MEDVIA member ExeVir is creating llama-derived antibody drugs to provide immunocompromised patients with protection from diseases like COVID-19 and dengue. Though it hasn’t all been smooth sailing since the company’s inception at the start of the pandemic, ExeVir’s solutions hold a lot of promise for the future.

29 April 2024

This story starts in a seemingly unlikely place for health innovation: in a green field in Flanders with a llama named Winter. This may seem less strange to those familiar with the Flemish biotech scene: The region has a decades-long association with llamas due to their very special antibodies.

Llamas have two types of antibodies: conventional with a heavy chain and a light chain (like humans), but also heavy chain-only antibodies of which the antigen-binding part, the VHH, can be isolated. VHHs are smaller and lighter, meaning they’re better at accessing and binding to hidden epitopes on pathogens like bacteria and viruses.

VHHs can also be linked together like small building blocks, making the technology modular and capable of targeting multiple epitopes at once. This means they’re uniquely suited tools in the ‘arms race’ with complex or rapidly evolving diseases, such as viruses developing new variants to evade vaccines.

Rapid mobilization in the early days of the pandemic

Let’s get back to Winter. In the late 2010s, this specific llama had been immunized with proteins of the MERS and SARS viruses by researchers from the Flemish Institute for Biotechnology (VIB). When the COVID-19 pandemic hit, researchers tested if the llama had developed antibodies that could help in the battle against this new, related virus. The screening showed very promising potentials.

To fast-track drug development, the VIB research was spun-out into a new biotech company: ExeVir, which rapidly raised a €42 million Series A. Progress moved at breakneck speed in that first year, CSO Viki Bockstal says: “In those early days, we were all in lockdown, and ExeVir was a virtual company. Despite this, we were able to make extraordinarily rapid progress and had a SARS-CoV-2 antibody drug candidate ready for clinical trials in less than a year.”

ExeVir completed the Phase Ia and Ib patient trials in 2021, with impressive results. But as the company prepared for Phase 2 in late 2021, the virus was mutating. “When we got the first in vitro data demonstrating our drug’s activity against Omicron BA.2, we could see that our molecule had very limited potency against this new variant,” Bockstal shares. “We decided to put the Phase 2 clinical study on hold and go back to the drawing board.”.

More than a one-trick llama

The ExeVir team refused to be disheartened. They went back to the farm, where llama Winter had been peacefully munching away at grass this whole time. Early in the pandemic, Winter had been re-inoculated with the spike protein of the new SARS-CoV-2 virus, to prepare for the possibility of future variants of the virus. This meant that in 2021, the ExeVir team were quickly able to access a new, extensive library of promising second-generation candidate molecules that would be able to target even more conserved epitopes in the virus.

“Winter’s immune system did a really great job,” explains Jeanne Bolger, ExeVir’s Chair, who joined the Board at that time, impressed by the company’s agility and resilience. “Based on these new antibodies, we’ve been able to generate drug candidates that target three epitopes in the virus. They are highly conserved binding sites that haven’t mutated in any of the variants of concern or interest so far. With three separate stable targets, we’re minimizing the risk of viral escape and potency loss in the future, creating a variant-proof solution that should be able to help many people in the long-term.”

Protecting our most vulnerable

The multi-specific antibody cocktail is particularly important for immunocompromised patients such as people with AIDS, as well as those undergoing cancer treatments or who are on immunosuppressive drugs, and the elderly. These patients often don’t respond well to vaccines, as their immune systems are simply too weak to mount a response.

“For many people, COVID-19 is not very high on the agenda anymore,” says Bockstal. “Vaccines have done an amazing job in protecting many of us from hospitalization and death. However, there is still an urgent medical need for an additional layer of protection for elderly and immunocompromised patients in terms of both prophylactics and treatments.”

At this point, all the antibody drugs granted conditional approval in Europe earlier in the pandemic have lost their potency against the new circulating strains. “At ExeVir we’re creating a new generation of antibody therapies that can protect vulnerable people against both current and future strains of the SARS-CoV-2 virus,” states Bolger. “When we started out, it was an emergency response situation; now we’re fighting a marathon battle.”. ExeVir’s second-generation drug candidates are due to enter clinical trials in the coming year.

Dengue: a deadly disease

With their second-generation COVID-19 drugs in development, ExeVir is already turning its gaze towards the future. The company was recently awarded an R&D grant by VLAIO for pre-clinical development of an antibody solution targeting the mosquito-borne disease dengue.

Listed as one of the World Health Organization’s top threats to global health, dengue infects about 400 million people and leads to upwards of 40,000 deaths every year. Anyone visiting or living in an endemic region is at risk, which currently corresponds to about 3.9 billion people – nearly half of the world’s population. But even this astronomical figure is on the rise: the incidence of the disease is exploding, due to travel, urbanization, and climate change, as global warming is causing dengue mosquito ranges to expand even well into Europe.

“As with our COVID-19 treatments, we envision these antibodies as an additional layer of protection for vulnerable populations living in dengue-endemic regions, as well as people traveling to these areas,” Bockstal explains. “There are two approved dengue vaccines, but they have their shortcomings. They’re both live attenuated vaccines, meaning they can’t be given to people who are older, pregnant or immunocompromised. Our antibodies could provide protection for these people whose needs aren’t being met by the currently available vaccines.”

The current dengue vaccines also require more than one shot and take several weeks before they’re effective. This means families holidaying in dengue-affected areas often don’t obtain the protection they need for themselves or their children. An antibody solution could be massively beneficial as a temporary prophylactic. “With antibodies, you’re immediately protected, so they’re ideally suited for travelers,” explains Bockstal. “This is especially important for children, who are most at risk of dying from the disease.”

Plans for pandemic preparedness

ExeVir’s expansion into dengue reflects the young biotech’s ambition, according to Bolger. “From the very beginning we said to our investors ‘we don’t want to be a one-trick pony’. The aim was always to use our technology platform to create antibody drugs that can make a real difference in a range of infectious diseases. With COVID-19, we showed that we can deploy this technology very fast in an emergency. But we also want to play a role in pandemic preparedness and position ourselves so that we can provide solutions for both current diseases and future outbreaks.”

By Amy LeBlanc. Images: Winter the llama ©Tim Coppens