Verseon’s Precision Anticoagulants Prevent Clotting Without Excess Bleeding Risk in Preclinical Studies Interview with:
Anirban Datta, PhD

Director Discovery Biology
Verseon Corporation What is the background for this study?

Response: Today’s anticoagulant market is dominated by the NOACs. These oral anticoagulants require less constant monitoring and have reduced drug and food interactions compared to their predecessors, warfarin and heparin. However, there is still a significant bleeding risk associated with the NOACs. This is particularly problematic when they are co-dosed with antiplatelet drugs. While life-long therapy combining an oral anticoagulant with one or two antiplatelet drugs is desired for the many patients suffering from both non-valvular atrial fibrillation and coronary artery disease, current treatment guidelines limit such therapy to a maximum of six months to a year due to safety concerns.

At Verseon, we are developing a novel class of precision anticoagulants that combine efficacy comparable to the NOACs with a significantly reduced bleeding risk in preclinical testing. We believe that this profile can have a positive impact on the lives of the many patients in need of long-term anticoagulation-antiplatelet combination therapy.

We are currently advancing two development candidates toward clinical trials in 2018. VE-1902, our first development candidate, is scheduled to enter phase I in the first half of the year. What are the main findings?

Response: At the recent AHA Scientific Sessions, we presented preclinical data for our second development candidate, VE-2851. Like our first candidate, VE-2851 also shows excellent efficacy paired with low bleeding risk in preclinical testing, and is only a few months behind VE-1902 in development.

Our preclinical data shows that VE-2851 potently inhibits thrombin and is highly selective against a panel of related serine proteases. The candidate displays pharmacokinetics suitable for oral dosing and was well tolerated in a 14-day dose-range finding study.

In preclinical efficacy models, such as the arteriovenous shunt thrombosis model, VE-2851 demonstrates comparable efficacy to marketed anticoagulants. Similar to our first development candidate, VE-2851 likewise potently inhibits thrombosis, but does not disrupt platelet function.

Activated platelets play an important role in wound healing, hemostasis, and healthy tissue growth. By either directly or indirectly inhibiting thrombin, the NOACs are known to also reduce platelet activation, which may, in turn, increase a patient’s bleeding risk.

Our preclinical data clearly show that Verseon’s anticoagulants are much weaker inhibitors of thrombin-mediated platelet activation. VE-2851, for instance, shows about 40-fold weaker inhibition of platelet activation in vitro and allows up to 5-fold higher maximum platelet activation in vivo compared to the NOACs. This distinguishing feature provides a biological rationale for the improved hemostatic control of our drug candidates and for the resulting lower bleeding risk observed in preclinical bleeding time tests. What should clinicians and patients take away from your report?

Response: The incidence of coronary artery disease in patients presenting with atrial fibrillation is high (34%). This large patient population suffering from multiple cardiovascular diseases is poorly served by current drugs, which cannot provide safe, long-term anticoagulant-antiplatelet combination therapy.

The recent COMPASS trial has shown that a combination therapy of aspirin with sub-therapeutic doses of Xarelto® (2.5 mg twice daily) effectively decreases the incidence of major adverse cardiovascular events in patients with stable atherosclerotic vascular disease. However, the trial has also confirmed an increased risk of major bleeding events.

The pharmacological profile of Verseon’s anticoagulants may allow them to become the first drugs that do not increase patients’ bleeding risk when co-administered with antiplatelet drugs, making them suitable for long-term use in this setting. Both of our development candidates act as potent anticoagulants without disrupting platelet function, which may significantly reduce the risk of major adverse cardiovascular events when used in conjunction with antiplatelet drugs. What recommendations do you have for future research as a result of this study?

Response: There is a large unmet medical need for anticoagulants with lower bleeding risk that our new class of drug candidates is well-suited to address.

Our first candidate VE-1902 is on track to enter phase I trials in the first half of 2018, and VE-2851 is only a few months behind in development. With the help of our advisory board of distinguished cardiologists, we are in the process of designing strategies for phase I and II studies that will demonstrate the unique capabilities of our precision anticoagulants. Is there anything else you would like to add?

Response: Another well-documented shortcoming of the current anticoagulants is their reliance on clearance through the kidneys (between 27% and 80% for the NOACs). Patients with atrial fibrillation are already at a higher risk of renal dysfunction. It is thus of paramount importance that such patients take an anticoagulant with low renal clearance in addition to low bleeding risk.

Among the anticoagulants in the market and in the discovery pipeline, to the best of our knowledge our first candidate VE-1902 stands alone in providing just this combination of low bleeding risk and low renal clearance. This has the potential to benefit the many patients, particularly older patients, with impaired kidney function.

We are excited to have two drug candidates heading to the clinic next year. From the outset, the goal of Verseon’s computer-driven approach to drug discovery has been to develop multiple high-quality drug candidates per program for clinical trials, in order to drastically increase our chances of success.

Using this platform, we are developing drug candidates for a range of diseases. Our pipeline currently comprises eye-drop or oral drugs for diabetic macular edema, oral treatments for hereditary angioedema, and anticancer agents for multidrug resistant cancers.

Disclosures: Dr. Datta is an employee of Verseon Corporation. Thank you for your contribution to the community.

Citation: AHA 2017 abstract

Abstract 19503: An Improved Potent Direct Thrombin Inhibitor Shows Efficacy With Low Bleeding Risk

Anirban Datta, Chengpei Xu, Daniel Clemens, Subhadra Dash, Kenneth Lin, Stephenie Chang, Georg Neckermann, Elaine To, Lev Igoudin, Samuel Keutzer, Piotr Zalicki, Sivan Sizikov, Angels Estiarte, Kevin Short, Timothy Shiau, David Williams, Mohan Sivaraja, David Kita

Note: Content is Not intended as medical advice. Please consult your health care provider regarding your specific medical condition and questions.