Navigating a Novel Therapy Frontier: Gene Therapy's Stunted Impact on Leukodystrophies


CGTLive takes a look at the path gene therapies have blazed in leukodystrophies, the challenges they’ve faced, and the road they’ve paved.

Leukodystrophies are a group of inherited neurological disorders in which genetic mutations affect the myelin sheath, and are categorized as rare diseases, with a prevalence of around 1 in 7000 live births. Researchers have identified more than 50 types of leukodystrophies, with some common types including adrenoleukodystrophy (ALD), metachromatic leukodystrophy (MLD), Krabbe disease or globoid cell leukodystrophy, and Canavan disease.1

Despite their rarity, leukodystrophies are a prime target for gene therapy as most affected patients have a single gene mutation responsible for the disease phenotype. Substantial progress has been made in the field, with 2 gene therapies approved for leukodystrophies in the United States (US) in 2022 and 2024: bluebird bio’s elivaldogene autotemcel (eli-cel/Skysona) for cerebral ALD and Orchard Therapeutics’ atidarsagene autotemcel (arsa-cel/Lenmeldy) for early-onset MLD.2,3

Prohibitive Pricing

Leukodystrophy gene threrapy timelines post-approval

(Click to expand)

Although these leukodystrophy gene therapy approvals have enriched the market in the United States, the same access to these products cannot be found in Europe, where price negotiations and reimbursement agreements have struggled to reckon with prohibitively high price tags—eli-cel is available for $3 million and arsa-cel for $4.25 million in the US. The US approval of eli-cel followed its 2021 approval by the European Medicines Agency, however, by the end of the year, bluebird announced that it was withdrawing its European Union (EU) marketing authorization along with its United Kingdom (UK) filing for the therapy following price disputes in Germany with another approved but now unavailable for the European market gene therapy product, betibeglogene autotemcel (Zynteglo), making eli-cel only available in the US.4

Arsa-cel has been approved under the name Libmeldy in the European Union, United Kingdom, Iceland, Liechtenstein, and Norway since in 2020. The therapy nearly followed the same path as eli-cel in Europe, although the agencies finally came to an agreement after years of price negotiations, the latest of which only concluded early in 2024.5 Although approved for use in all 27 member states of the EU, arsa-cel is permanently reimbursed in only 116 (FIGURE 1).

Alessandro Aiutti, MD, PhD, deputy director, clinical research, and head, Clinical Research Unit, San Raffaele Telethon Institute for Gene Therapy, and Group leader, Pathogenesis and therapy, primary immunodeficiencies unit, and full professor, Università Vita Salute San Raffaele, and chief of clinic, Pediatric Immunohematology Unit, San Raffaele

Alessandro Aiutti, MD, PhD

Credit: San Raffaele

“These therapies are complex and production is expensive. The research and development is long and complex, because these are personalized treatments... But these also are treatments that are given once and they're potentially curative. So, it will be really important in the future to reduce the cost associated with the manufacturing, the cost associated with the development. But these types of treatments are potentially breakthroughs. So, we really need to find a balance between moving further with research and accessibility of these new treatments to patients,” Alessandro Aiutti, MD, PhD, the deputy director of clinical research and head of the Clinical Research Unit at San Raffaele Telethon Institute for Gene Therapy, the group leader of Pathogenesis and therapy within the primary immunodeficiencies unit, and a full professor at the Università Vita-Salute San Raffaele, as well as the chief of clinic at the Pediatric Immunohematology Unit of San Raffaele, told CGTLive®.

A Necessary Limited Distribution

Arsa-cel is available under a limited distribution model that includes 5 centers of excellence trained as qualified treatment centers (QTCs) across Europe. Aiutti was involved with clinical trial investigations for the therapy at San Raffaele, which is now a QTC for administering the therapy. 

Orchard is planning to implement arsa-cel's rollout in the US under a similar limited distribution model, with 5 QTCs administering the therapy in the country. As of March 2024, the M Health Fairview Masonic Children’s Hospital in Minnesota is in the final stages of qualification, and Children’s Healthcare of Atlanta, Children's Hospital of Philadelphia, Texas Children’s Hospital, and UCSF Benioff Children’s Hospital San Francisco are in the qualification process.7

Madeleine Powys, MBBS, Children's Hospital at Westmead, Sydney

Madeleine Powys, MBBS

Credit: Research Gate

“These are rare diseases, it's important that you have centers of excellence that are QTCs where there's expertise from both a clinical perspective, but also a nursing, laboratory perspective. We have key relationships with the manufacturing laboratory, and also, of course, the sponsors. That's been really important in the onboarding of this product at our hospital,” Madeleine Powys, MBBS, a former locum consultant of pediatric BMT and leukemia at Royal Manchester Children’s Hospital (RMCH), now at Children's Hospital at Westmead, in Sydney, Australia, told CGTLive about her experience with Libmeldy at RMCH. “So, there's been an enormous amount of effort put into the training of the staff—the clinical staff, the laboratory staff, and our nursing staff—on the various complex steps that need to occur to make sure that the product is safely collected, manufactured and delivered into our patients.”

Expanding Newborn Screening

ALD and MLD, like many other leukodystrophies, primarily affect infants and young children, creating an extremely time-sensitive environment for gene therapies to have the most effect, similar to approved gene therapy onasemnogene abeparvovec-xioi (Zolgensma) for spinal muscular atrophy (SMA). Such conditions necessitate newborn screening to identify patients and administer gene therapy sooner and may lead to more clinical benefit, as such is the case of Zolgensma, wherein treated children with presymptomatic SMA were found to achieve age-appropriate motor milestones.8 Notably, MLD has not yet joined X-linked adrenoleukodystrophy on the US Recommended Uniform Screening Panel (RUSP).9

"With lentiviral therapies, you have to harvest the bone marrow of a baby. If the disease starts really early, the earliest they can get into the baby is like 5 to 6 months,” Maria Escolar, MD, the chief medical officer of Forge Biologics, told CGTLive. Forge is developing gene therapy FBX-101 to be infused intravenously after hematopoietic stem cell transplant in children with Krabbe disease. Krabbe was added to the RUSP in February 2024.10

Maria Escolar, MD, chief medical officer, Forge Biologics

Maria Escolar, MD

Credit: Forge Biologics

Fast identification of patients is made especially important when manufacturing of ex vivo gene therapy takes weeks—both arsa-cel and eli-cel are autologous, lentiviral, ex-vivo gene therapies. For reference, bluebird stated in January 2023 that the average time for manufacturing and release of arsa-cel was 44 days.11

“[Newborn screening] is super important because the transplant only works when you're presymptomatic. So, if those babies get identified, we want them to get the transplant, hopefully, in the first month of life. And then those babies could then get gene therapy, and many [can be helped]... We hope that these babies get referred very quickly so that we can prevent both the damage in the brain and, in the future, also prevent the peripheral nerve disease,” Escolar said.

Looking Ahead for Leukodystrophy Gene Therapies

Besides FBX-101, a number of gene therapies are in development for other leukodystrophies. These include gene therapy programs for Canavan disease by Aspa Bio, a subsidiary of BridgeBio Pharma, and Myrtelle, and SwanBio Therapeutics’ gene therapy program for adrenomyeloneuropathy, the milder, adult form of ALD.

These therapies are all currently being evaluated in recruiting phase 1/2 trials: these are Aspa’s CANaspire trial (NCT04998396) of BBP-812, Myrtelle’s trial of rAAV-Olig001-ASPA, and SwanBio’s PROPEL trial (NCT05394064) of SBT-101. FBX-101 is similarly being evaluated in the currently recruiting REKLAIM phase 1/2 trial (NCT05739643). These gene therapies have all shown some promise so far to show a benefit for patients with leukodystrophies and hope to face a smoother path to approval and market than paved by trailblazers eli-cel and arsa-cel.

1. Leukodystrophy. Webpage. Cleveland Clinic. June 3, 2021.
2. bluebird bio Receives FDA Accelerated Approval for SKYSONA® Gene Therapy for Early, Active Cerebral Adrenoleukodystrophy (CALD). News release. bluebird bio. September 16, 2022.
3. FDA Approves First Gene Therapy for Children with Metachromatic Leukodystrophy. News release. Orchard Therapeutics. March 18, 2024. Accessed March 18, 2024.
4. bluebird bio. Form 8-K. October 21, 2021.
5. NHS in yet another negotiated discounted deal for game-changing Libmeldy drug. News coverage. March 11, 2022.
6.Beneluxa Initiative announces successful conclusion of Libmeldy price negotiations, directly benefiting patients in three countries. News release. Beneluxa. January 2024.
7. Orchard Therapeutics Outlines U.S. Launch Plans for Lenmeldy™ (atidarsageneautotemcel), the Only Approved Therapy for Children with Early-onset Metachromatic Leukodystrophy. News release. Orchard Therapeutics. March 20, 2024.
8. Strauss KA, Farrar MA, Muntoni F, et al. Onasemnogeneabeparvovec for presymptomatic infants with two copies of SMN2 at risk for spinal muscular atrophy type 1: the Phase III SPR1NT trial. Nature Medicine. Published online June 17, 2022. doi10.1038/s41591-022-01866-4
9. Recommended Uniform Screening Panel. Webpage. Health Resources & Services Administration. August 2023.
10. U.S. panel adds rare brain disease to newborn screening list, after push from families. News article. Quinn Eastman. Science. February 2, 2024. Accessed May 22, 2024.
11. Orchard Therapeutics Highlights Recent Progress Across HSC Gene Therapy Portfolio and Outlines Key 2023 Milestones. News release. Orchard Therapeutics. January 9, 2023.
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