The age of gene editing: The first EMA approval of a CRISPR-CAS9 medicine for beta thalassaemia and sickle cell disease

by | May 10, 2024 | Executive Summary


  • Overview of the Casgevy approval by the European Medicines Agency (EMA).
  • Summary of the pivotal Casgevy trials.
  • Specific regulatory support Casgevy received from the EMA.
  • Wider regulatory considerations for gene-editing medicines.

Casgevy approval – the first Gene Editing Medicinal Product

The first gene-editing medicinal product (GEMP) has been approved by the European Medicines Agency (EMA).

Casgevy (exagamglogene autotemcel) received a conditional marketing authorisation (CMA) for the treatment of beta thalassaemia and sickle cell disease in the following settings:1

  • Transfusion-dependent β-thalassemia (TDT) in patients 12 years of age and older for whom haematopoietic stem cell (HSC) transplantation is appropriate and a human leukocyte antigen (HLA)-matched related HSC donor is not available. 
  • Severe sickle cell disease (SCD) in patients 12 years of age and older with recurrent vaso-occlusive crises (VOCs) for whom haematopoietic stem cell (HSC) transplantation is appropriate and a human leukocyte antigen (HLA)-matched related HSC donor is not available.

Full myeloablative conditioning must be administered before infusion of Casgevy.

The approval was based on the interim results of two ongoing studies and a follow-on 15-year registry-based study to monitor its long-term safety profile.1

Highlights from Casgevy’s pivotal studies

Study 111

In the registrational study for patients with beta-thalassemia, 42 patients aged between 12 and 35 years were given one dose of Casgevy. Of the 42 patients, 39 maintained haemoglobin levels above 9 g/dL and did not need to undergo blood transfusions for 12 months (see Table 1 for more details on the 111 study).1

Study 121

In the registrational study for patients with sickle cell disease (SCD), 29  patients between the ages of 12 and 35 years received one dose of Casgevy. Of the 29 patients, 28 went 12 months without any painful crises and all 29  were able to avoid hospitalisation for painful crises for 12 months (see Table 1 for more details on the 121 study).1

Table 1 – overview of pivotal studies for Casgevy1

StudyConditionDesignPrimary EndpointResults
111Transfusion-dependent β-ThalassemiaSingle-arm, open-label, multi-site, single dose, Phase 1/2/3 study in subjects 12 to 35 years of ageProportion of subjects who achieved TI12, defined as maintained weighted average Hb ≥9 g/dL without red blood cell (RBC) transfusions for at least 12 consecutive months any time after Casgevy infusion.42 patients received a single dose.

Number of patients who reached T112: n=39; CI (80.5, 98.5).

P= <0.0001 P-value (1-sided against a 50% response rate.
121Severe sickle cell diseaseSingle-arm, open-label, multi-site, single-dose, Phase 1/2/3 study in subjects 12 to 35 years of age (inclusive)Proportion of subjects who achieved VF12, defined as absence of any severe(VOC) for at least 12 consecutive months after Casgevy infusion.29 patients received a single dose.

VF12: n=28; CI (82.2%, 99.9%)

P= <0.0001 P-value (1-sided against a 50% response rate).
131β-thalassemia or Sickle Cell Disease Treated with Autologous CRISPR-Cas9open-label, rollover study designed to evaluate the long-term safety and efficacy of exa-cel in subjects who received exa-cel in a parent study, completed or discontinued said parent study, and are followed in study 131 for a total follow-up of 15 years after exa-cel infusion.

Special EMA regulatory pathways for Casgevy

Due to its novel therapeutic and developmental nature – with potential for benefit to patients – Casgevy received extra support from the EMA through the PRIME scheme. Casgevy also satisfied the criteria for CMA.


Casgevy was deemed eligible for the EMA’s PRIority MEdicines (PRIME) scheme in 2020 for treating sickle cell disease.1 PRIME offers medicine developers early and enhanced support which is tailored to the relevant stages of development. A key benefit of being eligible for the PRIME scheme is that it enables medicines to go through accelerated assessment. Medicine developers are appointed rapporteurs early. They are also offered a kick-off meeting with a multi-disciplinary team of experts from the EMA, to receive scientific advice at any stage of development, particularly at major development milestones.

Another benefit of PRIME is that medicine developers can begin discussions with important stakeholders including health technology assessment (HTA) organisations earlier in development, too.


At the time of filing the MAA, the sponsor is required to submit an orphan maintenance report, demonstrating that orphan criteria are still met, to maintain the designation.

As sickle cell disease and beta-thalassemia are considered rare diseases, Casgevy was granted orphan drug designation (ODD) and was also able to maintain ODD when the CMA was granted.

Orphan conditions Casgevy met at the time of CMA:1

  • Both diseases affect fewer than 5 in 10,000 people,
  • both conditions are seriously debilitating and life-threatening, and
  • Casgevy was considered to be of significant therapeutic benefit, when compared to existing therapies.

Protocol Assistance

Protocol assistance (scientific advice) was taken for Casgevy on several occasions, concerning the following important development aspects:1

  • The adequacy of the non-clinical package.
  • The proposed primary and secondary efficacy endpoints in support of both indications.
  • The use of the efficacy and safety data to support the benefit/risk profile in both indications.
  • The proposed registry-based study to evaluate long-term safety and effectiveness of Casgevy.
  • Comparability strategy and approach to establishing the commercial drug product release specification.
  • Adequacy of the planned genomics package to assess the potential for off-target editing.


Conditional marketing authorisations are considered relevant when the medicinal product in question addresses an unmet clinical need or is developed in the interest of public health. The caveat is that the data collected to support an approval aren’t comprehensive enough to warrant a full MA. Therefore, conditional approval is based on the benefit of the medicinal product being immediately available outweighing the risk that additional data are needed. At the time of the CMA, efficacy was based on interim data from ongoing, single-arm, open-label trials with limited patient numbers. Comprehensive data will be provided from the ongoing and future planned post-authorisation studies – including a registry study.

The wider regulatory landscape for gene-editing therapies

The increasing presence of gene-editing medicinal products (GEMPs) in development marks a shift in the way regulatory authorities evaluate novel medicines. A recent paper from Tavridou et al., 2024, summarised the insights the EMA has gained so far from 16 Scientific Advice (SA) procedures conducted with companies developing CRISPR products and other GEMPs between 2019 and 2022.2

Tavridou et al. recognised that there is limited scientific guidance available to encompass GEMP development. However, regulatory authorities are learning from the recent Casgevy approval and numerous GEMP products currently in development, to gain insights into how these novel therapies will shape future regulatory frameworks.2

A major theme that emerged from the Tavridou et al paper related to the need for GEMP developers to seek SA early in development to discuss GEMP-specific implications; specifically, its potential for off-target toxicity effects; characterisation and control of starting materials, and distinguishing in vivo vs ex vivo editing.2

Such considerations warrant early discussion with regulatory agencies as the quality and non-clinical aspects of GEMP development are closely associated with the clinical safety and efficacy of these novel medicines. In particular, the risk of off-target effects of GEMPs, which are confounded by the fact that currently there are no analytical methods to assess potential gene editing errors.2

From a clinical perspective, Tavridou et al., highlighted the benefit of SA to discuss the best clinical trial designs for first-in-human or pivotal trials. GEMPs are being developed predominantly for rare diseases, therefore determining heterogeneity of patients included in trials, as well as adequate long-term follow-up studies to assess efficacy and safety must be properly assessed.


The therapeutic landscape is changing. Casgevy marks the first approval for a CRISPR-cas9 medicine in Europe and there are several other GEMPs currently in development including zinc finger nucleases, transcription activator-like effector nucleases (TALENs), editors and prime editors.2 The question therefore becomes: is the current scientific guidance and regulatory evaluation able to keep up with this shift in medicine development?

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Nicole Brooks, Regulatory Consultant / Copywriter


1: European Medicines Agency (2024). Casgevy Assessment Report. EMA/6332/2024 Committee for Medicinal Products for Human Use (CHMP). Procedure number: EMEA/H/C/005763/0000. Available from:

2: Tavridou A, Rogers D, Farinelli G, Gravanis I, Jekerle V. (2024). Genome-editing medicinal products: the EMA perspective. Nat Rev Drug Discov. 23(4):242–3. Available from: