SKYSONA (Elivaldogene autotemcel)

Cerebral adrenoleukodystrophy (CALD) is an X-linked genetic neurodegenerative disease that most severely affects individuals assigned male at birth. The genetic mutation leads to impaired or loss of adrenoleukodystrophy protein (ALDP) expression. X-linked adrenoleukodystrophy is established in a male (assigned male at birth or AMAB) with suggestive clinical findings and elevated very long chain fatty acids (VLCFA), with the majority having inherited a pathogenic variant in the ABCD1 gene. While female (assigned female at birth or AFAB) carriers can develop spastic paraparesis most often in adulthood, adrenal function is generally not impaired. CALD typically only affects AMAB in childhood and AFAB with CALD are very rare. Defective function of ALDP leads to the accumulation of very long-chain fatty acids (VLCFAs), which occurs in plasma and all tissue types but most prominently in the adrenal cortex and white matter of the brain and spinal cord. VLCFAs initiate an inflammatory cascade ultimately leading to inflammatory cerebral demyelination. In general, once clinical symptoms appear, the clinical course is rapid with progressive cognitive and neurologic deficits leading to major disability including cortical blindness, incontinence, requirement for tube feeding, loss of communication, loss of ambulation, loss of voluntary movement, and ultimately premature death. Prior to the approval of elivaldogene autotemcel, there were no approved treatments for CALD in the US. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is considered the standard of care and has been shown to stabilize neurologic function, with better outcomes observed in patients treated at the early stages of cerebral involvement and among those who receive human leukocyte antigen (HLA)-matched transplant versus HLA-mismatched transplant. Challenges associated with HSCT include serious immunologic complications, including transplant-related mortality, graft rejection, and graft-versus-host disease. Elivaldogene autotemcel is an autologous hematopoietic stem cell (HSC)-based gene therapy which adds functional copies of the ABCD1 cDNA into patients’ HSCs through transduction of autologous CD34+ cells with Lenti-D lentiviral vector. After infusion, transduced CD34+ HSCs engraft in the bone marrow and differentiate into various cell types, including monocytes (CD14+) capable of producing functional ALDP. Functional ALDP can then participate in the local degradation of VLCFAs, which is believed to slow or possibly prevent further inflammation and demyelination. <a id="