Why are there only 20 cell and gene therapies in Europe?

In 2020, we wrote about why there were only 11 cell and gene therapies in Europe. A bit over four years later, there are 20 –  almost twice as many. But is it such a big improvement? Take a look overseas, the U.S. market currently counts 43. 

However, since 2020, the European Medical Agency (EMA) has made notable progress in approving advanced therapy medicinal products (ATMPs) – the European regulatory designation for cell and gene therapies. The most recent instances are the conditional marketing authorization for Casgevy in February 2024 and Durveqtix’s approval in July 2024. 

Still, it seems Europe is lagging behind the U.S. What’s the reason behind this and how has the situation evolved in the last few years? 

What’s the European cell and gene therapy landscape like?

In Europe, there are currently over 250 clinical trials for cell and gene therapies, yet only 20 accessed the market. Actually, 27 obtained the EMA stamp of approval but seven were retrieved from the market. 

While this number of approvals can seem disappointing at first glance, the reality is that it’s a bit too soon to be expecting results – many of these technologies are brand new, and decades-old discoveries are only just reaching the market. For example, the development of Strimvelis, approved in 2016, took more than 20 years. The approval of Chondrocelect in 2009 took nine years since its developer, TiGenix, was founded.

Cem Zorlular, chief executive officer (CEO) of Er-Kim said it is important to recognize that most gene therapies are very effective, but also very expensive modalities to solve intractable, unmet healthcare needs. As such, the biggest factor that has determined the path of individual treatments is unmet patient needs.

“In contrast, non-essential gene therapies will always fall flat in Europe, as Europe has historically accepted only incremental premiums on incremental innovation, and only if there is robust comparative data. Because of that, insisting on gene therapies for diseases where patients have an improvable condition and well-established standard of care will likely remain a non-starter or possible only at a much lower price point. On the contrary, for diseases where gene therapy is the only option, these therapies tend to do well in Europe,” explained Zorlular.

If the time scale wasn’t daunting enough, research and development (R&D) also burns cash quickly. A big chunk of the total money invested goes into meeting the quality, safety, and efficacy standards set by the regulatory authorities. This step seems to represent one of the biggest challenges for developers.

In fact, when regulations for ATMPs were first released in Europe, it appeared that authorities and researchers were on different wavelengths. “In 2007, new European Union (EU) regulations on advanced therapies came in, which added more, very frustrating years to the development,” said Graziella Pellegrini, one of the developers of one of the first EMA-approved AMTPs, Holoclar. “It seemed that we had to start from scratch.”

How does Europe compare to the U.S., and the EMA to the FDA?

Phillipe Chambon, founder and managing director of EG 427, pointed out that reports by the Alliance for Regenerative Medicine highlight a stark funding disparity between Europe and the United States for cell and gene therapy (CGT) companies.

“Despite Europe having 581 cell and gene therapy developers compared to 1,230 in North America, funding levels are disproportionately low. In the first three quarters of 2024, U.S. cell and gene therapy companies secured $11.8 billion, nearly six times the $2 billion raised in Europe, equating to almost 3 times more funding per developer.“

Chambon sees this funding gap as mirroring the trend seen in 2023, underscoring a consistent challenge for European developers in accessing capital critical for innovation and growth in this sector. “Looking specifically at the public market, the gap is even broader, confirming the difficulty in fostering additional new ‘champions’ in Europe,” added Chambon.

Concerning the regulatory side of things, both frameworks aim to balance innovation with safety and efficacy, but they differ in terminology, categorization, regulatory interactions, approval pathways, and manufacturing and commercialization requirements. 

According to Parijat Jain, vice president of cell and gene therapy at BioIVT, “these differences significantly impact the market access for these therapies, with the EU often having a more detailed classification system and potentially stricter requirements for approval compared to the U.S., which has more uniform reimbursement policies and fewer jurisdictional complexities compared to Europe.”

Buse Baran, commercial operation lead at Er-Kim also sees a fundamental difference between what drives both agencies’ approaches. “The EU’s approach is perceived as more cautious, with a greater emphasis on long-term risk assessment and harmonization across diverse regulatory environments. The U.S., on the other hand, fosters faster market access through streamlined processes, particularly for therapies addressing unmet medical needs.”

While the EMA is centralizing the approvals for each EU Member State, each has its own regulatory agency which delays post-approval commercialization. The FDA’s process is much more straightforward.

Chambon notes that the EMA is taking positive steps toward harmonizing and simplifying the regulatory process at a European level, with the clinical trial regulation (CTA) adopted in 2022, a unified procedure serving as a noteworthy example.

However, there is still a long way to go. “It remains a centralized channel attempting to reconcile significant discrepancies across individual Member States, which ultimately retain regulatory authority. This fragmented approach is especially problematic for cell and gene therapies, a still new and thus rapidly evolving field that demands regulatory agencies to be at the cutting edge of scientific expertise,” said Chambon.

Thankfully, this could change as the FDA and the EMA are leaning towards more collaboration in the future. Peter Marks, director of the FDA’s Center for Biologics Evaluation and Research (CBER), highlighted the potential for increased collaboration between both agencies to streamline the regulatory process for innovative therapies. He pointed to the joint review process already underway between the two agencies as a significant step forward.

This collaboration could serve as a model for other international regulators, creating opportunities for harmonized standards and processes. Marks also suggested the idea of a global registry, which could simplify and align regulatory efforts worldwide, potentially accelerating the approval of therapies across multiple regions. This type of collaboration is particularly relevant for emerging areas like cell and gene therapies, where consistent global guidelines could reduce the development burden for companies while ensuring patient safety and treatment efficacy.

If so much work goes into regulation, why are there so many withdrawals?

It seems complicated enough to reach the market with a cell or gene therapy, but the struggle isn’t over at that point. The EMA can still withdraw a marketing application due to safety issues or if the company doesn’t apply (and pay) for a renewal of the marketing authorization after five years.

That was the case of Glybera, the first gene therapy to receive approval in Europe. Its developer, uniQure, decided to not renew its market authorization after the therapy’s commercial failure in Europe and difficulties reaching the U.S. market. With a very small target market and a price of one million euros, it was the most expensive treatment back in 2012, making it hard to convince governments and private insurance companies to pay for it.

In fact, only one person was treated with Glybera after its approval. Elisabeth Steinhagen-Thiessen, the doctor who prescribed it, had a lengthy fight with the German authorities and the insurance company to make them pay for the treatment. After the withdrawal, three doses left were given to patients for one euro each.

A big challenge for cell and gene therapies is that they often target conditions that affect a very small number of patients. “Pharmaceutical companies are not much interested in unprofitable rare disease,” commented Pellegrini.

In the case of Strimvelis, there are only about 14 people per year in Europe and 12 in the U.S. diagnosed with its target disease, a rare form of genetic immune deficiency called ADA-SCID. The numbers are better for Holoclar, with around 1,000 people annually in Europe being eligible – burn victims who have become blind but whose eyes have not been too extensively destroyed. Still, it is far short of a blockbuster.

There are exceptions, such as Imlygic, a therapy from Amgen approved in 2015 for the treatment of late-stage melanoma, with over 56,000 new cases across the EU each year.

It’s fair to say that the majority of withdrawals have been made for business reasons, not safety issues. This highlights the fact that receiving EMA approval does not guarantee commercial viability – the product can still be an economic failure.

What’s next for cell and gene therapy in Europe?

Unfortunately, the current state of the European cell and gene therapy landscape is pushing some European companies to prioritize the U.S. market. “Without significant changes, companies founded in the EU will continue to focus their development efforts on the U.S. market and seek relocation and large funding rounds there. This trend continues to undermine the growth and success cycle of the biotech industry within Europe, limiting its potential to establish a globally competitive ecosystem,” said Chambon.

Chambon also thinks viewing gene therapy as viable only in the context of rare diseases as we currently view it is outdated. “Gene therapies are often mistakenly seen as suitable only for rare diseases due to their historically high manufacturing costs, which have led to pricing challenges, particularly within Europe’s healthcare systems.” Thinking widespread disease and gene therapy could be one way to go, according to him.

Zorlular agrees there is a need for a change in the European way of thinking. “European market access, and to an extent its regulatory model, is designed to be ‘no-fault’ from an efficacy and cost-effectiveness perspective. The idea is to avoid making the mistake of ‘wasting’ money on something unless certain it will work. It is a common tenet of innovation and fostering innovation that there will be some risk and waste. So, the EU should look to foster more risk-taking in its approach to innovation. This shift in risk-taking, if it happens, may drive a lot of tactical changes.”

To keep up with the U.S. pace, there will need to be a change in Europe, but is Europe ready or even willing to make those changes? Or will it keep its more cautious approach? Only time will tell.