Periodic Reporting for period 3 - Smart-4-Fabry (Smart multifunctional GLA-nanoformulation for Fabry disease)
Reporting period: 2020-01-01 to 2020-12-31
Lysosomal storage disorders (LSDs), such as Fabry, Gaucher, Hunter, and Sanfilippo diseases are a group of rare diseases that currently lack a definitive cure. LSDs individually occur with incidences of less than 1:100,000; but as a group, the incidence is about 1:5,000 - 1:10,000, representing a serious global health problem. Therefore, development of new treatments for this type of rare diseases has become a key priority for European Research policy.
For instance, the lack of α-galactosidase A (GLA) activity in Fabry disease (FD) patients causes the accumulation of glycosphingolipids (such as Gb3) in the vasculature leading to multiple organ pathology, and the death of patients before 45 years old. Enzyme replacement therapy (ERT), which is the most common treatment of LSDs, exhibits several drawbacks: short plasma half-life (high uptake of the GLA by the liver and high degradation rate), poor biodistribution, high immunogenicity, and low capability to cross biological barriers such as the blood brain barrier (BBB). In this scenario, an appropriate nanoformulation of the GLA enzyme is foreseen as a critical step to improve the ERT.
In the frame of Smart-4-Fabry EU project (#720942), a new GLA nanoformulation (nano-GLA) more effective than current treatment for FD patients has been obtained. The Committee for Orphan Medicinal Products (COMP) recommended the designation of this new medicinal as an orphan medicinal product for the treatment of Fabry disease. Upon this recommendation, the new medicinal nanoformulation was included in the Community Register of orphan medicinal products
Such gain in the efficacy would further allow lowering the clinical dose and spacing the administration schedule for FD patients (currently being administered every other week). The final benefit will be seen as a considerable reduction on the FD treatment cost and a substantial improvement in the quality of life for FD patients.
The Smart-4-Fabry project has lasted 48 months and has contemplated the necessary activities to advance the innovative nano-GLA from a solid experimental Proof of Concept (TRL3) to the regulatory preclinical phase (TRL5-6). The one-step & green, DELOS platform based on the use of compressed CO2 has been used for the manufacturing of this novel nanoformulation with high quality.
Several research groups with experience in nanomedicine, molecular self-assembling and preclinical testing (CIBER-BBN/Spain, Aarhus University/Denmark, Technion/Israel- and Joanneum Research/Austria), together with a recognized company in the field of regulatory preclinical testing (Covance Laboratories/UK), a nanomedicine early adopter pharmaceutical company (Biokeralty/Spain), a SME specialized on
Pharmaceutical development & technology transfer of the DELOS nanoformulation platform (Nanomol Technologies/ Spain), a SME for the development& production of enzymes (LEANBIO/Spain), a recognized CRO in developmental processes of biological products, experts on industrial nanosafety (BioNanoNet/ Austria) and drug regulation (DDR/ Spain), have joined efforts to advance the new nanomedicine for Fabry disease treatment to an advanced stage of preclinical development.
For instance, the lack of α-galactosidase A (GLA) activity in Fabry disease (FD) patients causes the accumulation of glycosphingolipids (such as Gb3) in the vasculature leading to multiple organ pathology, and the death of patients before 45 years old. Enzyme replacement therapy (ERT), which is the most common treatment of LSDs, exhibits several drawbacks: short plasma half-life (high uptake of the GLA by the liver and high degradation rate), poor biodistribution, high immunogenicity, and low capability to cross biological barriers such as the blood brain barrier (BBB). In this scenario, an appropriate nanoformulation of the GLA enzyme is foreseen as a critical step to improve the ERT.
In the frame of Smart-4-Fabry EU project (#720942), a new GLA nanoformulation (nano-GLA) more effective than current treatment for FD patients has been obtained. The Committee for Orphan Medicinal Products (COMP) recommended the designation of this new medicinal as an orphan medicinal product for the treatment of Fabry disease. Upon this recommendation, the new medicinal nanoformulation was included in the Community Register of orphan medicinal products
Such gain in the efficacy would further allow lowering the clinical dose and spacing the administration schedule for FD patients (currently being administered every other week). The final benefit will be seen as a considerable reduction on the FD treatment cost and a substantial improvement in the quality of life for FD patients.
The Smart-4-Fabry project has lasted 48 months and has contemplated the necessary activities to advance the innovative nano-GLA from a solid experimental Proof of Concept (TRL3) to the regulatory preclinical phase (TRL5-6). The one-step & green, DELOS platform based on the use of compressed CO2 has been used for the manufacturing of this novel nanoformulation with high quality.
Several research groups with experience in nanomedicine, molecular self-assembling and preclinical testing (CIBER-BBN/Spain, Aarhus University/Denmark, Technion/Israel- and Joanneum Research/Austria), together with a recognized company in the field of regulatory preclinical testing (Covance Laboratories/UK), a nanomedicine early adopter pharmaceutical company (Biokeralty/Spain), a SME specialized on
Pharmaceutical development & technology transfer of the DELOS nanoformulation platform (Nanomol Technologies/ Spain), a SME for the development& production of enzymes (LEANBIO/Spain), a recognized CRO in developmental processes of biological products, experts on industrial nanosafety (BioNanoNet/ Austria) and drug regulation (DDR/ Spain), have joined efforts to advance the new nanomedicine for Fabry disease treatment to an advanced stage of preclinical development.
The work performed by the Smart-4-Fabry consortium partners from the beginning of the project to the end of the period covered by the third report (from M37 until M48) has permitted to:
- Achieved the regulatory preclinical stage on the development of nanoGLA-v4 for Fabry disease treatment.
- Developed a peptide targeted nanoliposomal drug product, containing a novel GLA drug substance produced in CHO cell line
- Established Critical Quality Attributes & specifications for the nano-GLA, and validated by EMA in a Scientific Advice procedure
- Scaled-up, produced and characterized pre-GMP pilot batches for regulatory pre-clinical trials using the DELOS platform and as the basis for cGMP compliant manufacturing process, following a Quality by Design approach
- Demonstrated superior efficacy compared to current treatment and non-nanoformulated GLA in a Fabry KO mouse model
- Recognized the significant benefit that nano-GLA can offer to Fabry disease patients by the Committee for Orphan Medicinal Products (COMP). Therefore, nano-GLA has been designated by the European Comission as an orphan medicinal product for the orphan condition: treatment of Fabry disease.
- Performed GLP safety and toxicity studies in rodents
- Filed the IP protection of nano-GLA through a selection patent application, EP21382062.
- Hold a first exploitation Workshop focused in the identification of Key Exploitable Results and Partner’s exploitation interests.
- Dissemination of the results in several international conferences and events related to nanotechnology, nanomedicine and rare diseases, and in a virtual final workshop open to the wide research community.
- Achieved the regulatory preclinical stage on the development of nanoGLA-v4 for Fabry disease treatment.
- Developed a peptide targeted nanoliposomal drug product, containing a novel GLA drug substance produced in CHO cell line
- Established Critical Quality Attributes & specifications for the nano-GLA, and validated by EMA in a Scientific Advice procedure
- Scaled-up, produced and characterized pre-GMP pilot batches for regulatory pre-clinical trials using the DELOS platform and as the basis for cGMP compliant manufacturing process, following a Quality by Design approach
- Demonstrated superior efficacy compared to current treatment and non-nanoformulated GLA in a Fabry KO mouse model
- Recognized the significant benefit that nano-GLA can offer to Fabry disease patients by the Committee for Orphan Medicinal Products (COMP). Therefore, nano-GLA has been designated by the European Comission as an orphan medicinal product for the orphan condition: treatment of Fabry disease.
- Performed GLP safety and toxicity studies in rodents
- Filed the IP protection of nano-GLA through a selection patent application, EP21382062.
- Hold a first exploitation Workshop focused in the identification of Key Exploitable Results and Partner’s exploitation interests.
- Dissemination of the results in several international conferences and events related to nanotechnology, nanomedicine and rare diseases, and in a virtual final workshop open to the wide research community.
Smart-4-Fabry ends up with a practically completed preclinical phase, including part of the regulatory toxicology studies needed to support a first in human clinical trial. With the achievement of this objective, the project has strategically contributed to the adoption of Key Enabling Technologies (KETs), such as nanotechnology, industrial biotechnology and advanced materials in Europe, through the demonstration of the capacity to get a more efficient, sustainable and safer therapy.
The orphan drug designation, in addition to being a recognition of the significant benefit that the new nano-GLA offers compared to products already authorized for Fabry disease, has important implications in the transfer and translation of the new therapeutic product towards more advanced phases of development.
Smart-4-Fabry will have a wide impact on improving the pharma&biotech industry competitiveness: it will have a direct impact on the companies (involved in the project), allowing the generation of a new, highly competitive product that will, additionally, open new markets. Indeed, the project success opens a pathway for tailored solutions to other LSD and other pathologies, since the following feats have been achieved:
- Peptide nanoliposomes as an effective nanoformulation platform for biomolecule intravenous delivery (patent protected and validated at preclinical level for GLA enzyme)
- Robust DELOS nanomedicine manufacturing process, green process easy to scale-up:
to achieve high control over molecular self-assembling
to produce the required quantities of the nanomedicine for pre-clinical in vivo testing and clinical trials with the required quality
- Provision of protocols and strategies for the adequate physicochemical and biological characterization of biomolecule-loaded nanoliposomes, and identification of Critical Quality Attributes.
- Well-designed data collection and presentation for communication with regulatory authorities, which could be implemented for other nanoliposomal products.
Thus, fulfilment of Smart-4-Fabry impacts on a major health problem, the shortage existence of new therapies for rare diseases, which constitutes a priority societal challenge as shown in the H2020 Work Programmes.
The orphan drug designation, in addition to being a recognition of the significant benefit that the new nano-GLA offers compared to products already authorized for Fabry disease, has important implications in the transfer and translation of the new therapeutic product towards more advanced phases of development.
Smart-4-Fabry will have a wide impact on improving the pharma&biotech industry competitiveness: it will have a direct impact on the companies (involved in the project), allowing the generation of a new, highly competitive product that will, additionally, open new markets. Indeed, the project success opens a pathway for tailored solutions to other LSD and other pathologies, since the following feats have been achieved:
- Peptide nanoliposomes as an effective nanoformulation platform for biomolecule intravenous delivery (patent protected and validated at preclinical level for GLA enzyme)
- Robust DELOS nanomedicine manufacturing process, green process easy to scale-up:
to achieve high control over molecular self-assembling
to produce the required quantities of the nanomedicine for pre-clinical in vivo testing and clinical trials with the required quality
- Provision of protocols and strategies for the adequate physicochemical and biological characterization of biomolecule-loaded nanoliposomes, and identification of Critical Quality Attributes.
- Well-designed data collection and presentation for communication with regulatory authorities, which could be implemented for other nanoliposomal products.
Thus, fulfilment of Smart-4-Fabry impacts on a major health problem, the shortage existence of new therapies for rare diseases, which constitutes a priority societal challenge as shown in the H2020 Work Programmes.