CAR-T Commercialization Strategies: Views From Novartis And Kite

At recent industry events, Novartis and Kite Pharma highlighted opportunities and addressed challenges they face as they prepare to commercialize their CAR-T therapies. A report from Datamonitor Healthcare.

In regenerative medicine, a major inflection point has been reached in chimeric antigen receptor T-cell (CAR-T) therapy, a personalized immune-based approach to treating various hematological cancers. CAR-T therapy involves the extraction of autologous T cells, which areare then genetically engineered to express CAR and reintroduced back into the patient, where the cells are expected to target cancer cells. The US Food and Drug Administration approved the first such CAR-T product, Novartis AG's Kymriah (tisagenlecleucel-t), on August 30, 2017, and the next therapy soon followed with the approval of Kite Pharma Inc.'s Yescarta (axicabtagene ciloleucel; axi-cel) on October 18, 2017. Being the first, Kymriah's approval clearly marks a milestone, but as David DiGiusto, PhD, executive director of stem cells and cellular therapeutics operations in pediatric transplantation and regenerative medicine at Stanford University, expressed at the September 2017 KNect365 Cell & Gene Therapy (CGT) Bioprocessing & Commercialization meeting in Boston, this is only really the dawn of discovery, and is the start of a long road in effectively and profitably marketing these types of advanced therapies. At the CGT meeting in September 2017 and at the Alliance for Regenerative Medicine (ARM) Meeting on the Mesa in San Diego in October 2017, both Novartis and Kite, as well as other stakeholders, discussed various aspects of manufacturing and commercialization that will impact their success in the CAR-T market.

Novartis Takes Outcomes-based Approach To Reimbursement

Kymriah represents the first in a new major oncology treatment modality

Kymriah's approval is revolutionary for many reasons. According to DiGiusto, it showed that cell therapies can become viable medicines, especially for diseases that are largely out of reach of drugs and biologics. DiGiusto predicts that in the future, a patient is not going to get a pill as often as a cell; in other words, regenerative medicine is the future of medicine.

Kymriah is indicated for B-cell precursor acute lymphoblastic leukemia that is refractory or in second or later relapse, in patients up to 25 years old. The therapy has remarkable response rates, with 83% of patients achieving complete remission or complete remission with incomplete blood count recovery within three months of infusion, based on the pivotal Phase II ELIANA trial. At launch, Novartis says there will be 20 centers ready for patient treatment – increasing to 32 by the end of 2017 – linked to its Morris Plains, NJ manufacturing plant. It expects the "vein-to-vein" time – the time between cell apheresis and reintroduction of cells back into the patient – to be 22 days. A Marketing Authorization Application (MAA) filing in the EU is planned for Q4 2017.

Novartis sets the bar in CAR-T with an outcomes-based deal with the CMS

Novartis has set a list price of $475,000 for Kymriah, a much lower figure than anticipated, but still relatively high in the industry. At a panel on the implications of commercialization at the ARM meeting, all of the participants agreed that patient access was critical. To address that issue, in what may become the norm in cell and gene therapy reimbursement, Novartis has established an outcomes-based pricing deal with the Centers for Medicare and Medicaid Services (CMS), and is planning similar arrangements with private payers.

In the CMS agreement, Novartis will only get paid if and when patients respond to Kymriah by the end of the first month (note that this is in contrast to the three-month measurement for complete remission used in the pivotal trial; Novartis was not immediately available for comment). As more indications are approved for Kymriah (it is also in development for diffuse large B-cell lymphoma, chronic lymphocytic leukemia, and multiple myeloma), Novartis also has plans to establish indication-based pricing for the therapy based on clinical efficacy. (Also see "Novartis Begins CAR-T Payment Experiments With Outcomes-Based Contract With CMS" - Pink Sheet, 30 Aug, 2017.) Speaking at the 2017 ARM meeting, Pascal Touchon, senior vice president and global head of oncology strategy and business development at Novartis Oncology, pointed out that creative financing models such as these are not new territory for Novartis. As an example of this, Touchon cited the arrangements the company has made around the congestive heart failure drug Entresto (valsartan + sacubitril) with Aetna Inc., Cigna Corp., Humana Inc., and Harvard Pilgrim Healthcare. (Also see "Novartis Woos Payers With Data Showing Entresto Earns Its Keep" - Scrip, 16 Nov, 2016.)Value-based pricing is an important step, but can the system handle it?

According to Touchon, it was important for Novartis to find ways to play a role in the complex US system, and to be able to show value for patients and all stakeholders. He admits, however, that the biggest challenge for this outcomes-based approach is that the system is not organized for such a scheme yet. Traditional reimbursement mechanisms in the US were not set up to deal with advanced therapies, agreed Eric Faulkner, vice president of precision and transformative technology solutions in value demonstration, access, and commercial at Evidera, in the same panel. Still, the willingness of the CMS to engage in such an arrangement is a watershed event, says Bob Azelby, chief commercial officer of Juno Therapeutics Inc. (a fellow CAR-T developer that has come up against its own challenges in development (Also see "Juno Ends JCAR015 Development In ALL, Cementing Third Place CAR-T Position" - Scrip, 1 Mar, 2017.) ), and marks a big step forward. Now the challenge will be how to operationalize such an arrangement. In a separate panel discussion, Anthem Inc.'s medical director for care management, John Goldenring, MD, went a step further, questioning whether advanced therapies like Kymriah are appropriate for health plans, or if they should be nationalized, suggesting the possibility of establishing a special government-supported fund to pay for them. Outside of the US, Touchon says reimbursement will be even more difficult, and is something that he says "keeps me awake at night." (Also see "Cell And Gene Therapies: Where Few Standard Rules Apply" - Scrip, 6 Oct, 2017.) Novartis has stated that it is interested in outcomes-based reimbursement in Japan; however, that country has never implemented that kind of payment model to date.

Securing a supportive and favorable reimbursement and market access environment is a major priority in 2018 for the ARM, said executive director Michael Werner. Also critical is breaking down barriers to the adoption of new payment and financing models, which were discussed by Novartis and others, enabling value-based payment reform, and addressing patient portability.

CAR-T patient follow-up will be critical

Post-marketing surveillance in the CAR-T area will also play a big role, and Novartis has committed to a multicenter, observational study that will involve at least 1,000 patients who will be followed for 15 years after product administration. Wilson W Bryan, the director of the office of tissues and advanced therapies at the Center for Biologics Evaluation and Research at the FDA, pointed out that such monitoring would also be helpful early on in development to check for safety signals. In fact, in a pilot project, the FDA has proposed creating two databases that will evaluate safety and manufacturing information for CAR-T therapies targeting cluster of differentiation (CD)19. The project will involve several sponsors across the entire product class, and according to Bryan, the hope is to not only establish a safety profile for anti-CD19 CAR-T therapies and an approach to help individual sponsors (which is particularly relevant for cell and gene therapy), but also to learn what the FDA can do to improve its own skills.

Kite Pharma Ramps Ups Manufacturing

Yescarta will follow Kymriah onto the CAR-T market

Like Kymriah, Yescarta is an autologous cell therapy that had priority review with the FDA, and was approved ahead of its Prescription Drug User Fee Act target action date of November 29, 2017. Notably, the FDA waived a review of Yescarta under an advisory committee, indicating that many of the questions that would have come up had been answered during Kymriah's advisory committee meeting. (Also see "Kite’s Axi-Cel CAR-T: No Adcomm, No Problem" - Pink Sheet, 11 Aug, 2017.) Kite's first indication has a larger patient population than Kymriah's: adult patients with relapsed or refractory large B-cell lymphoma, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma. This translates into about 7,500 US patients, compared with the 600 eligible for Kymriah, and likely impacted the list price for Yescarta at $373,000, 22% lower than Kymriah's $475,000. Upon approval, Kite Pharma did not disclose any value-based reimbursement agreements in effect; however, the company has indicated that active discussions with commercial and government payers are ongoing. (Also see "Gilead/Kite Pricing For Yescarta Undercuts Novartis's CAR-T Kymriah" - Scrip, 18 Oct, 2017.)Kite also filed an MAA for axi-cel with the European Medicines Agency on July 31 2017, putting it ahead of Novartis in Europe. An approval is expected sometime during the first half of 2018. Data from Kite's pivotal ZUMA-1 trial, which supported both regulatory filings, showed an 82% objective response rate after a single infusion of axi-cel; in addition, 44% of patients were in ongoing response (including 39% in complete response) at the 8.7-month median follow up.

Manufacturing preparation and variabilities in process development are important considerations

Kite's vice president of product sciences, Marc Better, PhD, discussed the preparations the company is making to manufacture Yescarta, stressing the importance of early planning. He highlighted how rapidly cell therapy R&D can take place, saying for Kite that it was just over two years from investigational New Drug Application to Biologics License Application filing. Kite has built a commercial manufacturing facility near Los Angeles International (LAX) Airport, and Better explained that when considering autologous cell manufacturing, it was critical to keep in mind that you are heavily dependent on shipping companies and airplanes (hence Kite's close proximity to LAX). This facility will be working with approximately 16 site-certified patient centers at launch where the cells are harvested, with an estimated "vein-to-vein" time of 17 days. Currently, Kite has the capacity to make 4,000 patient lots per year, and in most cases it can produce two doses from each patient lot. This level of production will be required to make a robust commercial process, according to Better.

In cell therapy, the adage goes that the process is the product. Process development is a key operation that involves improving robustness, producing a closed or automated process, reducing unnecessary sampling/steps, ensuring the best materials are used and that they are appropriate for the pivotal clinical trial commercial product, and aiming to reduce cost. But process development comes with many challenges, and Better explained that it is important to understand the sources of process variability. In autologous cell therapy, with the cellular starting material coming from patients, differences from donor to donor become the most significant source of process variability. Unum Therapeutics Inc.'s chief technology officer, Geoffrey Hodge, also agreed, pointing out that in this field it is not possible to control your incoming material, as you can in other industries. Alan Smith, PhD, executive vice president of technical operations at Bellicum Pharmaceuticals Inc., specifically spoke of variability in diseases, pre-treatment, age, gender, and phenotype. Besides patient differences, other potential sources of variability include liquid handling (eg cell counts and measuring small volumes) and raw material.

Gilead's commercialization know-how and Kite's manufacturing expertise: a winning formula?

When it comes to commercialization, Kite will also have the backing and expertise in the industry from its new parent Gilead Sciences Inc., which bought Kite for $12 billion in August 2017 [See Deal]. The move puts Gilead into a leading position in the CAR-T and immuno-oncology fields. Still, Gilead is inexperienced in these areas, and has stated that one of the major draws of the deal was Kite's manufacturing process, which Gilead believes is scalable and will become highly efficient and cost-effective. Concurrent with Yescarta's launch, Kite is introducing an integrated technology platform that is expected to track that entire vein-to-vein process, and provide shipping and manufacturing updates.

Can Anyone Make Money?

Access has, and always will be, a major pain point in cell and gene therapy. For now, Novartis has set the benchmark in the CAR-T space by launching with an outcomes-based approach and planned indication-specific pricing. But according to David DiGiusto, the next question to ask is can any one company really make any money? Developers that have invested large amounts of money into R&D of cell and gene therapies will need to recoup their costs. Big Pharma firms such as Novartis and Gilead have the bandwidth to allocate significant R&D spending toward these advanced therapies while relying on other products in their portfolio to help make up the difference; however, smaller biotechs do not have that luxury. Beyond access and profitability lies the potential expansion of the CAR-T field, including application in solid tumors, and a move from autologous to allogeneic, or off-the-shelf, therapy. With nearly 900 ongoing trials in regenerative medicine at the halfway point in 2017, and $4.25 billion raised in total global financings, the field is on track for more discoveries to address these questions.

Adapted from Datamonitor Healthcare.