for the treatment of diabetic complications
Evolva is developing EV-077 for the treatment of diabetic complications. It 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. Additional patent applications are pending in all major territories. Evolva owns all rights to EV-077.
The treatment of complications of diabetes
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.
Diabetes causes chronic vascular inflammation and indeed most of the diabetes disease burden results from increased vascular inflammation, thus in diabetics one observes:
- 2-4 x more micro & macro vascular complications vs. non-diabetics
- 2-4 x increase in cardiovascular mortality vs. non-diabetics
- 2-3 x increase in stroke
- 12.5% of all cases of blindness
- 42% of all cases of end stage renal disease
- 50% of all non-traumatic amputations
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.
In July Evolva announced the completion of a Phase I multiple ascending dose study with an extended-release oral formulation of EV-077 for the treatment of complications of diabetes. The aim of the study was to evaluate the safety, kinetic and pharmacodynamic profile of EV-077 given twice daily and to determine the minimal effective and the maximum tolerated dose. Although the dosage form was not optimised, complete inhibition of platelet activation was obtained at the lowest dose tested (120 mg BID) whilst the maximum tolerated dose was 600 mg BID.
In parallel with the Phase I programme, Evolva sponsored an ex vivo study to investigate the in vitro effect of EV-077 on platelet aggregation of patients with type 2 diabetes and coronary artery disease (CAD). The study data suggest that EV-077 might, in addition to the stand-alone effects seen in Phase I, also have beneficial effects when provided in addition to aspirin in type 2 diabetics with CAD. The data were presented in July 2011 at the XXIII Congress of the International Society on Thrombosis and Haemostasis (ISTH) in Kyoto, Japan.
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 is currently ongoing and the intention is to enrol up to 64 evaluable patients. The study is randomised, double-blind, and placebocontrolled, and investigates the efficacy and safety of EV-077 in type 2 diabetics with a heightened risk of diabetic vascular complications. Measurements include 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 August 2012, Evolva announced top-line results for the first 32 patients enrolled in the Phase IIa study. The initial analysis shows 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.
Evaluation of the data of the first 32 patients of the Proof-of-Concept study was part of the adaptive design agreed with the German regulatory authority BfArM. Evolva is exploring, in consultation with BfArM, how to best address the liver enzyme elevations, for example by using lower doses in a next group of patients. The initial analysis supports the hypothesis that lower doses will demonstrate efficacy.
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.
EV-077 for the treatment of viral infections
EV-077 and related compounds have also been investigated for their potential in the prophylaxis and treatment of viral diseases. This investigation was supported by the US Defense Threat Reduction Agency.
Evolva has shown in preclinical studies that EV-077 has similar or better performance than Oseltamivir (Tamiflu®, Roche) in reducing the severity of influenza infections Moreover, a combination of Tamiflu® with EV-077 provided added benefits over each treatment alone on all parameters tested. During 2011, the US Food and Drug Administration (FDA) cleared Evolva’s request to test EV-077 in man, under an Investigational New Drug application for influenza. However, Evolva does not currently intend to initiate clinical studies in this indication without a partner.
EV-077 in vitro inhibits platelet aggregation in type-2 diabetics on aspirin Thrombosis Research
Pharmacodynamic effects of EV-077: results of an in vitro pilot investigation in healthy volunteers Journal of Thrombosis and Thrombolysis
Single ascending oral dose pharmacokinetics and pharmacodynamics study of EV-077: the specific inhibitor of prostanoid- and isoprostane-induced cellular activation. European Journal of Clinical Pharmacology
The dual thromboxane receptor antagonist and thromboxane synthase inhibitor EV-077 is a more potent inhibitor of platelet function than aspirin. Journal of Thrombosis and Haemostasis
Effect of Pharmaceutical interventions targeting thromboxane receptors and thromboxane synthase in cardiovascular and renal diseases. Request download