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Varespladib

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A Drug That Failed Heart Patients Might Save Snakebite Victims

In the pharmaceutical industry, failure is expensive. When a drug doesn't work for its intended purpose, companies typically shelve it and move on. But sometimes, a failed drug gets a second chance at life—in an entirely unexpected way.

Varespladib is one of those drugs. Developed originally to prevent heart attacks, it proved useless for that purpose and potentially even harmful. The clinical trial was halted. The company moved on. End of story.

Except it wasn't.

A few years later, scientists realized that the same mechanism that made varespladib a poor heart drug might make it an excellent antidote to snake venom. Today, this abandoned cardiovascular medication is being studied as a potential first-line treatment for snakebite envenomation—the kind of drug you could swallow in the field, immediately after being bitten, before you ever reach a hospital.

Understanding What Varespladib Actually Does

To understand why varespladib's story took such a dramatic turn, you need to know a bit about how inflammation works in your body—and how snake venom destroys tissue.

Both processes involve an enzyme called phospholipase A2, or PLA2 for short. Think of enzymes as molecular machines: they grab onto specific molecules and transform them into something else. PLA2 specifically attacks the membranes that surround your cells. It clips fatty acids off these membrane molecules, releasing a compound called arachidonic acid.

This matters because arachidonic acid is the starting ingredient for a whole cascade of inflammatory signals. When your body needs to respond to an injury or infection, PLA2 kicks off the process. The released arachidonic acid gets converted into prostaglandins, leukotrienes, and other compounds that cause swelling, pain, fever, and all the other hallmarks of inflammation.

Now, here's where it gets interesting. Your body has several different versions of PLA2, designated with Roman numerals: type IIA, type V, type X, and so on. Different tissues produce different types. And crucially, different snake species have evolved their own versions of PLA2 as key components of their venom.

Varespladib is a small molecule that blocks multiple forms of PLA2. It fits into the enzyme's active site—the part that normally grabs onto cell membranes—and prevents it from doing its job. The theory was simple: block PLA2, reduce inflammation, prevent the inflammation-driven damage that contributes to heart disease.

The Cardiovascular Disappointment

The story begins with Eli Lilly and a Japanese pharmaceutical company called Shionogi. Together, they developed varespladib in the 1990s, aiming to create an anti-inflammatory drug. In 2006, a small biotech company called Anthera Pharmaceuticals acquired the drug and began seriously pursuing it as a treatment for acute coronary syndrome.

Acute coronary syndrome is the medical term for what most people call a heart attack or unstable angina. It happens when a fatty plaque in one of the heart's arteries ruptures, triggering inflammation and blood clots that block blood flow to the heart muscle. The theory behind using varespladib was compelling: elevated levels of a particular PLA2 type (sPLA2, the "s" standing for "secretory," meaning it's released outside cells) had been observed in patients with cardiovascular disease. These elevated levels seemed to predict who would have future heart attacks.

Moreover, PLA2 appeared to modify low-density lipoproteins—the so-called "bad cholesterol"—in ways that made them more likely to stick to artery walls. By blocking PLA2, perhaps you could reduce inflammation, improve cholesterol handling, and prevent the cascade of events leading to heart attacks.

Early trials looked promising. Phase II studies showed that varespladib did indeed reduce PLA2 activity, lower LDL cholesterol levels, and decrease markers of inflammation like C-reactive protein. When combined with statin drugs (the standard cholesterol-lowering medications), it pushed these markers down even further.

Encouraged by these results, Anthera launched a large Phase III trial in 2010, called VISTA-16. This was the definitive test: give varespladib to patients who had just experienced an acute coronary syndrome and see if it prevented subsequent cardiovascular events.

In March 2012, the trial was halted.

An independent safety monitoring board reviewed the data and found that varespladib wasn't just failing to help patients—it might actually be harming them. The final results, published in 2014, confirmed this concern. Patients taking varespladib had more heart attacks, not fewer. The drug that was supposed to reduce cardiovascular events was actually increasing them.

The biological explanation remains somewhat unclear. It's possible that the types of PLA2 blocked by varespladib play some protective role in the cardiovascular system, or that inhibiting these enzymes shifts the balance of inflammatory signals in an unfavorable direction. Whatever the mechanism, the conclusion was unambiguous: varespladib was not a viable heart drug.

Enter the Snakes

While varespladib's cardiovascular story was ending, an entirely different chapter was about to begin.

Snakebite is a neglected global health crisis. The World Health Organization estimates that five million people are bitten by venomous snakes each year. Of these, roughly 400,000 suffer permanent injuries—lost limbs, chronic pain, disfigurement—and between 80,000 and 140,000 die. The burden falls overwhelmingly on poor, rural communities in tropical countries: farmers, laborers, children walking barefoot to fetch water.

The standard treatment for venomous snakebite is antivenom: antibodies harvested from horses or sheep that have been injected with snake venom. These antibodies bind to venom components and neutralize them. The problem is that antivenom must be administered intravenously in a medical facility, it requires refrigeration, it's expensive, and it often causes severe allergic reactions. For a farmer bitten in a remote field, hours from the nearest hospital, antivenom may as well not exist.

This is why researchers have long searched for a different kind of treatment: a small molecule drug that could be taken orally, that remained stable at room temperature, that could be administered immediately after a bite by anyone, anywhere. Something you could carry in your pocket like aspirin.

In 2016, scientists published the first report suggesting that varespladib might be such a drug.

The connection was straightforward once you saw it. Many snake venoms contain PLA2 enzymes as key toxic components. These venom PLA2s attack cell membranes just like the human versions do, but with devastating efficiency. They cause the local tissue destruction that makes snakebites so horrific: the swelling, the hemorrhaging, the death of muscle tissue. Some venom PLA2s also have neurotoxic effects, interfering with nerve-muscle connections and causing paralysis.

If varespladib could block human PLA2, could it also block snake venom PLA2?

Promising Results From Laboratory and Animal Studies

The answer, remarkably, was yes—and not just for one type of snake.

Researchers tested varespladib against PLA2 enzymes from 28 different snake species, representing venomous snakes from six continents. The drug showed strong inhibition across this remarkably diverse set of targets. This breadth matters enormously for a potential field treatment. A snakebite victim in rural India might be bitten by a cobra, a krait, or a Russell's viper. A victim in Central America might encounter a fer-de-lance or a rattlesnake. A universal treatment needs to work against all of them.

Animal studies were equally encouraging. When researchers gave varespladib to mice and pigs that had been injected with snake venom, the drug reduced tissue damage, prevented paralysis, and improved survival. In one striking experiment using coral snake venom—one of the most dangerous snake groups in the Americas—varespladib methyl (the orally bioavailable form of the drug) protected pigs from the lethal effects of envenomation.

The mechanism has been visualized at the molecular level. When scientists crystallized varespladib together with a snake venom toxin called MjTX-II, they could see exactly how the drug works. Varespladib wedges itself into a hydrophobic channel in the toxin protein—a groove normally used to grab onto cell membrane components. By blocking this channel, varespladib prevents the toxin from doing its membrane-destroying work. The toxin becomes, essentially, a locked gun with no way to fire.

Why a Failed Heart Drug Works Against Venom

There's a satisfying evolutionary logic to varespladib's dual potential. Both human inflammatory PLA2 and snake venom PLA2 evolved from the same ancestral enzymes. Snakes essentially weaponized a molecular tool that all animals have, cranking up its activity and sometimes adding new toxic properties. But the core structure remains similar enough that a drug designed to block the human version can also block the snake versions.

This is actually a common pattern in drug discovery. Many successful medications were originally developed for one purpose but found their true calling elsewhere. Sildenafil was developed as a heart medication before becoming Viagra. Minoxidil was a blood pressure drug before it became a baldness treatment. Drugs, like people, sometimes find unexpected second careers.

From Laboratory to Field: The Challenges Ahead

In 2019, the United States Food and Drug Administration granted varespladib orphan drug status for the treatment of snakebite. This designation—which provides various incentives for developing treatments for rare diseases—recognized the drug's potential even though it hasn't yet been approved for this use.

But significant hurdles remain before varespladib could become a standard snakebite treatment.

First, while PLA2 is important in many snake venoms, it's not the only toxic component. Snake venoms are complex cocktails containing dozens or even hundreds of different proteins and peptides. Some, like the metalloproteinases that cause hemorrhaging, aren't affected by varespladib at all. A complete snakebite treatment might need to combine varespladib with other drugs targeting different venom components.

Second, clinical trials in humans are still needed. Animal studies are encouraging, but they can't tell us everything about how the drug will perform in actual snakebite victims. The VISTA-16 experience is a sobering reminder that drugs can behave unexpectedly in human trials.

Third, even if varespladib proves safe and effective, getting it to the people who need it most presents enormous logistical challenges. The communities most affected by snakebite are often the hardest to reach with any medical intervention. A pill is certainly easier to distribute than refrigerated antivenom, but distribution networks, education, and affordability all remain obstacles.

The Three Faces of Varespladib

It's worth noting that varespladib exists in several different forms, each designed for a specific delivery method.

The base molecule, varespladib itself, is the active drug but doesn't absorb well when swallowed. For oral use, chemists created varespladib methyl—a modified version with an extra chemical group attached. This prodrug (a term for an inactive precursor that gets converted to the active form inside the body) passes through the stomach and intestines into the bloodstream, where enzymes quickly snip off the methyl group, releasing active varespladib. Different pharmaceutical identification codes appear in the literature: LY333013 and S-3013 for the methyl prodrug, A-002 for its later designation.

For intravenous delivery, there's varespladib sodium—a salt form designed to dissolve readily in IV fluids. This version, coded as LY315920, S-5920, or A-001, was investigated for a different application altogether: preventing acute chest syndrome in patients with sickle cell disease.

Sickle cell disease is a genetic condition where red blood cells become misshapen and sticky, causing them to clog small blood vessels. Acute chest syndrome is a life-threatening complication where these problems occur in the lungs, leading to severe respiratory distress. It's the leading cause of death in sickle cell patients.

Researchers noticed that PLA2 levels spike dramatically just before and during acute chest syndrome episodes—much more than in other complications of sickle cell disease. Blood transfusions, which lower PLA2 levels, reduce the risk of acute chest syndrome. This suggested that blocking PLA2 might prevent these dangerous episodes.

Anthera conducted a Phase II trial of intravenous varespladib sodium in sickle cell patients at risk for acute chest syndrome. The FDA had granted orphan drug status for this application in 2007. However, this indication was later withdrawn, and the sickle cell program—like the cardiovascular program—was ultimately abandoned.

The Biology of PLA2: Why It Matters So Much

To fully appreciate varespladib's story, it helps to understand just how central phospholipase A2 is to both health and disease.

Every cell in your body is enclosed by a membrane made of phospholipids—molecules with a water-loving head and two water-fearing fatty tails. Billions of these molecules arrange themselves into a double layer, creating a barrier that separates the cell's interior from the outside world. PLA2 enzymes attack the second fatty tail of these phospholipids, snipping it off and releasing arachidonic acid.

In normal physiology, this is useful. Arachidonic acid and its derivatives are signaling molecules that coordinate the immune response, regulate blood pressure, maintain the stomach lining, and perform dozens of other functions. Your body carefully controls PLA2 activity to produce just enough of these signals.

Problems arise when PLA2 activity goes out of control. In cardiovascular disease, excess PLA2 may promote inflammation in artery walls and modify LDL cholesterol in harmful ways. In snake envenomation, injected venom PLA2 attacks tissues with no regulation at all, dissolving cell membranes and triggering massive inflammatory cascades.

The fascinating thing is that snake venom PLA2s have evolved to be far more potent than their mammalian cousins. Some have acquired entirely new toxic properties: neurotoxins like β-bungarotoxin from kraits don't just destroy membranes but specifically target nerve terminals. Others have lost their enzymatic activity entirely but retained the ability to insert into membranes and punch holes in them.

Varespladib's broad effectiveness against diverse snake venom PLA2s suggests it's targeting something fundamental about how these enzymes work. By blocking the site where they grab onto membrane lipids, it neutralizes both the enzymatic and the membrane-disrupting activities.

Looking Forward

The transformation of varespladib from failed heart drug to potential snakebite treatment illustrates something important about pharmaceutical development. Our understanding of biology is incomplete, and drugs don't always do what we expect them to do. Sometimes that's bad news, as the VISTA-16 trial demonstrated. But sometimes it opens unexpected doors.

For the millions of people who live with the daily risk of snakebite—farmers, herders, forest workers, children in rural villages—varespladib represents hope for something that doesn't exist today: a treatment that can be given immediately, in the field, by anyone. Not as a replacement for antivenom and hospital care, but as a crucial first intervention that buys time and reduces damage while help is sought.

Whether varespladib fulfills this promise remains to be seen. Clinical trials must be completed, manufacturing challenges addressed, distribution networks established. The path from laboratory discovery to routine medical practice is long and uncertain.

But the scientific foundation is encouraging. A drug designed to calm the fires of inflammation in diseased arteries turns out to neutralize the ancient chemical weapons that snakes evolved millions of years ago. It's a reminder that biology, for all its complexity, often reuses the same molecular tools across vastly different contexts—and that sometimes, a failed solution to one problem becomes the answer to another.