Recent headlines suggest that the biotech industry as a whole is experiencing a downturn, yet in spite of this narrative the momentum for advanced therapies continues to persevere. Many companies in the cell and gene therapy space are dedicated to bringing these novel therapies to the patients who need them. Researchers are diligently creating new methods for cell and gene editing as well as therapeutic delivery to increase safety, accessibility, and affordability.
It was another exciting year on the regulatory front as three new therapies were approved in 2022 with four more cell and gene therapies slated later this year. Two innovative therapies are making industry headlines as the first allogeneic T-cell therapy in the world nears approval and a novel CRISPR gene editing therapy is expected to get the greenlight to treat sickle cell disease. The current outlook estimates that as many as 16 therapies across the cell and gene space could reach patients next year; the active pipeline is an encouraging sign of what’s to come for the future of cell and gene therapies.
The space has made incredible developments over the past decade and yielded exciting clinical results with those advancements, but work is still to be done to ensure that they can reach the patient populations they intend to serve. Industry leaders are finding innovative strategies and building technologies that may ultimately create greater access once the treatments become available.
Increasing Accessibility in Advanced Therapies
The advanced therapy industry has shown great promise in treating rare and genetic diseases, but have encountered roadblocks in safety, affordability, and accessibility. The patient populations of these diseases have long been without options, these advancements have inspired hope and the possibility of receiving an effective treatment. However, these immense efforts are in vain if they come with detrimental or life-threatening side effects or are simply unaffordable for the patients they intend to treat.
Many developers in the industry are exploring alternative methods of production and delivery that hope to reduce costs and time to market, while increasing safety and efficacy. Several companies are developing novel approaches in allogeneic cell therapies, gene editing, and non-viral delivery methods to achieve this, and are even on the verge of regulatory approvals for these innovative technologies.
Allogeneic Ushers in a New Era for Cell Therapies
Autologous cell therapies are considered “vein to vein” and are produced by collecting the patient’s immune cells, sending them off for treatment, and returning them to be administered to the patient. This process is time sensitive and has significant manufacturing constraints that ultimately lead to increased costs.
Autologous cell therapies have seen promising results but come with the aforementioned challenges. One of the pioneers in cell therapy, Atara Biotherapeutics, does not require the patient’s own immune cells to be harvested. Instead, the treatment can be administered through general donor cells. Their leading product Ebvallo is on track to become the first approved allogeneic T-cell therapy of its kind and aims to provide a treatment for Epstein-Barr virus-positive, post-transplant lymphoproliferative disease (EBV+ PTLD) in patients who have undergone at least one prior therapy.1
Atara continues to move its product to market after receiving positive feedback from both the European Commission and FDA last month. This therapy offers a new hope to patients that historically have a survival rate of weeks to months. Because this treatment does not rely on the patient’s cells and can leverage unrelated donor cells, the hope is that this treatment offers an affordable, lifesaving new opportunity for patients with relapsed or refractory EBV+ PTLD.
The Rise of New Gene Editing Technologies
Despite the market downturn for the biotech industry, the gene editing sector is seeing continued growth. Where many biotech companies are laying off and cutting R&D budgets, gene editing companies such as Arbor Biotechnologies are making plans to expand their workforce by up to 25% over the next year.2 With increasing research budgets, positive clinical results, and a strong pipeline of products, this is indicative of where the gene editing field is heading soon.
CRISPR was discovered 10 years ago and has made incredible advances in this time. The technology works as a pair of genetic scissors to make extremely precise alterations to DNA to target diseases. With this technology, developers can fight diseases at the genetic level that have long been thought untreatable; clinical trials are showing fantastic efficacy, and in some cases are yielding curative results. Vertex Pharmaceuticals in partnership with CRISPR Therapeutics are slated for an anticipated regulatory decision in 2023 for their sickle cell disease CRISPR therapy that has already changed the lives of its recipients.
Intellia Therapeutics and Regeneron Pharmaceuticals published first-ever clinical data for their in vivo CRISPR-Cas9-based therapy to treat transthyretin (ATTR) amyloidosis.3 They have engaged with the FDA and plan to provide an update on a pivotal path later this year. The current constraints of this technology center around the size of the nuclease, researchers are assessing alternative enzymes but following its promising clinical results and demonstrated efficiencies the CRISPR technology will remain a valuable tool in the genetic therapies’ arsenal.
In June, a new version of gene editing, called base editing, made its debut in the clinic to treat familial hypercholesterolemia, a common cause of heart disease. The process of base editing can correct the specific mutation that causes the underlying disease and can represent an advance under the right circumstances. If a patient population with one or two common mutations are presented for the same indication, they can all be treated with the same therapy through base editing. A technique called prime editing has also proved useful in a mutation, or a hot spot of several mutations that can be treated with a smaller insertion or rewriting fragment. With the rise of these new and exciting gene editing technologies, companies must allow the patient indication and population to dictate the most advantageous technology that will ultimately serve the most patients in the safest and efficacious manner.
The Pursuit of Non-Viral Therapeutic Delivery Methods
The clinical success of gene therapies relies on the type and design of the gene delivery vector used in development or administration. The most common gene modification vectors are lentivirus and adeno associated virus (AAV), only 6% of therapies currently leverage non-viral delivery methods. (See Below Therapeutic Vectors, Alliance for Regenerative Medicine H1 Report, September 20224). The choice between viral and non-viral vectors is presently dictated by the tissues and organs targeted for delivery and while viral methods are the most popular option, this method presents several limitations.
Challenges with viral vectors include constraints with tissue tropism, and the inability to re-dose due to their high immunogenicity and resulting inflammatory response. Viral vectors also have defined constraints in the amount of cargo they can carry, the large Cas9 nuclease traditionally used is a challenging fit. Non-viral vectors include plasmid, transposon, and nanoparticles which can offer safer delivery, a minimized immune response, and can avoid excessive inflammation. Lipid nanoparticles (LPNs) are commonly used and are seen as the most advanced approach when specifically targeting liver tissues. The limitations of these vectors are not as well-known as viral methods, but researchers are working to learn more and adapt them for use in other tissues and cell types such as lung, immune, and hematopoietic stem cells.
Carmine Therapeutics out of Cambridge recently closed its Series A round of financing to develop its next generation non-viral gene therapy.5 Its platform allows for greater control over immune response, and simple, inexpensive manufacturing by leveraging red blood cells. Non-viral vectors provide an opportunity to improve affordability with reduced costs of development as well as expand accessibility of gene therapies to diseases that have been inaccessible with viral-based approaches.
As these groundbreaking technologies continue to move through the pipeline, the industry has an opportunity to overcome critical hurdles. Gene editing and non-viral delivery methods could offer a new safer alternative to patients who previously did not have viable treatment options, expanding to new patient populations with unmet clinical needs. Many of these innovations come with reduced time and costs to develop, making them more affordable and accessible to patients in need.
Even during these challenging times, great efforts are being made across the industry to sustain momentum in the advanced therapy space. With these breakthroughs, the industry has a chance to bring hope to serve more patients than ever and reach entirely new populations with clinical unmet needs.