Piclidenoson - Can-Fite Biopharma

At a glance

Originator Can-Fite BioPharma
Developer Can-Fite BioPharma; Fondazione Telethon
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
Phase II COVID 2019 infections
Preclinical Oculocerebrorenal syndrome
Discontinued Colorectal cancer; Dry eyes; Glaucoma; Ocular hypertension; Osteoarthritis; Rheumatoid arthritis; Solid tumours; Uveitis

Most Recent Events

30 Jan 2024 Ewopharma exercises its right to expand the distribution agreement with Can-Fite Biopharma to include the indication of pancreatic cancer
29 Jan 2024 Phase-III COMFORT-2 clinical trials in Plaque psoriasis (PO) prior to January 2024
30 Nov 2023 Can-Fite Biopharma plans a clinical trial for oculocerebrorenal syndrome

Development Overview

Introduction

Piclidenoson is a 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, uveitis and Lowe syndrome (oculocerebrorenal syndrome). 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. The drug modulates of signalling proteins like PI3K, PKA, PKB/Akt, IKK and NF-kB, resulting in de-regulation of the Wnt/β-catenin pathway and inhibition of inflammatory cytokine production. The company is developing both oral as well as topical formulation of piclidenoson. Oral formulation is in clinical development for plaque psoriasis in several countries. Topical formulation is in preclinical development for the treatment of plaque psoriasis in Israel. Clinical development of oral formulation for COVID-2019 infections, dry eye syndrome, glaucoma, ocular hypertension, uveitis, rheumatoid arthritis, solid tumours and colorectal cancer and preclinical development for osteoarthritis is discontinued. Preclinical development for oculocerebrorenal syndrome is underway in Israel.

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 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.

The company discontinued the clinical development for COVID-2019 infections in the US, Romania, Bulgaria and Israel, as it is focusing its resources on other clinical programmes.

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

Company Agreements

In March 2021, Can-Fite Biopharma entered a distribution agreement with Ewopharma for piclidenoson and namodenoson. Under the terms of the distribution agreement, Ewopharma will pay to Can-Fite $US2.25 million upfront with up to an additional $US40.45 million payable upon the achievement of regulatory and sales milestones plus 17.5% royalties on net sales. In exchange, Ewopharma will have the exclusive right to market and sell piclidenoson in Central Eastern European (CEE) countries and namodenoson in CEE countries and Switzerland. Ewopharma has the right to extend the distribution agreement to new indications that Can-Fite may identify for its drug candidates. In January 2024, Ewopharma exercised its right to expand the distribution agreement to include the indication of pancreatic cancer and the transaction terms of the distribution agreement are applicable to such indication.^[3]^[4]

In August 2023, Can-Fite Biopharma and Fondazione Telethon signed an agreement outlining their collaboration for the development of piclidenoson for the treatment of Lowe syndrome.^[5]

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.^[6]

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^[7]^[8]

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.^[9]^[10]^[11]

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.^[12]

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^[13]^[14]

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^[15].

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^[16]^[17].

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^[18].

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^[19]^[20]. 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^[21]. 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^[22].

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^[23].

Key Development Milestones

COVID-19 infections

In November 2021, Can-Fite Biopharma announced that it has taken a strategic decision to discontinue its COVID-2019 infections program and to focus its resources on other clinical programmes, all in advanced clinical trials^[24].

In November 2021, Can-Fite Biopharma announced that it has terminated the phase II trial in COVID-2019 infections as the company intends to focus its resources on other clinical programmes^[24]. The trial was initiated in March 2021 to evaluate the benefits of treatment with piclidenoson plus standard supportive care (SSC) vs. placebo plus SSC in patients hospitalized with moderate to severe COVID-19 infections. The randomised, double blind, placebo-controlled trial intends to enroll 40 patients in the US, Romania and Bulgaria. Patients are randomized in a 1:1 ratio to receive 2 mg Piclidenoson twice daily or placebo, and treated for up to 28 days. Efficacy will be assessed through standard measures of clinical and respiratory status at Day 29, including the proportion of patients alive and free of respiratory failure, as well as the proportion discharged home without need for supplemental oxygen. Safety and pharmacokinetic data will also be captured^[25]. Previously in September 2020, the US FDA issued a “safe to proceed” notice for an investigational new drug (IND) application of piclidenoson for a phase II study in COVID-19 infections. Can Fite Biopharma plans a phase II trial fin COVID-19 infections. ^[26]. Earlier, Can Fite Biopharma submitted the IND application to US FDA in July 2020. The IND application was based on feedback and guidance from the FDA from prior pre-IND advice^[27]^[28]^[29].

In July 2020, Can-Fite Biopharma announced that it has amended phase II COVID-19 study protocol based on inputs from US FDA and its pre-IND filing^[30]. In June 2020, the US FDA, in response to a previously filed pre-IND, provided a guidelines regarding potential use of piclidenoson for treatment of patients with COVID-2019 infections with moderate to severe symptoms. The response allows Can-Fite to proceed with submission of IND application to conduct a phase II trial. The planned trial intends to evaluate the efficacy and safety of piclidenoson, when added to the standard of care treatment, for COVID-19 infections. Previously 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^[31]^[32].

In April 2022, Can-Fite Biopharma completed the phase II trial that evaluated the safety and efficacy of piclidenoson (CAN-COR1; NCT04333472). In November 2021, the company had announced that it has terminated the trial in COVID-2019 infections as the company intends to focus its resources on other clinical programmes^[24]. The trial was initiated in June 2020. Patients were randomized 1:1 to receive Piclidenoson 2mg every 12 hours orally with standard care (intervention arm) or standard care alone (control arm). The duration of viral shedding, time to clinical recovery (TTCR) and treatment-emergent adverse events in 28 days were the primary endpoint of the trial. The randomised, open-label trial enrolled 6 patients in Israel and Bulgaria ^[33]^[34]. In April 2020, Can-Fite BioPharma received approval in Israel for COVID-2019 trial. In March 2020, Can-Fite BioPharma Ltd. had announced that it submitted piclidenoson for a compassionate use program to treat coronavirus patients to the Institutional Review Board in Israel^[35]^[36].

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^[37]^[2].

Dry eyes

Clinical development in dry eyes is discontinued for piclidenoson in 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^[38]^[39]^[40]^[41]^[42]^[43]^[44]^[45]. 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^[46].

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^[47].

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^[48]^[16]^[49].

Glaucoma and Ocular hypertension

As of October 2021, clinical development for piclidenoson in glaucoma and ocular hypertension is discontinued (Can-Fite BioPharma pipeline, October 2021).

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^[50]. 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)^[51]. The trial was initiated in October 2010, and enrolled 89 patients in Israel and Bulgaria. No safety issues were reported^[52]^[53]^[54]^[46]. Second cohort studying twice-daily 2mg of piclidenoson was approved by the Bulgarian regulatory authority in December 2014^[55]^[56]. In May 2010, Israeli Ministry of Health had approved the trial^[57]. 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^[53]^[40]^[58]^[59]^[60].

Osteoarthritis

As of October 2021, clinical development for piclidenoson in osteoarthritis is discontinued (Can-Fite BioPharma pipeline, October 2021).

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^[61].

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

Plaque psoriasis

In December 2023, Can-Fite Biopharma announced that it received a positive response from the US FDA on the Pediatric Study Plan for the treatment of children suffering from psoriasis with Piclidenoson^[62]. In August 2023, Can-Fite Biopharma announced that it submitted a pediatric study plan to the US FDA for the treatment of adolescents suffering from psoriasis with piclidenoson. The plan has been submitted to allow enrollment of adolescents with psoriasis to Can-Fite’s upcoming two phase III pivotal clinical psoriasis studies, aiming at registration of piclidenoson with both the FDA and the European Medicines Agency (EMA) for the treatment of plaque psoriasis^[63]

As of January 2024, Can-Fite Biopharma initiated pivotal Phase III COMFORT-2 trial to evaluate the efficacy and safety of piclidenoson in patients with moderate to severe plaque psoriasis^[64]^[65]

In June 2023, Can-Fite Biopharma announced that it has received positive feedback and advice from the US FDA with respect to non-clinical and clinical development and registration plans for piclidenoson for the treatment of patients with moderate to severe plaque psoriasis. The FDA provided advice and requested two phase III safety and efficacy trials and also encouraged the company to enroll adolescent patients due to the strong safety profile of the drug demonstrated in prior clinical studies. The company announced the intention to conduct two phase III trials in parallel, including adolescent patients^[66]. In April 2023, Can-Fite announced that it has received a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) with respect to the submission of a registration plan for a pivotal phase III clinical trial for the treatment of moderate to severe psoriasis. The pivotal phase III study and the safety of the 3 mg twice daily dose of piclidenoson were accepted by the agency. The Company intends to initiate a prospective double-blind, placebo-controlled and randomised clinical trial with piclidenoson aimed at demonstrating clinical safety and efficacy for the treatment of moderate to severe psoriasis sufficient to support a marketing authorization application^[67]. Earlier, in January 2023, Can-Fite Biopharma submitted a market registration plan to the European Medicines Agency (EMA) for piclidenoson for the treatment of moderate to severe plaque psoriasis.The company has submitted a comparable data package to the US FDA and expects a similar response. Registration plans for both the EMA and US FDA include final efficacy and safety results from Can-Fite’s successful COMFORT™ phase III study^[68]. As of August 2022, Can-Fite Biopharma announced their intentions to obtain marketing approval of piclidenoson from the US FDA^[69]. In July 2022, Can-Fite Biopharma announced plann to submit marketing plan to the US FDA and Marketing Authorization Application (MAA) to the European Medicines Agency for piclidenoson in moderate to severe psoriasis^[70]. In April 2021, Can-Fite Biopharma announced potential marketing registration filings and New Drug Application to the US FDA and Marketing Authorization Application (MAA) to the European Medicines Agency (EMA), for piclidenoson in the US and Europe. The Company initiated a series of preclinical studies recommended as requirement by the regulatory bodies. The data from the preclinical studies to be submitted with the phase III data to support the filings^[71]. In June 2022, a phase III COMFORT-1 trial, evaluating the efficacy and safety of piclidenoson in patients with moderate to severe plaque psoriasis, met its primary end point with statistically significant improvement in efficacy response when compared with placebo^[72]. In April 2022, Can-Fite completed the phase III COMFORT-1 trial in patients with moderate to severe plaque psoriasis (NCT03168256; EudraCT2017-000214-27; CF101-301PS). The study was designed to have four arms, piclidenoson 2 mg, 3 mg, 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 was initiated and dosed first patient in August 2018. Enrolment of 528 patients was completed in Israel, Bulgaria, Canada, Croatia, Moldova, Bosnia and Herzegovina, Poland, Serbia, and Romania. In September 2018, the first patient was dosed in Israel. The enrolment in the trial was completed in September 2021. In April 2021, Can-Fite conducted an interim analysis with an Independent Data Monitoring Committee (IDMC) which recommended based on the positive data and favorable safety profile to continue the patient enrolment. In October 2020, the Independent Data Monitoring Committee (IDMC), which conducted an interim analysis of the company’s phase III Comfort-1 trial of piclidenoson in the treatment of moderate-to-severe plaque psoriasis, recommended, based on the positive data, to continue the study with the original sample size and drop one dose group. An optimal dose has been found and the study can be concluded earlier than has been originally planned. In January 2022, the company announced that the study completed the enrolment of approximately 400 patients with moderate to severe plaque psoriasis. In September 2022, the company released updated clinical data from the trial^[73]^[74]^[75]^[76]^[77]^[78]^[11]^[78]^[79]^[80].

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^[81]. 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^[82]^[83]^[80].

As of April 2022, topical formulation of piclidenoson is in preclinical development for the treatment of plaque psoriasis. In the similar month, Can-Fite Biopharma released preliminary results from preclinical studies which evaluated the topical formulation in psoriasis model^[84].

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^[85].

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)^[86]. 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^[87]^[88]^[89]^[90]. 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^[91]^[92]^[93]^[94]. Interim results were reported in January 2014^[95]^[40]. 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^[96]^[97]. Enrolment of 326 patients was completed in June 2014, in the US, Bulgaria, Romania and Israel^[55]^[53]^[98].

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^[99]^[100]. 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^[48]^[101]. The study has met its primary objectives^[102].

In January 2022, Can-Fite released preclinical data of Piclidenoson for treatment of psoriasis in humans^[103] .

Rheumatoid arthritis (RA)

As of November 2020, clinical development for piclidenoson in rheumatoid arthritis is discontinued due to the lack of efficacy of the drug as per Can-Fite Biopharma's interim analysis^[26].

In November 2020, Can-Fite BioPharma terminated the phase III ACRobat trial intended to evaluate the efficacy and safety of piclidenoson as a first line treatment compared to methotrexate for the treatment of early rheumatoid arthritis due to interim analysis results (NCT02647762; CF101-301RA). 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 was initiated in October 2017 and enrolled 244 patients in Bosnia and Herzegovina, Canada, Israel, Romania, Serbia and Moldova^[104]^[105]^[106].The first patient was dosed in October 2017^[107]^[108]. 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^[109]^[110]^[82]^[111]. 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^[112]^[113]^[114]^[88]^[89]. 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^[97]. In April 2017, Can-Fite reported receiving approval from the Institutional Review Board (IRB) of the Barzilai Medical Centre in Israel. In October 2020, the Independent Data Monitoring Committee IDMC for the interim analysis of the Acrobat™ rheumatoid arthritis phase III study recommended not to continue this study. Before November 2020, the company conducted a detailed analysis which showed that although piclidenoson efficacy was significantly superior to placebo, the study missed the primary endpoint which was non-inferiority vs. the comparator methotrexate. The Company decided to stop this study and to focus on the developments that showed promising data including psoriasis, NASH and liver cancer. In November 2021, the company presented the data from the trial at the American College of Rheumatology Convergence 2021 (ACR/ARP-2021)^[115]^[26]^[76].

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^[111]^[116].

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^[117]. 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^[118]^[41]^[42]^[119]. Additional results were reported in January 2014^[95].

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^[120]^[121]^[122]^[123]. 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^[124]^[125].

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^[126]^[127]^[128].

Results have been reported from a phase IIa trial of piclidenoson in rheumatoid arthritis in Israel^[129]^[130]^[131].

Seikagaku Corporation has completed a phase I single-dosing trial of piclidenoson for the treatment of RA in Japan^[132]. Seikagaku's code is SI 615. Initiation of this trial triggered a payment of $US1 million to Can-Fite^[133]. 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^[134].

Uveitis

As of October 2021, clinical development for piclidenoson in uveitis is discontinued (Can-Fite BioPharma pipeline, October 2021).

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 ^[135]^[136].

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^[137].

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^[18].

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^[138]. Interim results showed that piclidenoson appeared to stabilise the disease for at least two months in at least a third of patients^[139].

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^[140].

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^[141].

Inborn metabolic brain disorders

As of August 2023, Preclinical development for inborn metabolic brain disorders is underway in Israel^[5].

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^[142].

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^[143].

Financing information: As at June 2021, Can-Fite Biopharma has received approximately $US 20 million in upfront and milestone payments to date with additional potential milestone payments of up to approximately $US 130 million, plus double-digit royalties on net sales following regulatory approval, considering the out-licensing agreements for namodenoson [see ADIS Insight drug profile800013700] and piclidenoson in several territories^[144].

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^[145].

During the first half of 2014, Can-Fite raised NIS15.9 million ($US4.62 million) for its expenses^[146].

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^[147].

In November 2011, Denali (later OphthaliX) raised more than $US6 million through private placement from investors, including Can-Fite^[13].

Patent Information

In November 2019, Can-Fite BioPharma announced that the U.S. Patent and Trademark Office issued patent number 10,265,337 entitled "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^[148]^[149].

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"^[150].

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^[151].

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^[151].

As of June 2014, Can-Fite portfolio includes 120 issued and pending patent applications^[152].

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^[82].

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^[151].

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^[152].

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^[153].

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^[154]^[21].

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^[155]. The same patent was granted in Japan in December 2015^[156].

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^[157]. 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^[158].

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^[159].

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^[160]^[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^[161].

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^[151]. 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^[162].

Drug Properties & Chemical Synopsis

Route of administration PO, Topical
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
A16 (Other Alimentary Tract and Metabolism Products)

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
A16 (Other Alimentary Tract and Metabolism Products)

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

Download PNG Download MOL file
CAS Registry Number 152918-18-8

Indication	Biomarker Function	Biomarker Name	Number of Trials
dry eyes	Outcome Measure	syndecan binding protein	1
intermediate uveitis	Detailed Description	adenosine A3 receptor	1
keratoconjunctivitis sicca	Outcome Measure	syndecan binding protein	1
plaque psoriasis	Detailed Description	adenosine A3 receptor	2
plaque psoriasis	Eligibility Criteria	adenosine A3 receptor	1
plaque psoriasis	Outcome Measure	Poly-g-D-glutamate Folic acid adenosine A3 receptor Adenosine 2 more biomarker names Show less	1 1 1 1
posterior uveitis	Detailed Description	adenosine A3 receptor	1
rheumatoid arthritis	Outcome Measure	Estrogen receptor alpha (ER alpha) C-reactive protein (CRP) adenosine A3 receptor acrosin 2 more biomarker names Show less	1 1 1 2
rheumatoid arthritis	Detailed Description	Estrogen receptor alpha (ER alpha) C-reactive protein (CRP) adenosine A3 receptor acrosin 2 more biomarker names Show less	1 4 2 1
rheumatoid arthritis	Eligibility Criteria	Rheumatoid factor crystallin, gamma D C-reactive protein (CRP) adenosine A3 receptor 2 more biomarker names Show less	1 1 3 1
rheumatoid arthritis	Official Title	Adenosine	1
rheumatoid arthritis	Brief Summary	adenosine A3 receptor	1

Drug Name	Biomarker Name	Biomarker Function
Piclidenoson - Can-Fite Biopharma		acrosin	Detailed Description, Outcome Measure
	Adenosine	Official Title, Outcome Measure
	adenosine A3 receptor	Brief Summary, Detailed Description, Eligibility Criteria, Outcome Measure
	C-reactive protein (CRP)	Detailed Description, Eligibility Criteria, Outcome Measure
	CFB	Outcome Measure
	crystallin, gamma D	Eligibility Criteria
	Estrogen receptor alpha (ER alpha)	Detailed Description, Outcome Measure
	Folic acid	Outcome Measure
	Poly-g-D-glutamate	Outcome Measure
	POTE ankyrin domain family member F	Outcome Measure
	Rheumatoid factor	Eligibility Criteria
	syndecan binding protein	Outcome Measure

Indication	Phase 0	Phase I	Phase II	Phase III	Phase IV
Uveitis	-	1	1	-	-
Ocular hypertension	-	1	1	-	-
Glaucoma	-	1	1	-	-
SARS-CoV-2 acute respiratory disease	-	-	1	-	-
Rheumatoid arthritis	-	2	3	2	-
Plaque psoriasis	-	1	1	4	-
Posterior uveitis	-	-	1	-	-
COVID 2019 infections	-	-	2	-	-
Osteoarthritis	-	1	1	-	-
Dry eyes	-	-	1	1	-
Keratoconjunctivitis sicca	-	-	1	1	-
Open-angle glaucoma	-	-	1	-	-
Intermediate uveitis	-	-	1	-	-

Indication	Qualifier	Patient Segment	Phase	Countries	Route / Formulation	Developers	Event Date
COVID 2019 infections	-	-	Phase II	Bulgaria	PO / unspecified	Can-Fite BioPharma	22 Nov 2021
COVID 2019 infections	-	-	Discontinued (II)	Israel	PO / unspecified	Can-Fite BioPharma	26 Nov 2021
COVID 2019 infections	-	Adjunctive treatment	Discontinued (II)	Bulgaria, Romania, USA	PO / unspecified	Can-Fite BioPharma	26 Nov 2021
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	-	-	Discontinued (II)	Bulgaria, Israel	PO / Tablet	Can-Fite BioPharma	19 Oct 2021
Ocular hypertension	-	-	Discontinued (II)	Bulgaria, Israel	PO / Tablet	Can-Fite BioPharma	19 Oct 2021
Oculocerebrorenal syndrome	-	-	Preclinical	Israel	unspecified / unspecified	Can-Fite BioPharma, Fondazione Telethon	24 Aug 2023
Osteoarthritis	-	-	Discontinued (Preclinical)	Israel	PO / unspecified	Can-Fite BioPharma	19 Oct 2021
Plaque psoriasis	-	Monotherapy	Phase III	Bosnia-Herzegovina, Bulgaria, Canada, Croatia, Israel, Moldova, Poland, Romania, Serbia	PO / Tablet	Can-Fite BioPharma	10 Dec 2019
Plaque psoriasis	-	-	Phase III	Unknown	PO / Tablet	Can-Fite BioPharma	29 Jan 2024
Plaque psoriasis	-	Monotherapy	Phase II/III	USA	PO / Tablet	Can-Fite BioPharma	31 Jul 2011
Plaque psoriasis	-	-	Preclinical	Israel	Topical / unspecified	Can-Fite BioPharma	05 Apr 2022
Rheumatoid arthritis	MTX-naïve MTX-naïve patients	Early-stage disease, In adults, In the elderly	Discontinued (III)	Canada, Israel, Moldova	PO / Tablet	Can-Fite BioPharma	30 Nov 2020
Rheumatoid arthritis	-	-	Discontinued (III)	Bosnia-Herzegovina, Romania, Serbia	PO / Tablet	Can-Fite BioPharma	30 Nov 2020
Rheumatoid arthritis	-	-	Discontinued (II)	Bulgaria, Czech Republic, Poland, USA, Ukraine	PO / Tablet	Can-Fite BioPharma	30 Nov 2020
Rheumatoid arthritis	-	-	Discontinued (I)	Japan	PO / Tablet	Can-Fite BioPharma	30 Nov 2020
Solid tumours	-	-	Discontinued (I)	USA	PO / unspecified	Can-Fite BioPharma	29 Apr 2005
Uveitis	-	Monotherapy	Discontinued (I)	USA	PO / Tablet	Can-Fite BioPharma	19 Oct 2021

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 T_max 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 C_max 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. AUC_inf 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, AUC_0-24h was 601 ± 163.6 ng.h/mL. Pharmacokinetic parameters were linearly proportional to dose^[168].

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^[167].

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^[96].
^[94]

Phase III:

In the phase III COMFORT™ trial, Piclidenoson showed a good safety profile. GI-related adverse events were 1% for Piclidenoson vs. 6% for otezla, nervous system disorders were 0.7% for Piclidenoson, 9.9% for Otezla and 3.3% for the placebo. The discontinuation rate was significantly higher for otezla compared with piclidenoson^[73]^[72]^[80].

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^[102].

Rheumatoid arthritis

Phase III

Results from the phase III ACRobat trial of piclidenoson for the treatment of early rheumatoid arthritis demonstrated that piclidenoson was safe and very well tolerated. The proportion of patients experiencing any treatment emergent adverse events (TEAEs) were similar for all groups (17%, 25%, 26%, and 29%, respectively) and the majority of TEAEs were mild^[115]^[108].

Phase II

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^[126].

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%)^[131].

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^[130].

Dry eyes

In a phase II, 12-week trial, piclidenoson was safe and well-tolerated in patients with moderate to severe dry eye syndrome^[48].

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^[50]^[51].

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^[168].

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^[170].

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^[172].

Results from preclinical studies demonstrated that piclidenoson treatment in mouse models of inborn metabolic brain disorders (Lowe syndrome) leads to a significant decrease of the urinary loss of proteins in diseased animals^[5]

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^[129].

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^[131].

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^[166].

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^[169].

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^[172].

In preclinical studies piclidenoson destroyed pathological skin cells. Results from study reported that, in a cell culture of human HaCaT cells, incubated with Piclidenoson, cell apoptosis was induced with an increase in the caspase protein, known to mediate apoptotic responses^[103] .

In an imiquimod-induced skin psoriasis model, daily treatment with topical piclidenoson significantly inhibited the psoriasis lesion in treated animals as measured by the psoriasis area severity index (PASI) calculated based on observation of erythema, thickness, scaling, and a score of skin lesions^[84].

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^[139].

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^[48].

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^[50]^[51].

Results from the phase III ACRobat trial of piclidenoson for the treatment of early rheumatoid arthritis demonstrated that piclidenoson's efficacy was significantly superior to placebo, although the study did not meet the primary endpoint which was noninferiority vs methotrexate. At 12 and 24 Weeks, ACR20, ACR50 and ACR70 response rates were overall similar between the piclidenoson 1mg (which was more effective than the 2mg dose) and the MTX groups. The clinical benefits of piclidenoson 1mg (as reflected in the ACR50 and ACR70 response rates) seemed more pronounced after 24 weeks^[115]^[108].

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^[118].

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^[126].

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^[173].

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^[130].

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)^[131].

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^[96]^[165]. 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^[90]^[94].

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^[102].

Plaque psoriasis:

Phase III:

The phase III COMFORT™ trial of Piclidenoson, in patients with moderate to severe plaque psoriasis, met its primary end point with statistically significant improvement in efficacy response. The study data demonstrate that patients treated with oral Piclidenoson 2 mg or 3 mg twice daily, had clinically equivalent efficacy responses. At week 16, patients receiving Piclidenoson 3 mg demonstrated statistically significant improvement when compared with placebo, as measured by the Psoriasis Area and Severity Index (PASI) 75 response: Piclidenoson 3 mg: 9.7% vs placebo: 2.6% (p < 0.04). Secondary endpoint parameters at week 32 comparing Piclidenoson to the active control drug, Otezla, revealed inferiority with respect to PASI 75 (17% vs 26.2%, respectively) and PASI 50 (34.1% vs 49.5%, respectively), but revealed superiority of Piclidenoson as compared to Otezla in the Psoriasis Disability Index (PDI) (20.5% vs 10.3%, respectively, p < 0.05). A linear increase in the response of patients to Piclidenoson was achieved along the study period, on week 48 reaching PASI 50 in 90% of patients, PASI 90 in 10% of patients and PDI improvement in 60% of patients^[72]^[80].

Organisation	Involvement	Countries
Can-Fite BioPharma	Originator	Israel
Can-Fite BioPharma	Owner	Israel
Cipher Pharmaceuticals	Market Licensee	Canada
Ewopharma	Market Licensee	Central Europe
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
Fondazione Telethon	Collaborator	Italy

Expected Date	Event Type	Description	Updated
31 Dec 2020	Trial Update	Can Fite BioPharma plans a phase II trial for COVID-2019 infections in the US ^[26]	15 Mar 2021
31 Jul 2020	Regulatory Status	Can Fite announces intention to submit IND application with the US FDA for COVID-2019 infections by end of July 2020 ^[30]	29 Jul 2020
07 Apr 2020	Trial Update	Can-Fite BioPharma plans a phase II for COVID-2019 infections in Israel (PO) (NCT04333472) (700320274)	12 Jun 2020
31 Dec 2018	Trial Update	Can-Fite plans to initiate a pivotal, registrational phase III study in Plaque psoriasis in 2018 (NCT03168256) ^[163]	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) ^[164]	01 Nov 2017

Event Date	Update Type	Comment
30 Jan 2024	Licensing Status	Ewopharma exercises its right to expand the distribution agreement with Can-Fite Biopharma to include the indication of pancreatic cancer ^[4] Updated 02 Feb 2024
29 Jan 2024	Phase Change - III	Phase-III COMFORT-2 clinical trials in Plaque psoriasis (PO) prior to January 2024 ^[64] Updated 01 Feb 2024
30 Nov 2023	Trial Update	Can-Fite Biopharma plans a clinical trial for oculocerebrorenal syndrome Updated 11 Dec 2023
24 Aug 2023	Licensing Status	Fondazione Telethon and Can-Fite Biopharma agree to co-develop Piclidenoson ^[5] Updated 28 Aug 2023
24 Aug 2023	Phase Change - Preclinical	Preclinical trials in Oculocerebrorenal syndrome in Israel (unspecified route) Updated 28 Aug 2023
24 Aug 2023	Scientific Update	Pharmacodynamics data from a preclinical study in Oculocerebrorenal syndrome released by Can-Fite Biopharma ^[5] Updated 28 Aug 2023
18 Aug 2023	Regulatory Status	Can-Fite Biopharma submits pediatric study plan to US FDA for Plaque psoriasis (In adolescents) ^[63] Updated 21 Aug 2023
29 Jun 2023	Regulatory Status	Can-Fite Biopharma receives positive feedback from the US FDA with respect to non-clinical and clinical development and registration plans for phase III trial for Plaque psoriasis ^[66] Updated 03 Jul 2023
29 Jun 2023	Trial Update	Can-Fite Biopharma plans two phase III trials in Plaque psoriasis ^[66] Updated 03 Jul 2023
10 Apr 2023	Regulatory Status	Can-Fite Biopharma receives positive opinion from CHMP of the EMA with respect to the submission of a registration plan for a pivotal phase III trial for moderate to severe psoriasis ^[67] Updated 13 Apr 2023
10 Apr 2023	Trial Update	Can-Fite Biopharma plans phase III registrational trial for Psoriasis in the European Union (PO) ^[67] Updated 13 Apr 2023
10 Jan 2023	Regulatory Status	Can-Fite submits market registration plan to the European Medicines Agency for piclidenoson for the treatment of Plaque psoriasis ^[68] Updated 17 Jan 2023
12 Sep 2022	Trial Update	Can-Fite plans a pivotal Phase III registration trial for Psoriasis ^[73] Updated 05 Oct 2022
12 Sep 2022	Scientific Update	Updated adverse events data from a phase III COMFORT™ trial in Plaque psoriasis released by Can-Fite BioPharma ^[73] Updated 15 Sep 2022
22 Aug 2022	Regulatory Status	Can-Fite Biopharma plans to submit regulatory application to US FDA and EMA for the marketing approval in Plaque psoriasis ^[69] Updated 24 Aug 2022
29 Jun 2022	Scientific Update	Efficacy and adverse events data from a phase II COMFORT™ trial in Plaque psoriasis released by Can-Fite BioPharma ^[72] Updated 05 Jul 2022
27 Apr 2022	Trial Update	Can-Fite BioPharma completes a phase III trial in Plaque psoriasis (Monotherapy) in Croatia, Bulgaria, Bosnia-Herzegovina, Serbia, Poland, Moldova, Romania (PO) (NCT03168256) Updated 05 Jul 2022
21 Apr 2022	Trial Update	Can-Fite BioPharma completes a phase II trial in COVID-2019 infections in Israel and Bulgaria (PO) (NCT04333472) Updated 05 May 2022
05 Apr 2022	Phase Change - Preclinical	Preclinical trials in Plaque psoriasis in Israel (Topical) before April 2022 ^[84] Updated 07 Apr 2022
05 Apr 2022	Scientific Update	Pharmacodynamics data from a preclinical trial in Plaque psoriasis released by Can-Fite BioPharma ^[84] Updated 07 Apr 2022
13 Jan 2022	Scientific Update	Pharmacodynamics data from a preclinical trial in psoriasis released by Can-Fite ^[103] Updated 18 Jan 2022
29 Dec 2021	Biomarker Update	Biomarkers information updated Updated 31 Dec 2021
26 Nov 2021	Phase Change - Discontinued(II)	Discontinued - Phase-II for COVID-2019 infections (Adjunctive treatment) in Romania, Bulgaria and USA (PO) ^[24] Updated 02 Dec 2021
26 Nov 2021	Phase Change - Discontinued(II)	Discontinued - Phase-II for COVID-2019 infections in Israel (PO) ^[24] Updated 02 Dec 2021
22 Nov 2021	Phase Change - II	Phase-II clinical trials in COVID-2019 infections in Bulgaria (PO) (NCT04333472) Updated 05 May 2022
05 Nov 2021	Scientific Update	Efficacy and adverse events data from a phase III ACRobat trial in Rheumatoid arthritis presented at the American College of Rheumatology Convergence 2021 (ACR/ARP-2021) ^[115] Updated 04 Jan 2022
19 Oct 2021	Phase Change - Discontinued(I)	Discontinued - Phase-I for Uveitis (Monotherapy) in USA (PO) before October 2021 (Can-Fite BioPharma pipeline, October 2021) Updated 19 Oct 2021
19 Oct 2021	Phase Change - Discontinued(II)	Discontinued - Phase-II for Glaucoma in Bulgaria, Israel (PO) before October 2021 (Can-Fite BioPharma pipeline, October 2021) Updated 19 Oct 2021
19 Oct 2021	Phase Change - Discontinued(II)	Discontinued - Phase-II for Ocular hypertension in Israel, Bulgaria (PO) before October 2021 (Can-Fite BioPharma pipeline, October 2021) Updated 19 Oct 2021
19 Oct 2021	Phase Change - Discontinued(Preclinical)	Discontinued - Preclinical for Osteoarthritis in Israel (PO) before October 2021 (Can-Fite BioPharma pipeline, October 2021) Updated 19 Oct 2021
02 Sep 2021	Trial Update	Can-Fite completes enrolment in a phase-III clinical trials in Plaque psoriasis (Monotherapy) in Romania (PO) (NCT03168256) ^[75] Updated 08 Sep 2021
22 Apr 2021	Phase Change - II	Phase-II clinical trials in COVID-2019 infections (Adjunctive treatment) in Bulgaria (PO), Romania (PO) Updated 29 Apr 2021
21 Apr 2021	Regulatory Status	Can-Fite BioPharma announces intention to submit MAA to European Medicines Agency for Psoriasis ^[71] Updated 23 Apr 2021
21 Apr 2021	Regulatory Status	Can-Fite BioPharma announces intention to submit NDA to US FDA for Plaque psoriasis ^[71] Updated 23 Apr 2021
16 Mar 2021	Licensing Status	Can-Fite Biopharma entered a distribution agreement with Ewopharma in Central Eastern Europe ^[3] Updated 18 Mar 2021
08 Mar 2021	Phase Change - II	Phase-II clinical trials in COVID-2019 infections (Adjunctive treatment) in USA (PO) ^[25] Updated 08 Mar 2021
31 Dec 2020	Trial Update	Can-Fite Biopharma plans a phase II trial for Osteoarthritis ^[149] Updated 06 Jul 2021
30 Nov 2020	Phase Change - Discontinued(I)	Discontinued - Phase-I for Rheumatoid arthritis in Japan (PO) ^[26] Updated 19 Oct 2021
30 Nov 2020	Phase Change - Discontinued(II)	Discontinued - Phase-II for Rheumatoid arthritis in Poland, Czech Republic, Bulgaria, Ukraine, USA (PO) ^[26] Updated 19 Oct 2021
30 Nov 2020	Phase Change - Discontinued(III)	Discontinued - Phase-III for Rheumatoid arthritis (Early-stage disease, In the elderly, In adults) in Moldova, Canada, Canada, Israel (PO) ^[26] Updated 19 Oct 2021
30 Nov 2020	Phase Change - Discontinued(III)	Discontinued - Phase-III for Rheumatoid arthritis in Romania, Serbia, Bosnia-Herzegovina (PO) ^[26] Updated 19 Oct 2021
30 Nov 2020	Trial Update	Can-Fite Biopharma terminates Phase-III clinical trials in Rheumatoid arthritis in Bosnia-Herzegovina, Serbia, Romania, Moldova, Isarel, Canada due to interim analysis (PO) (NCT02647762) Updated 19 Oct 2021
30 Nov 2020	Trial Update	Can Fite BioPharma plans a phase II trial for COVID-2019 infections in the US ^[26] Updated 15 Mar 2021
06 Oct 2020	Regulatory Status	A separate Independent Data Monitoring Committee for the interim analysis of the Acrobat™ rheumatoid arthritis phase III study recommends not to continue the study ^[76] Updated 08 Oct 2020
06 Oct 2020	Regulatory Status	The Independent Data Monitoring Committee recommends to continue the phase III Comfort™ trial of piclidenoson for Plaque psoriasis based on the positive data ^[76] Updated 08 Oct 2020
03 Sep 2020	Regulatory Status	Can-Fite BioPharma receives safe to proceed notice from the US FDA for IND application in COVID-19 infections ^[28] Updated 03 Sep 2020
28 Jul 2020	Regulatory Status	Can Fite Biopharma submits an IND application to the US FDA in COVID-19 infections ^[29] Updated 29 Jul 2020
28 Jul 2020	Regulatory Status	Can-Fite Biopharma receives feedback from the US FDA in in pre-IND advice meeting in COVID-2019 infections ^[29] Updated 29 Jul 2020
15 Jul 2020	Regulatory Status	Can Fite announces intention to submit IND application with the US FDA for COVID-2019 infections by end of July 2020 ^[30] Updated 29 Jul 2020
01 Jun 2020	Phase Change - II	Phase-II clinical trials in COVID-2019 infections in Israel (PO) ^[33] (NCT04333472) Updated 12 Jun 2020
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 ^[32] Updated 19 May 2020
18 May 2020	Trial Update	Can-Fite Biopharma plans a phase II trial in COVID-2019 infections (Adjunctive treatment) in USA ^[31] ^[32] 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 ^[35] 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 12 Jun 2020
26 Mar 2020	Trial Update	Can-fite submitted a compassionate use treatment for Coronavirus patients in Israel ^[36] Updated 26 Mar 2020
18 Mar 2020	Phase Change - Preclinical	Preclinical trials in COVID-2019 infections in Israel (unspecified route) ^[37] 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) ^[37] 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 ^[6] 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 ^[106] Updated 05 Feb 2020
10 Dec 2019	Phase Change - III	Phase-III clinical trials in Plaque psoriasis in Canada (PO) ^[78] Updated 16 Dec 2019
30 Nov 2019	Patent Information	Can-Fite Biopharma has patent protection for piclidenson in USA ^[149] Updated 06 Jul 2021
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 ^[7] Updated 05 Aug 2019
05 Feb 2019	Patent Information	Can-Fite BioPharma receives patent allowance for A3 adenosine receptor (A3AR) agonists in USA ^[148] 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 ^[148] Updated 06 Feb 2019
15 Sep 2018	Phase Change - III	Phase-III clinical trials in Plaque psoriasis (Monotherapy) in Romania (PO) (NCT03168256) Updated 08 Sep 2021
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) ^[11] Updated 24 Aug 2018
06 Aug 2018	Licensing Status	Piclidenoson licensed to CMS Medical in China, Hong Kong, Macao and Taiwan ^[12] 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) ^[163] Updated 11 Sep 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 ^[9] Updated 12 Jan 2018
17 Nov 2017	Licensing Status	Can-Fite BioPharma terminates its licence to OphthaliX for piclidenoson in Opthalmic diseases ^[14] 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 ^[150] Updated 23 Oct 2017
07 Aug 2017	Trial Update	Can-Fite completes Human cardiodynamic safety trial for piclidenoson ^[85] 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 ^[81],,^[154] (NCT02647762) ^[164] Updated 01 Nov 2017
16 May 2017	Regulatory Status	Can-Fite BioPharma files a clinical trial application with the Health Canada in Canada ^[112] 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 ^[151] 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 ^[151] 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 ^[151] 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 ^[151] 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 ^[82] 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 ^[50] 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 ^[111] 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 74^th Annual Meeting of the American Academy of Dermatology (AAD-2016) ^[96] 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 ^[83] Updated 14 Jan 2016
17 Dec 2015	Patent Information	OphthaliX receives patent protection for piclidenoson in Japan ^[156] Updated 19 Dec 2015
07 Dec 2015	Trial Update	OpthaliX completes enrolment in a phase II trial in Glaucoma in Israel and Bulgaria ^[52] Updated 08 Dec 2015
28 Aug 2015	Licensing Status	Piclidenoson is no longer licensed to Seikagaku Corporation in Japan ^[22] 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 ^[152] Updated 13 Jun 2015
27 Apr 2015	Scientific Update	Updated efficacy data from a phase II/III trial in Psoriasis released by Can-Fite ^[165] 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 ^[90] Updated 02 Apr 2015
25 Mar 2015	Licensing Status	CF 101 market licensed to Cipher Pharmaceuticals in Canada ^[15] Updated 25 Mar 2015
20 Feb 2015	Patent Information	Can-Fite receives patent allowance for CF 101 in USA ^[153] 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 ^[86] 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 ^[98], 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 ^[135] 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 ^[91] 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 ^[44] 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 ^[44] Updated 22 Dec 2011
22 Nov 2011	Licensing Status	Denali Concrete Management acquires EyeFite and all its assets including the licence for CF101 ^[13] Updated 23 Nov 2011
21 Nov 2011	Company Involvement	Denali Concrete Management has been acquired by Can-Fite BioPharma ^[13] 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 ^[151] 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 ^[92] Updated 09 Jun 2010
31 Oct 2009	Scientific Update	Final pharmacodynamics data from a Preclinical trial in Osteoarthritis released by Can-Fite BioPharma ^[166] Updated 01 Apr 2010
15 Sep 2009	Patent Information	Can-Fite BioPharma has patent protection for adenosine A3 receptor agonist in USA ^[160] ^[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 ^[102] 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 ^[48] 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 ^[151] 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 ^[126] 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 ^[131] 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 ^[151] Updated 14 Jun 2017
16 Nov 2006	Scientific Update	Clinical data from a media release have been added to the Rheumatic Disease pharmacodynamics section ^[129] 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 ^[167] 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 ^[130] 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 ^[168] Updated 30 Nov 2004
29 Oct 2004	Scientific Update	Data presented at the 68^th Annual Scientific Meeting of the American College of Rheumatology and the 39^th Annual Meeting of the Association of Rheumatology Health Professionals (ACR/ARHP-2004) have been added to the Rheumatic Disease pharmacodynamics section ^[169] Updated 29 Oct 2004
04 Jun 2004	Scientific Update	A preclinical study has been added to the Cancer pharmacodynamics section ^[170] 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 ^[139] 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

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