Revacept (PR-15, GPVI-Fc)
Platelet adhesion to arterial vascular lesions and plaques plays a key role in the complications of atherosclerosis leading to acute coronary syndromes and myocardial infarctions as well as ischemic cerebral stroke.
Revacept is a human Fc fusion protein, which prevents the local activation of platelets at sites of vascular injury, acting like a “vascular coating”. Efficacy studies showed that revacept resulted in significantly reduced thrombus formation at these sites. However, systemic hemostasis is not affected.
In a first in man study, all doses were well tolerated, no drug-related adverse events occurred, bleeding time was not prolonged. No bleeding complications nor platelet depletion (thrombopenia) were observed.
A phase II study in patients with symptomatic carotid artery stenosis, TIA or stroke (NCT01645306) investigated cerebral infarctions/strokes by MRI tomography and clinical results, and blood parameters (e. g. platelet aggregation). The anticipated patient recruitment has been achieved – no relevant adverse effects have been observed. A first analysis of efficacy has shown beneficial effects for the patients.
A second investigator-initiated phase II clinical study in patients with coronary artery disease (NCT 03312855; EudraCT 2015-000686-32) is being carried out by the teams of Prof. Adnan Kastrati, German Heart Center, Munich and of Prof. Steffen Massberg, Großhadern Clinic of the Ludwig-Maximilian University, and at further large clinical entities who cooperate within the German Center for Cardiovascular Diseases (DZHK), and has recruited almost all anticipated patients. The study protocol has recently been published (Schüpke et al., 2019). Due to the blinded study design, the final analysis of efficacy will be done at the end of the trial. Moreover, a diagnostic blood test has been developed, which allows for risk stratification of patients.
Recently, an independent review by Arjun Majithia and Deepak Bhatt; Arterioscler Thromb Vasc Biol. 2019;39:546-557 has summarized the current state of the art of anti-platelet drugs. Beside those platelet inhibitors which have already been established in clinical routine, the review highlights newer developments, and mentions especially the advantages of Revacept as plaque-specific inhibitor of thrombus formation which does not incur risks of bleeding.
Fusion proteins with GPVI-Fc
The platelet inhibitory potential of GPVI-Fc was further increased by fusing it to the ecto-nucleotidase CD39 which inhibits local adenosine diphosphate (ADP) accumulation at vascular plaques, and hence to create a lesion-directed dual antiplatelet therapy. GPVI-CD39 effectively stimulated local ADP degradation, and led to a significantly increased inhibition of plaque-induced platelet thrombus formation under arterial flow conditions.