Periodic Reporting for period 1 - XVR011 Phase 2 (ExeVir's XVR011, a best in class nanobody-based biology that broadly neutralizes SARS-COV-1 and SARS-COV-2)
Reporting period: 2021-12-01 to 2022-11-30
XVR011, ExeVir’s lead candidate in 2021, emerged from the scientific research from the labs of highly regarded virologist Xavier Saelens and biochemist Nico Callewaert. Nonclinical data on the discovery and nonclinical development had been published in Cell and, as a preprint on BiorxIV. XVR011 consists of an antigen-binding domain derived from a lama fused to a Fc and had best-in-class potential, neutralizing SARS-CoV-2 and minimizing the development of lung damage in SARS-CoV-2 challenged hamsters. The Lama derived VHH’s Fc fused heavy-chain only antibodies are smaller than human antibodies and therefore are very suited to bind to small clefts of target antigen and attach to parts of a virus that are difficult to access for conventional antibodies. XVR011 neutralizes SARS-CoV-2, prevents ACE2 binding and destabilizes the spike protein, preventing the virus from entering human cells and therefore stopping viral replication. XVR011 binds to a highly conserved epitope that is poorly recognized by vaccine- or infection-induced antibodies and thus complements the patient’s response in a critical time window during which the patient’s immune system mostly reacts too slowly. This made XVR011 very effective against the SARS-CoV-2 variants that escaped immunity of the human host and were rapidly spreading in the population back in 2021. In May 2021, ExeVir had indeed demonstrated that XVR011 could neutralize all major variants of concern (VOC) and exhibited a unique, wide scope binding broadly across the Sarbecovirus clades. Furthermore, XVR011 had been optimized for stability, safety and manufacturability. A strong intellectual property rights (IPR) portfolio was filed very early on during the pandemic.
Early on in the development of XVR011, UCB, a European mid-size Biopharmaceutical company, assisted ExeVir with the formulation of XVR011 and production of the GMP clinical material for the clinical development in their 2000 liters BioPlant. In March 2021, the technology was transferred from UCB’s BioPlant to the large commercial contract development and manufacturer (CDMO), Millipore/Merck, to establish the process to produce first three consistency lots required for registration and commercial manufacturing thereafter. A clinical trial application was submitted to the Belgian regulators offices (FAHMP). At the end of February 2021, XVR011 received approval from the FAHMP to move into the Phase 1b/2. Approval from the Ethics Committee was obtained in April 2021. The first patient in was therefore expected early May 2021, at the time of the submission of this project application.
ExeVir had successfully raised 42M€ from both private and public entities since its creation to support the company through the clinical trial. It had also raised in May 2021, 2.9M€ from the Flemish government and 3,6M form the Walloon Region. However, to leverage the current global market demand, ExeVir had to accelerate its efforts.
The overall objective of the Horizon project was to demonstrate clinically that XVR011 is an efficacious therapeutic COVID-19 treatment with broad neutralizing activity across SARS-CoV-2 isolates and its rapid evolving variants. Indeed, with a Phase 1b clinical study underway, ExeVir needed to quickly progress to Phase 2, further strengthen its nonclinical data, together with VIB, and prepare the EMA and FDA regulatory packages, with Granzer. In order to ensure availability of product at launch, consistency lots had to be produced and commercial manufacturing had to be set-up, with the help of Millipore/Merck. Finally, ExeVir intended to ensure a successful communication and dissemination of the results. The expertise and knowledge acquired in the scope of this SARS-CoV-2 project would also be important in the development of other antiviral biologics directed against other viruses and pandemic threat candidates, e.g. as listed on the WHO Blueprint list of severe emerging diseases.
Early on in the development of XVR011, UCB, a European mid-size Biopharmaceutical company, assisted ExeVir with the formulation of XVR011 and production of the GMP clinical material for the clinical development in their 2000 liters BioPlant. In March 2021, the technology was transferred from UCB’s BioPlant to the large commercial contract development and manufacturer (CDMO), Millipore/Merck, to establish the process to produce first three consistency lots required for registration and commercial manufacturing thereafter. A clinical trial application was submitted to the Belgian regulators offices (FAHMP). At the end of February 2021, XVR011 received approval from the FAHMP to move into the Phase 1b/2. Approval from the Ethics Committee was obtained in April 2021. The first patient in was therefore expected early May 2021, at the time of the submission of this project application.
ExeVir had successfully raised 42M€ from both private and public entities since its creation to support the company through the clinical trial. It had also raised in May 2021, 2.9M€ from the Flemish government and 3,6M form the Walloon Region. However, to leverage the current global market demand, ExeVir had to accelerate its efforts.
The overall objective of the Horizon project was to demonstrate clinically that XVR011 is an efficacious therapeutic COVID-19 treatment with broad neutralizing activity across SARS-CoV-2 isolates and its rapid evolving variants. Indeed, with a Phase 1b clinical study underway, ExeVir needed to quickly progress to Phase 2, further strengthen its nonclinical data, together with VIB, and prepare the EMA and FDA regulatory packages, with Granzer. In order to ensure availability of product at launch, consistency lots had to be produced and commercial manufacturing had to be set-up, with the help of Millipore/Merck. Finally, ExeVir intended to ensure a successful communication and dissemination of the results. The expertise and knowledge acquired in the scope of this SARS-CoV-2 project would also be important in the development of other antiviral biologics directed against other viruses and pandemic threat candidates, e.g. as listed on the WHO Blueprint list of severe emerging diseases.
The project combined clinical development, nonclinical, regulatory and manufacturing activities and was a partnership between ExeVir, VIB, Granzer and Millipore. The proposal was composed of 8 work packages: clinical package, nonclinical safety and efficacy packages, clinical pharmacokinetics (PK) package, manufacturing and analytical package, regulatory package, project management and communication package and ethics requirements package. The consortium built together the necessary disciplines and expertise to address the key objectives of the project.
The proposal which was submitted in May 2021, started in Dec 2021. In the meantime, ExeVir had initiated a Phase 1a in parallel to its Phase 1b as mitigation to the COVID-19 summer down wave in Europe to accelerate the obtention of PK and does selection data to start the phase 2 as soon as possible. The non-clinical packages in terms of safety and efficacy have been reinforced. In particular, as the emergence of new variants accelerated, the team continued to regularly test the potency of XVR011. Regarding process manufacturing and the analytical package, all activities progressed, albeit with a slight delay due to a shortage of raw materials, which impacted the start of the 2000l batch manufacturing.
When Omicron first appeared and the disease progression evolved, the team took the decision to redesign the initially planned Phase 2. The new trial focused on the outpatient immunocompromised population. Inputs were taken from practicians and clinicians globally in order to understand how the disease was evolving and the patient needs. Unfortunately, Omicron BA.2 which started spreading end of February/March as a new VOC, had an negative impact on XVR011’s neutralization potency. Once the neutralization impact was confirmed by 2 external CROs, the team stopped the ongoing activities where possible.
Although XVR011 lost its neutralization potency against Omicron BA.2 and subsequent subvariants, it remains ready for Phase 2 subject to the appearance of susceptible SARS-CoV-2 variants than the Omicron lineage. However, ExeVir has very promising “second generation” molecules in late preclinical development targeting both the S1 and S2 region of the SARS-CoV-2 spike protein and neutralizing all variants of concern. These molecules can be used both as a therapeutic and prophylactic.
The proposal which was submitted in May 2021, started in Dec 2021. In the meantime, ExeVir had initiated a Phase 1a in parallel to its Phase 1b as mitigation to the COVID-19 summer down wave in Europe to accelerate the obtention of PK and does selection data to start the phase 2 as soon as possible. The non-clinical packages in terms of safety and efficacy have been reinforced. In particular, as the emergence of new variants accelerated, the team continued to regularly test the potency of XVR011. Regarding process manufacturing and the analytical package, all activities progressed, albeit with a slight delay due to a shortage of raw materials, which impacted the start of the 2000l batch manufacturing.
When Omicron first appeared and the disease progression evolved, the team took the decision to redesign the initially planned Phase 2. The new trial focused on the outpatient immunocompromised population. Inputs were taken from practicians and clinicians globally in order to understand how the disease was evolving and the patient needs. Unfortunately, Omicron BA.2 which started spreading end of February/March as a new VOC, had an negative impact on XVR011’s neutralization potency. Once the neutralization impact was confirmed by 2 external CROs, the team stopped the ongoing activities where possible.
Although XVR011 lost its neutralization potency against Omicron BA.2 and subsequent subvariants, it remains ready for Phase 2 subject to the appearance of susceptible SARS-CoV-2 variants than the Omicron lineage. However, ExeVir has very promising “second generation” molecules in late preclinical development targeting both the S1 and S2 region of the SARS-CoV-2 spike protein and neutralizing all variants of concern. These molecules can be used both as a therapeutic and prophylactic.
The XVR011 project led to increased knowledge in SARS-COV-2, new IPR and the first clinical trials with a VHH fused to an Fc. While due to the impact of Omicron on the neutralization potency of XVR011, the project did not come to full exploitation, nevertheless, it led to employment creation, people development, increasing manufacturing capacity of European CDMOs and multiple collaborations within and outside the consortium. Furthermore, the consortium safeguarded European technology competitiveness by having locally based expertise for infectious diseases and pandemic preparedness, which is also particularly critical in recent years where increasing geopolitical tension has highlighted the need for regional expertise.