January 2019 Edition Vol.11, Issue 1

The CAR-T First-Mover Advantage: Reality or Myth?

By Sharon Karlsberg and Robert Rovner, ZS Associates

The ‘first-mover advantage’ is something we’ve come to expect in the commercial world. The first to innovate and come to market usually reaps the greatest rewards, right? Facebook, Uber, and Google improved on technology brought to market by actual first-movers MySpace, Sidecar, and AltaVista, but then transcended them by addressing their weaknesses.

In the oncology world, we’ve ascribed similar benefits to first-to-market products with a novel mechanism of action, such as Ibrance (palbociclib), Imbruvica (ibrutinib), and Keytruda (pembrolizumab) and Opdivo (nivolumab). But as we’ve seen in the high-tech world, a truly disruptive product often presents a significant opportunity for “second-movers.” The chimeric antigen receptor (CAR) T-cell therapy market had two breakthrough first-movers approved in 2017 – Kymriah (tisagenlecleucel) and Yescarta (axicabtagene ciloleucel). Will their first-to-market advantage sustain long-term growth, or when we think of CAR-Ts in 2-3 years, will we look at these as the MySpace of the oncology therapy world?

At the 60th Annual Meeting of the American Society of Hematology (ASH 2018), there were a few updates to inspire confidence in the first-mover CAR-T cohort. For example, a multicenter retrospective study that evaluated the efficacy and safety of Yescarta in a real-world setting for relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) found similar complete response (CR), overall response rates (ORR), and toxicity rates to its registrational trial, ZUMA-1.1 Novartis also presented longer-term data from one of its pivotal trials, JULIET, evaluating Kymriah in heavily pretreated DLBCL patients, which continued to demonstrate strong durable responses.2

These products undoubtedly represent a significant breakthrough in cancer treatment; however, lengthy turnaround times (TAT) of approximately 17 to 22 days and significant toxicities like cytokine release syndrome (CRS) and neurotoxicity remain barriers to widespread and strong commercial adoption.3, 4 These weaknesses beg the question – is there a window of opportunity for second generation CAR-T platforms to challenge the presumed first-mover advantage of Kymriah and Yescarta? At ASH 2018, we saw evidence of companies making progress towards shorter – almost immediate – TATs, and fewer instances of severe toxicity that may spur broader uptake of this paradigm-shifting approach to cancer therapy.

“Off-The-Shelf” CAR-T Solutions

A major contributor to the lengthy TAT of the commercially available CAR-T products is that manufacturing is individualized for the patient. Additionally, because the patient’s T-cells are extracted in one location and their CAR-T cells are manufactured in another, this approach is riddled with logistical hurdles requiring costly and time intensive levels of tracking and coordination between the manufacturing facility, hospital, physician, and logistics providers.

Through partnerships with Servier and Cellectis, Allogene Therapeutics, led by former executives of Kite Pharma, aims to address this pitfall with their allogeneic, or “off-the-shelf”, CAR-T cells (UCART). Rather than individualizing CAR-T treatment for the patient, the UCART platform creates engineered T-cells from a healthy donor for use in multiple patients. Theoretically, this could significantly reduce the manufacturing and logistical complexities faced by Kymriah and Yescarta, and “represents the next transformative step in medicine, as it will potentially allow patients all over the world to quickly receive these potentially life-saving therapies in the most efficient and cost-effective way possible…,” according to Dr. André Choulika, Cellectis’ Chairman and CEO.5 However, will this new approach achieve similar clinical results to existing CAR-T products?

So far, early results are promising. Phase 1 data presented at ASH 2018 on UCART19 in R/R acute lymphoblastic leukemia (ALL) showed that 88% of evaluable patients achieved a CR, and no severe neurotoxicity was observed.6 In contrast, Kymriah, achieved an 83% CR rate in a similarly pretreated ALL population, with a 49% incidence of Grade 3 or higher CRS.7

Yet, Allogene isn’t alone in this “off-the-shelf” approach. Fate Therapeutics, which is in pre-clinical pursuit with its lead candidate FT819, presented potentially IND-enabling data at ASH 2018.If these “off-the-shelf” CAR-T platforms continue to show enhanced simplicity with potentially preferable clinical profiles, they may be enough to not only supplant existing CAR-T options, but dramatically expand commercial adoption of CAR-T.

“Point-of-Care” CAR-T Solutions

“Off-the-shelf” CAR-Ts are a promising approach to expediting treatment delivery, but they’re only one potential solution. Other manufacturers are preserving the autologous route to CAR-T treatment that Kymriah and Yescarta established, but rather than sending a patient’s own apheresed T-cells to a distant manufacturing facility for reprogramming, they’re bringing CAR-T manufacturing capabilities to the hospital.

Lentigen (a subsidiary of Miltenyi Biotec) is pursuing this “point-of-care” solution to CAR-T cell production with its CliniMACS Prodigy device, a compact tabletop device that allows for automated production of CAR-T cells within the hospital. This method may obviate the complex and costly delivery process plaguing current CAR-T products. Feasibility and reliability of this production method, however, remains unproven.

Early evidence at ASH 2018 shed some light on the promise of this “point-of-care” production method. In a Phase 1 clinical trial evaluating feasibility and safety of locally manufactured CAR-T cells with the CliniMACS Prodigy in R/R non-Hodgkins lymphoma patients, CAR-T cells were successfully generated for all patients and no production failures were observed.Although CAR-T production using the CliniMACS Prodigy was set for a 14-day TAT in the trial, a sufficient number of CAR-T cells were available for infusion within 8 days; future trials will likely evaluate shorter manufacturing timelines. With an 8-day TAT, the CliniMACS Prodigy device could reduce current CAR-T production timelines up to almost 65%, while still allowing Lentigen to capitalize on growing physician comfort with an autologous CAR-T approach established by the first-movers.

Going Non-Viral to Improve CAR-T Safety

Reducing logistical complexities and lengthy TATs will alleviate some commercial constraints preventing broader uptake of CAR-T, but it’s only one piece of the puzzle. Severe toxicity events like CRS and neurotoxicity have been major concerns with first-generation CAR-T products, as rates of Grade ≥3 CRS can be as high as 23% and 13% for Kymriah and Yescarta, respectively in R/R DLBCL.7, 10

Some manufacturers seek to reduce the frequency of these significant toxicities as another way to differentiate their products. If a CAR-T’s risk profile can be improved, it may even help move these therapies into earlier lines of treatment. Poseida Therapeutics is pursuing this opportunity with its novel autologous CAR-T product in multiple myeloma, P-BCMA-101.

What makes P-BCMA-101 unique is its two-pronged approach to combating CAR-T toxicities. First, P-BCMA-101 is manufactured using a non-viral piggyBac DNA modification platform, which reduces the risk of oncogenesis and mutagenesis relative to viral-based delivery systems used by existing CAR-T products. Second, the platform also allows for the delivery of larger transgenes to T-cells, including a safety switch that reduces or eliminates P-BCMA-101 during treatment in severe instances of toxicity.11

At this year’s ASH, Dr. Gregory et al. presented data from a Phase 1 trial evaluating P-BCMA-101 in R/R multiple myeloma patients which, in addition to showing a 100% ORR in patients receiving the planned Phase 2 dose, showed no evidence of severe CRS (Grade ≥3), and only 1 patient with low-grade (Grade 2) CRS. Additionally, no patients required safety switch activation, and no instances of neurotoxicity, DLTs or off-target toxicities related to treatment were observed.12 If P-BCMA-101 continues to show minimal levels of severe toxicity and promising efficacy, a non-viral approach may be the advantage that allows this second-mover to expand commercial adoption of CAR-Ts.

Second Mover Benefit? Only Time Will Tell

As we’ve seen with the high-tech industry, disruptive innovation can create many paths to commercial success. At ASH this year, we saw positive data from:

  • First-generation CAR-T pioneers, who demonstrated sustained clinical benefits of strong efficacy and ‘manageable toxicity’ in expanded real-world populations. The path to success for Kymriah and Yescarta may come from building loyalty and familiarity among the first oncologists to offer CAR-T therapy in their institutions.
  • Second-generation CAR-T improvers, who showed promising early clinical data with faster turnaround times, less toxicity, or both. These improvements could expand the number of patients eligible to receive CAR-Ts, creating a larger market for all.
  • Novel CAR-T rivals, such as Amgen’s AMG 420 bispecific T-cell engager (BiTE), which combines an off-the-shelf antibody approach with T-cell engagement to enhance BCMA-specific cell death in R/R multiple myeloma.

Only time will tell whether the second generation of CAR-T therapies will eventually supplant first-generation pioneers. However, with the rapid pace of development in cell therapies, we can be certain that innovations unlocked by up-and-coming CAR-T manufacturers will improve treatment options available to patients across ALL, DLBCL, multiple myeloma and many other malignancies in the years ahead.

References

1 Nastoupil, L., Jain, M., Spiegel, J., et al. (2018). Axicabtagene Ciloleucel (Axi-cel) CD19 Chimeric Antigen Receptor (CAR) T-Cell Therapy for Relapsed/Refractory Large B-Cell Lymphoma: Real World Experience. 60th Annual Meeting of the American Society of Hematology (Session: 627). San Diego: ASH. Retrieved December 15, 2018, from https://ash.confex.com/ash/2018/webprogram/Paper114152.html

2 Schuster, S., Bishop, M., Tam, C., et al. (2018). Sustained Disease Control for Adult Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma: An Updated Analysis of Juliet, a Global Pivotal Phase 2 Trial of Tisagenlecleucel. 60th Annual Meeting of the American Society of Hematology (Session: 626). San Diego: ASH. Retrieved December 15, 2018, from https://ash.confex.com/ash/2018/webprogram/Paper115252.html

3 Kite Pharma, Inc.; Gilead Sciences, Inc. (2018). YESCARTA (axicabtagene ciloleucel) Manufacturing. Retrieved December 15, 2018, from YESCARTA HCP: https://www.yescartahcp.com/car-t-technology

4 Novartis Pharmaceuticals, Co. (2018). KYMRIAH (tisagenlecleucel) Treatment Process. Retrieved December 15, 2018, from KYMRIAH HCP: https://www.hcp.novartis.com/products/kymriah/acute-lymphoblastic-leukemia-children/dosing-and-administration/

5 Cellectis. (2018, April 03). Cellectis and Allogene Therapeutics Intend to Continue Strategic Cancer Immunotherapy Collaboration to Accelerate Development and Commercialization of Allogeneic Off-the-Shelf CAR T Therapies. New York, New York, USA. Retrieved December 15, 2018, from http://cellectis.com/en/press/cellectis-and-allogene-therapeutics-intend-to-continue-strategic-cancer-immunotherapy-collaboration-to-accelerate-development-and-commercialization-of-allogeneic-off-the-shelf-car-t-therapies

6 Graham, C., Yellop, D., Jozwik, A., et al. (2018). Preliminary Data on Safety, Cellular Kinetics and Anti-Leukemic Activity of UCART19, an Allogeneic Anti-CD19 CAR T-Cell Product, in a Pool of Adult and Pediatric Patients with High-Risk CD19+ Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia. 60th Annual Meeting of the American Society of Hematology (Session 612). San Diego: ASH.

7 Novartis Pharmaceutical Corporation. (2017, August). Kymriah (tisagenlecleucel) Prescribing Information. Retrieved from https://www.pharma.us.novartis.com/sites/www.pharma.us.novartis.com/files/kymriah.pdf

8 Clarke, R., Van Der Stegen, S., Chang, C., et al. (2018). Pluripotent Cell-Derived Off-the-Shelf TCR-Less CAR-Targeted Cytotoxic T Cell Therapeutic for the Allogeneic Treatment of B Cell Malignancies. 60th Annual Meeting of the American Society of Hematology (Session: 703). San Diego: ASH. Retrieved December 16, 2018, from https://ash.confex.com/ash/2018/webprogram/Paper116843.html

9 Shah, N., Zhu, F., Taylor, C., et al. (2018). A Phase 1 Study with Point-of-Care Manufacturing of Dual Targeted, Tandem Anti-CD19, Anti-CD20 Chimeric Antigen Receptor Modified T (CAR-T) Cells for Relapsed, Refractory, Non-Hodgkin Lymphoma. 60th Annual Meeting of the American Society of Hematology (Session: 626). San Diego: ASH. Retrieved December 16, 2018, from https://ash.confex.com/ash/2018/webprogram/Paper110194.html

10 Kite Pharmaceutical, Inc. (2017). Yescarta (axicabtagene ciloleucel) Prescribing Information. Retrieved from https://www.fda.gov/downloads/UCM581226.pdf

11 Poseida Therapeutics. (2018, December 17). Technology. Retrieved from Poseida Therapeutics Company Website: https://poseida.com/technology/#piggybac

12 Gregory, T., Cohen, A., Costello, C., et al. (2018). Efficacy and Safety of P-Bcma-101 CAR-T Cells in Patients with Relapsed/Refractory (r/r) Multiple Myeloma (MM). 60th Annual Meeting of the American Society of Hematology (Session: 653). San Diego: ASH. Retrieved December 17, 2018, from https://ash.confex.com/ash/2018/webprogram/Paper111419.html

About the Contributors

Sharon Karlsberg is a principal in ZS’s San Francisco office. She has more than 20 years of experience in the healthcare industry, and she’s a founding member of the ZS oncology team. Sharon works on a variety of marketing and commercial strategy issues with leading biopharmaceutical manufacturers. Her experience includes market research, brand strategy, competitive readiness and scenario planning, biosimilars and new product launch. Sharon’s therapeutic area of expertise spans many specialty markets, with significant depth in oncology, both solid tumors and hematological malignancies. Sharon joined ZS in 2004. Previously, she worked in market research for the medical diagnostics industry, public and investor relations for the biotechnology sector, and product marketing at Boston Scientific, Neurovascular. Sharon holds an MBA and certificate in health management from the University of California Berkeley’s Haas School of Business, and a bachelor’s in genetics and cell biology from Dartmouth College.

 

Robert Rovner is an Associate Consultant in Strategy Insights and Planning at ZS Associates in San Francisco, and is a leading member of ZS’s cell and gene therapy team. His experience includes commercial strategy and transformation, pipeline and launch strategy, growth marketing and execution, and customer insights. Prior to entering management consulting, he conducted biomedical research at Stanford University and received his BS in Molecular, Cellular and Developmental Biology from the University of California, Los Angeles.

 

 

 

 

ZS is the world’s largest firm focused exclusively on helping companies improve overall performance and grow revenue and market share through end-to-end sales and marketing solutions—from customer insights and strategy, to analytics, operations and technology. More than 6,000 ZS professionals in 23 offices worldwide draw on deep industry and domain expertise to deliver impact for clients across multiple industries. To learn more, visit www.zs.com or follow us on Twitter and LinkedIn.

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