- the primary objective was met, by showing that KAND567 was safe and well tolerated in high-risk ST-elevation myocardial infarction patients,
- the secondary objective was met, by demonstrating signals of cardio-protective effects,
- these signals of cardio-protective effects are clinically relevant as they are markers for commonly used efficacy endpoints in myocardial infarction pivotal studies.
In
Primary endpoints confirm a favorable safety profile in
In total, 71 patients were recruited to the study and included in the evaluation of the primary endpoints. 37 patients were randomized into the KAND567 group and 34 patients into the placebo group. The evaluation of primary endpoints showed that:
- the number of adverse events in the two groups did not differ: 23 (62%) in the KAND567 group compared to 24 (71%) in the placebo group,
- the number of serious adverse events in the two groups did not differ: 12 (32%) in the KAND567 group compared to 11 (32%) in the placebo group,
- no adverse events or serious adverse events were considered to be related to administration of KAND567.
Secondary endpoints and immune markers confirm pharmacological effect and support for a maintained immune function
- resulted in an effective engagement of the targeted fractalkine axis, e.g. seen as:
- a statistically significant reduction of CX3CR1, i.e. the fractalkine receptor, on the cell surface on targeted immune cells over time in the KAND567 group compared to the placebo group (p ranging from <0.001-0.02 depending on time point),
- a statistically significant increase of free CX3CL1, i.e. the fractalkine ligand, in blood plasma over time (p<0.05),
- did not change the levels of main sub-types of leukocytes, indicating that the general immune function is maintained.
Secondary and exploratory endpoints provide signals of cardio-protective effects
Intramyocardial (IM) hemorrhage (secondary endpoint)
29 patients in the KAND567 group and 28 in the placebo group were assessed on IM hemorrhage on Day 3 by magnetic resonance imaging (MRI), showing:
- a trend of reduced frequency of IM hemorrhage in the KAND567 group compared to the placebo group (N=16, 57% and N= 11, 38% in the KAND567 and placebo group respectively, p=0.19). The level of IM hemorrhage in the placebo group is in line with prior studies in high-risk
STEMI patients¹.
Infarction size (secondary endpoint)
For subgroup analysis of infarctions size in patients without IM hemorrhage, 15 patients in the KAND567 group and 11 in the placebo group were included in the analysis of Day 90 MRI data showing:
- a more pronounced decrease of infarction size* in all patients without IM hemorrhage at Day 90, and that
- this decrease was numerically larger in the KAND567 group (p=0,15).
Left ventricular (LV) thrombosis (exploratory endpoint)
37 patients in the KAND567 group and 34 placebo group were assessed on LV thrombosis on Day 3 and Day 90 by MRI or echocardiography, showing:
- a statistically significant reduction of LV thrombosis in the KAND567 group compared to the placebo group (2.7% and 17,6% respectively, p=0.05). The level of LV thrombosis in the placebo group is in line with prior studies in high-risk STEMI².
Number of patients included in the respective analyses varies depending on available data at different time-points.
* GAD5-SD (%), Late gadolinium-enhanced MRI was used at Day 90 to compare infarction size in patients administered placebo or KAND567 using a thresholding of 5 standard deviations above the mean signal intensity from normal myocardium.
Signals of effects are markers for efficacy endpoints commonly used in pivotal studies
Further,
- Reduced IM hemorrhage is strongly associated with, and an independent marker of, a lower risk of heart failure.
- Reduced LV thrombosis is strongly associated with a lower risk of systemic embolism, including stroke.
“The signals of cardio-protective effects seen in the FRACTAL study are very encouraging, as they are established markers for the anticipated efficacy endpoints in upcoming phase IIb/III studies”, says
The way forward for KAND567 in cardiovascular diseases
In parallel with the continued detailed analysis of data,
Based on previous pivotal studies in the same disease and patient setting,
About the FRACTAL study
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, 37 and 34 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.
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References
- Impact of Intramyocardial Hemorrhage on Clinical Outcomes in ST-Elevation Myocardial Infarction: A Systematic Review and Meta-analysis https://doi.org/10.1016/j.jscai.2022.100444
- Left Ventricular Thrombus Following Myocardial Infarction: JACC State-of-the-Art Review. J Am Coll Cardiol 2022;79:1010-1022.
- FDA background document. Endocrinologic and Metabolic drugs Advisory committee meeting.
October 24-25, 2018 .
- Mortality in
STEMI patients without standard modifiable risk factors: a sex-disaggregated analysis of SWEDEHEART registry data.March 9, 2021 .
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