In 2017 the approval of the first CAR-T treatment took the world by storm, transforming the way cancer is treated. But two years later more than 500 CAR-Ts are in development. So how can pharma ensure its product stands out from the crowd?
In August 2017, Novartis made history after receiving FDA approval for Kymriah, the world’s first chimeric antigen receptor T-cell (CAR-T) therapy. The therapy was trialed in pediatric and young adult lymphoblastic leukemia patients suffering from the most aggressive forms of the disease.
They had very few options left, with prior lines of treatment failing to cure them of their cancer. The CAR-T was their last chance and only hope. Astoundingly, 83% achieved overall remission within just three months of treatment. Results of this nature were unheard of in oncology.
Reactions ranged from TIME magazine hailing the treatment “Cancer’s newest miracle cure” to outrage about the $475,000 price tag. But even Novartis’ biggest critics were clear about one thing – CAR-T is a game-changer in the way we treat cancer. But, Novartis could not retain a monopoly in for long.
After the approval of Kymriah, investors began to funnel cash into start-ups with CAR-T products in development. Big pharma also wanted a slice of the action. Aggressive deal-making quickly became central to the rise of CAR-T, with Gilead acquiring Kite Pharma for a mammoth $11.9B and Celgene buying Juno Therapeutics for $9B in a bid to develop the next big breakthrough.
Today, the CAR-T market is expected to increase at an annual rate of 30% until 2030. More than 500 CAR-Ts are in development, making competition fierce. Earlier this year Autolus was forced to delay and even discontinue molecules in its CAR-T pipeline due to both manufacturing difficulties and rising competitive pressures.
The clinical data readout for the AUTO5 trial showed that it “may not be differentiated from more advanced competitor programs.” The trial has been halted and Autolus is instead focusing on a successor that is due to start human testing next year.
This exemplifies how rapidly the market is changing. It is no longer enough to assume there will be interest in the product just because it is a novel CAR-T. So, what does pharma need to do to avoid being overtaken by the competition and to successfully commercialize the therapy?
“The idea behind CAR-T is simple – why not harness the power of the immune system to fight cancer?”
What is CAR-T?
CAR-T immunotherapy works by engineering T-cells to find, attack and kill cancer cells.
It represents a new paradigm in cancer treatment in which care is tailored to the molecular signature of the patient’s cancer.
All of us are exposed to genetic and environmental factors that result in the development of cancer cells throughout our lifetime. However, we don’t all develop cancer. This is because our immune system constantly detects and eliminates mutated cells. When patients do develop cancer, it is because the cells have evolved to hide from our immune system.
The idea behind CAR-T is simple – why not try to harness the power of the immune system to fight cancer?
CAR-T therapy enables our immune system cells – the T-cells – to once again be able to detect the evolved cancer cell, attack it and kill it. By bolstering our natural biology, we can move away from the destructive forces of chemotherapy.
Based on the source of the T-cells, there are two types of CAR-T cells in development – autologous and the allogeneic. Each has benefits and challenges which play an important role in designing both the product and the service behind the CAR-T.
“Impeccable service design will be key for companies looking to maximize commercial gains post-launch”
Novartis’ Kymriah and Kite Pharma’s YesCarta are examples of autologous CAR-Ts. The T-cells are collected from the patient’s blood, before being genetically engineered. Think one product, one patient. Allogeneic or “off-the-shelf” CAR-Ts are comprised of a healthy donor’s T-cells and they can be used in multiple patients. Think one product, many patients.
The autologous therapies are further down the development pipeline and some have been approved by the FDA and European Medicines Agency. However, the manufacturing process behind these medicines is challenging and the time between the initial treatment decision and infusion is often lengthy. Although allogeneic CAR-Ts could reduce some of the manufacturing challenges, these treatments come with several challenges and none have been approved at the time of writing.
Some speed bumps
As CAR-Ts have been racing towards regulatory approval, some speed bumps have been encountered along the way.
Besides the impressive outcomes of CAR-T clinical trials, serious and even fatal complications remain an issue, as the vast majority of patients with blood cancer, and all with solid cancers, still cannot be treated with CAR-Ts due to toxicity and efficacy challenges.
Even those patients treated with CAR-T therapy and who enter remission face a risk of relapsing. This is mainly because of tumor cells once again evolving to hide from detection by the CAR-T cells. As a result, it is essential to understand the science behind this diversity in patient response, as it could be the key to developing a leading product.
Although more information about side effects is still being gathered, one of the most common and dangerous complications is cytokine release syndrome (CRS). This is caused by the abnormally high release of chemical substances called “cytokines” into the blood. Naturally, T-cells release cytokines to stimulate the immune system, but in CRS, the massive release leads to life-threatening symptoms, requiring intensive care treatment.
Along with side effects including CRS, patients with allogenic CAR-Ts are also at risk for Graft-versus-Host-Disease (GvHD) in which the donor’s T-cells attack the recipient’s healthy tissue.
How to make your CAR-T stand out
CAR-T developers will need to overcome several challenges before successfully developing and launching a CAR-T.
Not only does the CAR-T need to be competitive in terms of its safety and
efficacy profile, but the supply chain will also need to be made more efficient and an impeccable service design will be key for companies looking to maximize commercial gains post-launch.
The ultimate goal of all CAR-T’s is to be curative while maintaining an acceptable safety profile. That’s why such a hefty price tag is attached to these therapies. However, no CAR-T has managed to cure all treated patients, yet.
So far, several different CAR structures have been developed in the hope of improving the persistence and efficacy of the treatment. Finding the ideal domains to target and include in the T-cells has led to the development of four CAR cell generations, each containing an increasing number of signaling domains.
Research is continuing to focus on finding new target antigens that will allow better personalization of treatment for each patient, leading to improved efficacy and durability of remissions.
One way to prevent the immune system from losing the ability to respond to cancer (antigen escape and loss), is by targeting multiple antigens simultaneously, with early studies in animal models indicating the value of dual targeting.
Additionally, there has been a focus on limiting toxicity and side effects by introducing control mechanisms. For example, genetically adding one or more suicide genes to the engineered CAR T-cells induces the death of these cells and acts as a safety switch to combat disease relapse and prevent complications such as GvHD.
With so many different areas of research, identifying the optimal CAR-T design will be key to commercial success.
The manufacturing process
One significant difference between CARTs and traditional treatments is the complex manufacturing processes. This has been a major barrier for Novartis with manufacturing issues preventing some doses of the drug from meeting specifications. This means the therapy could not be used in patients. As a result, the sales for Kymriah have been lower than expected – just $76M in 2018. To overcome these challenges the organization is overhauling its systems, incurring significant cost.
For autologous CAR-Ts, in which each therapy is designed specifically for the patient, the back and forth shipments coupled with design and quality control restrictions will prolong the development process.
The ability to manufacture a dose is also dependent on the availability of the patient’s T-cells, and as the patients are in the late stages of cancer this can be a challenge. An error at any stage could mean the patient is not able to receive the therapy, as we have already witnessed.
This lengthy vein-to-vein period contrasts wildly with what oncology patients are used to – rapid and aggressive treatment regimes. They know cancer evolves quickly to escape treatment, meaning the wait time can cause anxiety for doctors and patients.
In contrast, allogeneic treatments could solve part of this challenge by shortening the time between the treatment decision and the infusion, but safety concerns mean these products are yet to be deemed safe enough to be approved.
Overcoming these manufacturing challenges will not just improve the uptake of the product. It will ensure a positive experience for both patients and healthcare professionals, leading to a better relationship with the brand. Healthcare professionals will feel confident prescribing the product, knowing a dose will be reliably manufactured and supplied.
Although CAR-T patients have only been followed for a relatively short time, the data and insights are growing fast and will define the next generation of CAR-T therapies, providing the opportunity for better diagnosis, prognosis, treatment and monitoring.
Variation in clinical trial design is making it more difficult for doctors to understand if a patient is likely to respond to treatment. This includes deviation between the number of prior lines of therapy a patient is treated with, differences in the overall health of the participants, and whether they have been conditioned with chemotherapy regimens between trials.
While much effort has gone into understanding why some patients enter remission, little is known about why others enter remission and then relapse later down the line. By generating data and guidance on this, doctors can better understand which patients will benefit from the treatment, further empowering them when they are making a treatment decision.
For pharmaceutical companies, knowing which patients will respond well to the therapy will improve patient selection for future clinical trials. This will help justify the use of a CAR-T as an earlier line therapy.
A strategy for the future
Many challenges need to be overcome before a CAR-T therapy can reach wider patient populations. Doctors will need tailored support to guide them through this complex environment, from understanding how to identify the molecular signature of a patient’s cancer and how this informs the treatment choice, to monitoring in the aftermath of the treatment.
Healthcare professionals can be deterred by delays to treatment, which can take the form of manufacturing inefficiencies and a lack of clarity about which patients are eligible for treatment. An effective strategy for partnering with centers of excellence is crucial for overcoming this confusion.
Additionally, early alignment between the medical and commercial teams is essential. This ensures clinical trials and evidence generation are designed to highlight the value of the product, making it easier for doctors to understand if the CAR-T will benefit their patient and how it differs from the competition.
CAR-Ts are some of the most complex treatments on the market today and they are better viewed as an entire service offering, rather than a product. That’s the beauty of CAR-T. Forgetting about this journey – the barriers, challenges, highs and lows for all stakeholders involved – is the single biggest mistake CAR-T developers can make. Instead, we advise taking a service-led approach to commercialization. This will lay a solid foundation for your launch strategy and ensure you maximize commercial gains once the CAR-T is on the market.
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