Clinical deep dive

Disease State Overview
AADC deficiency is an autosomal recessive genetic disorder caused by mutations in the DDC gene. If a disease-causing mutation is present in the DDC gene, the AADC enzyme will be dysfunctional and unable to carry out typical functions. Normally, the AADC enzyme catylzes reactions that form neurotransmitters. Specifically, the AADC enzyme catalyzes the last step in the formation of the neurotransmitters dopamine and serotonin; dopamine is a precursor to the formation of epinephrine and norepinephrine. Therefore, in AADC deficiency, dopamine, serotonin, epinephrine, and norepinephrine are impacted, and the clinical symptoms seen in AADC deficiency are a result of a deficiency of these neurotransmitters. Symptoms vary over a wide spectrum, and patients may begin showing symptoms soon after birth or at a few months old; severity of the condition also varies from patient to patient. Approximately 80% of patients have a severe phenotype (no or very limited developmental milestones, fully dependent), but there have been some cases of milder phenotypes. The two most prevalent symptoms are decreased mucle tone (hypotonia) and oculogyric crises which are abnormal and involuntary typically upward rotation of the eyes, often along with uncontrolled movements and agitation. Additionally, patients may exhibit other movement disorders such as reduced movement (hypokinesia), excessive muscle tone (hypertonia), and other involuntary movements including prolonged muscle contractions (dystonia), writhing movements (athetosis), and spasmodic movements specifically in the limbs (chorea). Patients may also develop automonic dysfunction (dysautonomia) which can result in excessive sweating and salivation, temperature instability, drooping eyelids (ptosis), cardiovascular issues, hypoglycemic episodes, nasal congestion, and gastrointestinal symptoms. Patients usually present with developmental delay, decreased growth, intellectual disability and often do not meet normal milestones such as walking and talking. Behavorial issues and seizures are examples of less commonly seen symptoms. AADC deficiency is a chronic, debilitating, and potentially fatal condition. Patients with this condition are at an increased risk for early death due to the potential for medical complications (e.g., pneumonia, aspiration). Affected individuals often do not live through childhood, but those with less severe disease may live into adulthood.

Epidemiology
AADC deficiency is an ultra-rare genetic disorder. According to the National Organization for Rare Disorders (NORD), less than 350 patients with this condition have been identified in the literature. The estimated prevalence in the United States is approximately 1-2:1,000,000 newborns. AADC deficiency is more prevalent among certain Asian populations (specifically Taiwanese and Japanese). It is thought to be an underdiagnosed condition partly due to the nonspecific symptoms and its rare prevalence.

Treatment
Currently, there is no cure for AADC deficiency; however, there are several different pharmacotherapy options available as supportive therapy to help manage the symptoms associated with the condition. Clinical response to treatment is usually underwhelming and approach to treatment varies. Typically, a multidisciplinary team is needed to help with the various symptoms patients experience. Medications commonly used to treat this condition include those that directly activate dopamine receptors (i.e., dopamine agonists) or those that prevent the breakdown of dopamine (i.e., monoamine oxidase [MAO] inhibitors). Vitamin B6 or its active form pyridoxal phosphate (PLP) can be utilized because PLP acts as a cofactor for the AADC enzyme and may increase enzyme activity. Additional medications depend on patient specific symptoms to meet the needs of the patient (e,g., anticholinergics, melatonin, benzodiazepines). Eladocagene exuparvovec is currently approved in the European Union and the United Kingdom for the treatment of patients aged 18 months and older with a clinical, molecular, and genetically confirmed diagnosis of aromatic L-amino acid decarboxylase (AADC) deficiency with a severe phenotype.
 

Drug and clinical trial overview

Eladocagene exuparvovec was evaluated across three single-arm open-label clinical trials (compassionate use, phase 1/2,  and phase 2b) which included data for 26 patients in a single publication. Patients were eligible for inclusion if they had a confirmed diagnosis of AADC deficiency and classical symptoms of the condition. The trials enrolled patients who were ≥ 2 years of age or patients < 2 who had skull bones that could undergo surgery. The mean age at time of treatment was 4.1 years (range 1.7-8.5 years), and patients were followed for a mean duration of 5.4 years (range 2.0-10.2 years). All patients received the gene therapy via stereotactic surgery at a dose of 1.81 x 10¹¹ vector genomes (vg) of eladocagene exuparvovec with the exception of five patients in the phase 2b trial who received 2.37 x 10¹¹ vg. Therapies used to treat AADC deficiency (e.g., dopamine agonists, MAO inhibitors, anticholinergics) were prohibited during the first 12 months after surgery. The primary efficacy endpoint was the Peabody Developmental Motor Scales–Second Edition (PDMS-2) scores which assesses fine motor function. The Alberta Infant Motor Scale (AIMS) scale was also used to measure gross motor skills. At baseline, the mean PDMS-2 score was 10.4 ± 5.4. After treatment with eladocagene exuparvovec, the PDMS-2 score increased to 80.5 ± 43.4, 114.5 ± 55.2, and 116.1 ± 59.8 at one-, two-, and five-years post gene therapy administration, respectively which corresponded to a significantly higher score at each time point as compared to baseline (p <0.01 for each). The mean AIMS score at baseline was 1.8 ± 1.8 which increased to 18.8 ± 11.0, 26.9 ± 15.5, and 24.5 ± 15.0 at years one, two, and five, respectively after treatment (p <0.001 for each). Additional scales used to measure cognitive function and language ability included the Comprehensive Developmental Inventory for Infants and Toddlers (CDIIT) in the compassionate use trial and the Bayley Scale of Infant and Toddler Development, Third Edition (Bayley-III) in the other two clinical studies. These scales also showed improvements at from baseline at the one-, two-, and five-year follow-up timepoints. Cerebrospinal fluid (CSF) levels of dopamine and serotonin metabolites, homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) were also assessed. CSF HVA levels increased from 6.6 ± 11.2 nmol/L at baseline to 30.2 ± 16.7 nmol/L one year after treatment (p<0.001), while CSF 5-HIAA levels were not significantly different from baseline one year after treatment. AADC activity was assessed via positron emission tomography (PET) scans, which revealed higher levels of L-6-[18F] fluoro-3, 4-dihydroxyphenylalanine (18F-DOPA) uptake than at baseline at years one, two, and five post treatment. All patients who received eladocagene exuparvovec experienced a benefit, but younger age was correlated with quicker and greater improvement. No treatment-associated brain injuries were reported. Patients who experienced CSF leakage were treated accordingly with standard protocols. Many patients experienced mild to moderate dyskinesia which resolved months after treatment.