Periodic Reporting for period 2 - StopBleeding (The first effective and safe reversal agent to stop or prevent life-threatening bleeding in patients taking the emerging generation of anticoagulants.)
Reporting period: 2023-09-01 to 2025-03-31
Over 50 million patients globally rely on oral anticoagulants to prevent thrombosis and strokes. In recent years, there has been a significant shift from traditional, risk-prone anticoagulants to a new class known as Factor Xa Direct Oral Anticoagulants (FXa-DOACs), which are used by over 10 million patients in the EU and US. FXa-DOACs are praised for their predictability, safety, and efficacy. However, a major drawback remains: the lack of a safe and effective reversal agent. In cases of severe or uncontrolled bleeding—often life-threatening—patients currently face limited treatment options. This leads to over 400,000 hospital admissions annually, underscoring a critical unmet medical need.
To address this, VarmX has developed VMX-C001, a novel and safe bypass agent specifically designed to counteract the effects of FXa-DOACs. The innovation is positioned to be the first of its kind with the potential to significantly reduce morbidity and mortality related to bleeding complications in anticoagulated patients. Backed by substantial funding—a €2.5 million grant and €15 million in equity from the European Innovation Council (EIC)—VarmX aims to accelerate the scaling and cost efficiency of VMX-C001’s complex production process.
To address this, VarmX has developed VMX-C001, a novel and safe bypass agent specifically designed to counteract the effects of FXa-DOACs. The innovation is positioned to be the first of its kind with the potential to significantly reduce morbidity and mortality related to bleeding complications in anticoagulated patients. Backed by substantial funding—a €2.5 million grant and €15 million in equity from the European Innovation Council (EIC)—VarmX aims to accelerate the scaling and cost efficiency of VMX-C001’s complex production process.
VarmX undertook extensive development activities focusing on improving VMX-C001 production. The company collaborated with three Contract Research Organizations (CROs) and an academic laboratory to either create a new, more efficient cell line or optimize the existing Chinese Hamster Ovary (CHO) cell line used in the manufacturing process.
Cell Line Development (CLD) Strategy
VarmX’s CLD efforts followed a diversified strategy. Multiple platforms were tested to assess their potential to produce VMX-C001 with high yields and desirable activity profiles. Criteria for selecting the optimal clone included total yield, specific activity of the molecule, and robustness of the cell lines.
Despite the broad scope, none of the new cell lines tested met VarmX's strict benchmarks. The expected two- to four-fold increase in production efficiency did not materialize. As a result, VarmX chose not to proceed with generating a Master Cell Bank from any of the new candidates. Instead, focus shifted back to optimizing the manufacturing process using the current CHO-based cell line.
Process Optimization
The project then pivoted toward process development, aiming to lower the Cost of Goods Sold (COGS) by refining the existing production methods. The emphasis was placed on upstream processing—essentially, how the cells are cultivated and how VMX-C001 is initially produced—under the assumption that downstream purification steps would require minimal adjustments.
Various cultivation modes were evaluated, notably fed-batch and perfusion processes. Preliminary experiments had already shown that a switch to a fed-batch model could be promising. Design-of-Experiment (DOE) methodologies were used to systematically test combinations of cell culture parameters (e.g. pH, temperature, nutrient feeding rates). The data were analyzed using statistical software (SAS JMP), identifying conditions under which yields and activity were maximized without sacrificing quality.
The results validated the viability of using a fed-batch process as a cost-effective alternative to the existing perfusion method. Not only could this reduce production costs significantly, but it also positioned VarmX to be better prepared for potential large-scale production scenarios, assuming VMX-C001 gains commercial approval.
Currently, the most promising parameters from the DOE work are being tested at a 5-liter scale. This includes adapting the downstream steps, such as switching from continuous (used in perfusion) to batch harvesting. However, technical equipment issues have delayed full analysis, with comprehensive results expected in the second half of 2025.
Analytical Advancements
To support both process and product evaluation, VarmX expanded its analytical capabilities. An Octet analysis technique was introduced across all labs to standardize quantification of VMX-C001. Additionally, a clotting activity assay was implemented at VarmX's headquarters in Leiden. These tools not only enhance process development but also support future product pipeline efforts.
Further, Contract Development and Manufacturing Organizations (CDMOs) involved in VMX-C001 production have implemented and qualified critical assays for detecting Host Cell Proteins (HCP) and residual DNA. These are essential for maintaining compliance with regulatory standards and ensuring product safety.
Cell Line Development (CLD) Strategy
VarmX’s CLD efforts followed a diversified strategy. Multiple platforms were tested to assess their potential to produce VMX-C001 with high yields and desirable activity profiles. Criteria for selecting the optimal clone included total yield, specific activity of the molecule, and robustness of the cell lines.
Despite the broad scope, none of the new cell lines tested met VarmX's strict benchmarks. The expected two- to four-fold increase in production efficiency did not materialize. As a result, VarmX chose not to proceed with generating a Master Cell Bank from any of the new candidates. Instead, focus shifted back to optimizing the manufacturing process using the current CHO-based cell line.
Process Optimization
The project then pivoted toward process development, aiming to lower the Cost of Goods Sold (COGS) by refining the existing production methods. The emphasis was placed on upstream processing—essentially, how the cells are cultivated and how VMX-C001 is initially produced—under the assumption that downstream purification steps would require minimal adjustments.
Various cultivation modes were evaluated, notably fed-batch and perfusion processes. Preliminary experiments had already shown that a switch to a fed-batch model could be promising. Design-of-Experiment (DOE) methodologies were used to systematically test combinations of cell culture parameters (e.g. pH, temperature, nutrient feeding rates). The data were analyzed using statistical software (SAS JMP), identifying conditions under which yields and activity were maximized without sacrificing quality.
The results validated the viability of using a fed-batch process as a cost-effective alternative to the existing perfusion method. Not only could this reduce production costs significantly, but it also positioned VarmX to be better prepared for potential large-scale production scenarios, assuming VMX-C001 gains commercial approval.
Currently, the most promising parameters from the DOE work are being tested at a 5-liter scale. This includes adapting the downstream steps, such as switching from continuous (used in perfusion) to batch harvesting. However, technical equipment issues have delayed full analysis, with comprehensive results expected in the second half of 2025.
Analytical Advancements
To support both process and product evaluation, VarmX expanded its analytical capabilities. An Octet analysis technique was introduced across all labs to standardize quantification of VMX-C001. Additionally, a clotting activity assay was implemented at VarmX's headquarters in Leiden. These tools not only enhance process development but also support future product pipeline efforts.
Further, Contract Development and Manufacturing Organizations (CDMOs) involved in VMX-C001 production have implemented and qualified critical assays for detecting Host Cell Proteins (HCP) and residual DNA. These are essential for maintaining compliance with regulatory standards and ensuring product safety.
Early stability studies of VMX-C001 show that the molecule remains stable under standard storage conditions. This suggests that the drug might not need to be lyophilized (freeze-dried)—a step often required for protein-based therapeutics. This simplification could streamline drug preparation and make administration easier for healthcare providers, ultimately benefiting patients.
Should this stability be confirmed for VMX-C001 produced under the optimized process, it would further enhance the product's logistical and commercial appeal. It would remove one cost and complexity barrier and accelerate time-to-use in emergency settings.
VMX-C001 is developed to become the first safe bypass agent to restore coagulation in patients using FX-DOACS. Achieving a lower COGS is crucial not just for profitability but for making the drug accessible to a broad patient population.
Should this stability be confirmed for VMX-C001 produced under the optimized process, it would further enhance the product's logistical and commercial appeal. It would remove one cost and complexity barrier and accelerate time-to-use in emergency settings.
VMX-C001 is developed to become the first safe bypass agent to restore coagulation in patients using FX-DOACS. Achieving a lower COGS is crucial not just for profitability but for making the drug accessible to a broad patient population.