CAR-T Cancer Drugs Front And Center At ARM Investor Day

It is a pivotal time in the cell-based immuno-oncology field. Following the first generation of success in cell therapy – the use of stem cell transplantation in cancer – comes the next evolution in cancer treatment with chimeric antigen receptor T-cell (CAR-T) therapy. These statements echo the sentiments heard at the Alliance for Regenerative Medicine's (ARM’s) 2017 Annual Cell & Gene Investor Day on April 27 in Boston. Informa Pharma Intelligence's Datamonitor Healthcare was in attendance and reported back some of the key highlights.

"This is the beginning of a new field," commented David Epstein, an executive partner at Flagship Pioneering (formerly Flagship Ventures). He was referring to the impending approvals in the US of potentially the first CAR-T therapies to reach the market.

The US Food and Drug Administration is currently reviewing the Biologic License Applications for Novartis AG’s tisagenlecleucel-T (formerly CTL019) and Kite Pharma Inc.'s axicabtagene ciloleucel (formerly KTE-C19). (Also see "BLA Accepted: Novartis Inches Ahead In CAR-T Race With Kite" - Scrip, 29 Mar, 2017.) While both target the cluster of differentiation 19 (CD19) protein, the drug candidates are submitted for slightly different hematologic cancer indications and patient populations. Tisagenlecleucel-T has priority review for relapsed and refractory pediatric and young-adult acute lymphoblastic leukemia (ALL), whereas axicabtagene ciloleucel is filed for relapsed or refractory aggressive non-Hodgkin’s lymphoma (NHL). Both hold US breakthrough therapy designation, though neither are designated as regenerative medicine advanced therapies (RMATs), the special status pathway for regenerative medicines established in the US under the 21st Century Cures Act. (Also see "RAT Race Begins: FDA Accepting Regenerative Advanced Therapy Designation Requests" - Pink Sheet, 30 Jan, 2017.) However, all CAR-T therapies are classified as advanced therapy medicine products (ATMPs) in the EU, with an established regulatory pathway. (Also see "CAR T-Cells, Helping US Firms & An “Ambitious” Plan For Advanced Therapies In The EU" - Pink Sheet, 10 Apr, 2017.)

Due to the priority review, Novartis’ tisagenlecleucel-T is likely to be approved first, and that approval could come in September or October 2017. According to Informa Pharma Intelligence's Biomedtracker, the drug has a 92% likelihood of approval, 10% above the average for other drugs in this therapeutic class and phase. Kite Pharma's axicabtagene ciloleucel will not be that far behind, though, with approval anticipated in November 2017, at a likelihood of 93%. Both companies have also announced plans to file the CAR-T therapies in Europe in 2017.

Before this two-way race between Kite and Novartis, it had been a three-way competition to get the first CAR-T drug approved in the US, and that competition also included Juno Therapeutics Inc. However, due to two clinical holds put on its CAR-T candidate JCAR015, including following a high incidence of neurotoxicity that resulted in five patient deaths, Juno and partner Celgene Corp.[See Deal] terminated development in ALL, although the companies are still forging ahead with other CAR-T therapies in their program. (Also see "Juno Ends JCAR015 Development In ALL, Cementing Third Place CAR-T Position" - Scrip, 1 Mar, 2017.)

In a panel at the ARM investor day entitled "Immuno-oncology: What Are the Key Issues as First Products Approach Commercialization?" participants discussed topics ranging from the importance of the approved labels for such CAR-T drugs tomanufacturing and commercialization challenges. Regarding labels, Usman Azam, MD, president and chief executive officer of Tmunity Therapeutic Inc. (and formerly and most recently global head of cell and gene therapies at Novartis) said he anticipates Novartis and Kite will get approval for good, attractive labels for their targeted indications, and clear guidance on patient selection, providing great hope for patients who have few options. Azam did caution that there are still a lot of unknowns that the real world will establish.

Others on the panel warned, though, that the adoption and uptake of CAR-T therapies will not be won or lost on the labels alone. A big factor will be logistics. Flagship Pioneering's Epstein questioned how patients will be treated, and how many samples could be lost along the engineering and manufacturing process. Aaron Foster, PhD, vice president of product discovery at Bellicum Pharmaceuticals Inc., agreed that scalability will be critical, saying he could not imagine "making that many cells." Tmunity's Azam added that adaptive manufacturing is important, and questioned how regulators will review this. He also said that automation in manufacturing will be key, but doubts that an end-to-end automation process, or what he called "cell therapy in a box," would not be plausible. Azam suggested that the earlier companies test such manufacturing processes in clinical trials, the better placed they will be to implement these in practice.

Market Access And Pricing

In a discussion on patient access and administration of CAR-T therapies, there was consensus that clinical trial sites will be the ideal location to start. Tmunity's Azam believes these sites will be the initial focus, simply because the physicians there have been trained and may be the early adopters. Azam warned, though, that adoption will be a slow and steady build. Bellicum's Foster added that there will need to be an educational process with physicians. Kite has already announced plans to initially launch axicabtagene ciloleucel at high-end academic centers, which have experience with CAR-T therapies and transplantation, including 72 clinical trial sites. (Also see "Kite Pharma Details CAR-T Therapy Launch, Floats Pricing Benchmarks" - Scrip, 19 Oct, 2016.)

Unsurprisingly, neither Novartis nor Kite have given a clear indication of what their pricing strategies will be for their CAR-T therapies. These will likely be disclosed upon approval, as has been the practice with many recent drugs. Across all indications, the companies' products could each cost an estimated $300,000 in the US and $204,000 in Europe, according to investment banking firm Jefferies. Kite has gone so far as to say that axicabtagene ciloleucel will be priced along the lines of similar therapies, using as benchmarks Celgene's $150,000-per-year cost for two years of treatment with Revlimid (lenalidomide), Johnson & Johnson/AbbVie Inc.'s $160,000 per-year cost for Imbruvica (ibrutinib) and Amgen Inc.'s $180,000 price for Blincyto (blinatumomab). (Also see "Kite Pharma Details CAR-T Therapy Launch, Floats Pricing Benchmarks" - Scrip, 19 Oct, 2016.)

During a panel at the ARM meeting on commercial readiness and market access challenges, representatives from the pharmaceutical and biotech industries were in agreement that payers are enthusiastic about the potential cell and gene therapies bring to the treatment paradigm overall, but need to have certain mechanisms in place to pay for what are expected to be expensive medicines. Mark Trusheim, strategic director at the Massachusetts Institute of Technology's Center for Biomedical Innovation's New Drug Development Paradigms Initiative, stressed that payers do see real value in regenerative medicines, but pricing needs to be fair, efficient and affordable. He pointed out that Sovaldi (sofosbuvir) "cracked the system," and there is a drive to never have that happen again (in gene or cell therapy). Trusheim went on to say that if a therapy has outstanding data, this will make a big difference to payers, and there are many financing tools that may be used: "It will get figured out … as long as the science is exciting." According to Flagship Pioneering's Epstein, the challenge for CAR-T developers is to make money. At the onset of commercialization, it will be a slow process for adoption. He jokingly wished "the CAR-T people a lot of luck." When asked about what advice he would offer these companies in their discussions with payers, Epstein stressed the importance of being clear about the price levels, and thinking about whether or not these developers will be guaranteeing an outcome. He also suggested the importance of differentiating your company and product in your commercial offering.

Editor's note: This article adapted from a Datamonitor Healthcareopinion piece.