There is a lot of talk about cell and gene therapy and how they are here to change medicine. But why have only a few of them reached the market?
Only 10 Advanced Therapy Medicinal Products (ATMPs) – that is, cell and gene therapies – have been approved in Europe, most recently Alofisel from TiGenix. That is not much considering that the first one, curiously also from TiGenix, was approved nine years ago now.
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 took more than 20 years. And the approval of Chondrocelect in 2009 took nine years since TiGenix was founded. So those excited about CRISPR, which is only a few years old, will still have to wait.
Holoclar seemed like an exceptional case at the beginning: research and development started around 1996 and first clinical results were published just a year later. But in reality, Holoclar developer Graziella Pellegrini reports the product was under development for 25 years, demonstrating that R&D takes time and hype induced by media coverage (fortunately) doesn’t accelerate the market access.
If the time scale isn’t daunting enough, R&D also burns cash quickly. If you want to scare your investors, show them this map of all the money sinkholes along the drug development pathway:
One of the largest investments goes into meeting the quality, safety and efficacy standards set by the regulatory authorities, and this department seems to represent one of the biggest challenges for developers. When regulations for ATMPs were first released, 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”,” says Pellegrini. “It seemed that we had to start from scratch
But, thanks to frequent stakeholder consultations, these seemingly harsh requirements are constantly evolving to become simpler with the goal of fostering development and expanding patient access. After a series of multi-stakeholder meetings with experts and regulators, the EMA released in November new manufacturing guidelines specific for ATMPs, which did not exist until now.
Even with dynamic regulations, some products may only be authorized at the national level and not for the whole continent. There is a dedicated pathway to exceptionally approve and commercialize ATMPs only locally as hospital exemptions. This status includes several limitations: this designation is only for non-routine products and those custom-made for individual patients, and importing or exporting them is illegal – which can lead to the dangerous practice of stem cell tourism.
If so much work goes into regulation, why so many withdrawals?
It seems complicated enough to reach the market, but the struggle isn’t over even at that point. The EMA can still withdraw a therapy due to safety issues or because the product is simply no longer available from the company. The company itself can request it when it can no longer deliver the product or purely for business reasons. Unfortunately, ATMPs usually target orphan diseases and consequently have relatively small markets. Therefore, their use and the incentive to produce them is limited making them vulnerable to withdrawal.
Furthermore, a market authorization costs money to be maintained, so the product must be commercially successful in order for it to stay on the market. A perfect example is Glybera, uniQure’s (in)famous gene therapy, which has been withdrawn after its commercial failure in Europe and difficulties reaching the US market. At one million euro a pop, it is ‘the world’s most expensive treatment’, such that its prescriptions must be made on a case by case basis.
In fact, Glybera was used only once. Elisabeth Steinhagen-Thiessen, the doctor who prescribed it, has told the extreme difficulties she faced, which included preparing a submission “as thick as a thesis” for German regulators and personally calling the CEO of the German insurer DAK to ask for the money.
As reflected by its limited prescription scope, Glybera is not useful to patients or a sound investment for uniQure. So if no one is interested in it, it may well become unavailable and therefore withdrawn from the market.
In a similar example, Strimvelis is indicated for a disease affecting only about 14 people per year in Europe and 12 in the US. These statistics mean that the massive R&D investment behind it has to be returned on only a few highly expensive procedures. For Holoclar, only around 1,000 people annually in the whole of Europe will be eligible: burn victims who have become blind but whose eyes have not been too extensively destroyed. Even though this market is larger than that of Strimvelis, it is far short of a blockbuster.
“Pharmaceutical companies are not much interested in unprofitable rare disease,” comments Pellegrini. However, often doesn’t mean always, and there are ATMPs indicated for larger populations as in the case of Imlygic, a therapy from Amgen for late-stage melanoma that was approved in 2015. There are about 56,000 new cases of melanoma in France, Italy, Spain, Germany and the UK every year.
It’s fair to say that the majority of withdrawals have been made for business reasons, not safety issues. However, EMA approval is not a business evaluation and does not guarantee commercial viability – the product can still be an economic failure.
Since 2009, ten products have been authorized. However, we’ll see how long they last, as four of them have already been withdrawn. Clearly, we have a lot of lessons to learn from these failures; but what can we expect in the future? Will there be a wave of withdrawals following the new wave of approvals? We’ll have to wait and find out. From this history, developers can draw lessons in bringing sustainable products to the table. ATMPs no longer represent a private club, and there is no doubt that new products will be approved shortly.
This article was originally published on October 2016 and has since been updated.
Images via studioportosabbia, sindlera, bikeriderlondon /Shutterstock; schematics courtesy of the author
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