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EV-077

SER  150 (formerly EV-077)

Also known as: formerly EV-077-3201

EV-077-3201-2TBS

CAS 1384128-29-3

Evolva 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.

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.

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.

WO 2014011273

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:

Figure imgf000022_0002

see

WO 2011057262

/////////////// SEE……..http://drugsynthesisint.blogspot.in/2015/11/ev-077.html


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DR ANTHONY CRASTO

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 29 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 29 year tenure till date Aug 2016, Around 30 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 25 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 13 lakh plus views on New Drug Approvals Blog in 212 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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