Elivaldogene autotemcel

Identification

Summary

Elivaldogene autotemcel is a gene replacement therapy for treating early cerebral adrenoleukodystrophy comprising autologous hematopoietic stem cells transduced with a viral vector encoding ABCD1 complementary DNA for human adrenoleukodystrophy protein.

Brand Names

Skysona

Generic Name

Elivaldogene autotemcel

DrugBank Accession Number

DB16746

Background

Elivaldogene autotemcel is a gene therapy consisting of genetically modified autologous cells. It is used to provide functional copies of human adrenoleukodystrophy protein (ALDP) in patients with adrenoleukodystrophy,⁴ an X-linked genetic disorder characterized by missing or non-functional ABCD1 gene that codes for ALDP.¹ ALDP is a key protein that normally breaks down fatty substances in the body called very long-chain fatty acids (VLCFAs). Without sufficient levels of functional ALDP, VLCFAs accumulate in the body leading to inflammation and destruction of myelin, which is an insulating layer and essential component of nerves.⁵

Cerebral adrenoleukodystrophy is an inflammatory cerebral phenotype that more commonly affects young men: it is associated with progressive brain function loss and poor survival rates without treatment. Allogeneic hematopoietic stem-cell transplantation has been the primary treatment option; however, it is associated with a risk of graft failure and graft-versus-host disease (GVHD), calling for alternative treatment options. Gene therapy with autologous hematopoietic stem cells was introduced and investigated as a possible treatment for patients with adrenoleukodystrophy.¹ Elivaldogene autotemcel works by delivering genes into the patient's body to produce functional ALDPs. It was approved by the European Commission in July 2021 under the market name Skysona, and was later withdrawn in November 2021 at the request of the marketing-authorization holder.⁵ In September 2022, Skysona was approved by the FDA.⁶

Type

Biotech

Groups

Approved

Biologic Classification

Gene Therapies
Other gene therapies

Synonyms

eli-cel

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Pharmacology

Indication

Elivaldogene autotemcel is indicated to slow the progression of neurologic dysfunction in boys 4-17 years of age with early, active cerebral adrenoleukodystrophy (CALD). Early, active CALD refers to asymptomatic or mildly symptomatic (neurologic function score, NFS ≤ 1) boys who have gadolinium enhancement on brain magnetic resonance imaging (MRI) and Loes scores of 0.5-9.⁶

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Associated Conditions

Indication Type	Indication	Combined Product Details	Approval Level	Age Group	Patient Characteristics	Dose Form
Management of	Neurologic dysfunction		••••••••••••		••••••• ••••• •••••••• •••••••••••••••••••• ••••••	•••••••••• ••••••••••

Contraindications & Blackbox Warnings

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Pharmacodynamics

Elivaldogene autotemcel works to restore missing or low levels of adrenoleukodystrophy protein (ALDP) in patients adrenoleukodystrophy by delivering copies of genes that code for ALDP. While the drug aims to stabilize the disease by slowing down its progression, elivaldogene autotemcel is not expected to affect other manifestations of adrenoleukodystrophy such as adrenal insufficiency. The clinical impact of elivaldogene autotemcel on adrenomyeloneuropathy has not been studied.⁴

In one clinical study (Study ALD-102), all patients produced ALDP in CD14+ peripheral blood cells within one month of treatment and had a median CD14+ ALDP+ of 29.50%, indicating early expression of the transgene. At six months of follow-up, CD14+ ALDP+ cells slightly declined after drug infusion and stabilized by approximately six months of treatment.⁴ Elivaldogene autotemcel is typically not associated with treatment-related death or graft-versus-host disease.¹

Mechanism of action

Adrenoleukodystrophy protein (ALDP or ABCD1) is a half ATP-binding cassette (ABC) transporter localized in the peroxisomal membrane. It plays a role in peroxisomal beta-oxidation and the breakdown of very long-chain fatty acids (VLCFAs) in organs.³ Adrenoleukodystrophy is an X-linked genetic disorder caused by the mutations in the ABCD1 gene that encodes ALDP, leading to impaired production of ALDP.¹ The lack of functional ALDP leads to increased intracellular concentrations of VLCFAs and incorporation of VLCFAs into different complex lipids, including myelin sheaths that are particularly vulnerable to inflammation. VLCFA-induced myelin membrane instability leads to a pro-inflammatory brain environment, causing progressive, inflammatory cerebral demyelination and axonopathy. These pathological events can also be accompanied by oxidative stress and energy shortage in axons as well as non-cell-autonomous processes involving axon–glial interactions.²

Elivaldogene autotemcel consists of autologous CD34+ hematopoietic stem cells transduced ex vivo with a lentiviral vector encoding ABCD1 complementary DNA (cDNA). Following administration of elivaldogene autotemcel, autologous CD34+ hematopoietic stem cells engraft in the bone marrow and differentiate into various cell types, including monocytes (CD14+) that migrate to the brain, where they can further differentiate into macrophages and cerebral microglia that can produce functional ALDP. Functional ALDPs can promote the local degradation of VLCFAs in the brain, stabilizing the course of the disease to prevent further inflammation and demyelination. Following successful engraftment with genetically modified cells, the expression of ALDP is expected to be life-long.⁴

Absorption