On 17 August 2022, the USA's FDA announced that it had approved Zynteglo (betibeglogene autotemcel) for use in patients with transfusion-dependent beta-thalassemia (TDT).

This follows a priority review, fast track, and breakthrough therapy designations from the FDA. TDT is estimated to impact approximately 1 in 100,000 people within the general population, and is particularly prevalent in the Mediterranean, Middle East, Africa, central Asia, the Indian subcontinent, and the Far East, according to NORD’s rare disease database.

Zynteglo is a cell-based gene therapy which works to introduce a functional beta-globin gene to the patient’s blood cells. The therapy is the first of its kind to be approved for TDT and is intended to be curative with a single dose. Indeed, BlueBird Bio has stated that “89% (34/38) of evaluable patients in Phase 3 beti-cel studies achieved transfusion independence, which is defined as no longer needing RBC transfusions for at least 12 months while maintaining a weighted average Hb of at least 9 g/dL”.

How cost-effective is Zynteglo when compared to the current standard-of-care (SOC)?

Currently, patients with beta-thalassemia have two treatment options; either they received a stem cell transplant from a matched donor or receive regular blood transfusions (transfusion dependent patients). As a result, the disease has a major impact on a patient's quality of life.

Currently it is estimated that the lifetime cost of care for patients with TDT in the USA is $5.4 million. This accounts for 686 blood transfusions over the course of 39 years. Iron chelation therapy accounted for 68% of costs, while blood transfusions accounted for 30% of costs.

Zynteglo is to be marketed at a wholesale acquisition cost of $2.8 million in the USA. This is above the previously suggested price of $2.1 million by Bluebird Bio, a price that the USA's Institute for Clinical and Economic Review (ICER) found would meet commonly accepted value thresholds.

To mitigate the risk for payers facing such a high cost for the therapy, Bluebird Bio is offering an outcomes-based reimbursement model. The drug will be paid for in a single up-front payment and the payer will be refunded up to 80% of the cost of the therapy if the patient does not achieve and maintain transfusion independence up to two years following infusion.

Will Zynteglo be reimbursed in the European Market?

FDA approval of Zynteglo marks a promising step forward for innovation in rare diseases. However, this is not the first time that Zynteglo has received regulatory approval. On 29 May 2019, Zynteglo received conditional marketing authorisation from the European Commission following a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA). Zynteglo was approved as part of the EMA’s PRIME (priority medicines) and Adaptive Pathways programmes, and as such, received a swift approval.

Bluebird Bio priced Zynteglo at $1.8 million in Europe and offered a value-based pricing agreement which spread the cost of the treatment over five equal yearly payments, contingent on transfusion independence. However, issues arose when it came to communication between Bluebird Bio and regulators in each country. In a press release on 9 August 2021, Bluebird Bio said that it would be winding down its operations in Europe, citing “challenges of achieving appropriate value recognition and market access in Europe”. The company added that “European payers have not yet evolved their approach to gene therapy in a way that can recognize the innovation and the expected life-long benefit of these products.” Bluebird had previously removed Zynteglo from the German market after it was unable to reach a price.

What does this mean for emerging ATMPs in the European Market?

The impasse between Bluebird Bio and European stakeholders is a negative indicator for biotech companies anticipating a launch of similar products in Europe. Indeed, there are inherent issues associated with the reimbursement of innovative, high-priced medicines targeting rare diseases. In the case of Zynteglo, one example is that evidence of the durability of the treatment is not yet mature. There is an ongoing Phase III LTF-303 study which is assessing patients who have received Zynteglo, for up to 13 years. However, data collection is ongoing and the long-term consequences of Zynteglo are uncertain. There is a theoretical risk of hematological malignancies with Zynteglo, and patients must have their blood monitored for at least 15 years post-infusion.

Nevertheless, as the clinical pipeline is becoming more saturated with similar products, regulators within the European market must keep pace with innovation to ensure that patients with a high-level of unmet need are able to access the most promising treatments. It is worth noting that, although a specific rare disease affects few people, approximately 1 in 10 people in the United States are affected by the roughly 7,000 documented diseases.

Schemes to ensure faster access within Europe and its individual constituents do exist. The UK, for example, has the Innovative Medicines Fund to facilitate managed access agreements for approved drugs designed to treat rare diseases. Across Europe, the Innovative Medicines Initiative has been implemented with the aim of improving access to novel medicines across geographies. The European Federation of Pharmaceutical Industries and Associations (EFPIA) and The Association Of The British Pharmaceutical Industry (ABPI) also exist to power initiatives to promote faster and improved access to innovative medicines.

The structure of the USA's healthcare system does allow for a more flexible approach to risk, given the absence of formal regulation on prescription drug prices. Nevertheless, to soften the blow of upfront payments for payers, certain pharmacy benefit managers may offer payment plans. CVS Health, for example, have financial protection programmes which include a stop-loss policy and installment payment plan.

Conversely, only patients whose insurers cover the therapy will be eligible to receive it. This could pose as a substantial limiting factor if insurance formulary inclusion is limited. Additionally, Zynteglo is available only in Qualified Treatment Centres (QTCs) in the USA. Within such centres, administrators will be trained specifically to administer Zynteglo. The number and distribution of QTCs has yet to be revealed by Bluebird Bio.

Overall, the potential that gene therapies offer for patients with rare diseases is substantial. However, the European market has yet to identify feasible solutions to the risks posed by the reimbursement of such therapies.