Credit: Jason D. Williams, CCO, Wikimedia Commons
If you’re reading this, you’re probably aware of the massive strides the cell and gene therapy (CGT) industry has made in the last few years. Between 2017 and 2022, six CGT products were approved by the U.S. Food and Drug Administration, but we saw eight approvals in 2023 alone, and 2024 may see as many as 10 new approvals by year-end (Source: Pharmaceutical Technology).
It hasn’t been all smooth sailing, as the industry comes to grips with a new set of problems courtesy of all this commercial success.
To attempt to understand where the industry is, and where it might be going, I’ve put together a SWOT (Strengths, Weaknesses, Opportunities, Threats) analysis on the CGT ecosystem. This analysis is not exhaustive, and is intended more as a high-level overview of the industry as it stands, but it may provide clues about where the CGT space is headed in the next 5-10 years.
Strengths
The CGT industry’s singular massive strength is the potential for one-and-done cures, for both conventionally incurable and chronic conditions.
For the previously incurable genetic conditions, a solid example is Novartis’ Zolgensma, which effectively cures certain (otherwise fatal) pediatric forms of spinal muscular atrophy in patients under two years old.
For certain patients whose cancers have stopped responding to conventional treatments, there are now cell therapies that offer renewed hope. The story of Emily Whitehead is a prominent example of the power of cell therapies.
For liquid tumours specifically, we have:
- Abecma (Bristol Myers Squibb, 2seventy bio)
- Breyanzi (Bristol Myers Squibb)
- Carvykti (Johnson & Johnson, Legend Biotech)
- Kymriah (Novartis)
- Tecartus and Yescarta (Gilead, Kite Pharma)
Additionally, certain chronic conditions are now curable, or at least a single treatment can stave off symptoms for years.
This includes Hemgenix (CSL Behring) for hemophilia B, Lyfgenia (bluebird bio) and Casgevy (CRISPR Therapeutics and Vertex) for sickle cell disease, and Casgevy again for transfusion-dependent beta-thalassemia.
An inspiring story is that of Jimi Olaghere, whose sickle cell disease has been effectively cured by Casgevy. He even climbed Mount Kilimanjaro, a feat that would have previously been impossible (not to mention deadly).
If you have 36 minutes to spare, I highly encourage you to listen to and watch Jimi talk about his experience, both living with sickle cell disease and how his life has changed since Casgevy.
Weaknesses
Unfortunately, it’s not all good news for CGTs. This industry is still in its infancy, and there are many hurdles that are preventing patients from getting access to these life-saving and life-changing therapies, as follow:
- Cost
It’s no secret that CGTs are the most expensive therapies by dose on the plant. Hemgenix, CSL Behring’s gene therapy answer to hemophilia B, is pegged at $3.5 million per dose. For CAR T-cell therapies, estimates range from $500,000-$1 million per treatment round.
Not only are these price tags prohibitive for many developing nations (though companies like ImmunoACT in India are aiming to bring these prices down), but there’s a question of how even developed nations can afford these therapies, especially as CGTs become approved for more and more prevalent conditions.
These high price tags are more easily justifiable when it’s a matter of life or death (Zolgensma in spinal muscular atrophy, for example), but what about chronic conditions, where death is not imminent but quality of life is significantly reduced?
A key example of prohibitive pricing and deadly versus chronic conditions is sickle cell disease. It’s not a death sentence – at least in developed countries – but a person’s quality of life is significantly impacted. Watch Jimi Olaghere’s talk.
Nearly 8 million people live with this disease, many in the developing world. How can we make sure they all benefit from these cures?
- Complex Manufacturing
Unlike small molecule or biologics like monoclonal antibodies, CGTs are living therapies. This comes with the added cost of increased manufacturing complexity, and many processes within this production chain are reliant on manual interventions.
These manual steps not only increase costs due to increased labour hours, but also introduce variability between operators and introduce additional quality risks, making it harder to ensure consistent product quality at scale.
Though great strides are being made in automation and robotics (which I’ll touch on in the Opportunities section later), the current manual state of play contributes in part to these high prices.
- Side Effects
As with many therapies, CGTs have their fair share of side effects.
Viral vectors (e.g., AAV) can cause immune-related adverse events and are usually not re-doseable, while allogeneic cell therapies may introduce graft-versus-host disease. Autologous cell therapies, and many gene therapies, require conditioning regimens that may involve chemotherapy, which has its own risk and side-effect profile.
- Logistical Challenges
The current standard of practice for CGT storage is cryogenic freezing (at least below -80°C/-112°F). This limits the use of CGTs to locations with access to reliable cold chains.
As many CGTs require conditioning regimens, such as chemotherapy, and the treatment itself has side effect risks, patients of these therapies typically need to spend extended time in a hospital. This requirement tends to favour patients in developed nations/cities who also have the financial means/support network to accommodate these extended hospital stays.
- Financing Uncertainties
Though things are slowly improving in terms of overall biotech investment, CGT investment isn’t recovering as rapidly as their small molecule and biologic peers. This is likely due to many investors/Big Pharma looking for surer bets (in places like small molecule), and these players are less inclined to invest in longer-term, riskier plays: Consider how many investors were burned during the feverish CGT investment days of 2020 to early 2022.
Threats
Here are five big threats to the future of the CGT industry:
(Quick note: even though the acronym is SWOT, I’d prefer to end this on a positive note with Opportunities, so we’re covering Threats first.)
- Regulatory Hurdles
Regulators have dealt with small molecules for over a century, and biologics since the mid-’80s, but the CGT approval floodgates didn’t really open until about 2015 and will continue accelerating.
As regulatory guidance could shift more rapidly than in other modalities, therapeutic developers in this space may face additional, unexpected hurdles to obtain approvals.
- Competition with Other Modalities
The ultimate goal of any company operating within the biotech and pharma space, exclusive of modality, is serving patients. It matters less to patients and their doctors what kind of therapy they receive, and way more if the curative effects work as intended and with minimal side effects.
Therefore, CGTs are competing with every other modality out there. There’s a real chance that a small molecule or biologic will be developed for the exact condition that a CGT treats, but can invoke a cure at a fraction of the cost, with more efficacy, and/or with fewer side effects.
This is bad news for the market potential and long-term commercial viability of the cell or gene therapy that is being usurped. I’m not advocating for CGTs to be artificially prioritized but, instead, by proving superior efficacy and safety, certain CGTs will be the preferred treatment option for certain conditions.
- Doctor and Patient Adoption
From the doctor’s perspective, and especially for chronic conditions, the risk of adverse events may prove too costly to consider, especially if non-CGT alternatives exist.
Additionally, patients unfamiliar with CGTs may be deterred by the high out-of-pocket costs (depending on the medical system), extended hospital stays, and conditioning regimens, especially if more affordable and safer alternatives exist.
- Investor Perception
The numerous examples of approved therapies running into hurdles (Roctavian, Hemgenix commercializations; bluebird bio struggling with three approved CGTs) may make some investors wary of the potential for reliable returns. Given this unpredictability, many investors may lean toward more established modalities with clearer paths to profitability (especially in down economies).
This makes it exceptionally tough for early-stage CGT ventures that have brand-new, unproven technologies or limited clinical data. As investors and Big Pharma remain risk-averse, these early-stage players face the greatest difficulty in attracting much-needed capital.
On the other hand, there’s good reason for investor sentiment to improve in the short term, as Big Pharma’s interest seems to have picked up again with Novartis’ acquisition of gene therapy developer Kate Therapeutics and Roche’s acquisition of off-the-shelf CAR T developer Poseida Therapeutics. This may be a sign of thawing sentiment amongst potential CGT acquirers, and could lead to increased investor confidence going into 2025 (because for these investors, acquisitions equal liquidity events).
(It’s also important to note that, bucking the trend of investor trepidation into early-stage CGT biotechs, Kate Therapeutics is still pre-clinical as of the writing of this blog post.)
- Pricing Pressures
The extremely high cost of CGTs is a persistent weakness and continuing threat to this industry.
These hefty price tags can lead patients and health-care providers to favour less costly, repeat-dosing therapies. Additionally, both public and private payers may be unwilling to cover CGTs at scale, particularly if cost-effectiveness remains in question compared to conventional therapies.
On the flip side, artificially depressing prices (for example, through government-instituted price caps) may stifle future innovation. This is because all players within the space (from investors, Big Pharma and smaller innovators) may pivot away from developing new CGTs for fear of not earning a (substantial) profit.
Opportunities
Despite the challenges covered so far, the future looks undoubtedly bright for the CGT industry, in part due to the opportunities available to therapies within the space:
- Targeted Delivery
This means developing delivery methods that target tissues and organs beyond the liver. Increased delivery efficacy would not only reduce the severity of side effects (including the dreaded cytokine release syndrome), but would also reduce the amount of therapeutic API required per dose. The last point would hopefully lead to lower prices and more streamlined manufacturing.
Recent developments within targeted delivery include Flagship Pioneering’s launch of Mirai Bio, as well as NanoVation Therapeutics partnering with Novo Nordisk.
Localized or implantable delivery is another strategy; an example of this is Sernova’s Cell Pouch, a pancreatic implant that develops into a bio-hybrid organ that secretes insulin, glucagon and somatostatin to treat Type 1 diabetes.
- Robotics and Automation
As mentioned under Weaknesses, most current cell and gene manufacturing processes are highly manual and labour-intensive. This plays into the high prices commanded by CGTs, and manual processes also introduce quality risks and increase the likelihood of failed batches.
This is an area ripe for innovation by incorporating closed, robotic, automated manufacturing systems. Players in this space include Adva Biotechnology, Astraveus, Cellares, Cellular Origins, Lonza (their Cocoon platform), Limula, Multiply Labs, and Ori Biotech.
- Autoimmune Indications
There’s been increased interest in utilizing cell therapies to address chronic autoimmune diseases, including lupus and multiple sclerosis. Companies to watch in this space include Artiva Biotherapeutics, Kyverna Therapeutics, iCell Gene Therapeutics, Cartesian Therapeutics, Capstan Therapeutics, Cabaletta Bio, Sonoma Biotherapeutics, CRISPR Therapeutics, Caribou Biosciences, Nkarta, Inc. and Takeda.
- Allogeneic and In Vivo Generation of Cell Therapies
Allogeneic cell therapies (utilizing donor materials) would reduce variation that’s inherent to autologous cell therapies and would enable mass production of doses, thus driving down costs.
You can find a list of allogeneic cell therapy biotechs compiled by Labiotech.eu here.
Additionally, cell therapy manufacturing processes are ex vivo, meaning that manipulation of donor/patient cells to generate the therapeutic cell therapy product occurs outside the body. These processes are not only labour- and resource-intensive, but also cause multi-week turnaround times for autologous cell therapies, which may be too long a wait for those afflicted with aggressive cancers.
In Vivo generation of a cell therapy, wherein cells are transduced to their CAR-associated equivalents within the patient’s body by a vector, would not only circumvent ex vivo manufacturing, but would also enable large-scale dose manufacturing similar to allogeneic cell therapies.
In vivo strategies are still in their early days, as the latest clinical assets are in Phase I. You can check out my review of the sector here.
- Solid Tumours
The majority of currently approved cell therapy products are for liquid tumours, but there’s a whole host of solid tumours that have yet to be addressed. Challenges here are associated with the varied tumour microenvironment, which can throw up physical barriers, immune-suppressive cells, and other factors that can hinder cell therapies from effectively penetrating and attacking tumour cells.
Progress is being made in this space, with the first such approval in early 2024 with Iovance Biotherapeutics, Inc.’s Amtagvi for advanced melanoma. Turnstone Biologics is another player to watch in this space.
In summary, despite high costs, complex and manual manufacturing, and a murky financing environment, CGT’s potential to deliver one-time cures and solutions for chronic illnesses is making waves in the therapeutic landscape. We’ve shown conclusively the power of these medicines, and the major challenges facing the industry are commercialization and expanded patient access – challenges that are indicative of a maturing industry.
I firmly believe that overcoming these obstacles is a factor of when, not if. My money is on the future existence of untold, unknowable innovations across all aspects of the CGT pipeline – from the fundamental science to manufacturing to patient access – innovations that will ultimately bring CGT to the forefront of medicine.
If you’re looking for further insights from CGT industry leaders, I compiled a report based on 43 interviews conducted at this year’s Meeting on the Mesa. You can grab that report for free.
Anis Fahandej-Sadi
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