shutterstock_686272324.jpgThere’s no doubt that chimeric antigen receptor T-cell (CAR-T) therapies have been generating increased interest over the past four years at the American Society of Hematology’s (ASH) Annual Meeting. In 2014, 34 abstracts on CAR-T therapies were presented at ASH, a number that more than tripled to 110 abstracts by 2016. This year, more than 140 CAR-T abstracts were presented to a packed Georgia World Congress Center in Atlanta. While some questions about this novel approach to cancer treatment remain unanswered, one thing is for certain: CAR-T therapies are here to stay. 

A few of the most prominent CAR-T abstracts presented include a primary analysis readout of Novartis’ phase 2 trial of tisagenlecleucel (Kymriah) in adult relapsed/refractory diffuse large B-cell lymphoma (JULIET); long-term follow-up data of Gilead-Kite’s axicabtagene ciloleucel (Yescarta) in patients with refractory non-Hodgkin lymphoma (ZUMA-1); and Bluebird Bio’s astounding phase 1 results for bb2121 in heavily pre-treated multiple myeloma (CRB-401). 

These advancements have been among the key innovations that define 2017. They are important steps in ushering us further into the age of personalized medicine, and are only the beginning of a pipeline of cell and gene therapies that can offer enriched benefits to patients. 

However, beneath the buzz of unprecedented clinical efficacy and hope for a cure, there was an underlying hum of concern from those absorbing the clinical data that bridges into commercial realities. Can next-generation CAR-T enhancements effectively further reduce current manufacturing time to get to patients faster, and how will the healthcare system handle the high cost of these therapies? 

Expediting Manufacturing Timelines

While first-generation CAR-T therapies have demonstrated that they can be manufactured successfully while adhering to strict quality and safety standards, the current turnaround time for this process may range from two to three weeks. As demand for CAR-T therapies continues to grow, expand to more patients and potentially move to earlier lines of therapy, the ability to get to patients more quickly may become important. With each CAR-T treatment manufactured on a per-patient basis in approved processes, in-market CAR-T manufacturers will likely continue to focus on levers such as flawless logistics and chain of control to drive consistency and minimize timelines. However, as multiple presentations showed, next-generation platforms are rapidly emerging, which may expedite CAR-T synthesis itself. 

In his presentation, Dr. Partow Kebriaei, in collaboration with ZIOPHARM Oncology, presented follow-up data to an approach that may help decrease this timeline: the “sleeping beauty” (SB) system. The SB system allows for a non-viral integration of genetic material into T cells. Dr. Kebriaei demonstrated that eliminating the need for viral vectors may potentially allow for the manufacturing of the CAR-modified T-cells in less than two days. Further, it may allow for the production of modified T-cells at the point of care. Another method being explored is the use of “off the shelf” CAR-T therapies. Unlike current CAR-T therapies that genetically alter a patient’s own cells, “off the shelf” CAR-T therapies use cells from healthy donors, allowing them to manufacture treatment ahead of time in greater volume and at potentially reduced costs. Cellectis is currently leading the field in “off the shelf” CAR-T development with UCART123, which is being evaluated in two phase 1 trials for acute myeloid leukemia and blastic plasmacytoid dendritic cell neoplasm. However, both UCART123 phase 1 studies were subject to a clinical hold by the FDA in September following the death of a 78-year-old trial participant. ZIOPHARM Oncology is planning to initiate its first point-of-care clinical trial in 2018, and Cellectis is working closely with the FDA to resume both trials for UCART123. 

As CAR-Ts continue to expand across hematologic malignancies with solid tumors soon to follow, manufacturers need to proactively develop methods for increasing the speed and output of CAR-T products while also maintaining current quality and tracking standards. Some of this will be accomplished through additional clinical advancement, but the commercial efficiency and standards are also key levers—levers that each player in this space will look to maximize. 

The Economic Impact on Healthcare

With novel-novel combinations becoming more widespread, and innovation increasingly making some cancers into “chronic” conditions requiring long-term treatment with novel agents, cost is at the forefront of healthcare concerns. In recent years, multiple myeloma and melanoma are areas where novel-novel combinations have dramatically extended life for patients suffering with these cancers. They’ve also escalated spend. At the American Society of Clinical Oncology’s (ASCO) Annual Meeting in 2015, Dr. Saltz of Memorial Sloan Kettering Cancer Center presented total U.S. cost projections of nivolumab and ipilimumab in advanced melanoma, which totaled more than $170 billion annually. However, there are many ways to consider economic impact, and these projections are frequently challenged by economists. If we step back from the number and think about scale and pace of innovation, the question that clinicians, patients and society face—how to balance innovation with sustainable spend—is a real one. We know that drug spend itself is a large proportion of cost, but not the majority spend in many episodes of care, so it is more than the novel therapeutics and technologies themselves, but an important question to consider. 

As expected, CAR-T therapies have brought us to a new cost threshold. On one hand, these novel technologies present high comparative list prices of $475,000 for Kymriah in pediatric ALL (pedALL) and $373,000 for Yescarta in adult R/R DLBCL. On the other hand, they are lower than even British health officials thought would be justifiable for Kymriah in pedALL at $649,000, for example. However, it’s not about the list price, but the value. Recent studies are attempting to show that the high list prices of some CAR-T therapies are reflective of their true value. In his presentation at ASH, Dr. Yanni Hao examined the economic value of Kymriah in pedALL patients by demonstrating the increase in quality-adjusted life years (QALYs) relative to currently available treatments. Dr. Hao showed that Kymriah’s efficacy provides an increase of 2.31 to 4.29 QALYs relative to current treatments, which was then applied to cost effectiveness ratios from $100,000 per QALY to $300,000 per QALY. The result is a price for Kymriah ranging from $488,470 to $1,364,525, which means that the current list price of Kymriah is lower than the minimum calculated value-based price for QALYs gained.


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Part of the challenge of evaluating CAR-T therapies and other emerging technologies is defining the value of a year of life gained. How about two years? Four years? Ten years? It’s one of the hardest questions to answer in oncology, especially when we’re forced to think about the threshold for what our system could sustain. 

The hope is that the outcomes present long-term value and savings. The CAR-T launch with Kymriah this year has also taken us further to outcomes-based agreements as a step to mitigate pricing concerns. Novartis launched with a  “value-based” pricing arrangement for Kymriah in pedALL with CMS—that is, Novartis tracks patients’ treatment outcomes over time, and only requires payment if clinical response is achieved by the end of the first month after treatment is received. Gilead-Kite has yet to unveil a value-based pricing approach for Yescarta, but the CAR-Ts open the door to options including other novel payment models, which may become more common as we see more personalized, potentially high-priced, one-time treatments come to market. These personalized technologies also open the door to the potential for indication-based pricing, which could further enable payment for value based on effectiveness in specific indications, not just as a whole. 

So What Does All of This Mean? 

We’re in the early stages of a revolution in personalized treatment that may very well change the standard of care across several malignancies. Patients are benefiting from dramatic results in these early CAR-T leaders to the market, and that’s the goal. But there’s more work to be done. This is an instance in medicine where all stakeholders really need to come together—manufacturers, payers, providers and patients—to enable scale and sustainability. Ensuring the accuracy of patient selection to maximize response rate, and exploring novel financial models and outcomes-based agreements, will be critical. Reducing the turnaround time for CAR-Ts will require streamlining steps in the clinical development process, or exploring new modalities that enhance manufacturing efficiency itself. Companies that take steps in these directions—and continue to push beyond the buzz—will be well positioned to reap the rewards of promising advances in CAR-T therapy.  

Topics: oncology, Pharma, cancer, oncology manufacturer, CAR-T, American Society of Hematology, ASH 2017, clinical efficacy, commercialization