April 21, 2021
Of the estimated 6,800 rare diseases (defined here as affecting fewer than 200,000 people) that are caused by genetic mutations, more than 95% have no approved therapeutic option.1 Start-ups and established biopharmaceutical companies alike are developing potential gene therapies to address this key unmet medical need.
At the end of Q3 2020, 536 companies were developing gene therapies2 — up from 255 in 2018 and 69 in 2014, according to the Alliance for Regenerative Medicine (ARM).3 At the end of the first half of 2019, ARM reported that 366 gene therapy and 410 gene-modified cell therapy clinical trials were underway, accounting for nearly 75% of all regenerative medicine trials.4 By the end of Q3 2020, the number of gene therapy clinical trials had risen to 373, with 111 in phase I, 227 in phase II, and 35 in phase III.5
Approximately 750 gene therapies are in clinical development, and by 2025 the FDA expects to approve 10–20 new cell and gene therapies annually.6 Gene therapy clinical trials are currently evaluating treatments for severe combined immunodeficiency, eye diseases, HIV, sickle cell anemia, cystic fibrosis, congestive heart failure, hemophilia, cancer, and various other genetic disorders.3 Numerous CAR-T cell therapies are also in clinical trials targeting various types of cancer.
The value of the global market for genetic modification therapies, including direct gene therapies and gene-modified cell therapies such as CAR-T, is growing at a record pace. Various market research firms estimate a compound annual growth rate for the sector of 20-50%, with most in the 30-40% range,7-13 and the global value surpassing $5 billion by 2026.9,13
According to market insight firm Pharma Intelligence, approximately 55% of pipeline candidates are in vivo or gene therapies, and most of the ex vivo investigative therapies are autologous.7 CAR-T cell therapy is the most widely investigated ex vivo approach, with leading biomarkers including CD19, CD20, HER2, and CD30.14 Other cell types of interest for ex vivo therapies include natural killer (NK) cells, human stem cells (HSCs), and Listeria-based, tumor-infiltrating lymphocytes (TILs).7
Some gene therapies regulate the expression of genes through the delivery of RNA. The predominant technologies include RNA interference (RNAi), which halts production of disease-causing proteins; antisense interference and microRNA modulation (miRNA), which inhibit or enhance translation of mRNA into target proteins; and messenger RNA (mRNA), which generates therapeutic proteins.7 RNA therapies can also be administered in vivo or ex vivo.
CAR-T cell therapies have achieved commercial success more quickly than gene therapies in terms of generating significant revenue and profits, because CAR-T treatments can target diseases affecting larger patient populations (e.g., hematological cancers).
Currently, most gene therapies are licensed in the rare disease field and are administered locally to closed systems, such as the eye or brain, where the viral vector delivery vehicles are protected from attack by the immune system. AAVs are naturally occurring viruses found in the lungs of most humans, and thus there will always be some natural immunity to the AAV vectors used for GT. The closed systems theory limits the number of indications treatable by gene therapy, most of which are rare diseases that affect small patient populations.
There is hope that gene therapy will work for larger patient populations, such as hemophilia A and B, neurological disorders, and heart disease through systemic delivery. Toxicity issues have been raised about such systemic treatments using current vector delivery systems, highlighting future needs for novel vectors or non-viral delivery systems for treatments of this kind.
For instance, Dr. James Wilson at the University of Pennsylvania, one of the pioneers of gene therapy, publicly expressed grave concern about the safety of using high doses of AAV in gene therapies and, in fact, resigned his position from the Board of Directors of Solid Biosciences in January 2018 for this reason. His resignation was prophetic, because, in March 2018, the FDA placed a hold on Solid Biosciences’ clinical trial to treat Duchenne muscular dystrophy owing to reduced red blood cell and platelet counts in treated patients. A second clinical trial hold was placed on Solid Biosciences in 2019 and lifted in 2020.15-17
Using more advanced, modified viral vectors or non-viral gene delivery are potential solutions. Non-viral delivery is in its infancy, however, and further advances in nonviral solutions are needed to completely avoid the potential for immune responses.
The ongoing advances and increasing interest in both AAV-based gene therapies and LV-based CAR-T cell therapies, however, are creating an additional challenge. The most common systems for viral vector production require three to five plasmids as starting materials for transfection of the relevant therapeutic genes into mammalian cell lines. With so many biotech start-ups and big biopharma companies establishing pipelines of gene and gene-modified cell therapies, the demand for GMP plasmid DNA and viral vector manufacture has skyrocketed. So has the need for outsourced viral vector manufacturing services, due to the specialized expertise and production capabilities required.
As a result, there is limited availability of both key raw materials and manufacturing capacity. Most university-based centers used for the production of clinical trial materials have waiting lists of up to two years. 24=7 Larger-scale production facilities, mostly operated by contract development and manufacturing organizations (CDMOs), are as or even more limited and operate at high capacity-utilization rates. This issue is being addressed to some extent by investments on the part of raw material suppliers, drug developers and CDMOs serving the gene therapy sector (see the full report).
There are numerous factors that must be considered when establishing a manufacturing strategy for gene and gene-modified cell therapies. Many of the key development needs have been addressed in the road map for gene therapy established by the National Institute for Innovation in Manufacturing Biopharmaceuticals (NIIMBL) with the collaborative input of industry, academic, and government experts.18 First, the disease target, the dose for each patient, the size of the patient population, and the expected market penetration will dictate the quantity of product that must be produced.19
Whether the product is a gene or gene-modified cell therapy is a key consideration.20 Ex vivo therapies require transfection and cell expansion via cell culture, while in vivo treatments only require vector manufacture. Production processes for autologous therapies must be scaled out, while those for allogeneic treatments can be scaled up. The choices of viral or nonviral delivery and the specific vector type (i.e., lentivirus, recombinant AAV, plasmid DNA) have a direct impact on the optimum upstream and downstream manufacturing platforms — many of which are emerging or still under development — as well as control strategies and analytical requirements.21
The possible regulatory pathways must also be considered, particularly whether an expedited approval process will be sought, which will affect manufacturing timelines. Equally important is the decision regarding where manufacturing will take place — in house or at a CDMO.27 Either way, access to capacity in appropriately designed facilities leveraging appropriate technologies must be established.21
Other hurdles include the high cost of gene therapy development, which has led to record high prices for those products that have been approved. Compared with conventional biotherapeutics, process development and manufacturing costs are higher, while clinical development can be less costly, since CGT trials are typically smaller and quicker, albeit often more complex. There is also a need to increase the persistence of gene therapy treatments to ensure that they provide the desired therapeutic effect throughout the lifetime of patients. Technology that enables the development of gene therapies targeting multiple genes is needed in order to treat diseases that are driven by multiple dysfunctional or missing genes, such as Alzheimer’s disease and diabetes.22
In the short term, there is a fundamental need to establish robust, reliable, and readily scalable processes for the GMP manufacture of viral vectors and to install more production capacity so approved treatments can reach the market as quickly as possible. During development, most gene therapies have been produced in the lab using small-scale equipment that is operated manually and not practical for larger-volume manufacturing. Manufacturing issues — particularly scale-up challenges — for gene therapies are in fact a top concern for the FDA. 22
Equipment suppliers have made progress in developing bioreactors and downstream processing systems amenable to vector production (see the full report), but more work needs to be done.23
Despite these challenges, venture capitalists are eager to pump billions of dollars into both gene and cell therapy companies. A rapid return on investment (ROI) — along with the potential for these therapies to target the root genetic causes of disease and be truly curative — is the allure, with candidates moving from clinical trials to commercial approval in 4–5 years. Indeed, venture capital and large and mid-sized pharma companies are actively funding start-ups and more established firms focused on developing novel gene therapies, as well as investing in their own programs.7
In 2020, the regenerative medicine sector attracted $15.9 billion in financing through just the first three quarters of the year, shattering the previous record of $13.3 billion for all of 2018, despite the COVID-19 pandemic.5 Public financing continued to drive the sector through the end of Q3 2020, through both IPOs ($2.8 billion) and follow-on financing ($5.7 billion). Venture capital financing at $4.1 billion through the first three quarters of 2020 was also on track to surpass the previous record of $4.3 billion set in 2019. Gene therapy financing totaled $3.5 billion in Q3 2020 alone and $12 billion through the end of Q3, up 178% and 114% from 2019 levels, respectively.
With 25 years of experience in biotechnology, Jason brings a wealth of expertise in Advanced Therapies to the company. Prior to joining That’s Nice, he was SVP Business Development and a member of the senior management team for 17 years at Cobra Biologics, a CDMO providing services for Advanced Therapies which included viral vectors, plasmid DNA, proteins and live biotherapeutic products (LBPs). Before that, Jason worked at Excell Biotech and Stratagene Cloning Systems in various business development and sales positions. He began his career at Northwestern University managing a molecular and cell biology laboratory with several peer-reviewed publications. Jason holds a BA in biology and studio art from Knox College.
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