A new gene therapy for the fatal genetic disorder metachromatic leukodystrophy, or MLD, will carry a wholesale price of a whopping $4.25m, its manufacturer announced last week as the FDA approved what is now the world’s most expensive medicine.
Lenmeldy is the first therapy for the rare and devastating paediatric neuron disease that typically kills affected children before they turn seven
About 40 children are born with MLD in the US each year, reports CNN.
The treatment, atidarsagene autotemcelo (arsa-cel; Lenmeldy), is the first to treat children with the rare pre-symptomatic late infantile, pre-symptomatic early juvenile, or early symptomatic early juvenile MLD, the agency said.
MLD is caused by a mutation in the ARSA gene that results in sulfatides accumulating in the central nervous system and peripheral nervous system, leading to progressive dysmyelination, neuroinflammation and neurodegeneration.
Medpage Today reports that this causes loss of motor and cognitive functions and, ultimately, death. There is no cure for the disease.
MLD has three variants, depending on age at first symptom onset: late infantile (younger than 30 months); juvenile, which is subdivided into early juvenile (30 months to six years) and late juvenile (seven to 16 years); and adult (17 and older).
Earlier age or the presence of motor symptoms at onset are associated with a more severe, rapid disease course.
Lenmeldy/Arsa-cel, a one-time single-dose infusion, is made from a patient’s haematopoietic stem cells that have been modified to include functional copies of the ARSA gene.
The repaired cells are then infused back to the patient, where they begin to produce an enzyme that’s lacking in children with the disease.
Some of the cells eventually migrate to the bone marrow, where they continue to live and make new cells that also make the enzyme, providing a long-lasting benefit to patients.
The safety and effectiveness of arsa-cel were based on data from 37 children who received treatment in two single-arm, open-label clinical trials and in an expanded access programme in Milan. Children who received arsa-cel were compared with natural history data.
Arsa-cel significantly reduced the risk of severe motor impairment or death compared with no treatment. All children with pre-symptomatic late infantile MLD who received treatment were alive at six years, compared with 58% of children in the natural history group.
At five years of age, 71% of treated children could walk without assistance, and 85% had normal language and performance IQ scores, which had not been reported in untreated children, the FDA said.
Children with pre-symptomatic early juvenile and early symptomatic early juvenile MLD also showed slowing of motor or cognitive decline.
One-time treatment with arsa-cel showed the potential to restore enzymatic function to stop or slow disease progression with up to 12 years of follow-up (median 6.76 years), drug maker Orchard Therapeutics said.
The most common adverse events were fever, low white blood cell count, mouth sores, respiratory infections, rash, medical line infections, viral infections, gastrointestinal infections, and enlarged liver.
Arsa-cel treatment may be associated with blood clots or encephalitis, the FDA cautioned, and there is a potential risk of blood cancer associated with treatment, although no cases have been seen.
“Patients receiving this product should have lifelong monitoring for haematologic malignancies, including a complete blood count (with differential) annually and integration site analysis, as warranted, for at least 15 years after treatment, the agency said.
Makers recoup outlay
Manufacturers of gene therapies say the big prices reflect big benefits – the chance to be free of a disabling or even fatal disease – and they need to be able to recoup the steep costs of development, testing and manufacturing their products.
But health policy experts say that with the growing list of gene and cell therapies with exorbitant prices, it may strain the ability of states and other insurers to cover their costs, and ultimately limit patient access if plans begin to exclude the therapies as a class from coverage.
Dr Bobby Gaspar, co-founder and CEO of Orchard Therapeutics, called the treatment “paradigm-shifting medicine with the potential to stop or slow the progression of this devastating childhood disease with a single treatment”.
Price of hope
The first patients treated with Lenmeldy have now been followed for more than 12 years, and researchers continue to find gene-modified cells making the missing enzyme, he said.
“We can’t say that this will last a lifetime, but what we can say is that there is a long-term durable effect.”
MLD is an inherited disorder, and children born with it lack an enzyme needed to break down fatty substances called sulfatides. The build-up of these fatty materials eventually becomes toxic to nerves, leading to the progressive loss of movement and thinking.
Babies with MLD develop normally for a time and but then typically begin to lose the ability to walk and talk at around two-years-old. The disease advances rapidly, causing children to deteriorate into a vegetative state.
‘Exciting’ drug development
The Boston non-profit Institute for Clinical and Economic Review, or ICER, which evaluates the cost effectiveness of new drugs, published a final report on Lenmeldy last year and estimated that the cost of the therapy would match its expected benefits to patients if it were priced between $2.3m and $3.9m.
Experts agreed that even such hefty price tag would be worth its results. Children with the disease who aren’t treated usually die within five years of their diagnosis; the oldest patient to have the therapy has now been followed for more than 12 years and appears to be developing normally.
“It’s taking a child who would have had a miserable short life, and possibly giving them a normal life. And that’s worth a lot of money,” said Dr David Rind, chief medical officer for ICER. “This is one of the more exciting drugs we’ve looked at.”
Still, the price came in hundreds of thousands of dollars higher that even Rind expected.
“I do think this price is too high,” he admitted.
The last product to top the charts on a per-treatment basis was another gene therapy called Hemgenix, which was approved in 2022 to treat haemophilia B. Its list price was $3.5m for a one-time treatment.
Close behind that one is Elvevidys, approved in 2023 for muscular dystrophy at $3.2m, and Skysona, approved in 2022 for a disease related to MLD called adrenoleukodystrophy, which costs $3m for a one-time dose.
Even with a top tier price, the MLD treatment will not be a blockbuster, Rind noted, because the disease is so rare. Some gene therapies approved for rare diseases have disappeared because the companies that made them couldn’t make enough money to stay in business.
New possibilities for patients
This latest approval comes as the FDA is working to clear a backlog of cell and gene therapies awaiting its attention since the pandemic. The agency has hired more staff and set up a new “super-office”, the Office of Therapeutic Products, to oversee their regulation.
Lenmeldy has been available in Europe since 2020, but it took four more years to bring it to the US.
Dr Nicole Verdun, who was hired to head the new FDA initiative last year, said Lenmeldy’s approval is a sign that things are moving in the right direction.
“MLD is a devastating disease that profoundly affects the quality of life of patients and their families. This approval represents important progress in the advancement and availability of effective treatments, including gene therapies, for rare diseases.”
Earlier screening
Gaspar, of Orchard Therapeutics, said the company was supporting studies of newborn screening tests in the hopes of catching and treating the condition earlier, and screening is happening in some US states.
“More than 250 000 babies have been screened,” he said, and five babies with MLD have been identified. At least three of those babies have now been treated.
Medpage Today article – Pediatric Neuron Disease Gets Its First Gene Therapy (Open access)
Orchard Therapeutics final evidence report (Open access)
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