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  .
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   .
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   .
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         . 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  .
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  .
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    .
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  . 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)  . The trial was initiated in October 2010, and enrolled 89 patients in Israel and Bulgaria. No safety issues were reported     . Second cohort studying twice-daily 2mg of piclidenoson was approved by the Bulgarian regulatory authority in December 2014   . In May 2010, Israeli Ministry of Health had approved the trial  . 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      .
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  .
In April 2014, Can-Fite BioPharma reported that it had plans to initiate a phase II study in osteoarthritis  .
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  . The trial initiation will prompt a milestone payment of $US348600 to Can-Fite from Gebro Holding   . As at September 2018, the first patient has been dosed in Israel   .
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  . 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    .
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  .
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)  . 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     . 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     . Interim results were reported in January 2014   . 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   . Enrolment of 326 patients was completed in June 2014, in the US, Bulgaria, Romania and Israel    .
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   . 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   . The study has met its primary objectives  .
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   . In February 2020, Can-Fite Biopharma completed enrolment of 50% patients in the trial  .The first patient was dosed in October 2017   . 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     . 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      . 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  . 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   .
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  . 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     . Additional results were reported in January 2014  .
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     . 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   .
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    .
Results have been reported from a phase IIa trial of piclidenoson in rheumatoid arthritis in Israel    .
Seikagaku Corporation has completed a phase I single-dosing trial of piclidenoson for the treatment of RA in Japan  . Seikagaku's code is SI 615. Initiation of this trial triggered a payment of $US1 million to Can-Fite  . 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  .
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   .
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  .
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  .
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  . Interim results showed that piclidenoson appeared to stabilise the disease for at least two months in at least a third of patients  .
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  .
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  .
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  .
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  .
In January 2020, Can-Fite BioPharma raised $2.4 million following exercise certain warrants. The company intends to use the funds for working capital including progression of its phase III trials in psoriasis and the rheumatoid arthritis and for the preparatory work for the phase III liver cancer study [see Adis Insight Drug Profile 800013700] as well as other general corporate purposes  .
During the first half of 2014, Can-Fite raised NIS15.9 million ($US4.62 million) for its expenses  .
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  .
In November 2011, Denali (later OphthaliX) raised more than $US6 million through private placement from investors, including Can-Fite  .