”We have demonstrated that KAND567 is safe and tolerable at the dose level expected to be effective for treatment of high-risk
FRACTAL is an explorative phase IIa, randomized, two-armed parallel-group, placebo-controlled, double-blind, multi-centre trial with the primary objective to evaluate safety and tolerability and the secondary objective to evaluate cardio-protective effects after intravenous and oral administration of KAND567 in
In total, 71 patients were recruited to the study and 61 patients completed the required steps to be considered fully evaluable. The selected dosage of KAND567 resulted in an adequate plasma concentration of the drug candidate and expected effect on the fractalkine axis.
The analysis of the primary endpoints based on NHS’s end of study report shows
- that KAND567 and placebo had similar safety profiles. Accordingly, the trial oversight committee at
NHS concluded that KAND567 met the primary endpoint for safety and tolerability in myocardial infarction patients.
The analysis of the secondary endpoints shows signals of heart-protective effects:
- reduction of intramyocardial hemorrhage incidence (38% in the KAND567 group vs 57% in the placebo group). The level in the placebo group is in line with prior studies in high-risk
STEMI and hence the reduction in the KAND567 group is perceived to be clinically relevant as IM hemorrhage is strongly correlated with an increased risk of developing heart failure. - reduction of left ventricular (LV) thrombosis incidence (3% in the KAND567 group vs 15% in the placebo group). The level in the placebo group is in line with prior studies in high-risk
STEMI and hence the reduction in the KAND567 group is perceived to be clinically relevant as LV thrombosis is strongly correlated with an increased risk of cardioembolic stroke or systemic embolism. - all other markers of cardiac function and integrity were similar between patients receiving KAND567 or placebo, respectively, but all were numerically in favor of the KAND567 group when comparing change Day 3 and Day 90.
About the FRACTAL study design
The FRACTAL study is an explorative clinical phase IIa study of Kancera’s fractalkine-blocking drug candidate KAND567 when added to standard of care in
Participants were randomized (1:1) to receive intravenous infusion of KAND567 for 6 hours, followed by a bridging dose of up to 200mg KAND567 orally after the infusion (bridging dose dependent on the time of primary PCI procedure, followed by 8 doses of 200mg of KAND567, 8 hours apart, or, a matched placebo).
All participants who received any dose of KAND567 or placebo, and for whom any post-dose data were available were included in the safety analysis set. Any participant receiving any dose of KAND567 was treated as if they were allocated to the active arm. Of the 71 patients recruited in total, 35 and 36 patients were randomized to the KAND567 group and placebo group, respectively.
The primary objective was to evaluate safety and tolerability of KAND567, assessed on Adverse Events, Severe Adverse Events and Suspected Unexpected Serious Adverse Reactions, cumulatively for each arm from baseline up to day 90 and on safety laboratory parameters. The secondary objective was to evaluate signs of cardio-protective effects, which has been assessed through a range of inflammatory biomarkers and magnetic resonance imaging (MRI) markers.
About excessive inflammation in connection with myocardial infarction
Myocardial infarction is a leading cause of heart failure and cardiovascular death. The organ damage severity of myocardial infarction is partly dependent on the duration and extent of the primary ischemia, and secondarily due to lack of reperfusion in the microcirculation distal to the culprit lesion treated by primary PCI. Lack of reperfusion in the distal microcirculation despite a re-opened and patent epicardial vessel, is triggered by ischaemia-related damage of endothelial cells and cardiomyocytes, and accumulation and extravasation of blood and immune cells flowing into the microcirculation of the ischemic area; causing a reperfusion injury.
Excessive inflammation is suggested to be a major driving force for developing reperfusion injury, leading to adverse healing and remodelling and a final exaggerated extent of myocardial damage, loss of heart function, heart failure, and cardiovascular death.
Activation and migration of immune blood cells and platelets during the immediate reperfusion phase injury is regulated by chemokines, such as fractalkine, and their receptors. Shortly after induction of ischemia, chemokines are released which increases the expression of fractalkine ligand on the endothelium, increasing the capacity for vascular adhesion and infiltration of subsets of T cells and monocytes expressing the fractalkine receptor (CX3CR1). This immune-cell infiltration is correlated with increased risk for complications such as LV thrombosis, microvascular obstruction and intramyocardial hemorrhage, and leads to an increased three-year mortality risk.
Tissue hemorrhage following reperfusion is a dreaded complication in large vessel occlusion stroke with reperfusion with thrombolysis and/or thrombectomy. Significant hemorrhagic conversion of ischemic stroke leading to intracerebral bleeding, which occurs in up to 20% of patients and is strongly associated with worse patient outcomes.
KAND567, by firmly inhibiting the exaggerated acute inflammatory response mediated through the CX3CR1 pathway, may thus be hypothesized to provide organ protection by preventing ischemic thrombus formation and intra-tissue bleeding and thereby improve outcomes for patients undergoing acute reperfusion treatment strategies. This hypothesis will need to be tested in larger studies going forward.
Further information
The company will present the FRACTAL top line results at 15.00 CET
or contact:
Chief Scientific Officer,
Phone: +46 (0)73 520 4001
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References
- Velagaleti RS, Pencina MJ, Murabito JM, Wang TJ, Parikh NI, D’Agostino RB, Levy D, Kannel WB, Vasan RS. Long-term trends in the incidence of heart failure after myocardial infarction. Circulation. 2008;118:2057-2062.
- Boag SE, Das R, Shmeleva EV, Bagnall A, Egred M, Howard N, Bennaceur K, Zaman A, Keavney B, Spyridopoulos I: T lymphocytes and fractalkine contribute to myocardial ischemia/reperfusion injury in patients. J Clin Invest. 2015;125:3063-3076.
- Liu T,
Howarth AG , Chen Y, Nair AR, Yang HJ, Ren D, Tang R, Sykes J, Kovacs MS, Dey D, Slomka P, Wood JC, Finney R, Zeng M, Prato FS, Francis J, Berman DS, Shah PK, Kumar A, Dharmakumar R: Intramyocardial Hemorrhage and the "Wave Front" of Reperfusion Injury Compromising Myocardial Salvage. J Am Coll Cardiol: 2022 Jan ;79(1):35-48. doi: 10.1016/j.jacc.2021.10.034. - Andrade JBC, Mohr JP, Lima FO, Freitas de Carvalho JJ, Barros LCM, Nepomuceno CR, Ferrer JVCC, Silva GS,: Cerebrovasc JS: The Role of Hemorrhagic Transformation in Acute Ischemic Stroke Upon Clinical Complications and Outcomes. Dis: 2020 Aug;29(8):104898 doi: 10.1016/j.jstrokecerebrovasdis.2020.104898. Epub 2020 May 13.
- Reinstadler SJ, Stiermaier T, Reindl M, Feistritzer HJ, Fuernau G, Eitel C, Desch S, Klug G, Thiele H, Metzler B, Eitel I. Intramyocardial haemorrhage and prognosis after ST-elevationmyocardial infarction. Eur Heart J Cardiovasc Imaging. 2019
Feb 1 ;20(2):138-146. doi: 10.1093/ehjci/jey101.
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