On February 20, 2018 Kancera AB (publ) hereby reports results from a Phase I study in healthy subjects with the immunoregulating drug candidate KAND567 (Press release, Kancera, FEB 20, 2018, View Source;releaseID=1434356 [SID1234524054]). The study shows that KAND567 is safe and well-tolerated up to 500 mg twice daily for 7 days. The plasma levels achieved with KAND567 at that dose are five to ten times higher than the calculated effective level for therapeutic effect in humans. Upon further increase of the dose, a reversible increase in markers for liver effects was noted. The results also showed that KAND567 blocks the Fractalkine system by reducing the number of Fractalkine receptors on the surface of immune cells. Furthermore, results are reported from three preclinical disease models showing cardiovascular protection properties of KAND567. The company is now evaluating the conditions for continued clinical development of KAND567 against cancer and inflammatory cardiovascular injuries, e.g. in connection with infarction.
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Design
The study was a randomized, double-blind, placebo-controlled Phase I study in healthy subjects aimed at studying safety, tolerability and pharmacokinetic properties (uptake, plasma concentrations and excretion) of KAND567. In a first part of the study, KAND567 was given in increasing single doses (8 – 2500 mg) to groups of healthy subjects where a group received KAND567 with and without food on different occasions. In the second part of the study, KAND567 was given in increasing doses up to 7 days (300 – 800 mg twice a day). In total, 82 subjects have been included in the study, 62 of which received active substance and 20 placebo.
Results
Results from the single dose part of the study showed that KAND567 was safe and tolerable in single doses up to 2500 mg as no clinically relevant side effects were noted. The results also show that KAND567 is absorbed efficiently from the intestine to the blood independent of food, and that KAND567 stays in the blood long enough in humans to allow dosage one to two times a day.
In the multiple dose part of the study, KAND567 proved safe and well-tolerated at doses up to 500 mg twice a day (total 1000 mg) for 7 days. This dose is five to ten times higher than the calculated effective dose in humans. Dose-limiting side effects at 800 mg twice a day (total 1600 mg) included gastric side effects in the form of diarrhea and a clinically relevant increase in markers for hepatic impairment, which returned to normal level after the end of treatment. No other clinically relevant side effects of KAND567 were noted.
In the multiple dose part of the study, the effect of KAND567 on the Fractalkine system in the immune cells of the blood was also studied. After 7 days of treatment with KAND567 (300 mg, twice daily), the number of Fractalkine receptors on the cell surface significantly decreased in specific immune cells such as NK cells, T cells and monocytes. These findings, along with in vitro findings showing that KAND567 in whole blood blocks the Fractalkine signal in human immune cells at low concentrations, show that KAND567 blocks the Fractalkine system through two co-operating mechanisms.
"It is encouraging that the results of the Phase I study show that KAND567 blocks the Fractalkine system as hoped and the drug candidate is well tolerated in doses up to levels that are five to ten times above the calculated effective dose," says Thomas Olin, CEO Kancera.
"We will now continue to deepen our understanding of how KAND567 affects the liver in relation to the desired pharmacological effects to develop a clinical development plan for both chronic and acute treatment of inflammatory diseases and cancer, eg lymphoma. There is support for the benefits of short-term treatment with KAND567 against, for example, myocardial infarction, giving the project additional opportunities because of the good safety margin we have seen in short term treatment, "says Thomas Olin.
Strategy for continued evaluation and development of KAND567
In parallel with in-depth studies of efficacy and safety for KAND567, Kancera AB has started preparations for a possible clinical development program to study the effect of KAND567 in the treatment of lymphoma (blood cancer) and cardiovascular disease. This focus has the potential to result in two products; a tablet for oral longer-term treatment of lymphoma and a product for short term treatment following myocardial infarction.
The focus on lymphoma and inflammation of the heart vessels is based on the following results.
Lymphoma (a form of blood cancer)
In 2017, results were published that support the correlation of the Fractalkine system in immune cells with an aggressive disease in lymphoma and suggest that a blockade of the Fractalkine system could inhibit the disease (1). In view of these results, as well as Kancera AB’s results from the clinical Phase I study, which show that KAND567 affects the identified immune cells, Kancera AB has initiated a collaboration with Karolinska Institutet. The collaboration aims to prepare for a clinical study by evaluating biomarkers for the Fractalkine system in blood and cancer tissue and the effect of KAND567 on these biomarkers (in isolated blood from the patients), which may provide information on which patients could benefit clinically from treatment with KAND567.
Inflammation of the blood vessels, for example in myocardial infarction
In three preclinical animal models, KAND567 has shown cardiovascular protective anti-inflammatory properties by significantly reducing infarct size (internal report), stabilizing vascular plaque (internal report) that can cause infarction and reversing relapse (restenosis) after widening of the coronary artery with so-called vessel stents (2). These studies were carried out when the project was owned by AstraZeneca. Publications of independent research groups also support blocking of the Fractalkine system to protect the heart in the context of myocardial infarction (in animal models) (3) and that the Fractalkine system is an independent risk marker and driving factor behind the inflammation of the blood vessels and the heart muscle after a heart attack in humans (4). Together, these results provide support for KAND567 as a drug candidate for the treatment of vascular disease. The results also provide information on appropriate biomarkers for the identification of patients who could benefit from such treatment.
Oncotarget. 2017 Nov 3; 8(54): 92289–92299
Biomaterials. 2015 Nov;69:22-9
Exp Physiol. 100.7. 2015: 805–817
J Clin Invest. 2015 Aug 3; 125(8): 3063–3076
About the Fractalkine project
KAND567 is an orally available small molecule that blocks CX3CR1, the Fractalkine receptor. Fractalkine is an immunomodulating factor, known as a chemokine, which transmits signals via the CX3CR1 receptor, thereby controlling the function of immune cells and cancer cells. The amount of Fractalkine and its receptor CX3CR1 has been shown to be elevated in several cancers, inflammatory diseases and in heart disease.
Kancera AB’s drug candidate KAND567 is the most advanced small molecule drug candidate against CX3CR1 and has been shown to be effective against inflammation, pain and cardiovascular disease in several preclinical disease models.