Varespladib methyl (A-002)

Varespladib methyl in cardiovascular disease

Importance of the field: The high risk of recurrent cardiovascular events amongst patients with cardiovascular disease receiving evidence-based therapies has prompted investigations into complimentary treatments that may reduce residual risk. Analyses of clinical trials in statin-treated patients demonstrate that elevated lipid levels and an activated systemic inflammatory state are associated with a higher risk of recurrent cardiovascular events. Areas covered in this review: This article reviews evidence supporting the causal role for secretory phospholipase A(2) (sPLA(2)) in experimental atherosclerosis, the involvement of various sPLA(2) isozymes as mediators of pro-atherogenic lipoprotein remodeling and participants in vascular and systemic inflammatory responses, and the evidence that sPLA(2) inhibition reduces atherosclerosis in experimental models and biomarkers associated with cardiovascular events in coronary heart disease (CHD) patients. What the reader will gain: The experimental basis for sPLA(2) inhibition with varespladib methyl as a potential candidate for lowering recurrent cardiovascular events particularly in acute coronary syndrome patients is discussed. Take home message: Varespladib methyl therapy reduces atherogenic lipoprotein concentrations and systemic inflammatory markers in CHD patients. The future role of varespladib methyl in CHD patients awaits the results of ongoing clinical trials.

Varespladib

Anthera Pharmaceuticals is developing an oral formulation of varespladib (A 001; A 002; A-001; A-002; LY 315920; LY 333013; LY315920; LY333013; S 3013; S 5920; S-3013; S-5920; Varespladib methyl) for once-daily treatment of acute coronary syndromes. Varespladib acts by inhibiting secretory phospholipase A2 (sPLA2) and the drug is currently being evaluated in approximately 6500 patients with acute coronary syndromes receiving atorvastatin in the placebo-controlled VISTA 16 (NCT01130246) trial being conducted in North America and Europe. This review discusses the development history and scientific profile of this new compound.

Varespladib (LY315920) and Methyl Varespladib (LY333013) Abrogate or Delay Lethality Induced by Presynaptically Acting Neurotoxic Snake Venoms

The phospholipase A₂ (PLA₂) inhibitor Varespladib (LY315920) and its orally bioavailable prodrug, methyl-Varespladib (LY333013) inhibit PLA₂ activity of a wide variety of snake venoms. In this study, the ability of these two forms of Varespladib to halt or delay lethality of potent neurotoxic snake venoms was tested in a mouse model. The venoms of Notechis scutatus, Crotalus durissus terrificus, Bungarus multicinctus, and Oxyuranus scutellatus, all of which have potent presynaptically acting neurotoxic PLA₂s of variable quaternary structure, were used to evaluate simple dosing regimens. A supralethal dose of each venom was injected subcutaneously in mice, followed by the bolus intravenous (LY315920) or oral (LY333013) administration of the inhibitors, immediately and at various time intervals after envenoming. Control mice receiving venom alone died within 3 h of envenoming. Mice injected with O. scutellatus venom and treated with LY315920 or LY333013 survived the 24 h observation period, whereas those receiving C. d. terrificus and B. multicinctus venoms survived at 3 h or 6 h with a single dose of either form of Varespladib, but not at 24 h. In contrast, mice receiving N. scutatus venom and then the inhibitors died within 3 h, similarly to the control animals injected with venom alone. LY315920 was able to reverse the severe paralytic manifestations in mice injected with venoms of O. scutellatus, B. multicinctus, and C. d. terrificus. Overall, results suggest that the two forms of Varespladib are effective in abrogating, or delaying, neurotoxic manifestations induced by some venoms whose neurotoxicity is mainly dependent on presynaptically acting PLA₂s. LY315920 is able to reverse paralytic manifestations in severely envenomed mice, but further work is needed to understand the significance of species-specific differences in animal models as they compare to clinical syndromes in human and for potential use in veterinary medicine.

Varespladib (LY315920) Appears to Be a Potent, Broad-Spectrum, Inhibitor of Snake Venom Phospholipase A2 and a Possible Pre-Referral Treatment for Envenomation

Snakebite remains a neglected medical problem of the developing world with up to 125,000 deaths each year despite more than a century of calls to improve snakebite prevention and care. An estimated 75% of fatalities from snakebite occur outside the hospital setting. Because phospholipase A2 (PLA2) activity is an important component of venom toxicity, we sought candidate PLA2 inhibitors by directly testing drugs. Surprisingly, varespladib and its orally bioavailable prodrug, methyl-varespladib showed high-level secretory PLA2 (sPLA2) inhibition at nanomolar and picomolar concentrations against 28 medically important snake venoms from six continents. In vivo proof-of-concept studies with varespladib had striking survival benefit against lethal doses of Micrurus fulvius and Vipera berus venom, and suppressed venom-induced sPLA2 activity in rats challenged with 100% lethal doses of M. fulvius venom. Rapid development and deployment of a broad-spectrum PLA2 inhibitor alone or in combination with other small molecule inhibitors of snake toxins (e.g., metalloproteases) could fill the critical therapeutic gap spanning pre-referral and hospital setting. Lower barriers for clinical testing of safety tested, repurposed small molecule therapeutics are a potentially economical and effective path forward to fill the pre-referral gap in the setting of snakebite.

After FRANCIS: next steps in the clinical evaluation of varespladib methyl

Secretory phospholipase A(2) (sPLA(2)) represents a family of isoenzymes that participate in lipoprotein and inflammatory pathways, mediate atherosclerosis and enhance myocardial ischemic injury. The Fewer Recurrent Acute Coronary Events with Near-term Cardiovascular Inflammatory Suppression (FRANCIS) trial (NCT00743925) was a Phase II trial designed to examine the effects of varespladib methyl, a small-molecule inhibitor of sPLA(2), on plasma biomarkers in patients with acute coronary syndrome (ACS) who were treated with atorvastatin 80 mg and standard-of-care daily. Varespladib methyl significantly reduced low-density lipoprotein cholesterol and inflammatory biomarkers in ACS subjects treated with standard-of-care and atorvastatin 80 mg daily. There was a nonsignificant reduction in major adverse cardiovascular events at study completion; however, positive trends remained for unstable angina and myocardial infarction. In order to achieve the widespread use of varespladib methyl in ACS patients, completion of a prospective, randomized placebo-controlled trial in ACS patients and stable coronary artery disease patients with increased sPLA(2) activity will be required.