EV-077
SER 150 (formerly EV-077)
Also known as: formerly EV-077-3201
EV-077-3201-2TBS
CAS 1384128-29-3Evolva INNOVATOR
Evolva Sa
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.
Description
EV-077 is a small compound being developed for
the treatment of complications of diabetes. In Phase 2. Outlicensed to
Serodus in 2013.
Situation Overview
Diabetes and its complications are major global health care problems.
Based on estimates by the International Diabetes Federation (IDF),
there were 366 million diabetics worldwide in 2011, a number which is
expected to increase to 552 million by 2030. IDF estimates the number of
deaths in 2011 at 4.6 million and total spending on diabetic health
care at USD 465 billion.
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.
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
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. The mechanism of
action of EV-077 means that it can potentially ameliorate or prevent a
range of diabetic complications (including loss of kidney function,
reduced peripheral blood flow and increased risk of thrombosis) that
derive from the following chain of events:
- 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.
Clinical Trials
In November 2011, Evolva received regulatory clearance to progress
EV-077 into Phase IIa clinical studies for the treatment of
complications of diabetes. It is a single-centre study, conducted in
Germany. The study was a randomized, double-blind, and
placebo-controlled, and investigated the efficacy and safety of EV-077
in type 2 diabetics with a heightened risk of diabetic vascular
complications. Measurements included blood flow and platelet reactivity,
biomarkers for oxidative stress and vascular inflammation as well as
markers of the function of organs that are often impaired in diabetes
(e.g. kidney).
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.
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
Evolva has outlicensed 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.
http://www.google.com/patents/WO2014011273A2?cl=en
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
http://www.google.co.in/patents/WO2008089461A1?cl=en
(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:
see
WO 2011057262
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