ExeVir Bio Forges Ahead with Unique Next Generation COVID-19 Therapy and Appoints Dr. Jeanne Bolger as Chair of the Board of Directors
XVR011 has passed Phase 1A and 1B safety studies. It's a camelid antibody (from Llamas) that's smaller and simpler than human antibodies, so it lasts longer in the body. The antibodies are also called nanobodies. It's described in this paper:
Looks like their Phase 1b study of XVR011 was terminated, because the MAB was not as broad as they had hoped. I suspect any future product would have a new name and slightly different MAB,
The industry article below was published May 9, 2022, before the PRnewsWire article I cited above.
'ExeVir has returned to the drawing board after pausing work on its first-generation llama-derived Covid-19 antibody and is turning its R&D focus toward a preclinical second-gen attempt, Endpoints News has learned.
The Belgian biotech terminated a study of the antibody, dubbed XVR011, last month due to “change in company strategy for phase 2 design,” according to an update on clinicaltrials.gov. The biotech still awaits some data to confirm the scope of Omicron and its subvariants’ effect on the antibody, but ExeVir is likely to move forward without its first shot at treating the pandemic disease, CEO Torsten Mummenbrauer told Endpoints.
“In our case, what is really a bit, let’s call it frustrating, part, there was really no evidence from the database, from history, from whatsoever, that in this very specific epitope the virus is able to mutate, and then we saw three mutations very close to our binding epitope, which I’ve never seen before, really out of the blue,” Mummenbrauer said. The antibody, derived from a llama and originating from VIB research surrounding the SARS outbreak earlier this century, targeted a “special epitope” hidden within the spike protein that had shown high conservation against previous Covid variants in preclinical data.
ExeVir ran the antibody through a Phase Ia 30-patient healthy volunteer study in three cohorts, at 250 mg, 500 mg and 1000 mg. All patients completed the study, in which the antibody was found to be well-tolerated and had “quite nice PK curves,” and a half-life of about 17 days, Mummenbrauer said.
In a parallel Phase Ib study, with 27 patients across the same three dosing cohorts as Phase Ia, two patients experienced serious adverse events in the low-dose group. One patient had a pulmonary embolism and another had pulmonary disease, but both were “assessed as non-related by the investigator,” Mummenbrauer said.
But Omicron and its subvariants are putting a wedge in ExeVir’s plans. The biotech had hoped to move the antibody into a Phase II in immunocompromised patients in an outpatient setting, but ExeVir received “a bit disappointing data on the Omicron BA.2,” the CEO said.
“If the live virus confirms the pseudo virus data at this stage as having Omicron BA.2 and the follow-on variants, BA.3, BA.4, the epitopes seem to be very close to the BA.2, it doesn’t make sense for us to start a Phase II study at this stage, unfortunately,” Mummenbrauer said. The live virus data is expected in the next week or two, he said.
“I have to say, we do not have big hopes that the live virus data will be significantly different,” the CEO added. That means the biotech will likely have to lay off the clinical team from its workforce, he said, noting ExeVir has a total of about 15 employees and works with five consultants.
But, Omicron might not be a final blow to XVR011, if previous history informs the future.
Mummenbrauer pointed to Eli Lilly’s combo antibody being halted because of the Beta variant last summer but then resumed rollout in autumn 2021 following the rise of the Delta variant.
“We don’t know what might happen next winter. The Delta-like might come back, put XVR011 back into play,” Mummenbrauer said.
Nonetheless, ExeVir has prioritized its second-generation molecules for SARS-CoV-2 and, at a meeting last Thursday, the board decided on the indication for the company’s pipeline expansion beyond Covid-19, the CEO said.
“We have generated over the last year new libraries and identified new families of binders on different epitopes. And this time, we took a bit more time to optimize the molecules. So we are in a range of between 10 and maybe even up to a 100-fold higher potency,” Mummenbrauer said, referring to the company’s second attempt at a Covid-19 antibody. ExeVir is looking at various molecules that combine two epitopes to reduce the “risk of viral escape” and preclinical potency data “for all of them looks very exciting,” the CEO said.
ExeVir is in the process of evaluating the “manufacturability of the molecules.” An IND for a healthy volunteer Phase I is not likely until about mid-2023, Mummenbrauer said, noting the GMP component needs to be completed.
After the Phase I study, ExeVir would look to move immediately into a Phase II that could potentially be geared toward registrational design for conditional approval, “but it will depend of course on the medical need at that stage in this group of the immunocompromised people if the regulatory authorities are still willing to have that discussion,” the CEO said. He emphasized the medical need for immunocompromised patients who need protection beyond what is provided by the vaccines.
The biotech’s $50 million Series A — which included UCB, V-Bio Ventures, Fund+ and others 12 months ago — should bankroll the new antibody to the IND-ready stage, Mummenbrauer said.
“With a message like that, that’s not the easiest time point to talk,” the CEO said. “So I guess we will need to achieve some more inflection points — those in the second generation as well as on the beyond Covid pipeline to position us as a really attractive target again.”
The non-Covid indication was decided in the board meeting last week, but the company needs to “investigate the IP situation a bit further” before providing an update, the CEO said. ExeVir has “wanted to be an infectious company from day one,” he said. Prior to joining ExeVir in mid-2020, Mummenbrauer was in business development roles at Hookipa, MorphoSys and GlaxoSmithKline’s vaccines division.
“I’m still optimistic looking into the future and I think there will be big demand for our treatment against Covid in the future,” the CEO said.'
We really do need an updated MAB available right now, but it seems reasonably good news to us if their forecast is right, plus we should still have their next iteration waiting to go if a suitable new variant meets their development criteria, which importantly should result in a MAB with a broader coverage. There's just that worrying lack of coverage meanwhile.
New technology always faces more hurdles, I think - at the very least with trust, as we saw with the mRNA vaccines (which weren't really that new of a technology). I think the dMAB technology could be promising, but it'll be a couple of years before we see a product from it for viruses that most of us fear the most. I know that Zika has been seen at least a few times in continental U.S., but it's not a big problem so far. Most of the effort here has been in mosquito control.
Camels show strong resistance to many viral and microbial infections, including tetanus, foot-and-mouth disease and mad cow disease (or bovine spongiform encephalopathy). Their antibodies are several times smaller than those produced by other animals including humans. Dubbed 'nanobodies,' they can enter tissues and cells that other antibodies cannot. They can even interfere with enzyme binding sites, contributing to camels' remarkable disease resistance. Their size and ability makes them potentially valuable in biomedical research on a broad range of diseases including cancer, Alzheimer's disease and atherosclerosis.
Structures show that the nanobodies target two distinct epitopes on the SARS-CoV-2 spike protein. Multivalent nanobodies neutralize virus much more potently than single nanobodies, and multivalent nanobodies that bind two epitopes prevent the emergence of viral escape mutants.
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