Editing gene biology and reproductive genetic biotechnology as a 3D illustration.
Gene therapies hold promise for treating a wide range of diseases. Innovative companies such as bluebird bio and BioMarin are at the forefront of clinical development. Yet, firms face numerous challenges, in all phases, from pre-clinical through Phase 3. Furthermore, what is sometimes underappreciated is the fact that even when gene therapies obtain marketing authorization, they’re still often hampered by substantial delays between their date of approval and the time they launch. And it isn’t simply a matter of not having a payment or reimbursement system in place. Manufacturing and patient preparation delays figure prominently, too.
Reviewing the history of recently approved gene therapies, one often finds significant delays.
BioMarin’s Roctavian
In Europe, for example, BioMarin hasn’t yet infused a patient with Roctavian (valoctocogene roxaparvovec), which in August 2022 won approval from the European Medicines Agency (EMA) as a single-dose treatment for hemophilia A. Specifically, the EMA granted conditional marketing authorization to Roctavian for the treatment of severe hemophilia A (congenital Factor VIII deficiency) in adult patients without a history of Factor VIII inhibitors and without detectable antibodies to adeno-associated virus serotype 5 (AAV5). Roctavian’s price is expected to be around €1.5 million.
While analysts estimate 9,000 patients could be eligible for Roctavian in the European Union, thus far only 18 patients have had their AAV5 antibody status tested in Germany to determine if they are eligible Roctavian dosing. This follows BioMarin securing its first reimbursement deal in Germany.
BioMarin hopes to infuse its first commercial patient with Roctavian in the second quarter of 2023, nearly eight months after approval.
CSL Behring’s Hemgenix
In November 2022, CSL Behring gained Food and Drug Administration (FDA) approval for Hemgenix (etranacogene dezaparvovec) as a one-time gene therapy for certain hemophilia B patients. Tthe FDA awarded marketing authorization to Hemgenix for adults with hemophilia B (congenital Factor IX deficiency), who currently use Factor IX prophylaxis therapy, or have present or past life-threatening hemorrhage, or have repeated, serious spontaneous bleeding episodes. Hemgenix has a list price of $3.5 million.
As of April, CSL Behring hasn’t publicly announced that a hemophilia B patient has been infused, though patient preparation appears to be underway as a prelude to launch.
Bluebird bio’s Zynteglo and Skysona
Despite bluebird bio nabbing an approval for Zynteglo (betibeglogene autotemcel) in August of last year, it doesn’t appear that any beta thalassemia patient has been infused with the product. Though, as of the 29th of March, several beta thalassemia patients have entered the apheresis process (extraction of cells for modification via gene therapy). For Zynteglo, it’s estimated that there is a 70-90 day period between cell harvesting and treatment.
Bluebird bio’s Skysona (elivaldogene autotemcel) was approved in September of last year. Yet, as of late March, only two cerebral adrenoleukodystrophy patients have had their cells harvested, while one patient was treated with the gene therapy at Boston Children’s Hospital. For Skysona, it’s estimated that there is a 55-60 day period between cell harvesting and treatment.
Manufacturing hurdles
It’s quite the understatement to say that the commercialization of gene therapies is difficult. As a rule, gene therapies face steeper challenges at launch than traditional small and large molecule drugs and biologics do, which can limit their early adoption.
Market access hurdles are well-documented. The current payer system is not particularly well suited to accommodate single-dose therapies for which long-term treatment efficacy, risk–benefit ratios, and safety remain uncertain.
But equally important, patients face a highly complex and costly path to treatment, which includes the problem of relatively few and widely dispersed healthcare sites, and the need for extensive testing and preparation. Additionally, companies can face considerable supply chain, manufacturing, and distribution challenges in the effort to ensure just-in-time doses are available when and where they are needed.
The ever-increasing number of gene therapy candidates in the pipeline, along with a growing portfolio of new approvals, are stretching manufacturing capacity to its limits. Numerous reports indicate the gene therapy sector of the biopharmaceutical industry is experiencing a serious “capacity crunch.”
In the coming years, there is potential for acute shortages of manufacturing capacity, particularly at commercial scale of production. BioPlan, a leading source of independent strategic information and analysis for the life sciences industry, suggests that there is a 500% shortage of cell and gene therapy manufacturing capacity, meaning that five times the current capacity would likely be used if it were available.
In some cases, this is limiting the potential of approved products to launch on time, or, when launched, attain rapid uptake. In many others, it is slowing the development of products in the pipeline. These operational challenges can be just as impactful to growth as limited R&D funding, regulatory clinical holds, and market access hurdles.
Recently, manufacturing constraints have been reported for the CAR-T cell and gene therapy Carvykti during its ongoing U.S. launch. In Britain, Carvykti won’t launch for now. It appears that manufacturing issues are to blame. J&J’s Janssen has decided to withdraw the product from a reimbursement assessment that was going to be carried out by the National Institute for Clinical Health and Excellence.
Launch and commercialization of gene therapies isn’t easy. As Courtney Rice, Principal at Acadia Strategy Partners, says “gene therapies don’t sell themselves.” Besides the much talked about reimbursement issues, the cost and logistical complexity involved in standing up manufacturing at scale and administering a network of treatment centers is easy to underestimate.
The small and large molecule playbook, with launches that occur very soon after approval, isn’t easily applicable to gene therapies. So far, delay, or at least a launch pause, is the norm.