What are ATMPs and what is specific about them?
Advanced therapy medicinal products (ATMPs) are medicinal products for human use that are based on living material and prepared industrially or manufactured by a method involving an industrial process. ATMPs can be classified into three main categories – gene therapies, somatic cell therapies and tissue engineered products. Table 1 shows all ATMPs, which are commercially available in EU. Given that these therapies are typically indicated for very rare conditions, ATMPs often struggle with significant uncertainty on their clinical data due to the limited number of patients involved in their randomised controlled trials (RCTs) and lack of long-term effectiveness data. As a result, the manufacturers of these products face strong pushback from regulators and payers when it comes to obtaining marketing authorisation and reimbursement across countries.
Table 1 Approved ATMPs in the EU
|Approval and Withdrawal Date
|Rason for MA withdrawal
|Oct 2009 – Jul 2016
|Oct 2012 – Oct 2017
|Access restrictions and hefty maintenance costs
|Jun 2013 – Sep 2014
|Closure of an authorised EU manufacturing facility
|Sep 2013 – May 2015
|Aug 2016 – Oct 2019
|Insufficient clinical efficacy
|Kite Pharma EU
|AveXis EU Limited
|May 2019 – early 2022
What is the reason for the withdrawal of ATMPs from Europe?
Over the last decade, more than 15 ATMPs have received a marketing authorisation in Europe but in that time six have been withdrawn. Given the obvious clinical need for such products, why are so many manufacturers withdrawing from the market?
In the case of Glybera, the first gene therapy to obtain approval in Europe, the manufacturer did not renew the marketing authorisation in year 5. Its price of one million euros per patient made it very difficult for Glybera’s manufacturer to convince governments and private health insurance companies to pay for it and this, coupled with the very small patient population ensured it was a commercial failure.
Most recently, Bluebird Bio, the manufacturer of two of the most innovative gene therapies, has announced that they will withdraw the EU marketing authorisation for Skysona (elivaldogene autotemcel) as well as their UK application to the Medicines and Healthcare products Regulatory Agency (MHRA). Skysona is a one-time gene therapy indicated for the treatment of cerebral adrenoleukodystrophy (CALD). By early 2022, the company will also likely withdraw the marketing authorisation rights from the EU and UK for Zynteglo (betibeglogene autotemcel), another gene therapy indicated for the treatment of beta-thalassemia. Zynteglo was conditionally approved in the EU and UK with a price of €1.575 million ($1.8 million), of which €315,000 ($366,000) was to be paid upfront. It was agreed that the rest of Zynteglo’s price would only be paid if the drug continues to be effective. Although the drug was launched in Germany in 2020, the company eventually decided to withdraw it from the German market due to challenges with the reimbursement negotiations. Bluebird bio now plans to focus resources on the US market. The company highlighted that the European authorities were unable to recognise the true value of their one-time, potentially curative medicine and it was unsustainable for them to maintain their operations in Europe without obtaining sufficient reimbursement for Zynteglo across multiple countries in a reasonable timeframe.
Other issues to beset manufacturers are the potential withdrawal of a marketing application due to safety issues or lack of efficacy (e.g. Zalmoxis). ATMPs are currently most often developed for rare and previously untreated diseases. Hence, their clinical trials are usually conducted in very small number of patients, so some adverse events are only discovered when a product reaches the market.
What will happen with ATMPs in Europe moving forward?
The majority of ATMP product withdrawals have been due to commercial reasons rather than safety issues. Despite their curative potential and innovative nature, ATMPs represent a big challenge both for regulators and payers due to their high clinical uncertainty and hefty price tags. Managed access agreements and innovative contracting methods, such as payment-by-results or outcome-based rebates based on individual patient data are potential solutions. The development and implementation of such outcome-based agreements are, however, very complex and require the input of payers, therapy experts and manufacturers to ensure suitable data can be collected to reduce the uncertainty around long term effectiveness, ensure patient access to innovative medicines whilst also providing manufacturers with a suitable return on investment. Moving forward, if healthcare authorities do not become more flexible in their assessments of ATMPs and adaptive to innovative contracting models, we may see additional manufacturers withdrawing their cell and gene therapies from the European market due to lack of commercial viability.