LONDON – Exevir Bio NV added a further €19 million (US$22.6 million) to close its series A round at €42 million, providing the means to take its nanobody therapy for treating COVID-19 infection through to registration.

With ethics approval expected in the next few days, the phase Ib/II study of XVR-011 in hospitalized patients will get off the ground just nine months after Exevir was set up.

“In one to two weeks, we will be a clinical-stage company. That’s amazing progress,” said Torsten Mummenbrauer, CEO.

Speedy though it may be, Exevir could be considered an also ran, given Vir Biotechnology Inc. and Glaxosmithkline plc’s announcement last week that the data safety monitoring board said their antibody, VIR-7831, showed “profound efficacy” in preventing people at high risk of progressing to serious disease from requiring admission to hospital.

The effect of VIR-7831 was similar to that seen with two other antibody products, Eli Lilly and Co.’s bamlanivimab and Regeneron Inc.’s casirivimab/imdevimab, both of which recently received FDA emergency use approval. The trio would seem to preclude the need for another SARS-CoV-2 neutralizing antibody.

Torsten Mummenbrauer, CEO, Exevir

However, Mummenbrauer said, there already is some evidence of antibodies losing their affinity as SARS-CoV-2 mutates, with variants acquiring mutations in the receptor binding domain that is the target of existing antibody products.

“There is data showing viral escape from antibody therapies is already ongoing,” said Mummenbrauer. “We believe there will be a need for second-generation antibodies. Everyone is worried about variants of concern,” he told BioWorld.

In response, neutralizing antibodies are needed which bind to regions of the SARS-CoV-2 spike protein that are not evolving in response to human immune pressure, Mummenbrauer said.

The evidence from preclinical research is that its smaller size enables XVR-011 to bind to an epitope on the receptor binding domain of the spike protein that is not accessible to human antibodies. Analysis of 200,000 sequences from viral isolates shows the epitope is highly conserved. “There is very little mutation activity,” said Mummenbrauer.

Preclinical data published as a preprint on Biorxiv on March 8, by researchers at the Flanders Institute of Biotechnology (VIB) Center for Medical Biotechnology, in Ghent, Belgium, where XVR-011 was discovered, show that when the nanobody binds to the epitope, it traps the receptor binding domain in the “up” position. That prevents SARS-CoV-2 from interacting with the ACE2 receptor by which the virus enters the host cell.

In a mouse model expressing human ACE2, XVR-011-treated animals survived a SARS-CoV-2 challenge and had significantly reduced lung virus titers three days after infection, compared to controls. That effect was replicated with an inhaled formulation of the nanobody.

“The study demonstrates that the mutations in the viral spike protein of the recently observed SARS-CoV-2 variants of concern do not hamper neutralization by XVR-001,” said Xavier Saelens, scientific co-founder of Ghent-based Exevir. “This includes the variants first observed in South Africa, B.1.351 and the U.K. B 1.1.7, which are neutralized by XVR-011 with equal potency as earlier SARS-CoV-2 pandemic strains,” he said.

As Saelens noted, that contrasts with reported loss of activity due to these variants for several neutralizing antibodies that have received emergency use approval, and for several in clinical trials.

Clinical development will start with a three-arm phase Ib trial testing three different doses of intravenously administered XVR-011, with nine patients per arm. The aim will be to treat early, on the first day of being in the hospital if possible, to head off development of a damaging host immune response. “We have very potent binding, so there is a reasonable chance of preventing this,” said Mummenbrauer.

Assuming safety is demonstrated, that will be followed by a phase II study in 258 patients. The primary endpoint is to reduce the length of hospital stay by 30%.

Viral samples from all patients will be sequenced to get a view of the effectiveness of XVR-001 against different variants.

The extension of the series B was led by Fund+ with VIB, UCB Ventures, SFPI-FPIM, V-Bio Ventures, and new investors SRIW, Noshaq, Vives, Sambrinvest and several Belgian family offices.

In addition to providing backing through its corporate venture arm, UCB Pharma SA has helped design the bioprocess and has manufactured clinical trial supplies of XVR-011.

The series A also will allow Exevir to advance a subcutaneous formulation of XVR-001, providing the flexibility for the product to be administered in a primary care setting. This will use the same drug substance as the intravenous formulation; the only difference will be that greater dilution is required I.V.

Mummenbrauer said he expects subcutaneous administration to be another area where the small size of nanobodies has an advantage over antibodies. At concentrations that are likely to be effective, antibodies form a gel that is unsuitable for injection, a problem not seen with nanobodies, he noted.