The UK pipeline of advanced therapy medicinal products (ATMPs) entering clinical development continues to go from strength-to-strength in 2018, underpinned by a thriving research base and an increasing commercial focus from therapy developers. In this year’s preclinical research database, 875 projects were identified, compared to the 720 in 2017, suggesting substantial growth - of approximately 20% - in year-on-year research activity. This includes projects undertaken by 45 industrial therapy developers headquartered in the UK.
Consistent with the findings of the 2018 UK clinical trials database, oncology is the dominant therapeutic area with similarly high activity in ophthalmology. However, in the preclinical research database, comparatively greater levels of activity are identified in study of neurological disorders and cardiovascular disease with therapies targeting these disease areas generally appearing to be further away from the clinic.
The number of phase I or I/II trials that have progressed from the UK research base is accelerating on annual basis. Indeed, 13 such studies have been identified in our 2018 UK clinical trials database of which eight are sponsored by UK-headquartered commercial developers. These include six in vivo gene therapy trials, targeting Parkinson’s disease, haemophilia and ocular disorders respectively.
2018 has seen an emergence in research leveraging gene editing with significant activity identified in early stage projects that use CRISPR-cas9. There are now three UK clinical trials employing gene editing technologies - CRISPR and TALEN for ex vivo modification and zinc finger nuclease for an in vivo application, suggesting therapies in the gene editing space will be coming through the pipeline generated from UK research base in the approaching years. A further interesting technological trend is the appearance of numerous non-viral gene delivery approaches, ranging from cell penetrating peptides to lipid nanoparticles (LNPs). Although current utility is limited compared to their viral counterparts, an increase in research activity and clinical readiness is anticipated in the forthcoming years.
Introduction and methodology
The UK preclinical database covers preclinical research activity concerning cell, gene and other advanced therapies that the Cell and Gene Therapy (CGT) Catapult believes to be ongoing in the UK as of November 2018. It supersedes the database of 2017, and both remain available on our website.
As a centre of translational excellence in the UK, the CGT Catapult is helping its stakeholders within the UK and international community progress their portfolio of projects. The UK preclinical research database gives us a valuable mechanism for tracking cell and gene therapy trends and enables us to plan activities appropriately and identify needs for the sector going forward. It also complements the UK clinical trials database. The database is intended to be of use to academics, commercial organisations and investors operating in the cell and gene therapy space by providing insight and visibility into the diversity of preclinical research and demonstrating the rich science base in the UK. It is also used to provide an indication of the likely future directions of cell, gene and other advanced therapies.
Following on from the report that was undertaken in 2017, in this year’s edition, project data was collected using a secondary research approach in which information was captured by surveying the literature and through inspecting webpages belonging to relevant companies and academic principal investigators undertaking preclinical research. For the avoidance of doubt, all data presented here is publicly available.
Data concerning a large volume of projects were collected and these studies, detailed in this report, utilise a diverse variety of therapeutic agents in a wide assortment of disease areas. In keeping with the methodology used last year, the technology readiness level (TRL) of the projects captured varies from early to mid-stage translational research (which makes up the majority of projects captured) to projects in which clinical trials are expected to be undertaken in the next few years. The data show an approximate 20% increase in identified studies across the various TRLs.
Overview of preclinical research being undertaken in the UK
The preclinical research that has been identified this year covers a broad range of disease areas with oncological studies (including both haematological malignancies and solid tumours) being the most frequent with 124 projects (compared to 107 in 2017). This sum is closely followed by neurological disorders, having 119 projects (compared to 100 in 2017). Therefore, representing a 15% and 19% increase in the number of studies identified in these disease areas respectively since 2017. There is also significant activity in ophthalmological, cardiovascular and neurological research programmes; and this includes year-on-year increases in activity. Figure 1 provides details of a number of projects specific to each disease area. It should be noted that a single project may fall into more than one disease area.
In alignment with the range of disease areas represented by the preclinical research being undertaken in the UK, there are a wide assortment of therapeutic cell types being investigated. Figure 2 provides a broad overview of the types of therapeutic modalities being used and a further breakdown of the individual cell and viral vector types.
Consistent with the findings of last year’s report, the most widely used modality is tissue specific/stem progenitor cells at 27% and this is due to the diversity of therapeutic strategies that utilise these types of cells. These include studies into ophthalmology, neurological disorders and gastroenterological disorders amongst others. The second most widespread modality is MSCs/Stromal cells, which are most commonly used to develop therapies targeting cardiovascular and orthopaedic conditions. Approximately 18% of the preclinical programmes identified for this report use in vivo gene therapies, representing a 7% increase compared to the number of projects identified in 2017. Their utility includes studies into cardiovascular disease, neurological disorders, haemophilia and conditions of the eye. Pluripotent stem cells were found to comprise around 13% of the therapies studied and are similarly diverse with respect to the disease area to which they are applied. However, their use is more frequently investigated in early-stage translational research.
The heatmap below (Figure 3) provides details of the various bodies funding preclinical advanced therapy research in UK and the disease areas these organisations are targeting. The identified preclinical projects are supported by a wide range of funding organisations and private investment. With regards to the number of projects funded, the Medical Research Council (MRC) is the most prolific funding body, providing grants to over 180 projects.
The MRC provides research grants through various initiatives such as the biomedical catalyst: developmental pathway funding scheme (DPFS). This call provides funding to therapy developers as a bridge to commercialisation and regularly supports late-stage preclinical projects in the ATMP space. Innovate UK provides similar funding opportunities to SMEs through its biomedical catalyst primer and early stage awards.
The MRC also provides academic research funding via its involvement in the UK Regenerative Medicines Platform (UKRMP). The UKRMP is a joint initiative funded through the MRC, the EPSRC and the BBSRC. Its purpose is to support high quality UK research and translational activities in the field of regenerative medicine to accelerate development of novel therapies and to foster economic growth. The platform is divided into three research hubs: pluripotent stem cells and engineered cells; engineered cell environment; and acellular/smart materials – 3D architecture. Academics throughout the UK collaborate within these hubs depending on their area of expertise.
It is worth noting that in April 2018 there was a major reorganisation to the bodies that provide government research funding via the formation of UK Research and Innovation (UKRI). UKRI brings together seven research councils, including the MRC, the BBSRC, the EPSRC and Innovate UK and commands an annual budget of around £6 billion.
A number of late-stage preclinical projects currently receive funding through EU grants, particularly for cross-border collaborations. However, the following organisations also support late stage projects: Innovate UK, the MRC, the British Heart Foundation and the Wellcome Trust. In addition, Great Ormand Street Hospital (GOSH) funds numerous preclinical programmes via its charitable arm and these projects are primarily undertaken in collaboration with academics at University College London.
Figure 4 gives a further breakdown of the various streams funding preclinical research in the UK’s advanced therapy industry by providing the number of identified studies funded by each organisation.
Gene modification and emergence of new technologies
Figure 5 illustrates the usage of gene modification techniques for both ex vivo and in vivo gene therapy applications. In recent years, the number of studies utilising gene modification techniques has increased owing to improved understanding of these methods, and this trend will likely continue as more of these technologies approach the clinic. Although the majority of projects detailed in this study did not use gene modification techniques, we identified 143 projects in which gene modification was utilised. However, it is probable that the true figure is considerably higher than reported here and this discrepancy is explained by the difficulty in capturing this type of project information through the methodology used. On the whole, lentiviral gene modification is the predominant technique with 55 studies reported, in addition there were 13 reported instances of retroviral modification.
The identified lentiviral and retroviral methods of genetic modification are predominantly used in ex vivo gene therapy applications. On the other hand, the 11 examples of AAV modification identified are favoured for in vivo gene therapy applications.
The incidence of gene editing technology within the UK research base is on the rise. In 2018, 30 reported cases of CRISPR-Cas9 usage have been identified (compared to 19 in 2017’s report); and there are five cases of TALEN use (compared to two in 2017). However, it should be noted that the bulk of cases in which gene editing is utilised were in projects in the early stages of development and within academia. Nevertheless, with respect to new technology trends, it is encouraging to note that a single commercially-sponsored UK clinical trial has commenced in 2018 that utilises CRISPR-cas9 for ex vivo gene editing of haematopoietic stem cells for the treatment of transfusion-dependent beta-thalassemia. This is the first clinical trial that exploits CRISPR-cas9 in Europe. The preclinical development work for this therapy was not undertaken in the UK. However, it is likely as understanding of the technology increases, therapies for both ex vivo and in vivo applications will progress to the clinic from UK based research. Such uses of CRISPR-Ca9 currently being studied, within the UK ATMP academic community, include applications in immuno-oncology, neurology and for in vivo gene therapy application for treatment of respiratory disorders. Furthermore, TALEN use was identified for ex vivo gene modification in projects studying immune disorders amongst others.
A further technological emergence from this year’s report is the use of non-viral gene delivery methods; 12 studies were identified in 2018. Non-viral gene delivery methods may offer an attractive alternative to conventional viral gene delivery methods due to their lower cost of goods, increased payload capacity and reduced immunogenicity. Furthermore, they have utility in the context of ex vivo and in vivo applications.
Within the UK’s research base several companies have spun-out successfully from academia by developing non-viral gene delivery technologies. These include lipid nanocomplex particles, methods that deliver saRNA for the treatment of liver disorders (which has already reached the clinic in the UK) and cell penetrating peptide technologies for gene therapy applications in oncology.
Although use of non-viral gene delivery methods is currently limited compared to their viral counterparts, the former is becoming increasingly more common amongst the ATMP research base. However, numerous challenges exist including: toxicity issues, poorer targeting specificity compared to viral delivery methods and the need to understand process development requirements to translate to a GMP environment. Nevertheless, it is likely that more of these delivery methods will be approaching clinical use in the coming years, particularly in combination with gene editing techniques.
Progression of ATMPs from UK research base into the clinic
The pipeline of preclinical cell and gene therapy studies generated from the UK’s research base has grown robustly over the past 12 months, demonstrated by the number of therapies that have progressed to first in human studies. When examining the 2018 Clinical Trials Database, it can be observed that 13 new studies have progressed from the UK research base of which eight hold a UK-headquartered commercial sponsor. This compares to five trials that progressed from the UK research base in 2017 and three trials in 2016. This demonstrates significant acceleration in the number of preclinical programmes that have progressed to clinical trials from the UK research base in recent years.
Unsurprisingly, the most frequent therapeutic area for these trials in 2018 has been oncology, ranging from haematological malignancies such as multiple myeloma and B cell lymphoma to solid tumours, including hepatocellular carcinoma and endocarcinoma of the lung. However, interestingly, there has been significant clinical activity in the in vivo gene therapy space in 2018. Indeed, six phase I/II clinical trials, currently recruiting patients, are new to the 2018 clinical trials database having progressed from the UK research base. These include two trials for haemophilia, three trials for conditions of the eye and one trial for Parkinson’s disease; of these four out of six are sponsored by a commercial organisation headquartered in the UK.
Generation of heat maps from collated data
In order to provide a broad description of the diversity of projects that are currently being carried out throughout the UK, a series of heatmaps were generated using the data collated. In each case the therapeutic modality was plotted against the disease area in question and each data point within each heat map displayed represented a project specific to that area of work. This method was then used to assess the frequency and types of projects being carried out at a number of commercial organisation and universities throughout the UK on a regional basis. If further information is required concerning specific studies, we can be contacted via email on firstname.lastname@example.org.