Periodic Reporting for period 1 - OP2DRAIN (To deliver the first medical treatment dedicated to patients with haemorrhagic stroke)
Reporting period: 2022-07-01 to 2023-03-31
Cerebral Hemorrhage (ICH) is an unmet medical need that affects >350 000 patients yearly in the European Union, USA and in Japan. ICH results from the rupture of small arteries with subsequent leaking of blood into the brain, leading to cerebral hematoma. Healthcare is restricted to intensive nursing and monitoring. Because of the severity of the disease and of the absence of effective treatment, 75% of ICH patients die or have severe disability.
Up to now, stopping the bleeding early or neuroprotection of the brain did not show any positive effect in clinical trials, neither hematoma evacuation by a surgical approach. Nevertheless, one recent clinical trial opened a new hope. While the MisTIE program failed to demonstrate a clinical benefit with the gold standard thrombolytic agent (alteplase) to evacuate the hematoma, it highlighted for the first time a strong relationship between the volume of hematoma evacuated with such technology and the level of handicap one year after treatment. Thus, data from the real-world needs (patients) help us in designing our therapeutic solution to promote higher efficacy and safety.
Using our NANOp2lysis® platform, we are developing O2L-001, the first effective and safe treatment to remove intracerebral hematoma and reduce disability and death following ICH.
The NANOp2lysis® platform is a deep-tech technology to protect active enzymes by a reversible precipitation and to produce solid-state nanoparticles. Such particles can then be loaded at high concentration into tailored carrier (with specific targeting /slow delivery characteristics).
O2L-001 (derived from this platform) has been tailored to be locally injected, after minimally invasive surgery, via a catheter at the core of the hematoma. The gelation of the product at body temperature allows a local and extended delivery of our proprietary thrombolytic agent, OptPA, which is a new biological entity with the safest profile among thrombolytic agents.
The main characteristics of O2L-001 are thus the following:
-EASY, simplified model of administration (one-day treatment)
-EFFICACY, better thrombolytic effect on best translational model (vs gold standard)
-SAFE, reduced side effect (bleeding and neurotoxicity vs gold standard)
Prior to the production of the batch for the toxicological study, one of the objectives of the project is to optimize the manufacturing process of the drug substance, OptPA in terms of production and purification (removal of the principal impurities, the host cell proteins (HCP)) and of the drug product, O2L-001 to obtain a reproducible and robust manufacturing process and to define a suitable sterilization process.
In parallel, it is planned in the OP2DRAIN project to develop and qualify different analytical methods to characterize and release OptPA and O2L-001. These activities are key to produce large volumes with the aim to demonstrate and validate the reproducibility of the method and the absence of contaminants and bioburden, so that the product (O2L-001) obtained is comparable after each production.
The deliverable of this work package is the production of a GMP-like (Good Manufacturing Process) batch of OptPA and O2L-001 for the toxicological study.
The following objective, in the sequence of development, is to evaluate the maximum feasible/tolerated dose and the safety in the toxicology program using the GMP-like production. OptPA, the active substance of O2L-001, has been shown to have less pro-bleeding activity and less neurotoxicity capabilities than rtPA (Goulay et al., 2018). The objective of the program is to confirm, in the toxicology plan, the safety of the doses to be used in human (maximal tolerated dose - MTD, no observed effect level - NOEL/NOAEL). These studies are essential to support the application of an Investigational Medicinal Product Dossier (IMPD) / Investigational New Drug (IND) to obtain the authorisation for the clinical trial.
In parallel, to decrease the level of risk of the program as well as to attract investors, another objective is to follow up the discussions engaged with health authorities to present our technology, our development plan, to address specific questions and receive feedback from the health authority experts to ensure adequacy to guidelines and to favour the authorisation for the clinical trial.
Up to now, stopping the bleeding early or neuroprotection of the brain did not show any positive effect in clinical trials, neither hematoma evacuation by a surgical approach. Nevertheless, one recent clinical trial opened a new hope. While the MisTIE program failed to demonstrate a clinical benefit with the gold standard thrombolytic agent (alteplase) to evacuate the hematoma, it highlighted for the first time a strong relationship between the volume of hematoma evacuated with such technology and the level of handicap one year after treatment. Thus, data from the real-world needs (patients) help us in designing our therapeutic solution to promote higher efficacy and safety.
Using our NANOp2lysis® platform, we are developing O2L-001, the first effective and safe treatment to remove intracerebral hematoma and reduce disability and death following ICH.
The NANOp2lysis® platform is a deep-tech technology to protect active enzymes by a reversible precipitation and to produce solid-state nanoparticles. Such particles can then be loaded at high concentration into tailored carrier (with specific targeting /slow delivery characteristics).
O2L-001 (derived from this platform) has been tailored to be locally injected, after minimally invasive surgery, via a catheter at the core of the hematoma. The gelation of the product at body temperature allows a local and extended delivery of our proprietary thrombolytic agent, OptPA, which is a new biological entity with the safest profile among thrombolytic agents.
The main characteristics of O2L-001 are thus the following:
-EASY, simplified model of administration (one-day treatment)
-EFFICACY, better thrombolytic effect on best translational model (vs gold standard)
-SAFE, reduced side effect (bleeding and neurotoxicity vs gold standard)
Prior to the production of the batch for the toxicological study, one of the objectives of the project is to optimize the manufacturing process of the drug substance, OptPA in terms of production and purification (removal of the principal impurities, the host cell proteins (HCP)) and of the drug product, O2L-001 to obtain a reproducible and robust manufacturing process and to define a suitable sterilization process.
In parallel, it is planned in the OP2DRAIN project to develop and qualify different analytical methods to characterize and release OptPA and O2L-001. These activities are key to produce large volumes with the aim to demonstrate and validate the reproducibility of the method and the absence of contaminants and bioburden, so that the product (O2L-001) obtained is comparable after each production.
The deliverable of this work package is the production of a GMP-like (Good Manufacturing Process) batch of OptPA and O2L-001 for the toxicological study.
The following objective, in the sequence of development, is to evaluate the maximum feasible/tolerated dose and the safety in the toxicology program using the GMP-like production. OptPA, the active substance of O2L-001, has been shown to have less pro-bleeding activity and less neurotoxicity capabilities than rtPA (Goulay et al., 2018). The objective of the program is to confirm, in the toxicology plan, the safety of the doses to be used in human (maximal tolerated dose - MTD, no observed effect level - NOEL/NOAEL). These studies are essential to support the application of an Investigational Medicinal Product Dossier (IMPD) / Investigational New Drug (IND) to obtain the authorisation for the clinical trial.
In parallel, to decrease the level of risk of the program as well as to attract investors, another objective is to follow up the discussions engaged with health authorities to present our technology, our development plan, to address specific questions and receive feedback from the health authority experts to ensure adequacy to guidelines and to favour the authorisation for the clinical trial.
During the first semester of the OP2DRAIN project, several technical advances were made:
- In terms of purification and elimination of contaminants (Host Cell Proteins - HCP) in the OptPA drug substance, we have carried out very important work to get closer to the requirements of the health agencies. We have therefore worked with our CDMO to reduce the level of HCP measured by conventional techniques and we have also set up a quantitative mass spectrometry analysis to identify these contaminants and give a detailed spectrum to the health agencies.
- An industrial manufacturing process of O2L-001 has been developed and allow to obtain reproducible particle size distribution. This developed manufacturing process is suitable for an aseptic manufacturing to obtain sterile O2L-001 finished product.
All these technical progresses must be confirmed with the manufacturing of a confirmatory bath to support the greenlight of the toxicological batch manufacturing.
In parallel of the technological work, a regulatory document was submitted to the European Medicines Agency (EMA) in August 2022, in a “Protocol Assistance” dossier. This submission led to a good comprehension of the project specificities and challenges by the Agency. As with the FDA, a general agreement with the development plan was provided by the EMA and no major objection was raised. The experts provided encouraging and positive feedback on early results and proposed plans, as well as relevant advice to complete the development work and move safely toward clinical phases. The feedback strengthen our plans toward the clinical trials and allow us to establish a stronger toxicological program taking into consideration the EMA advice.
- In terms of purification and elimination of contaminants (Host Cell Proteins - HCP) in the OptPA drug substance, we have carried out very important work to get closer to the requirements of the health agencies. We have therefore worked with our CDMO to reduce the level of HCP measured by conventional techniques and we have also set up a quantitative mass spectrometry analysis to identify these contaminants and give a detailed spectrum to the health agencies.
- An industrial manufacturing process of O2L-001 has been developed and allow to obtain reproducible particle size distribution. This developed manufacturing process is suitable for an aseptic manufacturing to obtain sterile O2L-001 finished product.
All these technical progresses must be confirmed with the manufacturing of a confirmatory bath to support the greenlight of the toxicological batch manufacturing.
In parallel of the technological work, a regulatory document was submitted to the European Medicines Agency (EMA) in August 2022, in a “Protocol Assistance” dossier. This submission led to a good comprehension of the project specificities and challenges by the Agency. As with the FDA, a general agreement with the development plan was provided by the EMA and no major objection was raised. The experts provided encouraging and positive feedback on early results and proposed plans, as well as relevant advice to complete the development work and move safely toward clinical phases. The feedback strengthen our plans toward the clinical trials and allow us to establish a stronger toxicological program taking into consideration the EMA advice.
The expected success of the development of O2L-001 is an opportunity to scale up the company and to further develop the NANOp2Lysis® platform.
New developments are currently being evaluated to increase the portfolio of products of the company. Indeed, Op2Lysis wants to position as a key player in the treatment of all cerebral hemorrhage and to open the door beyond for vascular origin life threatening conditions. Op2Lysis developed a strong know-how in the protection and the vectorization of active proteins to develop GMP grade products.
New developments are currently being evaluated to increase the portfolio of products of the company. Indeed, Op2Lysis wants to position as a key player in the treatment of all cerebral hemorrhage and to open the door beyond for vascular origin life threatening conditions. Op2Lysis developed a strong know-how in the protection and the vectorization of active proteins to develop GMP grade products.