2009
05 Feb 2009 Trial Update Can-Fite BioPharma plans a phase II trial for Osteoarthritis in Israel (PO) (NCT00837291) Updated 16 Feb 2018
29 Jan 2009 Trial Update Can-Fite BioPharma completes enrolment in its phase II trial for Dry eyes in Israel Updated 30 Jan 2009
30 Dec 2008 Trial Update Can-Fite BioPharma completes enrolment in its phase IIb trial for Rheumatoid arthritis in Europe and Israel Updated 30 Dec 2008
01 Apr 2008 Trial Update Can-Fite BioPharma initiates enrolment in a Phase-IIb trial for Rheumatoid arthritis in Europe and Israel Updated 22 Aug 2008
19 Mar 2008 Phase Change - I Phase-I clinical trials in Rheumatoid arthritis in Japan (PO) Updated 19 Oct 2010
13 Mar 2008 Patent Information Can-Fite Biopharma files for patent protection for methods of production of piclidenoson in USA, China, India, Japan, Israel, Europe and India [117] Updated 14 Jun 2017
29 Feb 2008 Phase Change - II Phase-II clinical trials in Rheumatoid arthritis in Czech Republic (PO) Updated 31 Jan 2014
17 Jan 2008 Company Involvement Can-Fite BioPharma extends M-CRADA with the National Institutes of Health for the development of CF 101 in Uveitis Updated 18 Jan 2008
07 Jan 2008 Phase Change - Preclinical Preclinical trials in Uveitis in USA (PO) Updated 18 Jan 2008
31 Dec 2007 Phase Change - Preclinical Preclinical trials in Osteoarthritis in Israel (PO) Updated 31 Mar 2010
18 Jul 2007 Scientific Update Initial results from a phase IIb clinical trial in Rheumatoid arthritis added to the Rheumatic Disease therapeutic trials section [94] Updated 18 Jul 2007
30 Jun 2007 Phase Change - II Phase-II clinical trials in Psoriasis in Israel (PO) Updated 18 Jan 2008
26 Jun 2007 Scientific Update Data presented at the Annual European Congress of Rheumatology (EULAR-2007) added to the adverse events and Rheumatic Disease pharmacodynamics and therapeutic trials sections [99] Updated 26 Jun 2007
01 Feb 2007 Phase Change - II Phase-II clinical trials in Dry eyes in Israel (PO) Updated 05 Feb 2007
15 Jan 2007 Trial Update Can-Fite BioPharma completes enrolment in its phase IIb trial for rheumatoid arthritis in the US, Europe and Israel Updated 16 Jan 2007
31 Dec 2006 Phase Change - Preclinical Preclinical trials in Rheumatoid arthritis in Japan (PO) Updated 05 Jun 2007
29 Nov 2006 Patent Information Can-Fite Biopharma files for patent protection for adenosine A3 receptor agonists for Osteoarthritis in USA, Europe, Australia, Brazil, Canada, South Korea, China, Israel, Japan and Mexico [117] Updated 14 Jun 2017
16 Nov 2006 Scientific Update Clinical data from a media release have been added to the Rheumatic Disease pharmacodynamics section [97] Updated 16 Nov 2006
27 Sep 2006 Licensing Status CF 101 has been licenced to Seikagaku in Japan Updated 27 Sep 2006
11 Sep 2006 Phase Change - Preclinical Preclinical trials in Psoriasis in Israel (PO) Updated 16 Jan 2007
06 Sep 2006 Regulatory Status Can-Fite BioPharma has received approval from the Israeli Ministry of Health to conduct a phase II clinical trial with CF 101 in the treatment of dry eyes Updated 13 Sep 2006
30 Jun 2006 Phase Change - II Phase-II clinical trials in Rheumatoid arthritis in Poland (PO) Updated 31 Jan 2014
30 Jun 2006 Phase Change - II Phase-IIb clinical trials in Rheumatoid arthritis in Israel (PO) Updated 13 Sep 2006
30 Jun 2006 Phase Change - II Phase-IIb clinical trials in Rheumatoid arthritis in USA (PO) Updated 24 Jul 2006
24 Jun 2006 Phase Change - II Phase-II clinical trials in Rheumatoid arthritis in Ukraine (PO) Updated 22 Aug 2008
24 Jun 2006 Phase Change - II Phase-II clinical trials in Rheumatoid arthritis in Bulgaria (PO) Updated 21 Sep 2006
24 Jun 2006 Phase Change - II Phase-II clinical trials in Rheumatoid arthritis in Romania (PO) Updated 21 Sep 2006
24 Jun 2006 Phase Change - II Phase-II clinical trials in Rheumatoid arthritis in Serbia (PO) Updated 21 Sep 2006
20 Jun 2006 Scientific Update Results from a preclinical trial in patients with rheumatoid arthritis have been added to the pharmacokinetics section [133] Updated 23 Jun 2006
07 Feb 2006 Phase Change - Preclinical Preclinical trials in Dry eyes in Israel (PO) Updated 07 Feb 2006
20 Dec 2005 Scientific Update Data presented at the 69th Annual Scientific Meeting of the American College of Rheumatology and the 40th Annual Meeting of the Association of Rheumatology Health Professionals (ACR/ARHP-2005) have been added to the adverse events and Rheumatic disease therapeutic trials sections [98] Updated 20 Dec 2005
30 Nov 2005 Regulatory Status Can-Fite has filed an IND with the US FDA for rheumatoid arthritis Updated 13 Sep 2006
29 Apr 2005 Phase Change - Discontinued(I) Discontinued - Phase-I for Solid tumours in USA (PO) Updated 13 Sep 2006
29 Apr 2005 Phase Change - Discontinued(II) Discontinued - Phase-II for Colorectal cancer in Israel (PO) Updated 13 Sep 2006
30 Nov 2004 Scientific Update A clinical study has been added to the pharmacokinetics and adverse events section [134] Updated 30 Nov 2004
29 Oct 2004 Scientific Update Data presented at the 68th Annual Scientific Meeting of the American College of Rheumatology and the 39th Annual Meeting of the Association of Rheumatology Health Professionals (ACR/ARHP-2004) have been added to the Rheumatic Disease pharmacodynamics section [135] Updated 29 Oct 2004
04 Jun 2004 Scientific Update A preclinical study has been added to the Cancer pharmacodynamics section [136] Updated 04 Jun 2004
31 May 2004 Phase Change - I Phase-I clinical trials in Solid tumours in USA (PO) Updated 06 Jul 2004
01 Apr 2004 Scientific Update Data presented at the 95th Annual Meeting of the American Association for Cancer Research (AACR-2004) have been added to the Cancer therapeutic trials section [107] Updated 01 Apr 2004
30 Jun 2003 Phase Change - II Phase-II clinical trials in Rheumatoid arthritis in Israel (PO) Updated 24 Jul 2003
31 May 2003 Phase Change - II Phase-II clinical trials in Colorectal cancer in Israel (PO) Updated 18 Jun 2003
11 Apr 2003 Trial Update Can-Fite BioPharma has completed phase-I trials in the United Kingdom Updated 11 Apr 2003
31 Jan 2003 Licensing Status Can-Fite has signed an exclusive licence agreement with the NIH on a composition of matter patent that covers CF 101 Updated 13 Sep 2006
31 Dec 2002 Trial Update Can-Fite has completed a phase Ib clinical trial with CF 101 Updated 13 Sep 2006
31 Dec 2002 Phase Change - I Phase-I clinical trials in Colorectal cancer in United Kingdom (PO) Updated 11 Apr 2003
31 Dec 2002 Phase Change - I Phase-I clinical trials in Rheumatoid arthritis in United Kingdom (PO) Updated 11 Apr 2003
30 Jun 2002 Trial Update Can-Fite has completed a phase Ia clinical trial with CF 101 Updated 13 Sep 2006
31 Jan 2002 Trial Update Can-Fite has completed preclinical development of CF 101 Updated 13 Sep 2006
29 May 2001 Phase Change - Preclinical Preclinical development for Cancer in the US (PO) Updated 29 May 2001

References

  1. Can-Fite Initiates the Development of an A3AR Biomarker Test Kit to Predict Patients' Response to Company's Drugs.

    Media Release
  2. Can-Fite Updates on Clinical Milestone for its Phase III Rheumatoid Arthritis Study with Piclidenoson; Drugs Combating Rheumatoid Arthritis are Currently Introduced for the Treatment of the Coronavirus.

    Media Release
  3. Can-Fite to Explore the anti-Coronavirus Effects of Piclidenoson in Collaboration with Lewis Katz School of Medicine at Temple University.

    Media Release
  4. Can-Fite Signs Agreement with Kyongbo Pharm for the Distribution in South Korea of Piclidenoson in the Treatment of Psoriasis.

    Media Release
  5. Can-Fite Reports Second Quarter 2019 Financial Results & Provides Clinical Update.

    Media Release
  6. Can-Fite Signs Multi-Million Dollar Distribution Agreement for Piclidenoson in 3 European Countries with Gebro Holdings.

    Media Release
  7. Can-Fite Receives from Gebro Holdings $2,200,000 Payment as Part of Distribution Agreement for Piclidenoson in 3 European Countries.

    Media Release
  8. Can-Fite Announces Enrollment of First Patient in its Comfort(Tm) Phase III Trial of Piclidenoson in Psoriasis.

    Media Release
  9. Can-Fite Signs Multi-Million Dollar Development and Distribution Agreement for Piclidenoson and Namodenoson in China with CMS Medical.

    Media Release
  10. Denali Concrete Management Inc. Announces its Acquisition of CF101 for Ophthalmic Indications and the Completion of Above $6 Million Private Placement at $1.144 Per Share.

    Media Release
  11. Can-Fites Former Subsidiary OphthaliX Successfully Completes Merger with Wize Pharma.

    Media Release
  12. Can-Fite Signs Multi-Million Dollar Distribution Agreement for CF101 in Canada with Cipher Pharmaceuticals.

    Media Release
  13. Can-Fite Completed Patient Enrollment for the Phase II Trial in Dry Eye Syndrome with CF101.

    Media Release
  14. Can-Fite Signs MOU With the Korean Company Kwang Dong Pharmaceutical for Licensing CF101 Rights for Korea.

    Media Release
  15. Can-Fite and NIH Signed a Continuation of M-CRADA to Further Investigate CF101 for the Treatment of Uveitis.

    Media Release
  16. Can-Fite Receives FDA Approval to Conduct Phase I Study With CF102.

    Media Release
  17. Can-Fite Out Licenses Rights for its Drug, CF101, in Japan to the Seikagaku Corporation and Expects to Receive US$ 19.5 Million from Licensing Fees and Milestone Payments and Collect Substantial Royalties.

    Media Release
  18. Can-Fite Granted Patent on the Manufacturing of CF101 in Japan.

    Media Release
  19. Seikagaku Announces Termination of the License Agreement with Can-Fite BioPharma Ltd. for a Therapeutic Agent for Rheumatoid Arthritis.

    Media Release
  20. Can-Fite Executes Confidentiality Agreements with Pharmaceutical and Biotechnology Companies with Respect to Potential CF101 Commercialization Negotiations.

    Media Release
  21. Can-Fite Announces Pre-IND Submission to U.S. FDA for Piclidenoson in the Treatment of COVID-19 Infected Patients with Moderate-to-Severe Symptoms.

    Media Release
  22. Can Fite Received Approval for COVID-19 Clinical Trial in Israel, Patient Enrollment and Dosing to Commence Immediately.

    Media Release
  23. Can-Fite: Piclidenoson is Submitted for Compassionate Use Treatment for Coronavirus Patients in Israel.

    Media Release
  24. Can-Fite to Participate in Digital Bio-Europe Spring Partnering Conference; Looks to Partner on Co-Development of Piclidenoson for Coronavirus Treatment.

    Media Release
  25. OphthaliX to Conduct a Retrospective Analysis of the Phase III Dry Eye Syndrome Study Data Based on the A3 Adenosine Receptor Biomarker.

    Media Release
  26. OphthaliX to Retrospectively Analyze Phase III Dry Eye Syndrome Study Data Based on A3 Adenosine Receptor Biomarker.

    Media Release
  27. OphthaliX Announces Top-Line Results of Phase III Study with CF101 for Dry Eye Syndrome.

    Media Release
  28. Can-Fite Anticipates Results from Two Clinical Trials.

    Media Release
  29. Can-Fite BioPharma Announces Clinical and Corporate Developments for Near-Term Events.

    Media Release
  30. OphthaliX Inc. Announces the Completion of Patient Enrollment for the Phase 3 Dry Eye Syndrome Study.

    Media Release
  31. Denali Concrete Management Inc. Announces the Commencement of Patient Enrollment for the Phase 3 Dry Eye Syndrome Study.

    Media Release
  32. A Phase 3, Randomized, Double-Masked, Placebo-Controlled, Dose-Finding, Parallel-Group Study of the Safety and Efficacy of Daily CF101 Administered Orally in Patients With Moderate-to-Severe Dry Eye Disease

    ctiprofile
  33. OphthaliX Provides an Update on its Clinical Developments and Strategic Plans.

    Media Release
  34. Can-Fite BioPharma Announces the Initiation of Phase 3 in Dry Eye Syndrome.

    Media Release
  35. Can-Fite Announces Positive Results From Its Phase II Trial Treating Keratoconjunctivitis Sicca (Dry Eye Syndrome) With CF101.

    Media Release
  36. Can-Fite Commences Phase II Clinical Trial for Additional Indication of Dry Eye Syndrome.

    Media Release
  37. OphthaliX Announces Phase II Glaucoma Data.

    Media Release
  38. A Phase 2, Randomized, Double-Masked, Placebo-Controlled, Parallel-Group Study of the Safety and Efficacy of Daily CF101 Administered Orally in Subjects With Elevated Intraocular Pressure

    ctiprofile
  39. OphthaliX Announces Completion of Patient Enrollment in Phase II Glaucoma Study for CF101.

    Media Release
  40. Can-Fite Reports Financial Results for Nine Months Ended September 30, 2014.

    Media Release
  41. Can-Fite Subsidiary OphthaliX Provides an Update on its Clinical Developments and Strategic Plans.

    Media Release
  42. Can-Fite Announces Upcoming 2015 Clinical Milestones for its Pipeline of Drugs in 4 Indications.

    Media Release
  43. Second Part of the Glaucoma Phase II study has been Approved in a European Country.

    Media Release
  44. Can-Fite BioPharma Receives Israeli MoH Approval to Conduct a Phase II Clinical Trial Evaluating the Efficacy of CF101 in Patients with Glaucoma.

    Media Release
  45. Can-Fite's Subsidiary OphthaliX to Present at Ophthalmology Futures European Forum.

    Media Release
  46. Can-Fite Announces 2013 Milestones and Corporate Strategy.

    Media Release
  47. Can-Fite BioPharma to Initiate Phase II Clinical Trial with CF101 for the Treatment of Glaucoma.

    Media Release
  48. A Phase 2, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study of the Efficacy and Safety of Daily CF101 Administered Orally for 12 Weeks to Patients With Osteoarthritis of the Knee

    ctiprofile
  49. Can-Fite Completes 50% Patient Enrollment in its Phase III Psoriasis Trial.

    Media Release
  50. A Phase 3, 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

    ctiprofile
  51. Can-Fite Reports Second Quarter 2018 Financial Results and Provides Clinical Update.

    Media Release
  52. Can-Fite Reports 2016 Financial Results & Provides Clinical Update.

    Media Release
  53. Can-Fite Reports Financial Results for Nine Months Ended September 30, 2016 & Provides Clinical Update.

    Media Release
  54. Can-Fite Announces 2016 Clinical Milestones for its Pipeline of Drugs in Six Indications.

    Media Release
  55. Can-Fite Successfully Completes Human Cardiodynamic Safety Trial for Piclidenoson.

    Media Release
  56. Can-Fite Completes Phase II/III Trial for CF101 in Treatment of Psoriasis.

    Media Release
  57. Can-Fite to Present CF101 Psoriasis Data at Late Breaking Session of the EADV Congress in Copenhagen on October 10, 2015.

    Media Release
  58. Can-Fite Reports Financial Results for Six Months Ended June 30, 2015.

    Media Release
  59. Can-Fite Reports First Quarter 2015 Results.

    Media Release
  60. Can-Fite Reports Top-Line Results from Phase II/III Trial for CF101 in Treatment of Psoriasis.

    Media Release
  61. Interim Analysis Supports Continuation of Can-Fite's Phase 2/3 Psoriasis Clinical Study with CF101.

    Media Release
  62. Can-Fite BioPharma Announces Opening of CF101 Dermatology IND with Phase 2/3 Psoriasis Protocol.

    Media Release
  63. Can-Fite Initiates Preparatory Work for Psoriasis Phase III Trial with CF101.

    Media Release
  64. A Phase 2/3 Randomized, Double-Blind, Placebo-Controlled, Dose-Finding Study of the Efficacy and Safety of Daily CF101 Administered Orally in Patients With Moderate-to-Severe Plaque Psoriasis.

    ctiprofile
  65. Can-Fite to Present New Clinical Data from Further Analysis of its Clinical Studies of CF101 for the Treatment of Rheumatoid Arthritis and Psoriasis at OneMedForum and Biotech Showcase held in San Francisco, California.

    Media Release
  66. Gospodinov D, David M, Gheorghe N, Hristakieva E, Mateev G, Purcaru A, et al. Treatment of Plaque-type Psoriasis with Oral CF101: Data from a Phase II/III Phase 2 Clinical Trial. AAD-2016 2016; abstr. 3344.

    Available from: URL: https://www.aad.org/eposters/view/Abstract.aspx?id=3344
  67. New Data Shows High Efficacy for Can-Fite's CF101 in Rheumatoid Arthritis and Psoriasis Patients.

    Media Release
  68. Can-Fite Completes Patient Enrollment in its Phase II/III Psoriasis Trial; Final Results are expected in Q1 2015.

    Media Release
  69. Can-Fite-Completed Patient Enrollment for the Phase II Trial in Psoriasis With CF101.

    Media Release
  70. A Phase 2, Randomized, Double-Blind, Dose-Ranging, Placebo-Controlled Study of the Safety and Activity of Daily CF101 Administered Orally in Patients With Moderate-to-Severe Plaque Psoriasis

    ctiprofile
  71. Can-Fite to Develop CF101 for Psoriasis, Among Other Indications; The Company Will Commence Preparations for Phase II Clinical Trial in Psoriasis.

    Media Release
  72. Can-Fite Announces Positive Results from its Psoriasis Phase II Trial with CF101.

    Media Release
  73. Can-Fite to Present the Anti-Inflammatory and Anti-Fibrogenic Effects of Namodenoson in NAFLD/NASH Pre-clinical Studies at the 2018 International Liver Congress of the European Association for the Study of the Liver (EASL).

    Media Release
  74. Can-Fite Reports 2017 Financial Results & Provides Clinical Update.

    Media Release
  75. Can-Fite Completes 50% Patient Enrollment in Phase III Rheumatoid Arthritis Study & Implements Interim Analysis.

    Media Release
  76. Can-Fite Announces Enrollment of First Patient in its ACRobat Phase III Trial of Piclidenoson in Rheumatoid Arthritis.

    Media Release
  77. A Phase 3, Randomized, Double-Blind, Active- and Placebo-controlled, Parallel-group Trial to Evaluate the Efficacy and Safety of CF101 Compared to Methotrexate in the Treatment of Early Rheumatoid Arthritis

    ctiprofile
  78. Can-Fite Gears Up for ACRobat, its Phase III Trial of Piclidenoson in Rheumatoid Arthritis.

    Media Release
  79. Can-Fite Receives IRB Approval to Commence Patient Enrollment in Phase II NAFLD/NASH Trial in Q1 2017.

    Media Release
  80. Can-Fite Reaches Agreement with EMA on Pivotal Phase III Clinical Trial with Piclidenoson (CF101) in Rheumatoid Arthritis.

    Media Release
  81. Can-Fite Files Clinical Trial Application in Canada for Piclidenoson Ahead of Upcoming Acrobat Rheumatoid Arthritis Phase III Study.

    Media Release
  82. Cipher Pharmaceuticals Reports 2015 Financial Results.

    Media Release
  83. Can-Fite Submits Phase III Protocol to IRB for CF101 in the Treatment of Rheumatoid Arthritis.

    Media Release
  84. A second pivotal trial of piclidenoson for the treatment of rheumatoid arthritis

    ctiprofile
  85. A Phase 2, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study of the Efficacy and Safety of Daily CF101 Administered Orally as Monotherapy for 12 Weeks to Patients With Active Rheumatoid Arthritis and Elevated Baseline Expression Levels of Peripheral Blood Mononuclear Cell A3 Adenosine Receptors.

    ctiprofile
  86. Can-Fite BioPharma Announces Top-Line Results of Phase IIb Study with CF101 as a Monotherapy for Rheumatoid Arthritis.

    Media Release
  87. Can-Fite's Level II ADRs Commence Trading on the U.S. OTC Markets.

    Media Release
  88. Can-Fite Completed Patient Enrollment for the Confirmatory Phase IIb Trial in Rheumatoid Arthritis Patients With CF101.

    Media Release
  89. Can-Fite: First Patient was enrolled to the Phase IIb Rheumatoid Arthritis Trial.

    Media Release
  90. Can-Fite: CF101 May Be Effective for the Treatment of Crohn's Disease.

    Media Release
  91. A Phase 2, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Dose-Finding Study of the Safety and Efficacy of Daily CF101 Administered Orally, When Added to Weekly Methotrexate, in Patients With Active Rheumatoid Arthritis.

    ctiprofile
  92. A Phase IIb Study Testing the Combination of Methotrexate and CF101 in Rheumatoid Arthritis Patients Failed to Achieve Primary Efficacy Endpoint.

    Media Release
  93. Can-Fite BioPharma Expands its Pipeline by Licensing Allosteric Modulators from Leiden University and the NIH.

    Media Release
  94. Can-Fite Reports Results of a Phase IIb Clinical Study in Rheumatoid Arthritis with CF101, an A3 Adenosine Receptor Agonist. The Results Support Further Clinical Development of CF101.

    Media Release
  95. Can-Fite Progresses Through Clinical Trials: Completed Enrolment of 250 Patients in Phase IIb Rheumatoid Arthritis (RA) Trial.

    Media Release
  96. Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study of the Safety and Efficacy of Daily CF101 Administered Orally, When Added to Weekly Methotrexate, in Patients With Active Rheumatoid Arthritis

    ctiprofile
  97. Can-Fite Presents Results Showing a Correlation between High Expression of the Receptor Target for Its Drug CF101 and Rheumatoid Arthritis Patients' Response to the Drug.

    Media Release
  98. Nahir AM, Reitblat T, Molad Y, Rosner I, Mader R, Caspi D, et al. Early phase II clinical trial of RA patients treated with CF101, an A(3) adenosine receptor agonist. 69th-ACR-40th-ARHP-Late 2005;12 (plus poster) abstr. L7.

  99. Fishman P, Strand V, Markovits D, Nahir M, Reitblat T, Molad Y, et al. Clinical evidence for utilizationof the A3 adenosine receptor as a target to treat rheumatoid arthritis: data from a phase II clinical trial. 2007-EULAR 2007; abstr. SAT0044.

  100. Phase I trial of CF 101.

    ctiprofile
  101. Can-Fite BioPharma: Seikagaku Corporation, the Exclusive Licensee of CF101 in Japan, Is to Commence Phase I Clinical Trial in Japan With CF101 for the Treatment of Rheumatoid Arthritis.

    Media Release
  102. SEIKAGAKU CORPORATION Consolidated Financial Results (Japan GAAP) (Summary) for the Fiscal 2012 (Year Ended March 31, 2013).

    Media Release
  103. OphthaliX to Initiate a Phase II study of CF101 for the Treatment of Uveitis.

    Media Release
  104. A Phase 2, Randomized, Double-Masked, Placebo-Controlled Study of the Safety and Efficacy of Daily CF101 Administered Orally to Subjects With Active, Sight-Threatening, Noninfectious Intermediate or Posterior Uveitis

    ctiprofile
  105. OphthaliX Successfully Completed Preclinical Studies Showing the Efficacy of CF101 for the Treatment of Anterior Uveitis.

    Media Release
  106. Can-Fite BioPharma Announces An Investment by New-York fund BPW Israel Ventures LLC and the Completion of a US$12 Million Financing Round.

    Media Release
  107. Can-Fite Announces Interim Results of Phase II Study of CF101 for the Treatment of Colorectal Cancer in a Late Breaking Abstract Presentation at AACR in Orlando.

    Media Release
  108. Can-Fite Initiates Phase I Multi-Center Trial of CF101 in Combination with Chemotherapy for Various Solid Tumors at Harvard Medical School.

    Media Release
  109. Can-Fite BioPharma Completes Two Phase I Trials of its Lead Anti-Cancer and Anti-Inflammatory Drug CF101.

    Media Release
  110. US Researchers Published Scientific Findings that are a Potential Breakthrough for Prevention of Neuropathic Pain by CF101.

    Media Release
  111. Can-Fite Successfully Completes Long-Term Toxicology Studies With CF101 in Full GLP Compliance With US FDA.

    Media Release
  112. Can-Fite Announces Exercise of Warrants for Cash Proceeds of $2.4 Million.

    Media Release
  113. Can-Fite Reports First Six Months 2014 Results.

    Media Release
  114. Can-Fite BioPharma Successfully Concludes $6,000,000 Public Offering With an Over-Subscription of 300%.

    Media Release
  115. Can-Fite Receives Notice of Allowance From U.S. Patent and Trademark Office for Osteoarthritis Drug.

    Media Release
  116. Can-Fite Issued Patent in Korea for Piclidenoson in the Treatment of Psoriasis.

    Media Release
  117. Can-Fite Biopharma Form 20-F, March 2017. Internet-Doc 2017;.

    Available from: URL: https://www.sec.gov/Archives/edgar/data/1536196/000121390016012161/f20f2015_canfitebiopharma.htm
  118. Can-Fite Granted Notice of Allowance for Patent Covering Manufacturing Process of CF101 in the U.S.

    Media Release
  119. Can-Fite Receives Notice of Allowance in U.S. for Psoriasis Patent.

    Media Release
  120. Can-Fite Reports First Quarter 2014 Results.

    Media Release
  121. Can-Fite CEO Issues Letter to Shareholders.

    Media Release
  122. OphthaliX Announces CF101 is Granted Patent in Japan for Intraocular Pressure a Key Cause of Glaucoma.

    Media Release
  123. European Patent Office Grants a Patent for the Treatment of Sjogren's Syndrome.

    Media Release
  124. Can-Fite Granted U.S. Patent for Utilization of A3 Adenosine Receptor as Biomarker to Predict Patient Response to CF101 in Autoimmune Inflammatory Indications.

    Media Release
  125. OphthaliX Announces Issuance of Chinese Patent for the Treatment of Dry Eye Disorders.

    Media Release
  126. Use of an adenosine A3 receptor agonist for inhibition of viral replication. Internet-Doc 2020;.

    Available from: URL: https://patents.google.com/patent/US7589075?oq=7589075
  127. Can-Fite granted US patent on CF101 for Rheumatoid Arthritis (RA). The patent confers exclusive right to CF101 in the treatment of RA until 2023.

    Media Release
  128. Can-Fite Files Two New Patent Applications Relating to Very Important Therapeutic Indications.

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  129. Drugs with Mechanism of Action Utilized by Namodenoson Are Recommended by Leading U.S. Researchers to Be Developed to Combat Liver Cancer.

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  130. Can-Fite Reports First Quarter 2017 Financial Results & Provides Clinical Update.

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  131. Can-Fite Reports Positive Results from Further Analysis of Phase II/III Psoriasis Trial.

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  132. Bar-Yehuda S, Rath-Wolfson L, Del Valle L, Ochaion A, Cohen S, Patoka R, et al. Induction of an antiinflammatory effect and prevention of cartilage damage in rat knee osteoarthritis by CF101 treatment. Arthritis-Rheum 2009;60(10):3061-3071.

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  133. The Drug CF101 Is Not Metabolized in the Liver and Can Be Used as Potential Therapy for Liver Related Conditions.

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  134. van Troostenburg A-R, Clark EV, Carey WDH, Warrington SJ, Kerns WD, et al. Tolerability, pharmacokinetics and concentration-dependent hemodynamic effects of oral CF101, an A3 adenosine receptor agonist, in healthy young men. Int-J-Clin-Pharmacol-Ther 2004;42(10):534-542.

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  135. Fishman P, Madi L, Yehuda SB, Rath-Wolfson L, Ochaion A, et al. Inhibition of adjuvant induced arthritis by an A3 adenosine receptor agonist is mediated via down-regulation of PKB/Akt. Arthritis-Rheum 2004;50 (Suppl.)(9):369-370.

  136. Fishman P, Bar-Yehuda S, Ohana G, Barer F, Ochaion A, et al. An agonist to the A(3) adenosine receptor inhibits colon carcinoma growth in mice via modulation of GSK-3-beta and NF-kappa-B. Oncogene 2004;23(14):2465-2471.

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  137. Can-Fite Files Patent Application to Treat Cytokine Release Syndrome, a Potentially Life-Threatening Complication of CAR-T Cell Therapy.

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  138. Szabo C, Hasko G, Scott G, et al. Effects of the selective A3 receptor agonist N6-(3-iodobenzyl)-adenosine-5'-N-methyluronamide on the production of pro-inflammatory mediators, and on the development of endotoxic shock and carrageenan induced arthritis. Naunyn-Schmiedebergs-Arch-Pharmacol 1998;358 (Suppl. 2)(1):730.

  139. Interim analysis of rheumatoid arthritis phase II clinical trial demonstrates strong activity of CF101 as an anti-rheumatics drug. Company-Communication 2005;[1 page].

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