EU Hat Trick For Bluebird’s Beta-Thalassemia Gene Therapy
Executive Summary
bluebird bio is set to enter the EU market with the first gene therapy for transfusion-dependent β-thalassemia, after the European Medicines Agency reviewed its product in record time. Bluebird believes that the agency’s Priority Medicines (PRIME) and adaptive pathways programs have been instrumental in smoothing its path.
bluebird bio has scored a series of firsts with its life-changing beta-thalassemia gene therapy, Zynteglo, after the European Medicines Agency today recommended that the product should be marketed in the EU.
Zynteglo, formerly referred to as LentiGlobin, is the first gene therapy recommended for approval in the EU for transfusion-dependent β-thalassemia (TDT). According to the EMA, it underwent the fastest ever review for an advanced therapy medicinal product (ATMP) at the agency – taking 150 days of active review time under the EU’s accelerated assessment pathway. Finally, this is the first gene therapy that the small US biotech company has submitted for regulatory approval.
The EMA’s human medicines committee, the CHMP, adopted a positive opinion for a conditional marketing authorization for Zynteglo at its March meeting, which took place this week. The marketing authorization application for bluebird’s gene therapy – the company’s lead product – was the only MAA up for an opinion at the meeting. (Also see "LentiGlobin Hogs The Limelight At CHMP’s First Amsterdam Meeting" - Pink Sheet, 25 Mar, 2019.)
bluebird CEO Nick Leschly said the company was “beyond impressed” with the EMA and its staff and the process it had run.
The committee’s verdict on Zynteglo came as no surprise. Bluebird’s thunder was well and truly stolen when the UK Thalassaemia Society and the Italian Associazione Veneta Lotta alla Talassemia put out a joint statement late on March 25 saying the product had been approved. The move forced bluebird to issue a statement stressing that “no opinion had yet been issued by the CHMP.” (Also see "Bluebird’s Gene Therapy LentiGlobin Coming Into Land In The EU?" - Scrip, 26 Mar, 2019.)
Also at the meeting, the CHMP’s first in Amsterdam after moving from London earlier this month, there were three positive opinions on therapeutic indication extension requests. They relate to two Celgene products used in the treatment of myeloma – Revlimid (lenalidomide) and Imnovid (pomalidomide) – and Genzyme’s stem-cell mobiliser, Mozobil (plerixafor).
The CHMP recommendations will now be sent to the European Commission, which has 67 days to take a legally binding decision valid throughout the EU.
Life-Changing Treatment For TDT
Zynteglo (autologous CD34+ cells encoding βA-T87Q-globin gene) is a one-time gene therapy that is expected to dramatically change the course of TDT and the health and quality of lives of patients with the disease. The goal of the treatment is to enable patients with TDT to produce hemoglobin at sufficient levels to allow lifelong independence from blood transfusion.
The present management of TDT, including regular blood transfusions every two to four weeks and daily iron chelation therapy, can have many psychological and social consequences. Also, in many patients TDT-related morbidities can lead to a shortened life span.
Zynteglo adds functional copies of a modified β-globin gene into a patient’s own stem cells, thereby addressing the underlying genetic cause of the disease. The CHMP’s positive opinion covers the product’s use in adult and adolescent patients 12 years and older who do not have a β0/β0 genotype and who need regular blood transfusions to manage their disease and have no matching donor for a stem cell transplant.
Speed Of Review
The speed at which the CHMP reviewed the MAA for Zynteglo is largely thanks to bluebird having secured a place on the EMA’s Priority Medicines (PRIME) scheme in 2016. Under PRIME, developers of drugs for unmet needs are offered enhanced scientific and regulatory support from the EMA and the likelihood of having their product reviewed under the accelerated assessment procedure. The fast-track mechanism can cut the time it takes the EMA to evaluate an MAA from up to 210 days to up to 150 days (not counting clock stops when applicants have to provide additional information). The company filed its MAA in early October 2018.
As for the EMA, it said its interactions with the company under the scheme “led to a more robust application package to demonstrate the medicine’s benefits and risks, which allowed accelerated assessment of Zynteglo in 150 days, the fastest advanced-therapy medicinal product (ATMP) review time to date.”
The average review time for ATMPs “is normally close to 210 days active review time,” excluding the time taken by the applicant to respond to the questions from the CHMP, the EMA told the Pink Sheet. The CHMP’s next fastest review for an ATMP was for Novartis’s CAR T-cell therapy, Kymriah (tisagenlecleucel), which was reviewed in 172 days (active review time, not including clock stops).* There are currently 15 investigational ATMPs in the PRIME scheme.
Zynteglo had also been accepted onto another program the EMA has been testing to improve timely access for patients to new medicines, adaptive pathways.
The review process was “incredibly efficient”, bluebird's Leschly told the Pink Sheet. “[The EMA had] great questions, actually really informative questions, very reasonable questions. I wouldn’t say it was enjoyable because this is always very hard work and very taxing and stressful and it’s nerve-wracking but at the end of the day we certainly feel a lot stronger for it and I have to say very impressed with EMA and look forward to continuing to work with them on our subsequent products.”
More Data Still Needed
The positive CHMP opinion was supported by efficacy, safety and durability data from bluebird’s Phase 1/2 HGB-205 study and the completed Phase 1/2 Northstar (HGB-204) study as well as available data from the ongoing Phase 3 Northstar-2 (HGB-207) and Northstar-3 (HGB-212) studies, and the long-term follow-up study LTF-303.
Conditional marketing authorizations (CMAs) are granted for products with less complete data than normally expected, in cases where the benefit of a medicine being made immediately available to patients outweighs the risk inherent in the fact that not all the data are yet available. CMA holders are required to complete specific obligations (ongoing or new studies, and in some cases additional activities) with a view to providing comprehensive data confirming that the benefit-risk balance is positive. Once comprehensive data on the product have been obtained, the CMA may be converted into a standard MA.
US Filing And Manufacturing
Whereas bluebird’s US filing will be based on data from the company’s all-new manufacturing process, the EMA looked at data from the old manufacturing process as well as the new.
Leschly said. “That’s what’s actually been great about the European agency’s willingness to say, ‘hey we know the lion’s share of the data came out of your two original studies’ but in parallel we have been running the study with the new manufacturing process and they were very gracious in saying ‘listen, get as much data as you have on that to show that it is indeed working in the way we hope that it is’.”
“Nobody wants a drug out there if it’s not the best drug for patients," the bluebird CEO continued. “The EMA saw that early data as part of the review process and so this is approval of the new manufacturing process. That’s a lot easier from our perspective because you don’t want two separate supply chains. This is all good news and certainly will also be considered as the US filing starts to kick into gear.”
The first European sales are likely to be in Germany by the end of the year. (Also see "Bluebird Bio's Zynteglo Flies Through Its CHMP Review " - Scrip, 29 Mar, 2019.)
*This article was updated on April 1 to include a comment from the European Medicines Agency on the time it took to review the ATMP Kymriah.
Additional reporting from Alexandra Shimmings.
From the editors of Scrip Regulatory Affairs.