Cell and Gene Therapies: Six Global Trends We Are Watching in 2024

Published February 15, 2024

2023 was a busy year for cell and gene therapies (C&GT). There were regulatory approvals in the U.S. and EU, including both in rare pediatric conditions with no current effective options (e.g., Duchenne muscular dystrophy (DMD)), as well as in indications where competition is better established (e.g., hemophilia A and B).

Towards the end of the year, the FDA approved not one, but two sickle cell gene therapies on the same day, creating instant competition between them. One of these therapies, CASGEVY™, came with the added distinction of bringing the much talked-about CRISPR technology to patients, merely a decade after the publication of the pivotal papers on its scientific backing.

Beyond scientific and regulatory advancements, pricing for gene therapies in the U.S. reached USD 3.5M (HEMGENIX^®), but some manufacturers chose price points well below (e.g., CASGEVY, USD 2.2M). While the access woes continued in Europe, Biomarin’s ROCTAVIAN™ achieved access for Hemophilia A in Germany, at a price point slightly below EUR 1M per patient, through a novel outcome-based agreement.

We are early in 2024, but there is no doubt in any of our minds that the activity in this space will only continue to escalate. Here are a few trends Trinity Life Sciences is watching in 2024:

Will U.S. payers finally take a strong stance on managing C&GTs, leveraging competition vs. conventional options or within class?

U.S. payers thus far have not taken steps to block or limit access to the C&GTs beyond using the prior authorization process to ensure patients requesting cell or gene therapy administration are in line with FDA labels and trial populations. This payer approach is in alignment with expectations, considering the high unmet need in oncology and rare pediatric indications.

However, access conversations may not be as straightforward for gene therapies entering spaces with a multitude of conventional options (e.g., ROCTAVIAN in Hemophilia A). Failure to communicate a robust clinical and/or economic value argument vs. conventional therapies might open the door for payers to limit costly therapies to niche patient groups or seek substantial concessions on the price.

One major exception to the favorable access picture is the challenges faced by self-insured employer plans, which may end up carving out C&GT coverage to minimize exposure. Access can be improved by providing employers and small plans with coverage alternatives that can protect them from the financial risk (e.g., C&GT specific coverage).

Approval of LYFGENIA™ (bluebird bio) and CASGEVY (Vertex) on the same day by the FDA, and the pricing decisions by the two manufacturers (LYFGENIA price is ~40% higher than its competitor), brought forward the question of preferential utilization management between competing gene therapies. After the initial panic from the investors and hit on the stock, it appears bluebird has temporarily stemmed the tide by announcing a couple of major outcome-based contracts, covering approximately two thirds of the U.S. population. We will continue to watch similar within-class competitive entries in 2024 (e.g., Pfizer’s Hemophilia B asset).

Will we finally see uptake speed up for gene therapies?

As our colleagues explored in Trinity’s Gene Therapy Uptake: The Elephant in the Room white paper published last year, uptake of gene therapies in “low unmet need” indications has thus far been slow. For example, for Hemophilia A and B gene therapies in the U.S. and EU, treatment of first commercial patients came months after announcements of regulatory approvals. A slow ramp-up may not be surprising, considering the complexity of cell and gene therapy distribution and administration. However, success of these therapies in 2024 will be a critical indicator of future potential of gene therapies in similar indications where effective options exist, the value of gene therapy is mostly centered on lowering treatment burden (e.g., frequent injections), and indications with larger populations. Rapidly increasing utilization will suggest physicians and patients might finally be recognizing this value proposition.

If and when patients and physicians embrace the idea of a one-time therapy in place of a conventional chronic treatment, the next question will be whether health systems in the U.S. and globally can answer the added demand for staff and bed capacity. Some applications (e.g., CASGEVY/LYFGENIA) will also require patients to be admitted and monitored at the hospital after administration, in some cases competing with current CAR-T administration capacity. While this may not be an issue yet in 2024, it is a potential concern going forward.

How will FDA and EMA’s scrutiny around CAR-T safety impact perception of cell therapies?

Over the last few months of 2023, first the FDA and then the EMA decided to take a closer look into the safety of CAR-T cell therapies, especially in relation to secondary malignancies associated with the infused cells. Recently, Peter Marks, director of the FDA’s Center for Biologic Evaluation and Research, noted that some secondary malignancy risk exists, but CAR-Ts overall provide a positive benefit-risk profile in current oncology indications. In late January,  the FDA finally requested CAR-Ts to include a boxed warning on secondary malignancies.

Risk of a secondary malignancy might be acceptable in diffuse large B-cell lymphoma (DLBCL), adult acute lymphoblastic leukemia (ALL) or any other late line oncology indication, especially considering the risks of chemotherapy alternatives. However, the calculation is likely to be different in non-oncology indications, where CAR-Ts are starting to gain some traction in trials. For example, physicians and patients might think twice before committing to a CAR-T therapy in the immunology space, especially if other options with more tolerable profiles remain available.

How will CAR-T prices shift in Germany now that they are being assessed post-Orphan Drug Designation (ODD)?

In addition to its position as a major European market, Germany is critical from a pricing perspective due to public availability of negotiated prices for novel therapies. While net prices are often significantly lower vs. list prices in the rest of the major European markets, Germany is a clear indicator of payer willingness to pay for a new therapy across the continent. So far, CAR-T cell therapies were able to hold on to favorable pricing levels (~EUR 250-300K) in Germany. These outcomes were largely based on the EMA Orphan Drug Designation and the associated “Unquantifiable Added Benefit” rating, providing advantages in price negotiations.

However, as of late 2023/early 2024, CAR-Ts are one-by-one facing full benefit assessments by the G-BA, as they are losing their orphan drug protections by either exceeding the EUR 30M orphan sales threshold or removal of EMA ODD. There have been some positive outcomes in benefit assessments (e.g., BREYANZI^® in 2L DLBCL), but these are mixed with “No Added Benefit” designations (e.g., due to non-comparative trial design), which by law limit pricing opportunity to be benchmarked to the cheapest comparators, often low-cost generics.

If all goes according to the negotiation timelines, in the first few months of 2024 we should be able to see the price levels the manufacturers and the German sickness fund negotiators agree on. Unless of course “confidential rebates” become the norm quickly, making any discounts invisible to outsiders.

Will outcome-based agreements stick around this time?

We were all talking about outcome-based agreements when CAR-Ts first arrived in the market with previously unseen price points and the “one-time administration” promise. A number of agreements were announced and signed across countries (e.g., for KYMRIAH^® in the U.S., KYMRIAH/YESCARTA^® in Italy/ Spain). Uptake of outcome-based agreements, particularly for the CAR-Ts, has been somewhat mixed across countries. This was largely due to complexity of execution and challenges in agreeing on the outcomes triggering payments (e.g., in oncology survival is a robust and unbiased outcome, but may not be feasible to measure quickly).

The entry of gene therapies, at even higher price points vs. cell therapies, boosted the outcome-based contracting conversation. Given the uncertainty around durability of benefit and payers’ desire to minimize uncertainties/added costs, a number of agreements have been offered for new entrants. bluebird bio made waves in late 2023/early 2024, announcing two outcome-based agreements for LYFGENIA, which provide rebates if patients are hospitalized due to painful sickle-cell related episodes. These agreements cover the therapy for two thirds of the U.S. population. The impact of these agreements on utilization management is not immediately clear but will be interesting to watch as commercial plans announce medical policies.

State Medicaid entities play a critical role in access to gene therapies, as these products are often carved out of the capitated management agreements. While market dynamics (e.g., best price requirements for Medicaid) limited the willingness of manufacturers to enter outcome-based agreements initially, recent rule changes by the CMS have improved the feasibility of such contracts. In 2024, State Medicaid authorities are expected to enter new outcome-based agreements to provide access to gene therapies in individual or groups of states. In fact, in announcing their first commercial agreement, bluebird bio also hinted to ongoing discussions with 15 Medicaid agencies.

How will new technologies impact the overall cell therapy landscape?

A significant pain point for CAR-T cell therapy uptake so far has been manufacturing. Manufacturing autologous CAR-Ts is costly and cumbersome, requiring cells to be shipped back and forth. It takes two to three weeks at best (longer outside the U.S.), and supply fails to meet demand, with providers struggling to find “manufacturing slots” for patients in need. In response, novel manufacturing technologies with the promise of addressing these issues have drawn considerable investment from established players, as well as new entrants.

The manufacturing innovation with the longest history in the space is the introduction of “allogeneic” or “off-the-shelf” CAR-Ts (as opposed to autologous). Manufacturing of allogeneic CAR-Ts is accomplished through collection of immune cells from donors or differentiation from embryonic stem cells. Cells are then engineered to meet the needs of multiple patients, allowing “banking” of cells for quick shipment much like a monoclonal antibody or bi-specific. While several clinical trials are in progress using such cells, no products have been commercialized thus far. The latest setback to commercializing allogeneic CAR-Ts was the strategic change in direction to focus on earlier therapy lines, foregoing trials in late lines.

Another novel concept in CAR-T manufacturing is to introduce the cells into the patient soon after engineering in culture, allowing expansion of cells to therapeutic dose to happen in the body. Novartis’s T-Charge, and Umoja’s Vivovec platforms (recently partnered with AbbVie) are two good examples of this approach, with the potential to decrease turnaround time to two to three days.

Finally, distributed/on-site manufacturing of CAR-T cells is seen to be another effective solution. In on-site CAR-Ts, cells taken from the patient can be fed into a manufacturing instrument on site, removing the need to ship cells and limiting complexity of the manufacturing and administration process. Galapagos recently signed an agreement with Landmark Bio to leverage this technology in their products currently in clinical trials.

Trinity experts, focusing on various strategic challenges on the cell and gene therapy commercialization journey—from pre-clinical stages through development phases, to launch and lifecycle management—will continue to closely track development in the space to ensure robust support for our industry partners.