First CRISPR therapy seeks regulatory approval, but will it be able to avoid the pitfalls of other cell and gene therapies?


In a first for CRISPR-based therapies, the FDA, EMA and MHRA have all received regulatory filings for the product exagamglogene autotemcel (“exa-cel”), a treatment for sickle cell disease and transfusion dependent beta-thalassemia. The FDA has since confirmed that it has accepted the regulatory filing for review and has granted priority status to the sickle cell disease indication and scheduled a decision for December this year. Exa-cel is the result of a collaboration between Vertex Pharmaceuticals and CRISPR Therapeutics.

The innovative product is a cell therapy that works by inducing a patient’s red blood cells to produce foetal haemoglobin (the type of haemoglobin that is produced by a foetus in the womb, before a switch to adult haemoglobin is made after birth). The process works by extracting a patient’s hematopoietic stem cells, editing the DNA of the cells with CRISPR technology and infusing the edited cells back into the same patient.

The submissions to the regulatory authorities marks a huge step forward for CRISPR technology, which was discovered just over a decade ago and led to Emmanuelle Charpentier and Jennifer A. Doudna being awarded the Nobel Prize in Chemistry in 2020. What makes CRISPR special is that it can locate precise DNA sequences and either insert or delete base pairs (depending on the type of CRISPR technology used). This enables faster and more accurate editing of the human genome that was not before possible. Unsurprisingly, since CRISPR’s discovery there has been an explosion in research and in clinical trials aiming to treat genetic diseases.

As the first CRISPR-based therapy to file for regulatory approval Exa-cel is now the frontrunner in the race to market for CRISPR therapies. However, it joins a burgeoning cohort of other types of products that also employ cells as therapy and that involve altering genes. These “cell and gene therapies” include CAR-T, which has been revolutionary in treating certain blood cancers.

But unlike small molecules or biologics, these advanced treatments often target small patient populations that suffer from rare diseases, the hope is they may only need to be administered once and can be curative. Combined with the highly complex manufacturing required to make the therapies and the billions of dollars invested to develop them, single doses of a cell and gene therapy often attract record-breaking price tags that have necessitated the introduction of innovative pricing and reimbursement models so that health systems can afford to provide them to patients. Bristows has written about these previously here, including how these pricing models can impact licensing arrangements.

Even with these new pricing and reimbursement models, some cell and gene therapy companies have still struggled to reach agreement with health authorities on price, leading to the product being withdrawn from the market. In the EU, 25 cell and gene therapies (referred to as “advanced therapy medicinal products”) have been approved by the European Commission as of July 2023. But five of these products have since withdrawn their marketing authorisations and two have chosen not to renew[1]. One such product is Zynteglo (betibeglogene autotemcel), a cell and gene therapy for transfusion dependent beta-thalassemia produced by BlueBird Bio, making it a direct competitor of CRISPR-based Exa-cel.

In 2019, Zynteglo entered the market in Europe with a price tag of $1.8 million, which was to be spread across five yearly instalments provided that the recipient patient continued to be free from blood transfusions –  a so called “value based” pricing model.

The company made the decision to withdraw the product in Europe (including the UK) in March 2022 following a failure to agree pricing with European health authorities. The president of severe genetic diseases at the company, said “it became clear that European authorities were unwilling to recognize the value of a one-time, potentially curative medicine. The reality is that it would cost Bluebird more to deliver these therapies to patients than what European authorities were willing to pay.”[2]

Although approval of cell and gene therapies is largely centralised in the EU (via the European Commission upon review of the EMA), pricing and reimbursement must be agreed with each country in Europe individually and sometimes with each region of each country, such as in Italy. This can lead to long delays in reaching the market with no guarantee of any achieving any particular price.

A key issue is that, given the rarity of the conditions that therapies normally treat, most of those that receive regulatory approval are authorised by regulators based on limited data sets generated from clinical trials that have involved only a few patients, for whom few or no comparative treatments are currently available. In this scenario, regulators will often grant a conditional marketing authorisation (or a similar type of approval) to allow the therapy to be made available quickly for those in desperate need, but which involves a commitment from the pharmaceutical company to gather additional, real-world evidence on these relatively new therapies, whose long term benefits and safety profiles are currently not well known or understood. This makes pricing and reimbursement decisions by health authorities as well as private health insurers a long and difficult process, with no assurances that a company can convince them to pay for a treatment, even with the use of innovative payment models.

Further, cell and gene therapies are reliant on highly complex manufacturing, with many therapies being made-to-order using the patient’s own cells, meaning that manufacturing for autologous therapies needs to be located relatively close to patients.

The issues of price and the complexities of manufacturing are likely to be faced by almost every CRISPR-based therapy that intends to come to market, given that, by their nature, CRISPR-based therapies will always involve gene editing and therefore sit outside the traditional model established by small molecules or even biologics. To get ahead of these thorny issues, Exa-cel’s producer, Vertex, has reportedly already begun talks with health authorities across Europe, including the National Institute of Health and Care Excellence (NICE) and has begun to build manufacturing capacity. Vertex hopes to have pricing agreements in place before Exa-cel’s launch.[3]

And Vertex has reason to be optimistic. Other cell and gene therapies have managed to employ the innovative pricing models that are required to get European health authorities on board. Novartis’ Zolgensma, a viral-vector gene therapy to treat spinal muscular atrophy in children, was approved by the European Commission in 2020 and, at the time, was the highest price drug in the world, with a headline cost of over $2 (that crown has now been taken by CSL Behring’s Hemgenix, a gene therapy with a price of $3.5 million). Despite the high costs, Zolgensma has recorded sales of hundreds of millions per quarter globally and has negotiated deals with health authorities across Europe, the exact commercial terms of which are highly confidential.

In June 2021, the NHS treated its first patient with Zolgensma, with NHS England Chief Executive Simon Stevens saying at the time that “Spinal Muscular Atrophy is the leading genetic cause of death among babies and young children, which is why NHS England has moved mountains to make this treatment available, while successfully negotiating hard behind the scenes to ensure a price that is fair to taxpayers.”[4]

The key financial selling point of these therapies is that although the upfront cost may be large, they will hopefully in the long term save health systems millions. For example, in the US, it is estimated to cost between $5 million and $5.7 million to treat transfusion-dependent beta-thalassemia over a patient’s lifetime with the standard of care, which is blood transfusions[5]. This compares to the cost of $2.8 million for Zynteglo in the US, which is potentially curative.

With up to 200 cell and gene therapies in late stage development[6] and CRISPR-based therapies in clinical trials for everything from urinary tract infections to HIV[7], pharmaceutical companies and health systems must find a way to price these therapies or risk putting transformative treatments out of reach of the patients that need them.

Related content

On 13 September 2023, two of our experts in life sciences transactions, partners Claire Smith and Ellen Lambrix, navigated some of the key issues in cell and gene licensing deals.

In the Lexology-hosted webinar, Claire and Ellen considered the points from both a licensor’s and a licensee’s perspective – taking into account the complex IP landscape, the non-traditional routes to market for these therapies and the innovative payment models that are increasingly being agreed downstream with healthcare providers (owing to the high cost of treatments) – and the impact that these factors have on core licensing provisions, such as the licence grant and milestone and royalty payments.

Watch the recording below:


[1] CAT quarterly highlights and approved ATMPs

[2] Bluebird bio Community Update

[3] Vertex teases launch plans for first CRISPR gene editing therapy ahead of FDA decision

[4] NHS England strikes deal on life-saving gene-therapy drug that can help babies with rare genetic disease move and walk

[5] PB2339: Projected lifetime economic burden of transfusion dependent Beta-Thalassemia in the United States

[6] The Cellular And Gene Therapy Pipeline Predicament: A Health Insurer’s Perspective

[7] CRISPR Clinical Trials: A 2022 Update