Medical Policy

Policy Num:       05.003.007
Policy Name:     Gene Therapies for Aromatic L-amino Acid Decarboxylase Deficiency
Policy ID:          [05.003.007]  [Ac / B / M+ / P+]  [5.01.52]

Last Review:      September 22, 2025
Next Review:      September 20, 2026
 

Related Policies: None

Gene Therapies for Aromatic L-amino Acid Decarboxylase Deficiency

Summary

Description

Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare autosomal recessive neurodevelopmental disorder caused by biallelic pathogenic variants in the DDC gene, resulting in reduced or absent activity of the AADC enzyme. This enzyme, expressed in both central and peripheral tissues, catalyzes the conversion of L-DOPA and 5-hydroxytryptophan into the neurotransmitter's dopamine and serotonin, respectively. AADC deficiency leads to impaired synthesis of dopamine, serotonin, norepinephrine, and epinephrine, contributing to a broad spectrum of clinical manifestations. The phenotypic spectrum is heterogenous and reflect deficits in monoaminergic neurotransmission. Phenotype ranges from mild (e.g., mild delay in developmental milestones, ambulatory without assistance, mild intellectual disability) to severe (e.g., no or very limited developmental milestones, fully dependent on caregivers). Approximately 80% of affected individuals present with severe phenotype. Dopamine deficiency primarily contributes to motor symptoms such as hypotonia, dystonia, delayed motor development, and oculogyric crises; norepinephrine and epinephrine deficiencies affect autonomic functions including ptosis, hypoglycemia, and hypotension; serotonin deficiency may impair cognition, voluntary movement, and emotional regulation. Prior to the approval of eladocagene exuparvovec, no FDA-approved therapies were available. Standard of care involved off-label use of oral medications such as dopamine agonists, monoamine oxidase inhibitors, and pyridoxine, though their efficacy and durability remain poorly characterized due to limited case reports. Eladocagene exuparvovec is a recombinant adeno-associated virus serotype 2 based vector gene therapy product containing the complementary DNA of the human DDC gene under the control of the cytomegalovirus immediate-early promoter. It is produced in human embryonic kidney cells by recombinant DNA technology. It is administered in a single stereotactic surgery using a cannula that is FDA-authorized for intraparenchymal infusion.

Summary of Evidence

For individuals with AADC deficiency who receive eladocagene exuparvovec, the evidence includes an open-label, single-arm study compared with an external natural history cohort. Relevant outcomes are overall survival, disease-specific survival, change in disease status, functional outcomes, quality of life, treatment-related morbidity and treatment-related mortality. The single-arm study enrolled 13 pediatric patients with genetically confirmed AADC deficiency. Effectiveness was assessed at 48 weeks based on the achievement of new gross motor milestones, measured using the PDMS-2 scale, and compared to an external, untreated natural history cohort. One participant withdrew consent at week 23 and was excluded from the final analysis. Among the remaining 12 treated patients, 8 (67%) achieved at least one new gross motor milestone by week 48. Specifically, 3 patients achieved full head control, 2 patients achieved sitting (with or without assistance), 2 patients achieved walking backward, and 1 patient with a variant severe phenotype achieved unassisted sitting. In contrast, none of the 43 untreated patients with severe AADC deficiency in the natural history cohort had documented motor milestone achievement at their last assessment at a median age of 7.2 years (range 2 to 19 years). Notable limitations include 1) Single-arm design and reliance on an external historical control introduce potential biases and limit the ability to accurately estimate treatment effects. 2) Limited number of participants reduces statistical precision, particularly for safety outcomes. Rare but serious adverse events may not be captured, and long-term safety remains uncertain. 3) The data primarily reflects outcomes in patients with severe phenotypes; evidence for efficacy in milder forms of AADC deficiency is limited. 4) Long-term durability of treatment benefits and safety remains uncertain. Despite these limitations, the study design is considered methodologically acceptable in the context of a rare disease with no approved therapies. Several contextual factors support the conclusion of clinical benefit including large treatment effect size, which increases confidence in the findings and reduces the likelihood that the results are solely attributable to bias or confounding. Pharmacodynamic data also demonstrated post-treatment increases in levels of homovanillic acid in the CSF as a downstream metabolite of dopamine and putamen specific 18F-DOPA uptake indicating increases in AADC activity. Known risks, including procedural complications and dyskinesia, are considered manageable with appropriate monitoring and treatment. These risks are deemed acceptable given the severity of AADC deficiency and the absence of alternative treatment options. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Additional Information

Not applicable.

Objective

The objective of this evidence review is to determine if use of eladocagene exuparvovec in individuals with AADC deficiency improves the net health outcome.

Policy Statements

Eladocagene exuparvovec-tneq is considered medically necessary for individuals if they meet criteria 1 through 7:

1. Meets any 1 of the 3 diagnostic criteria for aromatic L-amino acid decarboxylase deficiency

   1. Biallelic pathogenic/likely pathogenic variants in dopa decarboxylase (DDC) gene OR

   2. One pathogenic/likely pathogenic variant plus a variant of uncertain significance AND aromatic L-amino acid decarboxylase enzyme activity in plasma < 5% OR cerebrospinal fluid or plasma neurotransmitter profile consistent with aromatic L-amino acid decarboxylase deficiency (see Policy Guidelines) OR

   3. Two variants of uncertain significance AND aromatic L-amino acid decarboxylase enzyme activity in plasma < 5% OR cerebrospinal fluid or plasma neurotransmitter profile consistent with aromatic L-amino acid decarboxylase deficiency (see Policy Guidelines)

2. Has persistent neurological defects (e.g., autonomic dysfunction, hypotonia, dystonia and other movement disorders, etc.)

3. Has anti-AAV2 antibody titer <1:1,200

4. Achieved skull maturity assessed by neuroimaging to allow placement of the stereotactic head frame for surgery

5. Does not have any contraindications that would preclude the surgical intraputaminal administration

6. Medication is being administered at United States Food and Drug Administration approved dosing by a healthcare professional (see Policy Guidelines)

7. Medication is planned to be administered in a medical center which specializes in stereotactic neurosurgery.

Eladocagene exuparvovec is considered investigational when the above criteria are not met.

Eladocagene exuparvovec-tneq is considered investigational for all other indications.

Repeat treatment with Eladocagene exuparvovec-tneq is considered investigational.

Policy Guidelines

Recommended Dose

Per the FDA label, the recommended dose is 1.8×10¹¹ vector genomes delivered as four 0.08 mL (0.45×10¹¹ vg) infusions (two sites per putamen-anterior and posterior) at a rate of 0.003 mL/minute (0.18 mL/hour) for a total of 27 minutes per site, administered in a single stereotactic surgery using a
cannula that is FDA-authorized for intraparenchymal infusion.

Dosing Limits

1 injection per lifetime

Supportive laboratory findings on neurometabolites Panel

Cerebrospinal fluid neurotransmitter profile typically demonstrates:

• Low levels of 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG);

• Normal concentrations of pterins (neopterin and biopterin);

• High concentrations of levodopa, 3-O-methyldopa (3-methoxytyrosine; 3-OMD), and 5-hydroxytryptophan (5-HT).

Plasma neurotransmitter (untargeted metabolomics) profile typically demonstrates:

• High level of 3-OMD;

• Low levels of 5-HIAA, vanillylmandelate (VMA), HVA, and dopamine-3-O-sulfate (D3OS);

• Low to normal level of 3-methoxytyramine sulfate (3-MTS).

Increased urinary concentration of vanillactic acid (VLA)

Other Considerations

Genetics Nomenclature Update

The Human Genome Variation Society nomenclature is used to report information on variants found in DNA and serves as an international standard in DNA diagnostics. It is being implemented for genetic testing medical evidence review updates starting in 2017 (see Table PG1). The Society's nomenclature is recommended by the Human Variome Project, the Human Genome Organization, and by the Human Genome Variation Society itself.

The American College of Medical Genetics and Genomics and the Association for Molecular Pathology standards and guidelines for interpretation of sequence variants represent expert opinion from both organizations, in addition to the College of American Pathologists. These recommendations primarily apply to genetic tests used in clinical laboratories, including genotyping, single genes, panels, exomes, and genomes. Table PG2 shows the recommended standard terminology- "pathogenic," "likely pathogenic," "uncertain significance," "likely benign," and "benign"- to describe variants identified that cause Mendelian disorders.

Table PG1. Nomenclature to Report on Variants Found in DNA

Table PG2. American College of Medical Genetics and Genomics and the Association for Molecular Pathology Standards and Guidelines for Variant Classification

Definition of Bi-allelic Variant

• Biallelic pathogenic/likely pathogenic variants in DDC OR
• One pathogenic/likely pathogenic variant plus a variant of unknown significance OR AND CSF OR plasma neurotransmitter profile consistent with AADC deficiency (see above) AND significantly reduced activity of the enzyme AADC in plasma
• Two variants of unknown significance AND CSF OR plasma neurotransmitter profile consistent with AADC deficiency (see above) AND significantly reduced activity of the enzyme AADC in plasma

Genetic Counseling

Genetic counseling is primarily aimed at patients who are at risk for inherited disorders, and experts recommend formal genetic counseling in most cases when genetic testing for an inherited condition is considered. The interpretation of the results of genetic tests and the understanding of risk factors can be very difficult and complex. Therefore, genetic counseling will assist individuals in understanding the possible benefits and harms of genetic testing, including the possible impact of the information on the individual’s family. Genetic counseling may alter the utilization of genetic testing substantially and may reduce inappropriate testing. Genetic counseling should be performed by an individual with experience and expertise in genetic medicine and genetic testing methods.

Coding

See the Codes table for details.

Benefit Application

BlueCard/National Account Issues

State or federal mandates (eg, Federal Employee Program) may dictate that certain U.S. Food and Drug Administration‒approved devices, drugs, or biologics may not be considered investigational, and thus these devices may be assessed only by their medical necessity.

Background

Aromatic L-amino Acid Decarboxylase Deficiency

Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare autosomal recessive disorder caused by pathogenic variants in the DDC gene, which encodes the AADC enzyme).^1, This enzyme is essential for synthesizing key neurotransmitters dopamine and serotonin by converting their precursors, L-DOPA and 5-hydroxytryptophan, respectively. AADC is expressed in both central and peripheral tissues. Loss or reduction of AADC activity leads to impaired production of dopamine, serotonin, norepinephrine, and epinephrine, resulting in accumulation of precursors and reduced levels of neurotransmitter metabolites.^2,

Clinical symptoms typically emerge in infancy and vary widely.^3,2, This variability in clinical presentation is related to deficiencies in dopamine, epinephrine, norepinephrine, and serotonin. Generally, decreased dopamine levels are responsible for movement-related symptoms such as hypotonia, dystonia, delayed motor development, and oculogyric crisis. Epinephrine and norepinephrine deficiencies affect autonomic functions such as ptosis, hypoglycemia, or hypotension. Serotonin deficiency can affect cognitive function, voluntary movement, and emotional state. AADC deficiency is broadly categorized into mild, moderate, and severe phenotypes.

• The severe phenotype is characterized by profound motor impairment, including the absence of head control and failure to achieve motor milestones. Affected individuals often experience severe hypotonia, feeding difficulties, oculogyric crises (prolonged dystonic eye and facial movements), and autonomic dysfunction. These patients are fully dependent on caregivers and may face early mortality due to complications from hypotonia and autonomic instability.

• The moderate phenotype includes patients who attain some motor milestones, such as head control, sitting, or standing, but are unable to walk independently. Symptoms are less severe than in the severe form but still significantly impact daily function.

• The mild phenotype involves less pronounced motor impairment, with individuals often achieving independent ambulation. These patients may live into adulthood and primarily exhibit autonomic symptoms, sleep disturbances, and behavioral issues, with minimal or no motor dysfunction

Approximately 80% of patients exhibit a severe phenotype^3, and require lifelong care. Disease symptoms do not spontaneously improve, and death often occurs in the first decade of life. The disease significantly impacts the quality of life of patients and their caregivers.

Epidemiology

Prevalence of AADC deficiency globally and within the United States is unknown, with fewer than 400 confirmed cases reported worldwide to date.^4, Wassenberg et al (2017) has identified 117 case reports in the literature, and estimated prevalence is roughly 1-2 in 1,000,000 newborns per the National Organization for Rare Disorders.^2, The condition appears to be more common in certain Asian populations, particularly in Taiwan, China, and Japan, likely due to a founder mutation.^5,1,

Diagnosis

AADC deficiency is frequently underdiagnosed or misdiagnosed due to its rarity and overlapping symptoms with more common neurological disorders such as cerebral palsy or epilepsy.^6,7, Although clinical signs typically emerge within the first few months of life, diagnosis is often delayed until childhood or even adulthood. Data from international patient registries show that while the average age of symptom onset is around 2.5 to 2.7 months, the average age at diagnosis can range from 9 months to over 3 years, with some cases diagnosed as late as the third decade of life.^8,2, This delay can lead to inappropriate management, missed opportunities for early intervention, and worsening of disease-related complications. Timely and accurate diagnosis is essential to initiate appropriate therapies, support developmental outcomes, and reduce the burden on patients and caregivers.^9,3,

Core diagnostic tests for AADC deficiency include single gene or genetic panel testing, CSF neurotransmitter metabolites panel, and a plasma AADC enzyme assay.^2, To confirm a diagnosis of AADC deficiency, at least 2 of the 3 core diagnostic tests should be positive. See Table 1.

Table 1. Diagnostic Tests to Confirm AADC deficiency^1,2,

  3-OMD: 3-O-methyldopa; 5-HIAA: 5-hydroxyindoleacetic acid; 5-HTP: 5-hydroxytryptophan; AADC: aromatic L-amino acid decarboxylase; CSF: cerebrospinal fluid; DDC: dopa decarboxylase; HVA: homovanillic acid; L-dopa: levodopa; MHPG: 3-methoxy-4 hydroxyphenylglycol.

AADC deficiency is currently not on the Recommended Uniform Screening Panel (RUSP) list of health conditions that experts recommend newborn screening in the US. There is growing interest and research around the potential for newborn screening for AADC deficiency. A specific test that measures 3-O-methyldopa in dried blood spots has been evaluated in a clinical trial trial in Taiwan as a candidate screening test.^10,

Treatment

Until recently, there were no FDA-approved therapies for AADC deficiency. Current approach has relied on off-label use of oral medications such as dopamine agonists, monoamine oxidase inhibitors, and pyridoxine (vitamin B6). These treatments have shown limited and variable effectiveness.^11,. Patients with the severe phenotype typically show no improvement in motor function. In contrast, individuals with mild or moderate phenotypes may experience notable gains in motor milestones such as improved head control, sitting, standing, or walking following dopamine agonist therapy. Additional benefits may include reductions in hypotonia, oculogyric crises, and autonomic symptoms^7,.However, due to the rarity of the disease and the limited number of published case reports, the response rate and long-term effectiveness of these therapies remain poorly characterized. Current management strategies may also be limited by undesirable side effects, which may lead to discontinuation of therapy. Consequently, there remains a significant unmet medical need for an FDA-approved therapy that can address the underlying cause of AADC deficiency across all phenotypes.

Regulatory Status

On November 13, 2024, eladocagene exuparvovec-tneq suspension (Kebilidi) was approved by the Food and Drug Administration (FDA) for the treatment of adult and pediatric patients with aromatic 13 L-amino acid decarboxylase (AADC) deficiency. This indication is approved under accelerated approval based on change from baseline in gross motor milestone achievement at 48 weeks post-treatment. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory clinical trial.

Eladocagene exuparvovec was approved as Upstaza by the European Medicines Agency on 18 July 2022, by the United Kingdom’s Medicinal Health Products Regulatory Agency in November 2022, and by Israel Ministry of Health in February 2023 for pediatric patients 18 months and older with the severe phenotype of AADC deficiency.

Rationale

This evidence review was created in July 2025 with a search of the PubMed database. The most recent literature update was performed through July 23, 2025.

Evidence reviews assess the clinical evidence to determine whether the use of a technology improves the net health outcome. Broadly defined, health outcomes are length of life, quality of life, and ability to function including benefits and harms. Every clinical condition has specific outcomes that are important to patients and to managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of a technology, 2 domains are examined: the relevance and the quality and credibility. To be relevant, studies must represent one or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. Randomized controlled trials are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Population Reference No. 1

Aromatic L-amino Acid Decarboxylase Deficiency

Clinical Context and Therapy Purpose

The purpose of eladocagene exuparvovec in individuals with AADC deficiency is to provide a treatment option that is an improvement on existing therapies. Potential benefits of this one-time therapy may include the following:

• Novel mechanism of action or approach may allow successful treatment of patients for whom other available treatments have failed.

• Successful treatment may reduce the potential for disease and standard treatment-related morbidity and mortality and improve quality of life.

The following PICO was used to select literature to inform this review.

Populations

The relevant population(s) of interest are individuals with AADC deficiency.

Interventions

The therapy being considered is eladocagene exuparvovec.

Eladocagene exuparvovec is a recombinant adeno-associated virus serotype 2-based gene therapy designed to deliver a copy of the DDC gene that encodes the AADC enzyme. Intraputaminal infusion of eladocagene exuparvovec results in AADC enzyme expression and subsequent production of dopamine in the putamen.

Comparators

The off label use of following therapies are considered standard of care- dopamine agonists, monoamine oxidase inhibitors, and pyridoxine.^2, Patients with the severe phenotype of AADC deficiency do not demonstrate any improvements in motor function in response to these SoC therapies. Initiation of dopamine agonists in patients with the mild and moderate phenotype can result in rapid improvements in gross motor function and achievement of new motor milestones (including improvements in head control, sitting, standing and walking) that would be unexpected in these phenotypes. Improvements in hypotonia, oculogyric crises, and autonomic dysfunction have also been reported.^7, Due to the rarity of the disease and the limited case reports published in the literature, both responder rate and durability of standard of care medications is not characterized. There remains an unmet medical need for an FDA-approved treatment to address AADC deficiency, regardless of phenotype.

Outcomes

The general outcomes of interest are overall survival, disease-specific survival, change in disease status, functional outcomes, quality of life, treatment-related morbidity, and treatment-related mortality (Table 2). Follow-up at 15 years is of interest to monitor outcomes.

Table 2. Health Outcome Measures Relevant to Aromatic L-amino Acid Decarboxylase Deficiency

  PDMS: Peabody Developmental Motor Scale, Second Edition. Cite: Folio R, Fewell R. Peabody developmental motor scales-2 (2nd ed.). Austin, TX: Pro-Ed; 2000.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Consistent with a 'best available evidence approach,' within each category of study design, studies with larger sample sizes and longer durations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

The clinical development program is summarized in Table 3 and consists of multiple interventional and observational studies. All studies are single-arm, open-label trials. The severity of AADC deficiency, the rarity of the disease, the lack of authorized treatment options, and the risk of disease progression precluded the conduct of a RCT in the target patient population. The FDA approval was based on the pivotal AADC-002 single-arm study. The manufacturer proposed using the surrogate outcomes of cerebrospinal fluid homovanillic acid as the primary endpoint to support accelerated approval. FDA reviewers concluded that the evidence was insufficient to establish HVA as a surrogate reasonably likely to predict clinical benefit and recommended using motor milestone achievement as the primary efficacy endpoint. However, motor milestone achievement was planned to be assessed at 2 years of age. However, up to the 01 March 2024 data cut, the median duration of follow-up among the treated patients was only 82 weeks (range 23 to 109 weeks). Consequently, motor milestone achievement at week 48 was used instead as an intermediate clinical efficacy endpoint to support accelerated approval in FDA’s review of the application. All patients (except for one subject who withdrew at 23 weeks) reached 48 weeks of follow-up. ^12,13,

The natural history cohort was sourced from a comprehensive review of published AADC deficiency literature through July 2022 which identified 156 publications that met the inclusion criteria. These 156 studies reported data on 288 unique patients with high-quality data that identified them as unique patients with high certainty. Disease phenotype (severity) was classified based on the achievement of motor milestones at the age of 24 months. The disease phenotypes were adjudicated to identify those that had similar disease characteristics (severe phenotype) as those included in clinical trials for eladocagene exuparvovec and hence could be used as a historical control. After adjudication, a group of 51 unique patients who had not participated in clinical studies for eladocagene exuparvovec and had similar disease phenotypes to the study patients (described as having no or little motor milestone achievement at 24 months) in the gene therapy clinical studies. These patients were used as a control group to compare acquisition of motor milestones with eladocagene exuparvovec-treated patients in study AADC-002. Among the 51 pediatric patients with the severe phenotype who were included in the natural history cohort , 8 pediatric patients were further excluded by the FDA clinical review team’s. Among these eight pediatric patients, three likely did not have the severe phenotype.

Table 3. Summary of the Clinical Development Program for Eladocagene Exuparvovec

  AADC: Aromatic L-amino acid decarboxylase; CSF: cerebrospinal fluid; DDC; dopa decarboxylase.  

Pivotal Study

Study characteristics, baseline patient characteristics, and results are summarized in Tables 4 to 6, respectively.

AADC-002 is an open-label, single arm study that enrolled 13 pediatric patients with genetically confirmed, severe AADC deficiency who had achieved skull maturity assessed with neuroimaging. The main efficacy outcome measure was gross motor milestone achievement evaluated at week 48 and assessed using the Peabody Developmental Motor Scale, Second Edition (PDMS-2). Patients treated with eladocagene exuparvovec were compared to an external untreated natural history cohort of 43 pediatric patients with severe AADC deficiency who had at least one motor milestone assessment after 2 years of age. Twelve of the 13 patients had the severe phenotype of AADC deficiency, defined as having no motor milestone achievement at baseline and no clinical response to standard of care therapies. The one remaining patient had a “variant” of the severe disease phenotype, with the ability to sit with assistance but with lack of head control. One study participant who withdrew consent at week 23 and dropped out of the study was excluded from the analysis. Eight (67%) of the 12 treated patients achieved a new gross motor milestone at week 48: 3 patients achieved full head control, 2 patients achieved sitting with or without assistance, 2 patients achieved walking backwards and the patient with the “variant” severe phenotype was able to sit unassisted. The two patients who achieved walking backwards at week 48 were treated before 2 years of age. The four patients who were unable to achieve new gross motor milestones at week 48 were treated between the ages of 2.8 and 10.8 years. In comparison, none of the 43 untreated patients with the severe phenotype had documented motor milestone achievement at last assessment at a median age of 7.2 years (range 2 to 19 years). No formal statistical hypothesis testing was planned in study AADC-002 and sample size was not based on statistical power consideration, rather, it was based on feasibility.^12,

Table 4. Summary of Pivotal Study

  AADC: aromatic L-amino acid decarboxylase; AAV2: Adeno-associated virus type 2; CSF: cerebrospinal fluid; DOPA: dopamine; FDA: food and drug administration; HVA: homovanillic acid; PET: positron emission tomography; PDMS-2: Peabody developmental motor scales-second edition; VG: vector genome 

Table 5. Summary of Baseline Demographics and Disease Characteristics in the Pivotal Study^12,

  a n=11 b n=12 SD: standard deviation

Table 6. Summary of Results in the Pivotal Study^12,

  a Motor milestones achieved at mastery level is defined as earning a score of 2 on the Peabody developmental motor scales- second edition. Note: Motor milestones are acquired sequentially, i.e., in the following order: full head control to walking with assistance. The study is still ongoing with only 3 patients having motor assessment at week 72 and week 96 visit by May 20, 2024.

The purpose of the study limitations tables (see Tables 7 and 8) is to display notable limitations identified in each study. This information is synthesized as a summary of the body of evidence following each table and provides the conclusions on the sufficiency of evidence supporting the position statement. Multiple limitations were noted. The FDA approved eladocagene exuparvovec based on new motor milestone achievement at week 48 compared to an untreated natural history cohort. While FDA describes the post hoc analysis of motor milestone achievement as an intermediate endpoint as the basis for accelerated approval, for the purpose of this review motor milestone achievement is considered a clinically meaningful outcome and appropriate for evaluating clinical benefit. The primary source of uncertainty stems from the post hoc nature of the analysis and the strong assumption of comparability between the treated cohort and the external historical control. Single-arm studies are inherently vulnerable to bias due to potential unmeasured differences between groups. Additionally, the natural history cohort data were sparse and inconsistent with highly variable time spans between the first and last reported motor milestone assessments (e.g., some did not have data at earlier age). This limits the ability to match patients and compare outcomes at equivalent time points between the groups. Despite these limitations, the use of single-arm studies and external controls is considered methodologically acceptable in the context of a rare disease with no approved therapies. Several contextual factors support the conclusion of clinical benefit.

• All enrolled patients had severe AADC deficiency, were at least two years old at baseline, exhibited poor or absent head control, and had no response to standard therapies. A substantial proportion achieved motor milestones by week 48 that exceeded expectations based on the natural history of the disease.
• The observed treatment effect was large, which increases confidence in the findings and reduces the likelihood that the results are solely attributable to bias or confounding.
• Pharmacodynamic data demonstrated post-treatment increases in levels of homovanillic acid in the CSF as a downstream metabolite of dopamine and putamen specific 18F-DOPA uptake indicating increases in AADC activity.
• Known risks, including procedural complications and dyskinesia, are considered manageable with appropriate monitoring and treatment. These risks are deemed acceptable given the severity of AADC deficiency and the absence of alternative treatment options.

Nonetheless, important limitations remain: First, limited sample size limit the precision of estimates, particularly for adverse events. Rare but serious harms may not be captured in clinical trials, and long-term safety remains uncertain. Second, the available data primarily reflect outcomes in patients with severe disease; evidence for treatment effects in milder phenotypes is limited.

Table 7. Study Relevance Limitations

  The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.  a Population key: 1. Intended use population unclear; 2. Study population is unclear; 3. Study population not representative of intended use; 4, Enrolled populations do not reflect relevant diversity; 5. Other. b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4. Not the intervention of interest (e.g., proposed as an adjunct but not tested as such); 5: Other. c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively; 5. Other. d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. Incomplete reporting of harms; 4. Not establish and validated measurements; 5. Clinically significant difference not prespecified; 6. Clinically significant difference not supported; 7. Other. e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms; 3. Other.

Table 8. Study Design and Conduct Limitations

  The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment. a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias; 5. Other. b Blinding key: 1. Participants or study staff not blinded; 2. Outcome assessors not blinded; 3. Outcome assessed by treating physician; 4. Other. c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication; 4. Other. d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials); 7. Other. e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference; 4. Other. f Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4. Comparative treatment effects not calculated; 5. Other.

Section Summary: Aromatic L-amino Acid Decarboxylase Deficiency

The primary evidence supporting the safety and effectiveness of eladocagene exuparvovec was derived from an open-label, single-arm study involving 13 pediatric patients with genetically confirmed AADC deficiency. Effectiveness was assessed at 48 weeks based on the achievement of new gross motor milestones, measured using the PDMS-2 scale, and compared to an external, untreated natural history cohort. One participant withdrew consent at week 23 and was excluded from the final analysis. Among the remaining 12 treated patients, 8 (67%) achieved at least one new gross motor milestone by week 48. Specifically, 3 patients achieved full head control, 2 patients achieved sitting (with or without assistance), 2 patients achieved walking backward, and 1 patient with a variant severe phenotype achieved unassisted sitting. In contrast, none of the 43 untreated patients with severe AADC deficiency in the natural history cohort had documented motor milestone achievement at their last assessment at a median age of 7.2 years (range 2 to 19 years). Notable limitations include 1) Single-arm design and reliance on an external historical control introduce potential biases and limit the ability to accurately estimate treatment effects. 2) Limited number of participants reduces statistical precision, particularly for safety outcomes. Rare but serious adverse events may not be captured, and long-term safety remains uncertain. 3) The data primarily reflect outcomes in patients with severe phenotypes; evidence for efficacy in milder forms of AADC deficiency is limited. 4) Long-term durability of treatment benefits and safety remains uncertain. Despite these limitations, the study design is considered methodologically acceptable in the context of a rare disease with no approved therapies. Several contextual factors support the conclusion of clinical benefit including large treatment effect size, which increases confidence in the findings and reduces the likelihood that the results are solely attributable to bias or confounding. Pharmacodynamic data also demonstrated post-treatment increases in levels of homovanillic acid in the CSF as a downstream metabolite of dopamine and putamen specific 18F-DOPA uptake indicating increases in AADC activity. Known risks, including procedural complications and dyskinesia, are considered manageable with appropriate monitoring and treatment. These risks are deemed acceptable given the severity of AADC deficiency and the absence of alternative treatment options.

Summary of Evidence

For individuals with AADC deficiency who receive eladocagene exuparvovec, the evidence includes an open-label, single-arm study compared with an external natural history cohort. Relevant outcomes are overall survival, disease-specific survival, change in disease status, functional outcomes, quality of life, treatment-related morbidity and treatment-related mortality. The single-arm study enrolled 13 pediatric patients with genetically confirmed AADC deficiency. Effectiveness was assessed at 48 weeks based on the achievement of new gross motor milestones, measured using the PDMS-2 scale, and compared to an external, untreated natural history cohort. One participant withdrew consent at week 23 and was excluded from the final analysis. Among the remaining 12 treated patients, 8 (67%) achieved at least one new gross motor milestone by week 48. Specifically, 3 patients achieved full head control, 2 patients achieved sitting (with or without assistance), 2 patients achieved walking backward, and 1 patient with a variant severe phenotype achieved unassisted sitting. In contrast, none of the 43 untreated patients with severe AADC deficiency in the natural history cohort had documented motor milestone achievement at their last assessment at a median age of 7.2 years (range 2 to 19 years). Notable limitations include 1) Single-arm design and reliance on an external historical control introduce potential biases and limit the ability to accurately estimate treatment effects. 2) Limited number of participants reduces statistical precision, particularly for safety outcomes. Rare but serious adverse events may not be captured, and long-term safety remains uncertain. 3) The data primarily reflects outcomes in patients with severe phenotypes; evidence for efficacy in milder forms of AADC deficiency is limited. 4) Long-term durability of treatment benefits and safety remains uncertain. Despite these limitations, the study design is considered methodologically acceptable in the context of a rare disease with no approved therapies. Several contextual factors support the conclusion of clinical benefit including large treatment effect size, which increases confidence in the findings and reduces the likelihood that the results are solely attributable to bias or confounding. Pharmacodynamic data also demonstrated post-treatment increases in levels of homovanillic acid in the CSF as a downstream metabolite of dopamine and putamen specific 18F-DOPA uptake indicating increases in AADC activity. Known risks, including procedural complications and dyskinesia, are considered manageable with appropriate monitoring and treatment. These risks are deemed acceptable given the severity of AADC deficiency and the absence of alternative treatment options. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Supplemental Information

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Practice Guidelines and Position Statements

Guidelines or position statements will be considered for inclusion in 'Supplemental Information' if they were issued by, or jointly by, a US professional society, an international society with US representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

National Institute for Health and Care Excellence

The National Institute for Health and Care Excellence published a highly specialized technologies guidance report on eladocagene exuparvovec for treating AADC deficiency on April 19, 2023.^17, The guidance makes the following recommendations:

Eladocagene exuparvovec is recommended, within its marketing authorization, as an option for treating AADC deficiency in people 18 months and over with a clinical, molecular and genetically confirmed diagnosis of AADC deficiency with a severe phenotype. Eladocagene exuparvovec is only recommended if the company provides it according to the commercial arrangement.

International Working Group on Neurotransmitter Related Disorders

In 2017, the iNTD conducted a systematic literature review on AADC deficiency and developed treatment guidelines.^2, These guidelines state "Gene therapy for AADC deficiency is currently under development in a research setting. Clinical trial results will determine whether further implementation of this promising therapy may occur in the future." as they were published prior to the US or EU approval of eladocagene exuparvovec.

U.S. Preventive Services Task Force Recommendations

Not applicable.

Medicare National Coverage

There is no national coverage determination. In the absence of a national coverage determination, coverage decisions are left to the discretion of local Medicare carriers.

Ongoing and Unpublished Clinical Trials

None

References

1. Himmelreich N, Montioli R, Bertoldi M, et al. Aromatic amino acid decarboxylase deficiency: Molecular and metabolic basis and therapeutic outlook. Mol Genet Metab. May 2019; 127(1): 12-22. PMID 30952622
2. Wassenberg T, Molero-Luis M, Jeltsch K, et al. Consensus guideline for the diagnosis and treatment of aromatic l-amino acid decarboxylase (AADC) deficiency. Orphanet J Rare Dis. Jan 18 2017; 12(1): 12. PMID 28100251
3. Rizzi S, Spagnoli C, Frattini D, et al. Clinical Features in Aromatic L-Amino Acid Decarboxylase (AADC) Deficiency: A Systematic Review. Behav Neurol. 2022; 2022: 2210555. PMID 36268467
4. Himmelreich N, Bertoldi M, Alfadhel M, et al. Prevalence of DDC genotypes in patients with aromatic L-amino acid decarboxylase (AADC) deficiency and in silico prediction of structural protein changes. Mol Genet Metab. Jul 2023; 139(3): 107624. PMID 37348148
5. Blau N, Pearson TS, Kurian MA, Elsea SH. Aromatic L-Amino Acid Decarboxylase Deficiency. 2023 Oct 12 [updated 2025 Jan 23]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; 19932025. PMID: 37824694.
6. Pearson TS, Gupta N, San Sebastian W, et al. Gene therapy for aromatic L-amino acid decarboxylase deficiency by MR-guided direct delivery of AAV2-AADC to midbrain dopaminergic neurons. Nat Commun. Jul 12 2021; 12(1): 4251. PMID 34253733
7. Wen Y, Wang J, Zhang Q, et al. The genetic and clinical characteristics of aromatic L-amino acid decarboxylase deficiency in mainland China. J Hum Genet. Sep 2020; 65(9): 759-769. PMID 32409695
8. Opladen T, Cortès-Saladelafont E, Mastrangelo M, et al. The International Working Group on Neurotransmitter related Disorders (iNTD): A worldwide research project focused on primary and secondary neurotransmitter disorders. Mol Genet Metab Rep. Dec 2016; 9: 61-66. PMID 27830117
9. Abukhaled M, Alrakaf L, Aldhalaan H, et al. Case report: Aromatic L-amino acid decarboxylase deficiency in three patient cases from the Kingdom of Saudi Arabia. Front Pediatr. 2022; 10: 1016239. PMID 36727005
10. Newborn Screening for Aromatic L-amino Acid Decarboxylase Deficiency (NCT02399761). Available at https://clinicaltrials.gov/search?term=NCT02399761. Accessed July 31, 2027.
11. Roubertie A, Opladen T, Brennenstuhl H, et al. Gene therapy for aromatic L-amino acid decarboxylase deficiency: Requirements for safe application and knowledge-generating follow-up. J Inherit Metab Dis. May 2024; 47(3): 463-475. PMID 37402126
12. Food and Drug Administration: Statistical Review for Eladocagene Exuparvovec (Approval History, Letters, Reviews, and Related Documents - Kebilidi). Available at https://www.fda.gov/vaccines-blood-biologics/kebilidi. Accessed on July 29, 2025.
13. Food and Drug Administration: Summary Basis for Regulatory Action for Eladocagene Exuparvovec. Available at https://www.fda.gov/media/184353/download?attachment. Accessed on July 29, 2025.
14. Chien YH, Lee NC, Tseng SH, et al. Efficacy and safety of AAV2 gene therapy in children with aromatic L-amino acid decarboxylase deficiency: an open-label, phase 1/2 trial. Lancet Child Adolesc Health. Dec 2017; 1(4): 265-273. PMID 30169182
15. Tai CH, Lee NC, Chien YH, et al. Long-term efficacy and safety of eladocagene exuparvovec in patients with AADC deficiency. Mol Ther. Feb 02 2022; 30(2): 509-518. PMID 34763085
16. Prescribing label for KEBILIDI (eladocagene exuparvovec-tneq) suspension for intraputaminal infusion. Available at https://www.kebilidi.com/prescribing-information.pdf. Accessed on July 29, 2025.
17. National Institute for Health and Care Excellence: Eladocagene exuparvovec for treating aromatic L-amino acid decarboxylase deficiency (Highly specialized technologies guidance). Published: 19 April 2023. Available at www.nice.org.uk/guidance/hst26. Accessed on July 29, 2025.

Codes

Policy History