Eladocagene Exuparvovec-tneq (Kebilidi)

Number: 1073

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses eladocagene exuparvovec-tneq (Kebilidi) for commercial medical plans. 

Note: Requires Precertification: 

Precertification of eladocagene exuparvovec-tneq (Kebilidi) is required of all Aetna participating providers and members in applicable plan designs. For precertification of eladocagene exuparvovec-tneq (Kebilidi), call (866) 752-7021 or fax (888) 267-3277. For Statement of Medical Necessity (SMN) precertification forms, see Specialty Pharmacy Precertification.

Note: Unless member's health plan has elected not to require, gene and cellular therapies must be administered at an Aetna Institutes® Gene Based, Cellular and Other Innovative Therapy (GCIT®) Network. For eladocagene exuparvovec-tneq (Kebilidi), see Aetna Institutes® GCIT Designated Centers. 

1. Exclusions

   Aetna considers members with any of the following exclusions not eligible for Kebilidi: 

   1. Anti-adeno-associated virus, serotype 2 (anti-AAV2) antibody titers greater than 1:1200; or
   2. Pyridoxine 5'-phosphate oxidase or tetrahydrobiopterin (BH4) deficiency; or
   3. Evidence of a clinically active infection.

2. Prescriber Specialties

   This medication must be prescribed by or in consultation with a neurologist, geneticist, or physician specializing in the treatment of inherited metabolic diseases.

3. Criteria for Initial Approval

   Aetna considers a single-dose intraputaminal infusion only of eladocagene exuparvovec-tneq (Kebilidi) medically necessary for the treatment of aromatic L-amino acid decarboxylase (AADC) deficiency when all of the following criteria are met:

   1. Member is 16 months through 10 years of age; and
   2. Member's cerebrospinal fluid (CSF) has abnormal levels of neurotransmitter metabolites associated with AADC deficiency (i.e., reduced levels of 5-hydroxyindoleacetic acid [5-HIAA], homovanillic acid [HVA] and 3-methoxy-4-hydroxyphenylglycol [MHPG]; with normal CSF pterins including neopterin and biopterin; and increased CSF levels of L-Dopa, 3-O-methyldopa [3-OMD] and 5-OH tryptophan [5-HTP]); and
   3. Member has decreased AADC activity in the plasma; and
   4. Member has documented AADC deficiency due to biallelic variants in the DDC gene; and
   5. Member has persistent neurological defects (e.g., developmental delays, movement disorders [dystonia, hypokinesia, hypotonia, oculogyric crises], autonomic dysfunction [hyperhidrosis, hypersalivation, hypotension, hypoglycemia, ptosis], intellectual disability) despite standard medical therapy (i.e., dopamine agonists, monoamine oxidase inhibitor, pyridoxine or other forms of vitamin B6); and
   6. Member is unable to ambulate independently with or without assistive device; and 
   7. Skull maturity of member is sufficient for stereotaxis, namely development of three distinct skull layers (inner and outer cortical and middle cancellous), is documented on a formal radiology report; and
   8. Brain MRI will be used for stereotactic planning and intraoperative navigation; and
   9. Kebilidi will be administered in a medical center which specializes in stereotactic neurosurgery; and 
   10. Dose will not exceed 1.8×10¹¹ vector genomes (vg). 

4. Testing

   Aetna considers the following tests and procedures medically necessary for members being considered for treatment with Kebilidi:

   1. Lumbar puncture to assess cerebrospinal fluid (CSF) for abnormal levels of neurotransmitter metabolites associated with AADC deficiency
   2. Measurement of activity level of the AADC enzyme in the plasma, which will be reduced in members with AADC deficiency
   3. Genetic testing to identify pathogenic variants in the DDC gene to confirm diagnosis of AADC deficiency
   4. Brain magnetic resonance imaging (MRI) for stereotactic planning and intraoperative navigation.

5. SmartFlow Neuro Cannula

Aetna considers FDA-authorized SmartFlow Neuro Cannula (ClearPoint Neuro, Inc.) medically necessary for intraputaminal administration of Kebilidi.

Aetna considers all other indications as experimental, investigational, or unproven.

Dosage and Administration

Kebilidi is a sterile suspension for intraputaminal administration with a nominal concentration of 5.6×10¹¹ vg/mL. Kebilidi is supplied in a single-dose vial that contains 2.8×10¹¹ vg of eladocagene exuparvovec-tneq in an extractable volume of 0.5 mL of suspension. Each mL of suspension contains 5.6×10¹¹ vg of eladocagene exuparvovec-tneq.

For single-dose intraputaminal infusion only. Kebilidi should be administered in a medical center which specializes in stereotactic neurosurgery.

Per the label:

• Confirm individual has AADC deficiency due to biallelic mutations in the DDC gene
• Recommended dose: 1.8×10¹¹ vector genomes (vg).
• Brain imaging for stereotactic planning and intraoperative navigation should be done prior to the procedure. Brain MRI was used in the clinical trial.
• Post stereotactic registration, mark the entry point on the skull. Surgical access through the skull bone and dura should be performed
• Administer a total dose of 1.8×10¹¹ vg (0.32 mL total volume) 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.

Source: PTC Therapeutics, 2024b

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Other CPT codes related to the CPB:
Anti-adeno-associated virus, serotype 2 (anti-AAV2) antibody titer – No specific code
62270	Spinal puncture, lumbar, diagnostic
61781 – 61782	Stereotactic computer-assisted (navigational) procedure; cranial, intradural and extradural (List separately in addition to code for primary procedure
70551 - 70553	Magnetic resonance (eg, proton) imaging, brain (including brain stem)
82542	Column chromatography, includes mass spectrometry, if performed (eg, HPLC, LC, LC/MS, LC/MS-MS, GC, GC/MS-MS, GC/MS, HPLC/MS), non-drug analyte(s) not elsewhere specified, qualitative or quantitative, each specimen)
86325	Immunoelectrophoresis; other fluids (eg, urine, cerebrospinal fluid) with concentration
88108	Cytopathology, concentration technique, smears and interpretation (eg, Saccomanno technique)
96521	Refilling and maintenance of portable pump
96522	Refilling and maintenance of implantable pump or reservoir for drug delivery, systemic (eg, intravenous, intra-arterial)
HCPCS codes covered if selection criteria are met:
Eladocagene exuparvovec-tneq – No specific code
Other HCPCS codes related to the CPB:
SmartFlow Neuro Cannula – No specific code
ICD-10 codes covered if selection criteria are met:
E70.81	Aromatic L-amino acid decarboxylase deficiency
ICD-10 codes not covered for indications listed in the CPB:
A00.0 – B99.9	Certain infectious and parasitic diseases
E53.1	Pyridoxine deficiency [phosphate oxidase or tetrahydrobiopterin (BH4) deficiency]
K50.00 – K52.9	Noninfective enteritis and colitis
L00 – L08.9	Infections of the skin and subcutaneous tissue
M00.00 – M02.9	Infectious arthropathies
T80.211A - T80.29XS	Infections following infusion, transfusion and therapeutic injection
T81.40XA - T81.49XS	Infection following a procedure
T82.6XXA - T82.7XXS	Infection and inflammatory reaction due to cardiac valve prosthesis, other cardiac and vascular devices, implants and grafts
T83.510A - T83.69XS	Infection and inflammatory reaction due to prosthetic device, implant and graft in urinary system and genital tract
T84.50XA - T84.7XXS	Infection and inflammatory reaction due to internal joint prosthesis, internal fixation device, other internal orthopedic prosthetic devices, implants and grafts
T85.71XA - T85.79XS	Infection and inflammatory reaction due to other internal prosthetic devices, implants and grafts
T86.03	Bone marrow transplant infection
T86.13	Kidney transplant infection
T86.23	Heart transplant infection
T86.33	Heart-lung transplant infection
T86.43	Liver transplant infection
T86.812	Lung transplant infection
T86.822	Skin graft (allograft) (autograft) infection
T86.832	Bone graft infection
T86.8421 – T86.8429	Corneal transplant infection
T86.852	Intestine transplant infection
T86.892	Other transplanted tissue infection
T86.93	Unspecified transplanted organ and tissue infection
T87.40 – T87.44	Infection of amputation stump
T88.0XXA - T88.0XXS	Infection following immunization

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Background

U.S. Food and Drug Administration (FDA)-Approved Indications 

• Kebilidi is an adeno-associated virus (AAV) vector-based gene therapy indicated for the treatment of adult and pediatric patients with aromatic L-amino acid decarboxylase (AADC) deficiency. 

Eladocagene exuparvovec-tneq suspension is branded as Kebilidi (PTC Therapeutics, Inc.) for intraputaminal infusion. Eladocagene exuparvovec-tneq is a recombinant adeno-associated virus serotype 2 (rAAV2) based gene therapy designed to deliver a copy of the dopa decarboxylase (DDC) gene which encodes the AADC enzyme. Intraputaminal infusion of eladocagene exuparvovec-tneq results in AADC enzyme expression and subsequent production of dopamine in the putamen. 

Aromatic L-amino Acid Decarboxylase (AADC) Deficiency

Aromatic L-amino acid decarboxylase (AADC) deficiency is an extremely rare and potentially life-threatening genetic disorder which is caused by mutations in the DDC gene that results in the inability to synthesize neurotransmitters such as dopamine and serotonin. Affected individuals may experience delays in gross motor function (head control, sitting, standing, and walking), hypotonia (weak muscle tone), and developmental and cognitive delays. Symptoms often appear within the first six months of life. More specific symptoms include oculogyric crises (a rare neurological disorder that involves involuntary, spasmodic eye movements which occur in the vast majority of affected individuals, typically starting in infancy), movement disorders (especially dystonia), and autonomic dysfunction (excessive sweating, temperature instability, ptosis, nasal congestion, hypoglycemic episodes) (Blau et al, 2023).

The worldwide incidence of AADC deficiency is not known. Fewer than 350 patients have been reported in the medical literature, of which half are Asian individuals, and a fifth are people with Taiwanese ancestry. Males and females seem to be equally affected. In 2024, the estimated prevalence of AADC deficiency in the United States is 1–2 in 1,000,000 live births (NORD, 2024).

The diagnosis of AADC deficiency is established by determination of biogenic amines (BAs) in cerebrospinal fluid (CSF), measurement of activity level of the AADC enzyme in the plasma, and genetic mutational analysis of the DDC gene (NORD, 2024; Orphanet, 2024). CSF from the lumbar puncture is analyzed to identify abnormal levels of metabolites involved in the molecular pathways of neurotransmitter synthesis. "The synthesis of neurotransmitters involves a cascade of numerous chemical reactions. In patients with AADC deficiency, the cascade stops where AADC is usually required to catalyze the chemical reactions. As a result, in cases of enzyme deficiency, the metabolites “before” AADC in the chemical reaction cascade will be increased, and those “after” will be decreased" (NORD, 2024). Measurement of activity level of the AADC enzyme in the plasma will be reduced in patients with the disease. Genetic testing can identify pathogenic variants in the DDC gene, confirming diagnosis. 

Per a 2017 consensus guideline by the International Working Group on Neurotransmitter Related Disorders (iNTD) for the diagnosis and treatment of a AADC deficiency, there are three core diagnostic tools used for identifying AADC deficiency: lumbar puncture, genetic testing, and AADC enzyme activity in the plasma. The guidelines provide a "strong" recommendation for: (i) low CSF levels of 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG), increased CSF levels of 3-O-methyldopa (3-OMD), L-Dopa and 5-OH tryptophan (5-HTP), and normal CSF pterins; (ii) compound heterozygous or homozygous pathogenic variants in the DDC gene; and (iii) decreased AADC enzyme activity in plasma. To diagnose AADC deficiency, genetic testing should be performed and at least two out of three core diagnostic tests should be positive. The authors state that "If local resources allow, we recommend performing all three key diagnostic tests in patients with this rare disorder" (Wassenberg et al, 2017).

AADC deficiency is considered a long-term, debilitating, and life-threatening condition because it can lead to multiple organ failure. Many affected children do not live through childhood, but some with milder disease do reach adulthood. Due to the rarity of the disease, there has been limited scientific evidence for the efficacy of most treatment options. Standard of care treatments have included medications to increase the concentration of dopamine in the nervous system (dopamine agonists) or to decrease its degradation (monoamine oxidase B [MAO-B] inhibitors). Vitamin B6 (pyridoxine) or its active form, pyridoxal phosphate (PLP) are often tried, as PLP normally assists AADC in its role as a cofactor and might therefore increase the residual activity of the enzyme (NORD, 2024). However, these therapies have provided variable results and do not treat the underlying cause of disease, which is related to the insufficiency or absence of AADC activity (Tai et al, 2022). 

Tai et al (2022) evaluated the long-term safety and efficacy from 3 clinical trials on eladocagene exuparvovec gene therapy in patients with AADC deficiency. A total of 26 patients (from three consecutive trials; compassionate use, phase 1/2, and phase 2b) who lacked developmental milestones, including head control, received bilateral intraputaminal infusions of eladocagene exuparvovec and had at least 1-year follow-up. The key efficacy endpoint for motor development was the Peabody Developmental Motor Scale, Second Edition (PDMS-2) scores. The authors found that rapid improvements in motor and cognitive function occurred within 12 months after gene therapy and were sustained during follow-up for greater than 5 years. An increase in dopamine production was demonstrated by positron emission tomography (PET) and neurotransmitter analysis. Patient symptoms (mood, sweating, temperature, and oculogyric crises), patient growth, and patient caretaker quality of life improved. Although improvements were observed in all treated participants, younger age was associated with greater improvement. There were no treatment-associated brain injuries, and most adverse events were related to underlying disease. Post-surgery complications such as CSF leakage were managed with standard of care. Most patients experienced mild to moderate dyskinesia that resolved in a few months. These observations suggest that eladocagene exuparvovec treatment for aromatic L-amino acid decarboxylase deficiency provides durable and meaningful benefits with a favorable safety profile.

In a modeling study, Simons et al (2023) compared long-term outcomes of eladocagene exuparvovec with standard of care in AADC deficiency. A cohort-based model with a lifetime horizon was developed, based on motor milestones, to estimate the long-term benefits for patients after treatment with eladocagene exuparvovec compared to best supportive care (BSC). The model takes a National Health Service (NHS) perspective using a United Kingdom (UK) setting. The model comprises two parts: the developmental phase, in which patients with initially no motor function can progress to other motor milestone states, and a long-term projection phase. Efficacy for eladocagene exuparvovec is derived from clinical trial data with a duration up to 120 months. As the incidence of AADC deficiency is low, data for key model inputs is lacking; therefore estimates of survival by motor milestone were based on proxy diseases. A disease-specific utility study provided quality of life inputs and a burden of illness study informed inputs for disease management. The authors report that the model indicates survival (25.25 undiscounted life years gained) and quality-of-life benefits (20.21 undiscounted quality-adjusted life years [QALYs] gained) for patients treated with eladocagene exuparvovec compared to BSC. Resource usage costs are greater for patients treated with eladocagene exuparvovec, mainly due to the increased life expectancy during which patients accrue additional healthcare resource usage. Scenario analyses indicate robust results. The authors concluded that patients treated with eladocagene exuparvovec were found to have improved survival and quality of life benefits compared to patients treated with BSC.

On November 14, 2024, Kebilidi became the first FDA-approved gene therapy approved in the U.S. for treatment of AADC deficiency. However, this therapy was approved in 2022 in the European Union but branded as Upstaza (PTC Therapeutics, Inc.).

Kebilidi is given by a infusion into the brain that delivers a functional copy of the DDC gene directly to cells in the putamen, a region of the brain involved in motor control. It is administered in a single surgical procedure via four infusions. This one-time procedure must be performed at a medical center specializing in stereotactic neurosurgery. Once infused, it promotes AADC enzyme expression and increases dopamine levels, aiding in movement, attention, learning and memory.

FDA-approval was based on the safety and efficacy data from an open-label, single-arm clinical study in 13 pediatric patients (aged 16 months to 10 years) who had a genetically confirmed diagnosis of AADC deficiency, no gross motor function, and who had achieved skull maturity assessed with neuroimaging. Other eligibility inclusion criteria required patients to have decreased AADC enzyme activity in the plasma; unable to ambulate independently (with or without assistive device); and persistent neurological defects (e.g., developmental delays, movement disorders [dystonia, hypokinesia, hypotonia, oculogyric crises], autonomic dysfunction [hyperhidrosis, hypersalivation, hypotension, hypoglycemia, ptosis], intellectual disability) despite standard medical therapy (i.e., dopamine agonists, monoamine oxidase inhibitor, pyridoxine or other forms of vitamin B6). Exclusions included anti-adeno-associated virus, serotype 2 (anti-AAV2) antibody titer higher than 1:1200, pyridoxine 5'-phosphate oxidase or tetrahydrobiopterin (BH4) deficiency, and evidence of a clinically active infection. 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 Kebilidi 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.

In the clinical trial (NCT04903288), a total of 13 patients received a single total dose of 1.8×10¹¹ vg of Kebilidi given as four intraputaminal infusions in a single stereotactic neurosurgical procedure via SmartFlow magnetic resonance (MR) compatible ventricular cannula. The median age was 2.8 years (1.3 to 10.8 years). Ten patients (77%) were Asian, 2 patients (15%) were White, and 1 patient was of “other” race. Gross motor milestone achievement at Week 48 was assessed in 12 of the 13 patients treated in the study (one patient dropped out of the study prior to week 48). Study results showed that at week 48, 8 (67%) of the 12 treated patients achieved a new gross motor milestone. The 4 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 (age range 2 to 19 years) with the severe phenotype had documented motor milestone achievement at last assessment. The safety and effectiveness of Kebilidi has not been studied in pediatric patients younger than 16 months of age or patients 65 years of age and older.

Kebilidi is contraindicated in patients who have not achieved skull maturity assessed by neuroimaging. Skull maturity is needed for stereotactic neurosurgical administration of Kebilidi.

The observed incidence of anti-adeno-associated virus 2 (AAV2) antibodies is highly dependent on the sensitivity and specificity of the assay. There is no clinical experience with Kebilidi in patients with pre-existing AAV2 neutralizing antibody at titers greater than 1:1200.

Labeled warnings and precautions include procedural complications and dyskinesia. Procedural complications included respiratory and cardiac arrest which occurred within 24 hours of the neurosurgical procedure and during post-surgical care. Moreover, Kebilidi administration has the potential risk for additional procedure related adverse events including cerebrospinal fluid (CSF) leak, intracranial bleeding, neuroinflammation, acute infarction, and infection. Dyskinesia, such as involuntary movements of the face, arm, leg, or entire body, was reported after administration of Kebilidi. All events were reported within 3 months of administration and 2 events required hospitalization.

The most common adverse reactions (incidence of 15% or more) were dyskinesia, pyrexia, hypotension, anemia, salivary hypersecretion, hypokalemia, hypophosphatemia, insomnia, hypomagnesemia, and procedural complications.

The FDA also authorized the SmartFlow Neuro Cannula (ClearPoint Neuro, Inc.), an infusion tube inserted into a target in the brain (parenchymal tissue), to deliver Kebilidi. The SmartFlow Neuro Cannula is currently the only FDA authorized device indicated for use to administer Kebilidi (FDA, 2024).

In November 2024, ClearPoint Neuro announced FDA de novo marketing authorization of SmartFlow Cannula for direct delivery of gene therapy to the brain. The SmartFlow Neuro Cannula is intended for intraputaminal administration of PTC Therapeutics' gene therapy Kebilidi for the treatment of AADC deficiency.

Kebilidi was FDA approved using the Accelerated Approval pathway. Continued approval will be based on results from the ongoing confirmatory clinical trial to verify Kebilidi’s clinical benefit (FDA, 2024).

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Appendix

The Peabody Developmental Motor Scales, Second Edition (PDMS-2) is a standardized assessment used to measure motor skills, identify motor deficits, and determine eligibility for disability services. It is composed of six subtests (Reflexes, Stationary, Locomotion, Object Manipulation, Grasping, Visual-Motor Integration) that measure interrelated motor abilities of children from birth through age 5 years of age. The PDMS-2 (2nd edition) is still in use; however, the PDMS-3 (3rd edition) was published in May of 2023.

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References