As High-Priced Immuno- & Gene Therapies Multiply, Who Pays and How?

Costing hundreds of thousands, even millions of dollars per individual, several immuno- and gene therapies have been approved to-date. Usage expansion of such therapies is now well underway and set to increase medium term.

So who pays and how? Discussions are taking place in earnest. This article¹ aims to aid these discussions by outlining CAR T-cell gene therapies for cancer and by opening-up the field to dialogue around financing solutions, including varied Health approaches.

Gene therapies

Gene therapies are essentially personalized medicines, developed for and tailored to an individual or small patient group for specific advanced cancers (currently representing a small area of oncology, but increasing), as well as for some rare diseases and genetic disorders. The treatment cost per-person, as shown in the examples below, goes far beyond conventional medicines.

CAR T-cell therapies – Kymriah® & Yescarta®

At the end of 2017, the US Food and Drug Administration (FDA) approved the first two gene therapies for advanced-stage cancer patients using genetically modified human immune cells; CAR T-cell therapies (see box below). Their costs reflect the sophisticated preparation which must also be produced individually for each patient, as well as high administration costs.

Kymriah® (Tisagenlecleucel), manufactured by Novartis, was approved by the FDA for patients under 25 years of age suffering from refractory lymphoblastic leukemia from B progenitor cells (ALL).

The National Cancer Institute estimates that every year in the US, about 3,100 patients aged 20 years and younger are diagnosed with ALL, which can be either B- or T-cell in origin, with B-cells being the most common. It is estimated that in about 15%-20% of patients, 300-600 patients a year, this cancer does not respond to initial conventional treatment or develops a recurrence².

The cost for Kymriah® is approximately $475,000 per patient.

Yescarta® was approved by the FDA shortly after for KitePharma. This works according to the same principle as Kymriah® and can be used in adult patients with refractory or recurrent large cell B-cell lymphoma^3,4 (the most common aggressive Non- Hodgkin’s lymphoma).

The number of potential Yescarta® therapy candidates in the US is significantly higher than for Kymriah®, at around 7,500 patients per year⁵. The cost is approximately $373,000 per case.

CAR T-cell therapies

Chimeric antigen receptor T-cells (CAR T-cells) are complex, individually programmed, cell-based cancer “drugs” with the outstanding property that they can strengthen and persist in treated patients.

CAR T-cell therapy is one of the most important and effective new developments for treating certain cancers; the therapy is FDA-approved as the standard of care for some forms of refractory non-Hodgkin lymphoma and pediatric relapsed acute lymphoblastic leukemia (ALL), and is available through clinical trials for other forms of blood cancer. These therapies are already also being used “off label” and for cancers for which they weren’t approved.

While the clinical development of CAR T-cell therapy is most advanced for lymphoma and leukemia, its use for solid tumors, such as prostate cancer, non-small cell lung
cancer, sarcomas and multiple myeloma, is increasingly being investigated^6,7.

What’s the process?

CAR T-cell therapies are performed individually, in contrast to most cancer therapies which are similar from patient to patient with minimal variation depending on, for example, histology and stage of disease.

The patient’s own T lymphocytes (T-cells) are isolated by a process called leukapheresis. They are then activated and genetically engineered (via virus transfer) in a specialized laboratory to express an artificial T-cell receptor, through which they are programmed to target antigens present on the surface of tumors. The T-cells, modified by CAR gene transfer, are then transferred back intravenously to the pretreated patient via a single infusion of what is effectively a “living, individually tailored drug”. When the CAR T-cells meet the antigens on the tumors, they are activated via the signal peptide, proliferate and become cytotoxic to cancer cells.

Making tumor cells visible to the immune system

Thus, a central problem of traditional cancer therapy seems to be at least partly solved: tumor cells that were previously “invisible” to the human immune system are made “visible” by an artificial receptor. CAR T-cells therefore combine the advantages of antibody-mediated and T-cell-mediated immunity. Once activated, the CAR-T cells proliferate and can persist in the patient for a certain time even after the disappearance of the tumor cells. This treatment therefore also seems to ensure a therapeutic effect in the event of a relapse.

Study basis for the FDA’s approvals

The FDA approval of Kymriah® (Tisagenlecleucel) was based on a global pediatric registration study, ELIANA, which the manufacturer conducted in recent years at a total of 25 different centers in Europe, North America, Japan and Australia. In 52 out of 63 patients (83%), complete remission was achieved within three months of infusion⁸. No minimal residual disease (criterion indicating a possible relapse) could be detected in the successfully treated patients. These results are notable, since for patient groups treated conventionally with chemotherapy, radiation and stem cell transplants, typically less than 10% survive for 5 or more years⁹.

The FDA’s approval of Yescarta® was based on a similar response rate of 82% found in phase 2 of the ZUMA-1 study with 101 patients, for diffuse large B-cell lymphoma. Even at a median follow-up of 8.7 months after treatment, 39% of patients still had complete tumor remission⁴. Here too, treatment success compared to traditional methods stands out: when patients with refractory large cell B-cell lymphoma were treated with conventional therapies, the median survival duration was approximately 6 months⁵.

Side effects and unknowns

The study results are encouraging, but severe side effects, including death, have been observed for these CAR T-cell therapies. At present, at this early stage of implementation, not enough is known about the side effects and long-term results.

For example, in the first months after administration of the infusion in the pivotal studies, ELIANA and ZUMA- 1, an increased release of cytokines (cytokine release syndrome, CRS) was observed for Kymriah® (79%) and Yescarta® (94%)^10,11. In most patients, the CRS symptoms were mild and flu-like, with fever and myalgia. However, if a very high concentration of inflammatory cytokines is released due to an overreaction of the immune system, this can lead to systemic cardio-vascular disorders or to multi-organ failure and death. In the studies, six fatal outcomes were reported due to CRS, despite the administration of steroids in 164 patients¹². Furthermore, severe neurological side effects, such as encephalopathy, aphasia (speech disorder) and delirium, were observed in 31% (ELIANA) and 18% (ZUMA-1) of the treated patients.

The mechanism for these side effects is not yet fully understood. It is also unclear as to why some patients do not respond to the therapy. According to Nature Biotechnology, the dose used in the studies was not clearly correlated to the response rate, severity of CRS or other signals¹³.

It is also not yet known if these therapies are a definite cure or an extended remission.

Furthermore, CAR T-cells destroy all cells, healthy and diseased, that have the corresponding target; it is unclear as to whether this will cause further damage to the treated patient in the long term.

Gene therapies for cancers and rare diseases set to increase

The two described, approved CAR T-cell therapies are being subsequently approved for other cancers and patient subsets.

Looking forward. As shown in figure 1, the number of clinical trials for CAR T-cell therapies has increased almost exponentially: at the end of 2017, a total of 300 CAR T-cell studies were registered worldwide, although the majority are still in phases 1 and 2^12,14. In 2017 alone, 87 further studies were added.

Figure 1: Development of worldwide CAR T-cell clinical trials since 1997, annually initiated and running total of ongoing trials. Source: ^12,14

The pharmaceutical industry is investing heavily in the development of new CAR T-cell therapies; for example, Glaxo-Smith-Kline (GSK), Novartis and Gilead have a combined investment reaching double-digit billions of dollars¹⁵. New cost-intensive CAR T-cell therapies are therefore likely to be approved for the treatment of other cancers in the medium term.

A similar trend is observed in gene therapies for rare diseases which impact 3.5–5.9% of the global population^16,17.

Financing considerations

Spreading the payment. The high cost of gene therapies is often made as a one-off payment and/or due within a short time period. Based on this aspect alone, the increasing use of these therapies can represent a severe financial balance sheet threat to healthcare providers and/or insurers.

To help overcome this issue, some pharmaceuticals accept payment in installments (e.g. over 5 years). However, such pay-over-time is problematic as health plan members may change employers, or the employer may change their health plan/insurance networks. There is therefore no certainty that the member receiving the gene therapy will remain on the health plan after receiving the treatment.

Savings potential. It’s important to note here that although the costs of these therapies are exceptionally high, if a therapy is a genuine cure, it could in some cases such as gene therapy for hemophilia, represent a total cost reduction compared to ongoing treatment costs.

Outcome-based models. At the same time, another consideration is that gene therapies (in contrast to other non-curative, conventional drug therapies) cannot be stopped or reversed if they prove to be ineffective or associated with severe side effects. Therefore, the risk of accumulating ongoing treatment costs in fact remains, and indeed total costs could be compounded by the need to return to conventional treatments and to treat any resulting severe side effects from the therapy.

Rebating therapy cost is one solution to unsuccessful treatment, as is provided, for example, by the manufacturers of Yescarta®. Such outcome-based models require pre-agreement between manufacturers, healthcare providers and/or insurers regarding the criteria for success and failure, and how severe side effects (caused by the therapy) and rebates are to be handled.

Contact us

At PartnerRe we are excited to be involved in discussions dealing with today’s risk and helping to shape future risk solutions for gene therapies. Please contact us to discuss this topic.

Kelly Munger
FSA, MAAA, Head of US Health
[email protected]

Matt Leming
Health Products Leader, Health
[email protected]

Tasha Barbour
Chief Business Development & Marketing Officer, Health
[email protected]

Missy Kveene
Vice President, Managing Director, PULSE + Plus™
[email protected]

This article is for general information, education and discussion purposes only. It does not constitute legal or professional advice of PartnerRe or its affiliates.