Periodic Reporting for period 2 - OP2DRAIN (To deliver the first medical treatment dedicated to patients with haemorrhagic stroke)
Okres sprawozdawczy: 2023-04-01 do 2024-06-30
Intracerebral Hemorrhage (ICH) remains one of the most devastating forms of stroke, affecting over 350,000 patients annually across the EU, USA, and Japan. It results from the rupture of small cerebral arteries and subsequent blood accumulation within the brain, forming a hematoma that exerts mass effect and triggers secondary injury. Current management is limited to intensive care and monitoring; no approved pharmacological treatment exists. Consequently, 75% of ICH patients either die or suffer from severe lifelong disability.
Previous clinical trials aiming to stop bleeding or protect brain tissue have failed to improve outcomes, and surgical evacuation of deep hematomas remains ineffective. However, the MISTIE III trial has provided valuable insights: while it did not demonstrate benefit for alteplase, it revealed a clear correlation between the extent of hematoma evacuation and functional recovery, validating hematoma volume reduction as a therapeutic target.
Building on these insights, Op2Lysis is developing O2L-001, a first-in-class treatment designed to safely and effectively remove intracerebral hematomas. O2L-001 is derived from the company’s proprietary NANOp2Lysis® platform, a deep-tech system enabling the stabilization of active enzymes through reversible precipitation into solid nanoparticles, followed by encapsulation in tailored carriers for targeted, controlled delivery.
O2L-001 is a locally administered hydrogel formulation containing OptPA, a novel engineered thrombolytic agent with enhanced fibrinolytic activity and an improved safety profile. After minimally invasive catheter injection, the formulation gels at body temperature, ensuring prolonged, localized release within the hematoma.
Key features of O2L-001 include:
• Ease of use: simplified, once-daily local administration
• Efficacy: superior thrombolytic activity in clinically relevant translational models compared to alteplase
• Safety: reduced risk of bleeding and neurotoxicity
The OP2DRAIN project aims to (i) optimize and scale up the manufacturing process for both the drug substance (OptPA) and the drug product (O2L-001); (ii) establish validated analytical methods for product characterization and release; and (iii) produce GMP-like batches for toxicology studies.
A subsequent objective is to conduct preclinical toxicology studies to determine the maximum tolerated dose (MTD) and no-observed-adverse-effect level (NOAEL), supporting the future IMPD/IND submission and authorization for first-in-human clinical trials.
In parallel, the project engages with regulatory authorities (EMA and FDA) to align the development plan with international standards, de-risk the translational pathway, and secure early scientific guidance in preparation for the clinical phase and Series A financing.
Previous clinical trials aiming to stop bleeding or protect brain tissue have failed to improve outcomes, and surgical evacuation of deep hematomas remains ineffective. However, the MISTIE III trial has provided valuable insights: while it did not demonstrate benefit for alteplase, it revealed a clear correlation between the extent of hematoma evacuation and functional recovery, validating hematoma volume reduction as a therapeutic target.
Building on these insights, Op2Lysis is developing O2L-001, a first-in-class treatment designed to safely and effectively remove intracerebral hematomas. O2L-001 is derived from the company’s proprietary NANOp2Lysis® platform, a deep-tech system enabling the stabilization of active enzymes through reversible precipitation into solid nanoparticles, followed by encapsulation in tailored carriers for targeted, controlled delivery.
O2L-001 is a locally administered hydrogel formulation containing OptPA, a novel engineered thrombolytic agent with enhanced fibrinolytic activity and an improved safety profile. After minimally invasive catheter injection, the formulation gels at body temperature, ensuring prolonged, localized release within the hematoma.
Key features of O2L-001 include:
• Ease of use: simplified, once-daily local administration
• Efficacy: superior thrombolytic activity in clinically relevant translational models compared to alteplase
• Safety: reduced risk of bleeding and neurotoxicity
The OP2DRAIN project aims to (i) optimize and scale up the manufacturing process for both the drug substance (OptPA) and the drug product (O2L-001); (ii) establish validated analytical methods for product characterization and release; and (iii) produce GMP-like batches for toxicology studies.
A subsequent objective is to conduct preclinical toxicology studies to determine the maximum tolerated dose (MTD) and no-observed-adverse-effect level (NOAEL), supporting the future IMPD/IND submission and authorization for first-in-human clinical trials.
In parallel, the project engages with regulatory authorities (EMA and FDA) to align the development plan with international standards, de-risk the translational pathway, and secure early scientific guidance in preparation for the clinical phase and Series A financing.
During the OP2DRAIN project, significant milestones were achieved, advancing both the technical and regulatory readiness of the program:
• Milestone 1 – GMP-like production of OptPA: A robust, scalable manufacturing process for the OptPA drug substance was developed and transferred to industrial scale. The process successfully achieved the targeted purity levels, including efficient removal of host cell proteins (HCPs), while maintaining a commercially viable yield and cost of goods. Industrial process for O2L-001:
The formulation and manufacturing process for O2L-001 were optimized to achieve a reproducible particle size distribution compatible with aseptic manufacturing. This process ensures the production of a sterile, stable final product suitable for preclinical and future clinical use.
• Milestone 2 - Regulatory de-risking: based on both FDA and EMA consultations, we have now in our hand a robust cahier des charges to fulfil both European and American requirements in terms of CMC, toxicology and clinical development.
• Milestone 3 – EMA consultation: A Protocol Assistance meeting with the European Medicines Agency (EMA) provided highly positive feedback. The agency raised no major objections, validated the overall development strategy, and recommended complementary actions to facilitate the transition toward the clinical phase. Combined with the constructive interactions initiated with the FDA, this represents a major de-risking step for the program.
• Milestone 4 – toxicology results: Acute and repeated-dose studies in rats demonstrated an excellent safety profile for O2L-001, with only limited, dose-dependent adverse effects observed at the highest tested concentrations. These data confirm the translational safety of the approach and support further GLP studies using the GMP-like material.
Collectively, these achievements demonstrate the maturity of the NANOp2Lysis® technology, the readiness of O2L-001 for regulatory toxicology, and the strong translational alignment of the development program.
• Milestone 1 – GMP-like production of OptPA: A robust, scalable manufacturing process for the OptPA drug substance was developed and transferred to industrial scale. The process successfully achieved the targeted purity levels, including efficient removal of host cell proteins (HCPs), while maintaining a commercially viable yield and cost of goods. Industrial process for O2L-001:
The formulation and manufacturing process for O2L-001 were optimized to achieve a reproducible particle size distribution compatible with aseptic manufacturing. This process ensures the production of a sterile, stable final product suitable for preclinical and future clinical use.
• Milestone 2 - Regulatory de-risking: based on both FDA and EMA consultations, we have now in our hand a robust cahier des charges to fulfil both European and American requirements in terms of CMC, toxicology and clinical development.
• Milestone 3 – EMA consultation: A Protocol Assistance meeting with the European Medicines Agency (EMA) provided highly positive feedback. The agency raised no major objections, validated the overall development strategy, and recommended complementary actions to facilitate the transition toward the clinical phase. Combined with the constructive interactions initiated with the FDA, this represents a major de-risking step for the program.
• Milestone 4 – toxicology results: Acute and repeated-dose studies in rats demonstrated an excellent safety profile for O2L-001, with only limited, dose-dependent adverse effects observed at the highest tested concentrations. These data confirm the translational safety of the approach and support further GLP studies using the GMP-like material.
Collectively, these achievements demonstrate the maturity of the NANOp2Lysis® technology, the readiness of O2L-001 for regulatory toxicology, and the strong translational alignment of the development program.
The OP2DRAIN project has delivered innovations that significantly advance the state of the art in thrombolytic therapy for ICH and in enzyme-based drug delivery:
• Innovative manufacturing and analytical processes:
The project established new methods for enzyme stabilization and encapsulation enabling high-concentration, controlled-release formulations. Analytical methods were pre-validated to anticipate GLP/GMP requirements and minimize subsequent validation risks.
• Novel translational paradigm:
By combining a new thrombolytic agent (OptPA) with a targeted delivery system (O2L-001), the project introduces a paradigm shift in ICH therapy: localized, sustained enzymatic hematoma evacuation with minimized systemic exposure and bleeding risk.
• Regulatory and industrial readiness:
Manufacturing of OptPA is now under transfer to Catalent Biologics, which will perform scale-up from 100 L to 250 L under GMP-compatible conditions. The readiness of this industrial partner confirms the scalability and robustness of the process.
• Strategic next steps:
To consolidate these achievements, the project will:
1. Complete analytical and process validations required for GMP batch release;
2. Conduct GLP toxicology studies (rats and pigs) using GMP-like material;
3. Finalize regulatory interactions to secure IMPD/IND submission.
The successful completion of O2L-001’s development will not only deliver a first-in-class treatment for ICH but also validate the NANOp2Lysis® platform as a scalable biotechnological asset. This platform can be leveraged to generate a pipeline of enzyme-based therapies for other vascular, thrombotic, or inflammatory indications and to enable novel collaborations in the fields of immunotherapy and controlled drug delivery.
• Innovative manufacturing and analytical processes:
The project established new methods for enzyme stabilization and encapsulation enabling high-concentration, controlled-release formulations. Analytical methods were pre-validated to anticipate GLP/GMP requirements and minimize subsequent validation risks.
• Novel translational paradigm:
By combining a new thrombolytic agent (OptPA) with a targeted delivery system (O2L-001), the project introduces a paradigm shift in ICH therapy: localized, sustained enzymatic hematoma evacuation with minimized systemic exposure and bleeding risk.
• Regulatory and industrial readiness:
Manufacturing of OptPA is now under transfer to Catalent Biologics, which will perform scale-up from 100 L to 250 L under GMP-compatible conditions. The readiness of this industrial partner confirms the scalability and robustness of the process.
• Strategic next steps:
To consolidate these achievements, the project will:
1. Complete analytical and process validations required for GMP batch release;
2. Conduct GLP toxicology studies (rats and pigs) using GMP-like material;
3. Finalize regulatory interactions to secure IMPD/IND submission.
The successful completion of O2L-001’s development will not only deliver a first-in-class treatment for ICH but also validate the NANOp2Lysis® platform as a scalable biotechnological asset. This platform can be leveraged to generate a pipeline of enzyme-based therapies for other vascular, thrombotic, or inflammatory indications and to enable novel collaborations in the fields of immunotherapy and controlled drug delivery.