WHAT HAPPENED

In mid-March 2024, the U.S. Food and Drug Administration (FDA) approved Lenmeldy (atidarsagene autotemcel), a gene therapy for the treatment of children with early-onset metachromatic leukodystrophy (MLD): pre-symptomatic late infantile (PSLI), pre-symptomatic early juvenile (PSEJ), or early symptomatic early juvenile (ESEJ) [1].

Marketing authorization by the European Medicines Agency (EMA) took place as early as mid-December 2020: the drug was named Libmeldy [2].

Treatment of MLD with Lenmeldy/Libmeldy involves a single infusion of a gene-therapeutic drug [3].

Lenmeldy/Libmeldy is offered by the UK’s Orchard Therapeutics, which was bought by Japan’s Kyowa Kirin for $478 million at the end of January 2024 [4].

 

PRICE INQUIRY

In the United States, Orchard has made Lenmeldy the most expensive drug of modern times, setting a wholesale acquisition cost (WAC) at $4.25 million, arguing that this is an acceptable amount given the clinical, economic, and societal importance of this treatment [1].

According to calculations by the U.S. Institute for Clinical and Economic Review (ICER), the economically acceptable cost of Lenmeldy is between $2.29 million and $3.94 million [2].

In Europe, Orchard has to negotiate with each country separately to purchase Libmeldy at public expense on a permanent basis. As a result, the drug is currently only available in a limited number of territories [3], and the final price varies from country to country. For instance, in Germany, the cost of Libmeldy is €2.475 million ($2.690 million) [4]. The UK is willing to pay £2.875 million ($3.664 million), although it received an undisclosed discount [5]. Ireland, Belgium, and the Netherlands have agreed to a discount raging from 25% to 65% off the original €2.875 million ($3.129 million), depending on the disease subtype [6] [7].

 

WHY IT MATTERS

Metachromatic leukodystrophy (MLD), also known as sulfatide lipidosis, is an autosomal recessive lysosomal accumulation disease caused by bi-allelic mutations in the gene encoding the enzyme arylsulfatase A (ARSA) [1] [2] [3] [4] [5]. ARSA deficiency results in the accumulation of sulfatides in the tissues that destroy the myelin sheath of nerve fibers, which cease to function properly [6] [7] [8]. This results in progressive psychomotor regression, culminating in the complete loss of motor, behavioral, and cognitive skills: patients lose the ability to move, speak, swallow, eat, and see [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19]. The prevalence of this very rare and life-threatening disease is up to 10 cases per million [20] [21] [22] [23] [24].

MLD cannot be completely cured, but allogeneic hematopoietic stem cell transplantation (HSCT) can halt or prevent the progression of central nervous system disorders in pre-symptomatic or early symptomatic patients, but it comes with risks of severe or fatal complications [25] [26] [27] [28] [29].

 

WHAT IT FOUND OUT

The efficacy and safety of Lenmeldy/Libmeldy in treating early-onset metachromatic leukodystrophy (MLD) in children (n=39) were studied in two clinical trials and the Expanded Access Program (EAP), and then compared to untreated natural history (NHx). The results, according to disease subtype (form), were as follows [1].

Among the most common adverse events in response to Lenmeldy/Libmeldy administration: febrile neutropenia and stomatitis, in the majority of cases severe.

Pre-symptomatic late infantile metachromatic leukodystrophy (PSLI MLD) [disease onset ≤ 30 months of age, absence of neurological signs and symptoms].

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All children with PSLI MLD who were treated with Lenmeldy/Libmeldy and followed until they were 6 years of age or older remained alive — compared to only 58% of children in the NHx group. At age 5 years, 71% of the subjects were able to walk without assistance and 85% had normal language and cognitive development — none of this was the case in the NHx group.

This is not to say that Lenmeldy/Libmeldy has unequivocally helped everyone:

  • Two children who had lost the ability to ambulate without support at ages 3.6 and 7.8 were able to ambulate with support at ages 8.1 and 11.6.
  • One child who experienced severe motor impairment lost the ability to locomote and sit without support by the age of 7.2 years and lost all motor function at the age of 9.9 years.
  • Two children were never able to get around on their own.

Pre-symptomatic early juvenile metachromatic leukodystrophy (PSEJ MLD) [disease onset > 30 months and < 7 years of age, absence of neurological signs and symptoms] and early symptomatic early juvenile metachromatic leukodystrophy (ESEJ MLD) [disease onset > 30 months and < 7 years of age, walking independently, ataxia, IQ ≥ 85].

Among children with PSEJ MLD or ESEJ MLD Lenmeldy/Libmeldy gene therapy resulted in a slowing of the decline in motor skills, language functions and cognitive abilities. Some children facing disease progression have died. Overall, further follow-up is needed to draw definitive conclusions.

 

THE ESSENCE

According to a systematic review and meta-analysis, differences in clinical outcomes after treatment of late infantile metachromatic leukodystrophy (LI MLD) and early juvenile metachromatic leukodystrophy (EJ MLD) with Lenmeldy/Libmeldy gene therapy (GT) or allogeneic hematopoietic stem cell transplantation (HSCT), as well as in the natural history (NHx) of the untreated disease can be summarized as follows [1].

Metachromatic Leukodystrophy (MLD) Treatment: Clinical Outcomes
Disease subtypeSurvivalMortality due to disease progressionGross motor functionCognitive skillsTreatment-related mortality
LI MLDLonger survival after GT compared with HSCT or NHxGT: 0% (within 3 years)
HSCT: 50% (within 1 year)
GT: improved in almost all
HSCT: improved in some
GT: improved
HSCT: almost unchanged
GT: no
HSCT: yes
EJ MLDSurvival similar after GT, HSCT, or ETGT: 15% (within 3 years)
HSCT: 20% (within 1 year)
GT: improved in many
HSCT: no improvement
GT: improved
HSCT: almost unchanged
GT: no
HSCT: yes

 

HOW IT WORKS

Treatment of metachromatic leukodystrophy with atidarsagene autotemcel (OTL-200) addresses the following steps. Autologous CD34+ hematopoietic stem cells are harvested from the patient and ex vivo transduced with a lentiviral vector by transferring complementary DNA encoding a functional ARSA gene, which are then infused back into the body. Once the genetically modified cells engraft in the bone marrow and repopulate the hematopoietic compartment, the ARSA enzyme they produce and secrete begins to function properly, breaking down sulfatides and preventing their harmful accumulation [1] [2].

 

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CURIOUSLY ENOUGH

Lenmeldy is the most expensive drug in the world at $4.25 million. Previously, the title of crazy-priced drugs belonged to gene therapies such as Upstaza (eladocagene exuparvovec) at $3.8 million, Hemgenix (etranacogene dezaparvovec) at $3.5 million, Elevydis (delandistrogene moxeparvovec) at $3.2 million, Skysona (elivaldogene autotemcel) at $3 million, and Roctavian (valoctocogene roxaparvovec) at $2.9 million for the treatment of aromatic L-amino acid decarboxylase deficiency (AADCD), hemophilia B, Duchenne muscular dystrophy (DMD), cerebral adrenoleukodystrophy (CALD), and hemophilia A.

Should we hope for the emergence of a $5 million cure?

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