Drug development

Snake venom in pharma; access to antivenom is a topic that needs attention

Over 100,000 people die each year as a result of snake bites, but access to antivenom is often a challenging task thanks to manufacturers dropping antivenom products from their production line. Abi Millar finds out how this problem is being addressed.

Snake bites are a major public health issue in many parts of the world. It is thought that over five million people are bitten each year, with up to 138,000 losing their lives and many more left permanently disabled. 

However, unlike many other problems of a similar magnitude, envenoming has tended to fall under the radar. It wasn’t till recently that the World Health Organization took note, formally classing snake bites as a ‘global health priority’ in May 2018.

“The people who are most affected by snake bites are rural impoverished people of the tropics, especially sub-Saharan Africa and southern Asia,” says Dr Nicholas Casewell, a senior lecturer and Wellcome Trust research fellow at the Centre of Snakebite Research and Interventions (CSRI). “Because these are disadvantaged populations, they don’t have much in the way of a political voice. So generally speaking governments and national health agencies do not seem to prioritise snake bites in the way they do many infectious diseases.”

The bitter irony of the situation is that snake bites can be effectively treated, if the patient receives the right medicine at the right time. Deaths from snake bites occur not because we don’t have a solution, but because, more often than not, these solutions aren’t accessible to those who need them. 

As an example, we can compare Australia and India, which have vastly different rates of snakebite mortality despite having snakes of similar toxicity. In Australia, antivenom products are easily obtained, meaning very few people die after being bitten. But in India, many people lack recourse to treatment, leading to 50,000 snakebite deaths a year. Nearly 97% of these deaths occur in rural areas, where patients are more likely to face delays accessing treatment. 

How antivenoms are manufactured

Part of the problem, says Casewell, is that there’s no such thing as a universal antivenom. 

“One of the biggest challenges we face with treating snake bites is that all the venoms of these different dangerous snakes vary, so you need to tailor your therapy towards the snakes that are causing the most bites in any particular region of the world,” he says. “Each variety can be used specifically against one, or typically a few, snake species found in that geographical area. But an antivenom that’s used to treat snake bites in Africa wouldn’t work in India or South America.”

First developed in the 1890s by a member of the Pasteur Institute, snake antivenoms are manufactured in a way Casewell calls “quite archaic really”. The snake is milked for its venom, and a tiny quantity of that venom is injected into an animal, causing an immune response. The antibodies in its blood are then extracted, purified and made into antivenom. 

Governments and national health agencies do not seem to prioritise snake bites.

“Antivenoms all consist of polyclonal antibodies that are raised in animals that are immunised with venom over a period of time,” says Casewell. “This causes a number of issues, including high cost to manufacture and deliver to patients, and there are also issues with adverse reactions because you’re injecting patients with large doses of foreign protein from animal origin. But despite these limitations they’re highly effective if received promptly after a bite.”

Since the side effects can be severe, antivenoms need to be administered intravenously in a hospital setting. This isn’t always possible within rural, low-resource communities, which may lack affordable means of transport. Unfortunately, waiting more than six hours is often fatal.

Low supply and low demand

Given the need for different types of antivenom, manufacturers typically develop products for their own part of the world. According to the World Health Organization, there are 46 laboratories producing animal-derived antivenoms, of which 31 (many of them in Latin America) are government-owned. Only one is based in sub-Saharan Africa, leading to something of a therapeutic vacuum. 

“This began in the 1990s when a number of major manufacturers withdrew their products from sale since they weren’t commercially viable,” says Casewell. “The issues relating to the failings of those antivenoms really have to do with the supply and uptake of antivenom on the ground.”

He notes that in Africa, it’s unusual for antivenoms to be subsidised or provided as part of the national health service, meaning individuals are generally required to purchase these products themselves. 

“The problem is that most of the people bitten by snakes are impoverished – they’re earning a couple of dollars a day,” he says. “But a single vial of antivenom might cost anything from $200, and you might need ten vials to affect a cure. For most of these people it’s simply unaffordable.”

A single vial of antivenom might cost anything from $200, and you might need ten vials to affect a cure.

Manufacturers responded to low demand by reducing production, leading to a vicious cycle of poor availability and high prices. The vacuum was filled with inferior, cheaper products, often imported from elsewhere. 

“Other products flooded into Africa that perhaps weren’t as effective as they should have been,” says Casewell. “Many of these been manufactured against snakes found in other parts of the world, and had been shown to have quite poor efficacy against snakes found in Africa. But for someone who’s purchasing antivenom for their hospital or pharmacy it’s quite difficult to understand these intricacies.”

This is one of the issues that the World Health Organization is looking to redress. Following the launch of its pre-market testing scheme, which will evaluate the safety and effectiveness of each product, health systems should have an easier time working out which antivenoms are most appropriate. 

The WHO has also set up a working group on snake bites, with a view to achieving a 50% reduction in snakebite deaths and disabilities by 2030. This will entail strengthening health systems, improving advocacy and gaining better data into the scale of the problem, on top of its work relating to antivenoms.

A more rational approach

Over the next few years, the research community and pharma industry should have an important role to play in improving antivenom availability. Casewell thinks there is scope to take a much more ‘rational approach’. 

“We probably need to have a much better understanding of what the toxins are in the different snake species that are biting and killing a lot of people,” he says. “At the moment to make an antivenom we just inject venom into an animal, and the animal will generate antibodies against everything in that venom. But in reality only a small proportion of those antibodies are going to be neutralising the toxins that cause pathology in patients.”

In laboratory research, only around 10%-20% of the antibodies in antivenom have been shown to be specific to venom proteins. If antivenom could be made more specific, the required therapeutic dose would be lower and the costs would come down.  

Plus, if we truly understand which toxins are doing the most damage, it may be possible to neutralise them in a more generic manner, developing treatments for use against many different types of snake.

If antivenom could be made more specific, the required therapeutic dose would be lower.

“One thing we’ve been looking at is whether it’s more informative to make antivenoms against venoms that cause a single type of pathology, rather than those in a single geographic region,” Casewell explains. 

While he thinks a true universal antivenom is some way off, he says there are plenty of new ideas out there, including monoclonal antibody approaches and those involving small molecule enzyme inhibitors. 

“Perhaps these new approaches wouldn’t obviate the need for a patient to get antivenom, but they might be enough to buy the patient some time,” he says. “Some might be safe enough to give in the community, maybe orally, enabling them to get to the hospital after that. I think that would have a substantial impact on outcomes.” 

Evidently, this is only one aspect of the problem. But with snakebite mortality now being treated with the urgency it merits, there is every hope of effecting real change. 

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