DDW Editor Reece Armstrong looks at the cell and gene therapy landscape, examining the challenges facing developers and the trends we can expect to see throughout the year.
There’s no doubt that cell and gene therapies present some of the most exciting opportunities for emerging drugs. This area of medicine, which turns our own bodies into agents of combat to fight disease, has quickly become one of the most promising fields in treating deadly diseases such as cancer, central nervous system disorders and even musculoskeletal conditions.
Last year saw the sector surge, with levels of investment hitting an all-time high at $22.7 billion, compared to $19.9 billion in 2020, according to the Alliance for Regenerative Medicine’s (ARM’s) Regenerative Medicine: Disrupting the Status Quo report. And whilst clinical trials activity decreased by around 15% compared to 2020, last year still saw a number of regenerative medicines reach the bedside. Among these include Zolgensma, Novartis’ gene therapy drug for spinal muscular atrophy (SMA), which made headlines in the UK for its £1.79 million price point per dose. This year too is off to a strong start, with two multiple myeloma CAR-T therapies approved from both Legend Biotech/Janssen and Bristol Myers Squibb/bluebird bio.
With the sector looking strong it would be easy to think of the cell & gene sector as being resilient to challenge but this is never the case in pharma: fierce competition can result in fluctuating valuations for listed companies and the regulatory hurdles of pharma means that many companies won’t ever see their product reach the bedside.
Cancer is king
Unsurprisingly, oncology remains the biggest focus for cell and gene therapy developers, accounting for 52% of clinical activity in 2021, according to ARM’s Regenerative Medicine: Disrupting the Status Quo report. Whilst it’s unlikely other disease areas will surpass this figure, in oncology at least, developers are levelling the playing field when it comes targeting both solid and liquid tumours.
Since 2017, a range of approvals by the FDA has resulted in cell therapies – in particular CAR-T-cell therapies – being used in the treatment of blood cancers. We’ve seen varying levels of success in these drugs being used to treat patients, but cases where patients have responded well or have gone into remission, means that these drugs generate a tangible amount of excitement.
In terms of clinical trials activity in oncology for cell & gene therapies, 55% of these were focused on liquid tumours, whereas 45% were targeting solid tumours – a clear indicator that solid tumours are catching up.
Speaking about emerging opportunities, Carlo Russo, CEO of Genenta, says that whilst “immuno-oncology treatment has been very successful in treating patients suffering from blood cancer,” its success has been limited “by the durability of the responses”. Russo believes that this presents a “really significant opportunity in developing treatments which are effective against solid tumours, and which have long durability to that efficacy.”
Indeed, this is something that Professor Dolores J. Schendel, CEO and CSO of Medigene agrees with. “I would expect to see more data coming from the use of cell-based treatments for solid tumours such as breast, ovarian, pancreatic or colorectal cancer. Solid cancers provide a whole new challenge for cell therapy,” Professor Schendel tells DDW.
This statement is backed up by an article in Blood Cancer Journal1 which outlines CAR-T cell therapies’ struggle to infiltrate solid tumours due to their immunosuppressive nature and the physical barriers they present.
As such, “in treating solid cancers, the persistence of the cell therapy and their ability to avoid tumour resistance mechanisms will be at a premium,” says Professor Schendel.
Manufacturing
As is always the case with pharmaceuticals, the industry’s capabilities to manufacture and produce these potentially life-saving therapies will be of concern.
The Covid-19 pandemic had an unmistakable effect on the pharmaceutical industry, with many clinical trials being forced to suspend activities, manufacturing bottlenecks becoming more of a concern and a greater focus placed on technology to mitigate lockdown restrictions.
For cell and gene therapies, Covid-19 was a “double-edged sword”, according to Kristin Thompson, Chief Business Officer at eureKARE. Thompson says that the development of Covid-19 vaccines, which used mRNA technology, resulted in wider acceptance for cell and gene therapies.
“On the flipside, much of biomanufacturing facilities are now focused on vaccine production which results in less capacity for other critical therapeutic areas,” Thompson adds.
According to Stephane Boissel, Chairman and CEO of SparingVision, one of the biggest challenges affecting cell and gene therapies is the bottleneck being caused by “access to manufacturing capacity from plasmids and vectors.”
Indeed, the growth of the cell and gene therapy market, coupled with the demand that the pandemic placed on manufacturing capacity, means the industry faces shortages of these crucial materials. These concerns have been ongoing for a number of years now and have forced the industry to rely on contract manufacturing organisations (CMOs) to gain ample amount of biological materials. The challenge is scale-up, but perhaps a traditional approach to manufacturing, as seen with the kind of one-size-fits-all batch approach, isn’t right for cell & gene therapies.
Professor Schendel certainly thinks so. “Because of the variation between patients, operating a consistent manufacturing process is one of the key concerns,” she explains.
Centralised processing, where one key manufacturing facility produces medicine, is one solution, but is something which places “extreme logistical demands on manufacturing,” Professor Schendel says. In her opinion, for cell therapies, one solution could be fully automated closed manufacturing systems that operate close to patients, which would remove any logistical constraints in getting time-sensitive therapies to the bedside.
Professor Schendel gives an astute example: “Starbucks might make perfect coffee if it had one centralised factory in Seattle, but it would be cold before it reached the customers. Better to have a reproducible beverage system running on every street corner.”
With all these challenges, CDMO Lonza believes that cell and gene therapy developers should be focusing on manufacturing at an early stage in their development process.
Behnam Ahmadian Baghbaderani, Executive Director, Global Head of Process Development, Cell & Gene at Lonza says: “Ensuring that a phase-appropriate but the scalable manufacturing process is designed early ensures that the process can seamlessly transition from early-stage to late-stage and commercial manufacturing, thus avoiding debilitating process failures and delays.”
Reimbursement
One key challenge for cell and gene therapies can often be the high-price points they bring with them.
Boissel is a “big believer in paying for things that work,” and thinks that the benefits of cell and gene therapies – which have longer-lasting effects coupled with reduced dosages – make them ultimately more cost-effective compared to chronic, lifelong treatments. The challenge for the market then, according to Boissel, is how much can a payor afford to pay upfront?
Indeed, this is the situation the UK has faced as advanced therapies have undergone the same pricing review assessments as regular medicines. Indeed, the National Institute of Health and Care Excellence (NICE) in the UK does have some flexibilities for pricing, with approved cell and gene therapies in the country being made possible due to highly specialised technology (HST) evaluations, the Cancer Drugs Fund (CDF) and the Innovative Medicines Fund (IMF). Whilst these initiatives provide more opportunity for advanced therapies to make it onto the NHS, developers in the sector still face a tougher assessment process in the UK compared to many other territories.
This is why it’s important to “establish cost effectiveness with the relevant health technology assessment body,” according to Dr Suzanne Saffie-Siebert, founder and chief executive officer of SiSaf.
However, Dr Saffie-Siebert also believes the industry needs to explore “innovative payment plans with payers such as pay for performance or staggered payment,” she says. These are ideas that have been presented to other areas of the industry such as for antimicrobials and would see cell and gene therapies reimbursed based on how they perform in the patient, rather than simply purchased at a base price.
Kristin Thompson, Chief Business Officer at eureKARE understands the issue.
“This is a very challenging issue, especially with some of the uncertainty regarding true efficacy of certain gene therapies and whether their effects can last a lifetime such as in the case of treatment for haemophilia A and B. Bringing efficacy into the pricing equation is certainly more of a patient-centred approach that we hope will continue,” she says.
What’s trending according to key players in the sector
“In general, we will see the scope of gene therapy approaches extended from rare diseases to more common conditions. Multiple clinical trials are already exploring the potential of gene therapy in neurological conditions like Parkinson’s and Alzheimer’s disease, and in blood diseases such as thalassemia and sickle cell disease. In cancer, the proven safety of cell and gene therapies means that they are now being used increasingly in combination with other therapeutic agents. The mysteries of cancer are starting to yield to the range of advanced therapies available and cell therapies – especially engineered cell therapies – are at the leading edge of that progress.” – Carlo Russo, CEO of Genenta.
“In gene therapy, re-engineered adeno-associated virus (AAV) vectors have been produced using various methods such as machine learning or directed evolution. These re-engineered vectors now have better tropism and require smaller doses, potentially avoiding the toxicities associated with the adverse events in previous therapies. One the other hand, these novel vectors may not have the same manufacturing capabilities after re-engineering.
However, researchers have been working to devise improved and scalable manufacturing processes that meet regulatory scrutiny, and continued dialogue with regulatory authorities throughout the development process to de-risk programs and platforms early and often will shape how successful these processes will be this year.” - Tuyen Ong, MD, CEO, Ring Therapeutics.
“The increased adoption of CGT’s in haematology, oncology and beyond to additional disease states, driven by evolution of a more traditional treatment model. This will be driven in a major way through breadth of ongoing research and an increased move to better tolerated, logistically simpler allogeneic platforms, such as the optimized Natural Killer (NK) cell therapies being developed at ONK Therapeutics. The use of big data and AL to direct the best patient candidates for CGT and to provide the best understanding of efficacy and benefits.” – Chris Nowers, CEO, ONK Therapeutics.
“An increased focus on in vivo approaches is what I believe will shape the cell and gene therapy sector throughout this year and in years to come.” – Andrew Scharenberg, Umoja Biopharma CEO.
“Fully booked service providers for manufacturing and sample analyses and more immune-oriented use of gene and cell therapies.” – CBO Aino Kalervo, and VP of Business Development Víctor Cervera-Carrascón, Tilt Bio.
On the manufacturing side of CGT, we expect to see a continued focus on standardised manufacturing platforms that can result in ease of manufacturing, greater product consistency and quality, lower cost-of-goods (COGS) and increased speed to clinic. Adopting standard platforms allows innovators to focus on the effector element of the therapies without worrying about reinventing the manufacturing process for each therapy. This will ultimately become critical for CGT success. Development of IPSC based manufacturing platforms for cell therapy, stable cell lines for viral vector manufacturing, nanoparticles (LNP, exosomes) for non-viral delivery and novel analytical methods will continue to be emphasised.” – Senthil Ramaswamy, Executive Director, R&D, Cell & Gene, Lonza.
Investment
Coming off the back of a record year for investment, it would be easy to think that the cell and gene therapy sector will see the same amount of funding as it received in the previous 12 months. Opinions on the matter however are mixed.
It’s no surprise that investors have wanted to gain a portion of what is an exciting and emerging field of science, one which offers many opportunities to treat a wide range of diseases. But, with only a small number of drug approvals compared to other sectors, there’s no doubt that the cell and gene therapy sector is a risky investment for many.
For Dr Suzanne Saffie-Siebert, the last two years of investment was primarily driven by venture capitalists (VCs) backed by so-called “tourist” investors who saw the success of mRNA vaccines for Covid-19 as opportunities for investment.
“However, the inherent investment risk of the sector due to long timelines for development and approval coupled with intense competition has caused many so-called tourist investors to leave the sector which in turn has reduced company valuations and made capital raising more challenging,” Dr Saffie-Siebert says.
Carlo Russo says that whilst companies that raised money during the last two years are in a stronger position than their competitors, biotech still “remains one of the most investable sectors”. However, “the objective measure of clinical success”, she says will only help re-energise the sector.
Umoja Biopharma CEO, Andrew Scharenberg thinks that the investment community will always be attracted to the sector due to the opportunities cell and gene therapies off for “transformative patient impact.”
The fact that these benefits “may not be attainable with small molecules or even simpler biologics, as well as long periods of market exclusivity,” Scharenberg says, means that “more complicated compounds are harder to copy and require more investment to compete with making them strong continued investment targets.”
However, whilst these comments largely reflect a positive outlook for investment in the industry, financing in Q1 of 2022 largely remained level with the backend of last year, hovering just over $500 million according to American Society of Gene & Cell Therapy’s (ASGCT) – Gene, Cell, & RNA Therapy Landscape Q1 report.
Despite this the industry is still expanding. With the sector still in its infancy and with growing regulatory approvals and steady funding, it makes sense the researchers will be drawn to such an exciting and promising field of work. According to the ASGCT, the gene therapy pipeline increased 16% from Q1 2021 with 3,579 gene, cell, and RNA therapies in development from preclinical through pre-registration stages.
New indications
For cell and gene therapies thus far the focus of their application has generally been in the field of oncology and rare diseases. But these therapies hold much promise in other modalities and, in parts, the industry has shifted its focus towards more prevalent diseases outside of cancer. Indeed, the Alliance for Regenerative Medicine’s (ARM’s) Regenerative Medicine: Disrupting the Status Quo report highlights that of the 2,406 clinical trials that took place last year in the sector, 59% of those were targeting prevalent diseases.
And the therapeutic potential of cell and gene therapies means there’s a lot of excitement around their possibilities.
“Extending the application of cell and gene therapies beyond their current scope of application in rare and complex disease into a broader scope of poorly treated high prevalence diseases areas, such as degenerative conditions, present a tremendous opportunity for these transformation products to radically change healthcare,” a spokesperson from the Cell & Gene Therapy Catapult told DDW.
Stephane Boissel expects to see “an increasing trend in targeting more complex modalities such as multigenic diseases or gene-agnostic approaches beyond the most targeted organs such as liver, muscle, or the eye.”
“Research into genomic medicines is only at its infancy. The sector still has a few things to crack obviously but I strongly believe that these modalities will be addressing a very large array of diseases in the next 20 years and become an important part of the drug landscape,” Boissel adds.
According to Richard Francis, CEO of Purespring Therapeutics, this has already started to happen. The development of Covid-19 vaccines during the pandemic not only brought widespread attention medicinal products (ATMPs) but also highlighted the possibilities of these therapies in areas outside of their typical modalities.
“Many millions of people have recently been vaccinated against Covid 19 with a genetically modified viral vector (a recombinant adenovirus expressing a Covid 19 protein). This genetic vaccination is an extension of the gene therapy modality,” says Francis.
In terms of what we can expect to see this year, a number of therapies are awaiting regulatory decisions that will affect their position on the market. PTC Bio’s gene replacement therapy for AADC deficiency – PTC-AADC – is currently undergoing regulatory assessment in Europe with the company hoping to receive a positive opinion from the Committee for Medicinal Products for Human Use (CHMP).
CellTrans is currently awaiting an FDA decision for its cell therapy Lantidra, a treatment for patients with brittle type 1 diabetes mellitus whose symptoms cannot be well managed despite insulin therapy. Last year the company hit a milestone for the therapy when an FDA advisory committee decided that the Lantidra demonstrate a favourable risk-benefit profile for particular patients. CellTrans is now awaiting an FDA decision for Lantidra to be approved as a biologic, where it could benefit diabetes patients who don’t respond to insulin.
Another key catalyst to look out for is a decision from the FDA on bluebird bio’s Thalassemia gene therapy, Zynteglo, after the FDA delayed its decision-making progress to review extra data on the treatment.
Key challenges from experts
“Manufacturing is a big deal, due to a lack of deep experience in the industry with making these types of very complex biologics at a large scale. In addition, the complex regulatory environment presents a second set of its own challenges, due to both lack of experience reviewing innovative new technologies that lack good comparators, and often, lack of animal models to help efficiently validate new technology in its earliest stages.” – Umoja Biopharma CEO, Andrew Scharenberg.
“One challenge is the perception that gene and cell therapies are treatments of last resort, when all other options have been exhausted. While this is unavoidable from a regulatory point of view, it does mean that CGT products are used in patients with advanced disease, whose natural defences are potentially weakened by exposure to multiple other treatments. That may not be the ideal starting point for cell therapies that tailor a patient’s own cells.” Carlo Russo, CEO of Genenta.
“For gene therapy, the high doses of adeno-associated virus (AAV) delivery required to induce a therapeutic response has led to various toxicities (hepatic, hemostasis, kidney diseases) and in some cases even death. The lack of re-dosability, limited tropisms, immune response, antecedent neutralizing antibodies, and high costs of manufacturing continue to be limiting factors in gene therapy field.” – Tuyen Ong, MD, CEO, Ring Therapeutics
“Development of specific therapeutic DNA/RNA sequences is relatively straightforward so the biggest challenge is translating exogenous sequences into therapeutic drugs. Exogenous sequences are very unstable and degrade rapidly, they trigger our immune systems, they cannot target specific cells and permeate their membranes, so formulation materials delivery mechanisms are required. Currently viral vectors and lipid nanoparticles are the only delivery technologies approved but they have significant limitations.” – Dr Suzanne Saffie-Siebert, founder and Chief Executive Officer at SiSaf
“Being able to accurately predict which treatments will work for specific patients is something that is extremely complex and developers in this space have to move quickly from animal models to clinical models. Building the right clinical models to suit a maximum number of patients, as well as rare individual cases, can be very challenging. Another area that can be tough to manoeuvre is IP, as we saw recently over the disputes surrounding CRISPR. Researchers have to be able to maintain IP while allowing the technology to be licensed and used by others so that it can continue to evolve and expand its potential application,” – Kristin Thompson, Chief Business Officer, eureKARE
Workforce
As the cell and gene therapy sector expands one of the biggest challenges for companies in the space will be attracting and retaining the right specialists for their pipeline. As an emerging sector, cell and gene therapies present some of the toughest challenges for the industry and as such, expertise can be lacking.
With the sector growing, the industry recognises the necessity of meeting the demand for jobs. In the UK for instance there has been high demand for expertise in the sector. The Cell and Gene Therapy Skills Demand Survey Report predicts a demand of 10,000 bioprocessing jobs in the UK by 2026.
The rapid scale-up of Covid-19 vaccines in the UK was a feat no doubt achieved by the sector’s expertise in being able to rapidly scale-up those types of therapies. Whilst bottlenecks did occur, it’s an example of what to expect from the industry when it comes to other ATMPs.
But challenges remain. The Skills Demand Survey Report presents a lack of graduate life sciences apprenticeship programmes as a key barrier. In fact, this barrier was identified by all but one company in Scotland and one in Wales during the report.
According to Richard Francis of Purespring Therapeutics, the Covid-19 pandemic exacerbated this issue.
“More of a long-term issue may manifest where Universities were closed – so the standard of students (no final year placements and work experience available), over this 2-year period may have taken a hit and maybe slightly less prepared to join CGT workforce compared to years previous,” he said.
A spokesperson for the Cell and Gene Therapy Catapult told DDW that the skills shortage is one of the biggest problems the industry faces.
“There is an ongoing and growing global shortage of skilled workforce in the cell and gene therapy industry, with 62% of employers intending to recruit and expand their workforces within the next two years, with most companies recruiting for skilled and experienced people at the same time,” they said.
It does seem that most regions have recognised the need for adequate training for cell and gene therapies, and there are now a range of courses offering cell and gene therapy specific training. For example, the Cell and Gene Therapy Catapult offers advanced therapy apprenticeships for advanced therapies which place students at an ATMP company whilst they complete their education.
In the US, the New Jersey Institute of Technology offers a master’s degree in cell and gene therapy sciences and the University of Georgia has a programme in Biomanufacturing and Bioprocessing.
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