SER 150 (formerly EV-077)
Oral thromboxane receptor antagonist and thromboxane synthase inhibitor
EV-077 is a small compound being developed for the treatment of complications of diabetes. In Phase 2. Outlicensed to Serodus in 2013.
In 2013, Serodus licensed the product candidate for the treatment of diabetic nephropathy and it is conducting phase II clinical trials on this research.
EV-077 is an oral, small molecule compound, belonging to a new structural class. Preclinical and early clinical studies indicate EV-077 has potential in reducing vascular inflammation by inhibiting the activity of prostanoids and isoprostanes – in particular in diabetes. Towards the end of 2011, the Russian Patent Office granted patent protection for EV-077 in the treatment of complications of diabetes for a term extending to 2026. Evolva has outlicenced EV-077 to Serodus in 2013. Serodus aims to bring EV-077 further through clinical development and at a future time point decide whether Serodus or a partner will conduct the final clinical trials.
EV-077 is in development as a potential pharmaceutical for the treatment of diabetic nephropathy and other diabetic complications. It is in Phase II clinical studies.
In 2013, Evolva out-licensed EV-077 to Serodus (Oslo, Norway). Serodus aims to bring EV-077 through Phase II and then decide whether or not to partner for the final clinical trials and commercialisation. Evolva is entitled to clinical and regulatory milestones as well as a single-digit royalty on sales. If Serodus sublicenses EV-077 then Evolva will receive up to 30% of Serodus’ total licensing income.
As of Q2 2015 Serodus continues active development of EV-077.
– See more at: http://www.evolva.com/ev-077/#sthash.4mgJ3E0f.dpuf
Patients with diabetes mellitus (DM) have increased propensity to generate thromboxane A2 (TXA2) and other eicosanoids which can contribute to their heightened platelet reactivity. EV-077 is a potent thromboxane receptor antagonist and thromboxane synthase inhibitor and thus represents an attractive therapy in patients with DM. However, the effects of EV-077 on pharmacodynamic (PD) profiles in patients with DM and coronary artery disease (CAD) while on antiplatelet therapy is poorly explored and represented the aim of this in vitro pilot investigation. Patients with DM and stable CAD (n = 10) on low-dose aspirin (81 mg/day) were enrolled and then switched to clopidogrel (75 mg/day) monotherapy for 7-10 days. PD assessments were conducted while on aspirin and on clopidogrel using light transmittance aggregometry following stimuli with U-46619 [TXA2 stable analogue (7 μM)], arachidonic acid [AA (1 mM)], collagen (3 μg/mL) and adenosine diphosphate [ADP (5 μM and 20 μM)] with and without in vitro EV-077. EV-077 completely inhibited U-46619-stimulated platelet aggregation (p = 0.005 for both aspirin and clopidogrel) and also showed a significant reduction of collagen-induced aggregation (aspirin p = 0.008; clopidogrel p = 0.005). EV-077 significantly reduced AA-induced platelet aggregation in clopidogrel (p = 0.009), but not aspirin (p = 0.667) treated patients. Ultimately, EV-077 significantly reduced ADP-mediated platelet aggregation in both aspirin (ADP 5 μM p = 0.012; ADP 20 μM p = 0.032) and clopidogrel (ADP 5 μM p = 0.007; ADP 20 μM p = 0.008) treated patients. In conclusion, in DM patients with CAD on aspirin or clopidogrel monotherapy, in vitro EV-077 exerts potent platelet inhibitory effects on multiple platelet signaling pathways. These data support that EV-077 has only additive platelet inhibiting effects on top of standard antiplatelet therapies. These findings warrant further investigation in ex vivo settings.
EV-077 is an oral, small molecule compound, belonging to a new structural class. EV-077 is being developed for the reduction of vascular inflammation by inhibiting the activity of prostanoids and isoprostanes ��� in particular in diabetes. Towards the end of 2011, the Russian Patent Office granted patent protection for EV-077 in the treatment of complications of diabetes for a term extending to 2026. Additional patent applications are pending in all major territories. Evolva has outlicenced EV-077 to Serodus in 2013.
Mechanism of Action
- Diabetic patients have a reduced sensitivity to insulin which increases overall glucose levels in the body;
- This increase in glucose increases oxidative stress;
- The oxidative stress generates a high level of isoprostanes and prostanoids;
- The isoprostanes and prostanoids chronically activate thromboxane prostanoid receptors, that are located on the walls of blood vessels (endothelial cells and smooth muscle cells) and the surface of platelets;
- Activation of the thromboxane prostanoid receptors causes vascular inflammation and increased platelet reactivity;
- An increased number of vascular events and a progressive deterioration of circulatory and renal function.
In May 2012, the study was terminated. Interim results for the first 32 patients enrolled in the Phase IIa study show promising efficacy data, indicating that 300mg EV-077 given orally twice daily to patients with type 2 diabetes provided anti-platelet activity, reduced exercise-induced proteinuria and increased forearm blood flow. This was achieved with only a slight increase in bleeding time. The analysis also indicated that EV-077 was generally well tolerated, with adverse events mostly limited to increases in liver enzymes, which were transient or resolved after discontinuation.
In parallel with the Phase IIa study, Evolva is conducting epidemiological studies to identify high risk diabetic patient subgroups that can potentially derive particular benefit from the administration of EV-077. Given success, this is expected to expedite both further clinical development (by reducing the size and duration of late stage clinical trials) and the eventual approval process.
Partners by Region
Journal of Thrombosis and Haemostasis (2011), 9(10), 2109-2111
Thrombosis Research (2012), 130(5), 746-752
European Journal of Clinical Pharmacology (2013), 69(3), 459-465
Biochemical and Biophysical Research Communications (2013), 441(2), 393-398
Journal of Thrombosis and Thrombolysis (2014), 37(2), 131-138
(Z)-6-((2S,4S,5R)-2-(2-chlorophenyl)-4-(2-hydroxyphenyl)-1 ,3-dioxan-5-yl)hex-4-enoic acid has the 3 groups all up, which has a dramatic effect on its biological activities: