3338_SM_CARTDevelopment_BlogLast year, the American Society of Clinical Oncology (ASCO) designated adoptive cell immunotherapy the 2018 clinical cancer “advance of the year” following the 2017 FDA approvals of Kymriah (Novartis) and Yescarta (Kite, a Gilead company). In the year since, we have seen some incremental, notable approvals in the cell and gene therapy space, but we have yet to see additional cell therapy approvals in oncology. However, like a duck sailing smoothly across the water, the relative inactivity above the surface conceals a flurry of development activity taking place below the surface in the oncology pipeline.

The Cancer Research Institute (CRI) published the results of its in-depth review of the global oncology cell therapy pipeline in Nature Reviews Drug Discovery just before this year’s ASCO meeting. Among the findings, the CRI highlighted that the current pipeline includes 1,011 active agents. By its count, 130 of those are CAR-T cell therapies targeting CD19—the same approach and target that Kymriah and Yescarta leverage today.

While at ASCO this year, my colleague, Jon Roffman, had the opportunity to sit down with Dr. Julie Vose, the head of hematology and oncology at University of Nebraska Medical Center. During their discussion, they explored this development dynamic in greater detail.

While on the surface this potential redundancy seems unsustainable, it may be an oversimplification to assume that all of these CD19 targeted CAR-T therapies are essentially “me too” therapies. What trends might be emerging beneath the statistic?

1. Further advances in technology: It’s likely that the broad CAR-T categorization is camouflaging advances that build on the foundation of today’s first-generation CAR-Ts. For example, dual-target and cocktail CAR-Ts targeting both CD19 and CD22 are currently being studied in clinical trials. Additionally, donor-derived allogeneic CD19 CAR-T cells and CD19-targeted “universal” CAR-T cells, which might provide an “off-the-shelf” alternative, are also being evaluated. While it’s technically reasonable to group these agents together under a CAR-T umbrella, there’s innovation here that will advance the field with learnings that should be more broadly applicable than a CD19 CAR-T use case.

2. Development of a “CAR-T backbone”: Despite having six PD-1/ PD-L1 immunotherapies now FDA-approved, we still see additional agents targeting this pathway in the pipeline as manufacturers develop in-house agents for use in combination with other in-house assets. It’s possible that we could see similar dynamics in cell therapy as well, with the potential for CAR-T therapy use in combination with other agents.

3. Development of “homegrown” assets: Particularly in Europe, we have historically seen academic institutions developing their own cell-based therapies. There are a number of academic medical centers with good manufacturing practice facilities, such that they are able to develop and manufacture CAR-T therapies for patients in-house. If academic institutions are developing their own “homegrown” CAR-T therapies for use in-house, this has the potential to reduce the cost of the drug for institutions, which, in turn, should make it more economically feasible to offer these innovative therapies to more patients. Time will tell whether homegrown therapies ultimately get licensed to biopharma manufacturers, or whether a path to having homegrown cell therapy assets is viable from a clinical, regulatory and commercial perspective.

Conversely, for therapies that are indeed more “me too” than breakthrough, how might they compete if FDA approved?

Considering the infrastructure required to offer CAR-T, and the many agents in development across tumors and targets, it’s unlikely that institutions will offer every approved agent. Once more agents are approved, institutions may diversify their offerings, endeavoring to offer options to a broader set of patients while limiting the agents they manage. Setting aside the potential advancements we discussed earlier, with 130 CD19-targeted CAR-T therapies in development, it’s likely that some in the pipeline will be more “me too” than breakthrough. How might these new entrants compete against first movers?

  • Clinical benefit: As Dr. Vose mentions in the video, physicians (and institutions that are capacity constrained by how many CAR-Ts they can offer) will be looking for some sort of clinical improvement, whether efficacy or safety. Higher overall response rates or durable responses for more patients would likely be of interest as we look to new agents to provide a more definitive “cure.” While physicians are getting more comfortable managing the cytokine release syndrome and neurotoxicity associated with current agents, a CAR-T that eliminated these side effects altogether would likely be of interest.
  • Price: Kymriah and Yescarta are both priced at $373,000 for adult diffuse large B-cell lymphoma patients. While these price points seem reasonable when compared with Zolgensma and Zynteglo’s prices ($2.1 million and $1.8 million respectively), they are still costly. These therapies represent tremendous innovation and potential cure for patients, so it isn’t unreasonable for these products to command a higher price. However, price could be an opportunity to differentiate for later entrants.
  • Customer experience: The current process for delivering CAR-T therapies asks a lot of patients and their families, as well as the institutions that offer them. Because these processes are so complex, they’re ripe with opportunities to differentiate, from ordering all the way through to administration and follow-up.
  • Expanding the definition of a CAR-T treatment center: If newly approved agents could be used in an outpatient setting or beyond centers of excellence, this could effectively open a new piece of the market, making CAR-T available to more patients. This would likely require some combination of fewer adverse events, a lower price point or a simplified customer experience.

While there may be some “me too” products in the pipeline, I’m incredibly optimistic about the breakthroughs in the making. Many agents in the pipeline could translate to innovation and potential cures for patients. However, the depth of development activity may also serve as a reminder to manufacturers to pause and consider where to invest to maximize impact and differentiation.


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Topics: oncology, oncology manufacturer, ASCO, CAR-T, FDA, cell and gene therapy, pharma manufacturer, clinical innovation, FDA approval, oncology pipeline, ASCO 2019, breakthrough therapies