NeuroVia’s lead drug candidate, NV1205 (sobetirome), is being developed for the treatment of X-linked Adrenoleukodystrophy (X-ALD). The compound has completed Phase 1 safety studies and the company is currently planning a Phase 1/2 study in X-ALD patients.
About X-Linked Adrenoleukodystrophy
X-linked adrenoleukodystrophy has a prevalence of approximately 1 in 17,500 live births. The disorder arises from a mutation of the ABCD1 gene on the X-chromosome. The ABCD1 gene encodes a protein (AdrenoLeukoDystrophy Protein, or ALDP) situated on the membrane of peroxisomes that facilitates the transport and degradation of very long chain fatty acids (VLCFA). In the absence of functional ALDP, VLCFA accumulate and can be harmful to cells, especially those of the Central Nervous System (CNS) where this accumulation can lead to a deterioration of the myelin sheaths surrounding nerve cells, thereby impairing nerve function.
The main sites of pathology of X-ALD are the CNS and the adrenal glands. While dysfunction of the adrenal glands can be controlled with hormone replacement therapy, CNS dysfunction is progressively problematic and in many cases can be rapidly fatal. The disease manifests in two main phenotypes: Cerebral ALD (CALD) and Adrenomyeloneuropathy (AMN). The two phenotypes are not mutually exclusive and virtually all males with X-ALD will develop AMN in early adulthood.
Cerebral ALD is found most frequently in childhood, where it is referred to as CCALD (Childhood CALD). Approximately 40% of young boys develop CCALD before reaching their teenage years. The disease is characterized by a lesion in the brain that initially causes behavioral symptoms. The symptoms can rapidly progress to loss of sensory functions (such as hearing and vision), followed by loss of motor functions (voluntary use of muscles). Eventually the disease becomes neurologically debilitating and ultimately leads to a vegetative state if not treated early by hematopoietic stem cell transplant. Patients that have already progressed to neurologic symptoms are often poor candidates for transplant and currently have no approved therapeutic alternatives.
X-ALD patients that reach adulthood begin to display signs of AMN as early as 18 years of age. AMN is a slowly progressive disease that affects primarily the spinal cord and leads to altered walking gait, incontinence, impotency and partial paralysis that can result in a patient relying on mobility-assist devices.
Additionally, a significant proportion of adults with AMN can spontaneously develop adult CALD characterized by a lesion in the brain. Transplant in this population has generally not been beneficial and the disease leads irreversibly to a vegetative state as it does in children.
X-ALD symptoms are more pronounced in males than in female carriers of an ABCD1 mutation since female carriers have one normal copy of the ABCD1 gene that provides some ability to process VLCFA. As a result, female carriers tend to have minimal or no symptoms through to early adulthood, but most of these females may develop some symptoms similar to adult males later in life.