Life sciences represent a healthy sector of the Dutch economy, with many universities and research centres as well as biotech and pharmaceutical companies working to the identification of new approaches to treatment.
NVFG, the Dutch association for pharmaceutical medicine, counts 848 members and five committees to support all the activities needed to develop, manufacture and distribute medicinal products. The Association Innovative Medicines groups 42 industrial members, mainly of which are involved in the development of biotechnological medicines. HollandBIO is the Dutch association for biotech companies, has 211 members, while at the country level there are almost 1800 companies in the life sciences sector, 682 of which are active in R&D.
We provide some examples of trends in Dutch R&D innovation referred both to the academia and the industry and that may impact on the activities of industrial pharmacists.
New models for R&D
The last decade has seen a progressive shift of the discovery step of drug development from the pharmaceutical industry towards universities and other R&D institutions. Collaborative research is becoming the “new normal”, a form of cooperation between public institutions and private companies which is also often rewarded by many financial incentives. Collaborative research allows the industry to decrease the risk implicit in R&D activities, especially with reference to early phase drug discovery, and novel and innovative approaches are now often identified within public research labs.
Both the academia and the industry need to optimally exploit their respective special qualities in order to learn from one another so to reinvigorate the poor R&D industrial pipelines. There are many features characterising academic R&D activities that need to adapt to the completely different mode of working typical of the pharmaceutical industry. The reasoning on these features is essential in order to stimulate the debate on how to revamp the industrial pipelines.
The regulatory framework supporting drug development has also to modify in order to accommodate many new technologies, i.e. artificial intelligence and real-world-based evidence, which are promising to deeply innovate how a medicine is being developed and approved. The European Medicines Agency (EMA) has launched in 2019 its new Regulatory Strategy to 2025, that will inspire the activities programmed for the next five days.
The European regulatory system for medicines (the ‘EU network’, or EMRN) includes all national medicines regulators (human and veterinary) from EEA member states, EMA and the European Commission. A central role of the EMRN is to provide support to innovation and development of new and better medicines. This goal can be achieved through the regular monitoring of emerging scientific and technological innovations and a constant interaction with the different stakeholders, in order to assess the availability of skills and competences within the regulatory network, or the need for specific expertise. These are also crucial to the development of new regulatory guidelines on emerging and innovative technologies.
The transformational research at the centre of EMA’s new Strategy includes among others cell-based therapies, genomics-based diagnostics, drug-device combinations, novel clinical trial design, predictive toxicology, real-world evidence, big data and artificial intelligence. Under this perspective, many are the possible competencies that can be provided by industrial pharmacists.
Many examples of innovation from the Dutch industry
The discovery and development of breakthrough therapies for diseases with large unmet medical need is the central focus of research activities of the Belgian’s biotech Galapagos. The company’s technological platform is based on the use of human primary cells to discover new molecular targets for small molecule drugs to act as inhibitors. The main focus area are rheumatoid arthritis, inflammatory bowel disease and fibrosis. The company’s pipe includes filgotinib, the first product already filed for registration, and a series if emerging drug development programs. In 2019, Galapagos signed with Gilead a transformative 10-year global research and development that should further contribute to the expansion of its R&D activities.
Pfizer Nederland’s platform of recombinant Adeno Associated Virus (rAAV) vector is used to create therapeutic genes able to directly enter target cells and act on the underlying cause of genetic disease. The company estimates tell of around 40 gene therapies that could be available for patients by 2023. Gene therapy hold the promise of a transformative cure, as it can restore the normal functions of the pathological gene, with a strong impact both on patients’ duration and quality of life. The main challenge to transfer this approach to therapy is reflected by size, both in terms of transferred genes and of manufacturing capabilities. Gene therapy based on rAAVs differs from the one using CRISPR-Cas9 techniques to integrate the functioning gene into patient’s chromosome. With rAAVs, the therapeutic gene acts as a blueprint to produce the missing or non-functioning protein. Diseases caused by single-gene alterations, e.g. hemophilia A/B and Duchenne’s, are Pfizer’s main targets for gene therapy based on this approach; the pipeline also include potential gene therapy solutions for a.o. Wilson’s disease, Friedreich’s ataxia and ALS. Marc Kaptein, Pfizer Nederland’s Country Medical Director, is also president of the NVFG, the Dutch association for pharmaceutical medicine, and board member of HollandBIO, the Dutch association for biotech companies.
Dutch Pharming Group is a biotech company specialised in the production of recombinant human proteins in host animals. Its main product, a protein replacement therapy for the acute treatment of Hereditary Angioedema (HAE) based on a recombinant human C1 esterase inhibitor, has been developed using the proprietary recombinant technology platform based on the use of the milk of transgenic rabbits. Under the guide of CEO Sijmen de Vries, Pharming new projects include the extension of the technology platform to develop new forms of administration of its leading product for hereditary angioedema, i.e. a liquid formulation to be administered also through nano-injections, for both prophylaxis and acute treatment of HAE. The pipeline is completed by the clinical development of protein replacement products in Pompe and Fabry diseases, the expansion of recombinant human C1 esterase inhibitor (rhC1INH) clinical development in pre-eclampsia, contrast induced nephropathy (CIN) and other potential large indications. Furthermore, the company has also in-licensed from Novartis the late-stage PI3K inhibitor (leniolisib), to be launched for the ultra-rare disease activated PI3K delta syndrome.
The use of oligonucleotide-based therapeutics to treat inherited retinal diseases is the main focus of ProQR, working at the development of RNA-based gene therapies for ophthalmology applications. Severe rare diseases characterised by limited therapeutic options are again the target of R&D activities. The development pipeline includes eight products to treat several forms of inherited blindness such as Leber’s congenital amaurosis, Usher syndrome and autosomal dominant retinitis pigmentosa. Another candidate medicine is targeted to treat Huntington’s disease. ProQR also generated two spin-out companies: Amylon Therapeutics is focusing on the development of therapies for diseases of the central nervous system, including a rare genetic disease which leads to strokes at mid-adulthood, called HCHWA-D; Wings Therapeutics is studying therapies for dystrophic epidermolysis bullosa.
Nanomedicine is an emerging field of development in pharmaceutical sciences. Teva’s nanoparticle albumin-bound (nab) paclitaxel, launched in 2019 in Germany (see here the EPAR), is for example the company’s first product of this category. Paclitaxel is a quite old, but key antitumoral drug, originally registered in 1993 as a concentrate solution for infusion. Despite the usefulness of the drug in treating many forms of cancer (i.e.breast cancer), its safety profile has been hampered by adverse effects (e.g.hypersensitivity reactions). This results in the need of using Cremophor EL and dehydrated ethanol as solvents to overcome the molecule’s insolubility in water, and in a complex procedure for administartion, requiring premedication with glucocorticoids and antihistamines and the use of non-PVC infusion sets. The current nanoparticles of paclitaxel overcome these issues, as they can be administered in the form of aqueous nano-suspension; this new formulation also showed an improved pharmacokinetic profile over organic solvent-based paclitaxel. The product is manufactured at Teva Operations Haarlem; the different steps of the procedure start from the formation of a nano-emulsion obtained by mixing paclitaxel organic solution with an aqueous albumin solution and subsequent homogenisation. This is followed by rapid dilution with saline to obtain a nano-suspension, where paclitaxel is non-covalently bound to albumin; finally, the organic solvent is removed by evaporation and aqueous saline rinsing.