If you are following Labiotech, you’ll have noticed that there is frequent news about exciting ATMPs (cell or genes therapies) under development. But why have only a few of them reached the market?

Only 8 Advanced Therapy Medicinal Products (ATMPs) – that is, cell and genes therapies – have been approved in Europe, most recently Zalmoxis from MolMed in 2016. As a refresher, the figure below summarises the approved products since 2009, when Tigenix blazed the trail to EU approval with its adipose-derived stem cell therapy. UniQure’s Glybera followed 3 years later as the first gene therapy approved worldwide. Despite this progress, there hasn’t been the wave of new therapies that you might imagine following the development of CRISPR, the ‘scientific discovery of the century’.

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So why are so few products reaching the market?

It’s a bit too soon to be expecting results — many of these technologies are brand new! CRISPR is only a few years old, and decades-old discoveries are only just reaching the market. For example, the development of Strimvelis from took more than 20 years! Tigenix was founded in 2000, and it only successfully brought Chondrocelect to market in 2009 – 9 years isn’t bad! As it turns out, this is a fairly standard timeline for bringing a drug to market.

Holoclar might seem like an exceptional case with a one-year turnaround: research and development started around 1996 and first clinical results were published in 1997! In reality, 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 weren’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:

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In 2015, public and private companies raised $10 billion, and about 70 treatments are in late-stage testing.” Technology Review

One of the largest investments is into the satisfaction of quality, safety and efficacy standards set by the 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: as Pellegrini remembers, “In 2007, new European Union (EU) regulations on advanced therapies came in, which added more — very frustrating — years to the development […] 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. The most recent conference, a multi-stakeholder meeting with experts and regulators, was held at the EMA in May this year to explore solutions to foster development and expand patient access in Europe. After authorities release new guidelines, they frequently update them to help companies through the development process.

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 authorizes exceptional ATMPs approved and commercialized 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. Until April 2012, approximately 60 treatments took this pathway.

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

It seems complicated just 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 this procedure when they have no longer the capacity to deliver the product or purely for business reasons. Unfortunately, ATMPs usually target orphan diseases and consequently have relatively small markets and therefore limited use and incentive for production, making them vulnerable to this.

Half of approved cell and gene therapy products on European market eventually failed commercialization and were withdrawn.” Christopher Bravery

Furthermore, a market authorisation has to be maintained, and since it costs money, the product must be commercially successful in order for it to stay on the market. What are some examples? Glybera, uniQure’s (in)famous gene therapy, is currently facing withdrawal given its commercial failure in Europe and difficulties reaching the US market. At a 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. Elisabeth Steinhagen-Thiessen revealed to Technology Review how it is complicated to prescribe the most expensive medicine in drug history:

She had to prepare a submission as thick as ‘a thesis’ for German regulators and then personally call the CEO of DAK, one of Germany’s large sickness funds, or insurers, to ask him to pay the $1 million price tag.”

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 U.S. These statistics mean that the investments have to be returned on only 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.

For this reason, Pellegrini comments, “Pharmaceutical companies are not much interested in unprofitable rare disease…” Often doesn’t mean always, since 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. In 2012, it was estimated that there were 56,000 new cases of melanoma in France, Italy, Spain, Germany and the UK, causing almost 9,500 deaths.

So it’s fair to say that the majority of withdrawals are made for business reasons, not safety issues. However, EMA appraisal is not a business evaluation: even if it grants approval, this does not guarantee commercial viability – the product can still be an economic failure.

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Since 2009, 8 products have been authorized, with half of them approved in the last 2 years. However, we’ll see how long they last: ¾ of products authorized prior to these have subsequently 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, considering how many products like the much-anticipated CAR-T therapies are in late stages of development. ATMPs no longer represent a private club: there is no doubt that new products will be approved shortly! 


Featured Image: studioportosabbia/shutterstock.com

Schematics courtesy of author

Figure 1: sindlera/shutterstock.com

Figure 2: bikeriderlondon/shutterstock.com


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