Kebilidi

Author: Michaela Price, PhD

Editors: Morgan McCullough & Kylie VanDerMolen

Today, we will be discussing Kebilidi (eladocagene exuparvovec-tneq). Kebilidi is manufactured by PTC Therapeutics, Inc. and was approved for the treatment of aromatic L-amino acid decarboxylase (AADC) deficiency. In the United States, the Food and Drug Administration (FDA) announced in November 2024 that they approved Kebilidi for the treatment of AADC deficiency in pediatric and adult patients.¹ It was previously approved as Upstaza by the European Medicines Agency, Medicinal Health Products Regulatory Agency, and the Ministry of Health to treat children with severe AADC deficiency in the European Union, United Kingdom, and Israel, respectively.² In this post, we will describe AADC deficiency, the previous standard of care therapies, and the characteristics of Kebilidi and its clinical trial, including some of the special designations under which Kebilidi’s application was approved.

Overview of Aromatic L-Amino Acid Decarboxylase Deficiency

AADC deficiency is an exceedingly rare, autosomal recessive disorder caused by pathological variants in the DOPA decarboxylase (DDC) gene.^3,4 The DDC gene encodes AADC, which is a key enzyme in the biosynthesis pathway for neurotransmitters, including serotonin, dopamine, norepinephrine, and epinephrine (Figure 1).^3-5 AADC deficiency reduces AADC enzymatic activity and thus impairs the synthesis of these neurotransmitters, which produces debilitating symptoms and severely limits patients’ quality of life.^3-5

The prevalence of AADC deficiency is difficult to measure, but the National Organization for Rare Disorders estimates it to be approximately 1-2 in 1,000,000 newborns.⁶ A 2017 study identified 117 patients with AADC deficiency worldwide.⁴ Less than 350 patients have been reported in the literature⁶ since its initial description in a 1990 twin case study.⁷ The case study described 2-month-old twins with a fairly extreme deficiency in AADC enzymatic activity with only 1% of normal levels in the liver and 1.7-7.5% of normal levels in the plasma.⁷ This was accompanied by several symptoms, including severe hypotonia, developmental delay, irritability, oculogyric crises (OGC).⁷ OGC are involuntary deviations of the eyes that may occur around the same time as involuntary movements by other parts of the face and body.³ OGC are experienced nearly universally among patients, as 98% of subjects reported experiencing OGC during their lifetime.³ Episodes can last for hours at a time and occur at a high frequency, presenting a huge challenge to individuals’ quality of life.³ Studies have shown that symptom onset usually occurs within the first year of life.^3,4 The most common initial symptoms are hypotonia, OGC, developmental delay, feeding problems, sleepiness, irritability, excessive sweating, and nasal congestion (Figure 1).³ Severe AADC deficiency has a profound impact on gross motor function to the point that patients are incapable of reaching the most basic motor milestones like controlling one’s own head.²

Figure 1. Overview of Aromatic L-Amino Acid Decarboxylase (AADC) Deficiency. AADC is an enzyme in the biosynthesis pathway of serotonin, dopamine, norepinephrine, and epinephrine.^3,4 Symptom onset typically occurs within the first year of life.^3,4 The most common initial symptoms experienced in an international cohort of subjects include hypotonia, oculogyric crises (a hallmark of AADC deficiency), developmental delay, feeding problems, and more.³ 5-HTP = 5-hydroxytryptophan; DBH = dopamine β-hydroxylase; PNMT = phenylethanolamine N-methyltransferase. The image was created by the author.

Available Treatments

Before November 2024, there were no FDA-approved treatments for AADC deficiency. However, there were three treatments that the field considered “standard of care” treatments for AADC deficiency, including dopamine agonists, monoamine oxidase inhibitors, and pyridoxal 5’-phosphate/pyridoxine.^2,3,7 

Dopamine Agonists: Dopamine agonists activate dopamine receptors. AADC deficiency severely reduces the amount of dopamine synthesized, so dopamine agonists may be useful for restoring dopamine receptor-mediated functions and compensating for the lack of naturally- synthesized dopamine. In an international cohort of patients, 83% of the subjects had been prescribed one of the following dopamine agonists: bromocriptine, pramipexole, rotigotine, and ropinirole.³ Rotigotine had the highest percentage of subjects that experienced benefits (82%), whereas pramipexole, bromocriptine, and ropinirole had significantly lower percentages of respondents that reported benefits from the medication (29%, 26%, and 13%, respectively).³ Importantly, dopamine agonists had adverse effects for a significant portion of patients. Half of the subjects reported adverse effects with rotigotine and ropinirole, whereas 38% of subjects reported adverse effects with pramipexole and 30% with bromocriptine.³ The high rate of adverse effects led to 25% of patients discontinuing their medication.³

Monoamine Oxidase Inhibitors (MAOIs): Monoamine oxidase is an enzyme that breaks down neurotransmitters, including dopamine, serotonin, and norepinephrine.⁸ MAOIs prevent the breakdown of these neurotransmitters, leading to increased neurotransmitter levels in the brain. In the context of AADC deficiency, patients may be able to naturally produce a small concentration of monoamines that would be protected by MAOIs from being broken down. Over 60% of the subjects in an international study tried an MAOI, such as selegiline and/or tranylcypromine.³ Benefits were reported by 35% of the subjects for selegiline and 18% of subjects for tranylcypromine.³ On the other hand, 27% of subjects reported adverse effects with selegiline and 6% for tranylcypromine.³ There were low medication discontinuation rates for both MAOI options (12% for selegiline, 6% for tranylcypromine).³

Pyridoxine: Pyridoxine is one of the six forms of vitamin B6 that is found in mammals.^9,10 Pyridoxine can be converted to a biologically active form of vitamin B6 like pyridoxal 5’-phosphate (PLP).^9,10 AADC is a PLP-dependent enzyme, which makes the synthesis of neurotransmitters dependent on PLP as well.¹⁰ In an international cohort of patients, 78% tried pyridoxine, but only 7% had noticeable improvement from the medication.³ None of the patients reported side effects from pyridoxine.³ These data indicate that the medication was well-tolerated, but had minimal benefits. 

Kebilidi Gene Therapy

Kebilidi is an adeno-associated virus serotype 2 (AAV2) vector-based gene therapy that is administered to patients in a single neurosurgical session.^1,2 During neurosurgery, surgeons deliver four infusions of Kebilidi into a brain region called the putamen.² The infused AAV contains a functional copy of the DDC gene that encodes the AADC enzyme.^2,5 Putamen cells take up the AAV and begin producing functional AADC in the putamen, leading to increased synthesis of neurotransmitters.²  

The Clinical Trial 

The safety and efficacy of Kebilidi was tested in an open-label, single-arm clinical study that enrolled 13 pediatric patients.^1,2 All clinical trial subjects were required to have a confirmed diagnosis of AADC deficiency, and analyses were completed by comparing subjects treated with Kebilidi to the natural progression of AADC deficiency in an untreated control cohort.^1,2 At baseline, all subjects had severe AADC deficiency, as exemplified by failing to achieve any gross motor milestones, having low AADC activity in the plasma, and failing to respond to therapies that were the standard of care.^1,2 The patients were treated with Kebilidi and monitored for adverse effects and changes in symptoms. One of the expedited programs that Kebilidi qualified for, the Accelerated Approval pathway, allows the product’s efficacy to be assessed using an intermediate clinical endpoint that should be able to be measured earlier than irreversible morbidity and mortality (IMM) and predict the product’s impact on IMM.^2,11,12 Treatment-induced changes in motor function can be measured early, and experts would expect early improvement in motor function to predict a long-term improvement in motor function and other long-term clinical benefits.² Therefore, motor function was measured as the intermediate clinical endpoint.^1,2 

The clinical study completed assessments to measure motor function in 12 of the 13 enrolled patients 48 weeks after receiving treatment.^1,2 The assessments demonstrated that Kebilidi had clinical efficacy since gross motor function improved in 8 of the 12 treated patients.^1,2 All 8 patients that improved reached a new gross motor milestone (full head control) on the Peabody Developmental Motor Scale second edition (PDMS-2).² Some of the patients improved dramatically. In terms of the highest motor milestone achieved, 2 patients were able to sit with or without assistance, 2 patients were able to walk backwards, and 1 patient was able to sit unassisted.² This reflects a massive improvement in motor function considering that all patients lacked head control at the beginning of the trial. The trial followed 44 untreated patients with AADC deficiency, and none of them had achieved any motor milestones at their last assessment.² Given the complete lack of improvement in untreated individuals, it was unexpected for two-thirds of the treated patients to reach new motor milestones and certainly unexpected for the improvement to be so stark.² Additional supporting data illustrated that Kebilidi increased the expression of dopamine metabolites in the cerebrospinal fluid and increased dopamine uptake in the putamen, consistent with Kebilidi’s mechanism of action.² There were some adverse reactions reported in the clinical trial, including dyskinesia (involuntary muscle movement), fever, low blood pressure, anemia, increased saliva production, insomnia, low ion levels, and procedural complications like cardiac and respiratory arrest.¹ Altogether, the FDA approved Kebilidi to treat AADC deficiency based on improved motor function (the intermediate clinical endpoint), additional supporting data, acceptable risks associated with Kebilidi considering the severity of AADC deficiency, and the lack of FDA-approved therapeutics for the disease.²

The Challenges of Pharmaceutical Development and the Need for Expedited Programs 

The Unmet Need: The available therapies described in the previous section arguably have limited benefits and often have adverse effects for patients with AADC deficiency. Prior to the development of Kebilidi, there was a clear unmet clinical need for a therapeutic to treat AADC deficiency, given the severity of the symptoms associated with the disease and the lack of available FDA-approved therapies. 

The Cost: The cost to develop a gene therapy and bring it to market is exorbitant. A recent calculation based on 25 cell and/or gene therapies estimated that research and development costs associated with the clinical development of a gene therapy would be an estimated US$1.94 billion.¹³ This is a massive financial burden that a clinical trial sponsor, the entity that is responsible for initiating the clinical trial (e.g. pharmaceutical company), would be taking on. 

The Regulatory Challenge: It is a near herculean challenge to bring a product from phase 1 clinical trials to the approval stage. One study suggests that phase 1 therapeutics have a 64-67% success rate at transitioning to phase 2, only 32-39% of phase 2 therapeutics successfully move to phase 3, 60-68% of phase 3 therapeutics will make it to a new drug application (NDA) or biologics license application (BLA), and then finally, there is a 83-86% likelihood of receiving FDA approval of the NDA or BLA.¹⁴ Suffice to say that there is significant risk associated with pharmaceutical development, and every sponsor must consider the likelihood of their product successfully navigating from phase 1 clinical trials to marketing authorization.

FDA’s Expedited Programs: The FDA has established several expedited programs that encourage the development of drugs, biologics, and medical devices that are meant to treat serious conditions where there is an unmet clinical need. The FDA defines serious conditions as those that significantly impact day-to-day functioning in a persistent, recurrent, or irreversible manner.¹⁵ These programs are extremely important for product development because they provide sponsors with benefits that ease financial and regulatory barriers. The high cost of development and the risk of failure in clinical trials make FDA’s expedited programs extremely valuable for a sponsor to acquire. PTC Therapeutics, Inc. took advantage of the financial and regulatory benefits that these expedited programs provided to develop Kebilidi to treat AADC deficiency.^1,2 Kebilidi qualified for several of the FDA programs that were launched to incentivize product development for serious disorders, including Accelerated Approval (Figure 2), Priority Review (Figure 3), an Orphan Drug Designation (Figure 4), and a Rare Pediatric Disease Priority Review Voucher (Figure 5).¹ The figures below detail the criteria required to qualify, the benefits earned by the sponsor, and the rationale for Kebilidi qualifying for each of the expedited programs.

Figure 2. Overview of the Accelerated Approval Pathway. To qualify for the Accelerated Approval pathway, the product must treat, prevent, or diagnose a condition with serious or life-threatening symptoms and fill an unmet need. In addition, the product’s efficacy should be assessed using a surrogate or an intermediate clinical endpoint that is measured earlier than and likely predicts its effect on irreversible morbidity or mortality (IMM).^2,11,12 Basing approval on a surrogate or an intermediate endpoint allows the clinical trial to be quicker and potentially smaller than it would be if the clinical trial was assessing the product’s effect on IMM.^12,15 According to the summary document, Kebilidi was approved based on an intermediate clinical endpoint (motor function) that was assessed 48 weeks after treatment and was expected to predict IMM.² The improvement in motor function was supported by additional data demonstrating increased expression of dopamine metabolites in the cerebrospinal fluid and dopamine uptake in the putamen, which show that AADC activity increased.² Additionally, Kebilidi meets the criteria for being a serious condition, and it fills an unmet need.^2,3 The image was created by the author.

Figure 3. Overview of the Priority Review Designation. To qualify for Priority Review, the product must treat, prevent, or diagnose a disease that has serious or life-threatening symptoms and, if approved, be a significant improvement compared to standard therapies.¹⁶ The benefit of having a Priority Review designation is that the FDA prioritizes reviewing the application and shortens the review period to 6 months as opposed to the standard review process that normally takes 10 months.¹⁶ Kebilidi met the criteria to qualify for the priority review designation because it treats a disease that has serious symptoms, including oculogyric crises and the inability to reach basic motor milestones like head control.^2,3 In addition, Kebilidi is the first treatment to be FDA-approved to treat AADC deficiency, and its efficacy in clinical trials represents a significant improvement compared to the standard of care therapies that have minimal benefits and adverse effects.^2,3 The image was created by the author.

Figure 4. Overview of the Orphan Drug Designation. To qualify for the Orphan Drug Designation, a product must treat, prevent, or diagnose a rare disease and/or the investment required to develop the product must outweigh expected sales.¹⁷ A condition is considered rare if it affects less than 200,000 people in the United States, according to Section 526 of the Federal Food, Drug, and Cosmetic Act.¹⁷ After qualifying, the product’s sponsor will earn tax credits, fee exemptions, and potentially, market exclusivity for 7 years.¹⁸ Kebilidi met the criteria to qualify as a treatment for a rare disease.^4,6 The image was created by the author.

 

 

 

 

 

Figure 5. Overview of the Rare Pediatric Disease Designation Priority Review Voucher Program. The Rare Pediatric Disease Designation has an associated Priority Review Voucher program. To qualify for the Rare Pediatric Disease Designation, a product must treat, prevent, or diagnose a condition that has serious or life-threatening symptoms that primarily affect pediatric populations (birth to 18 years of age), and the condition must be rare.^19,20 After qualifying, the product’s sponsor will receive a Priority Review Voucher that they can use for a different product of their choice.^19,20 Kebilidi met the criteria to qualify as a treatment for a serious pediatric disease that is rare.^2-4,6 Notably, this voucher program began phasing out at the end of December 2024 and will not be available for future marketing authorization applications.¹⁹ The image was created by the author.

 

The Outlook and Impact of Kebilidi

Kebilidi will continue to be monitored for safety and efficacy long-term in treated patients with AADC deficiency. According to the public letter that PTC Therapeutics, Inc. received for approval of Kebilidi’s BLA, the sponsor must conduct postmarketing studies to corroborate Kebilidi’s clinical benefit and confirm that the intermediate endpoint (motor function) did in fact predict IMM.²¹ The postmarketing studies will be completed at the end of 2028 and the final report is due at the end of September 2029.²¹ Continued FDA approval of Kebilidi is contingent upon the confirmatory trial substantiating its long-term clinical benefit.² 

Kebilidi has the potential to have a profound impact on patients’ lives, particularly for the patients that are the most severely impacted by AADC deficiency. Before Kebilidi’s approval, these patients were limited to off-label use of medications that had minimal benefits and adverse effects. However, the FDA’s expedited programs for serious conditions eased financial and regulatory barriers associated with product development enough that it sparked the development of Kebilidi for an exceptionally rare disease, effectively changing patients’ lives for the better. 

References

1. FDA approves first gene therapy for treatment of aromatic L-amino acid decarboxylase deficiency. Press release. FDA. Published November 14, 2024. Accessed December 12, 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapy-treatment-aromatic-l-amino-acid-decarboxylase-deficiency 
2. Kebilidi summary basis for regulatory action. FDA. Published November 13, 2024. Accessed January 16, 2025. https://www.fda.gov/media/184353/download?attachment 
3. Pearson TS, Gilbert L, Opladen T, Garcia-Cazorla A, Mastrangelo M, Leuzzi V, Tay SKH, Sykut-Cegielska J, Pons R, Mercimek-Andrews S, Kato M, Lücke T, Oppebøen M, Kurian MA, Steel D, Manti F, Meeks KD, Jeltsch K, Flint L. AADC deficiency from infancy to adulthood: Symptoms and developmental outcome in an international cohort of 63 patients. J Inherit Metab Dis. 2020;43:1121-1130. doi: 10.1002/jimd.12247
4. Wassenberg T, Molero-Luis M, Jeltsch K, Hoffmann GF, Assmann B, Blau N, Garcia-Cazorla A, Artuch R, Pons R, Pearson TS, Leuzzi V, Mastrangelo M, Pearl PL, Lee WT, Kurian MA, Heales S, Flint L, Verbeek M, Willemsen M, Opladen T. Consensus guideline for the diagnoses and treatment of aromatic l-amino acid decarboxylase (AADC) deficiency. Orphanet J Rare Dis. 2017;12:12. doi: 10.1186/s13023-016-0522-z
5. DDC gene. Medline Plus. Updated May 13, 2024. Accessed January 17, 2025. https://medlineplus.gov/genetics/gene/ddc/ 
6. Aromatic L-amino acid decarboxylase deficiency. National Organization for Rare Disorders. Updated November 14, 2024. Accessed January 16, 2025. https://rarediseases.org/rare-diseases/aromatic-l-amino-acid-decarboxylase-deficiency/ 
7. Hyland K, Clayton PT. Aromatic amino acid decarboxylase deficiency in twins. J Inher Metab Dis. 1990;13(3):301-304. doi: 10.1007/BF01799380. 
8. MAOIs (monoamine oxidase inhibitors). Cleveland Clinic. Updated August 30, 2023. Accessed January 4, 2025. https://my.clevelandclinic.org/health/treatments/25220-maois-monoamine-oxidase-inhibitors 
9. Stover PJ, Field MS. Vitamin B-6. Adv Nutr. 2015;6(1):132-133. doi: 10.3945/an.113.005207
10. Higdon J, Drake VJ, Delage B, Gregory JF. Vitamin B6. Linus Pauling Institute at Oregon State University. Updated May 2024. Accessed January 24, 2025. https://lpi.oregonstate.edu/mic/vitamins/vitamin-B6 
11. Accelerated approval. FDA. Updated February 24, 2023. Accessed December 12, 2024. https://www.fda.gov/patients/fast-track-breakthrough-therapy-accelerated-approval-priority-review/accelerated-approval 
12. Expedited program for serious conditions – accelerated approval of drugs and biologics guidance for industry. FDA. Published December 2024. Accessed January 24, 2025. https://www.fda.gov/media/184120/download 
13. Sabatini MT, Chalmers M. The cost of biotech innovation: Exploring research and development costs of cell and gene therapies. Pharm Med. 2023;37:365-375. doi: 10.1007/240290-023-00480-0
14. Hay M, Thomas DW, Craighead JL, Economides C, Rosenthal J. Clinical development success rates for investigational drugs. Nat Biotechnol. 2014;32:40-51. doi:10.1038/nbt.2786
15. Expedited programs for serious conditions – drugs and biologics guidance for industry. FDA. Published May 2014. Accessed January 28, 2025. https://www.fda.gov/files/drugs/published/Expedited-Programs-for-Serious-Conditions-Drugs-and-Biologics.pdf 
16. Priority review. FDA. Updated January 4, 2018. Accessed December 12, 2024.  https://www.fda.gov/patients/fast-track-breakthrough-therapy-accelerated-approval-priority-review/priority-review 
17. Orphan drug act – relevant excerpts. FDA. Updated March 9, 2018. Accessed December 12, 2024. https://www.fda.gov/industry/designating-orphan-product-drugs-and-biological-products/orphan-drug-act-relevant-excerpts 
18. Designating an orphan product: Drugs and biological products. FDA. Updated August 12, 2024. Accessed December 12, 2024.  https://www.fda.gov/industry/medical-products-rare-diseases-and-conditions/designating-orphan-product-drugs-and-biological-products 
19. Rare pediatric disease designation and priority review voucher programs. Updated September 27, 2024. Accessed December 12, 2024.  https://www.fda.gov/industry/medical-products-rare-diseases-and-conditions/rare-pediatric-disease-designation-and-priority-review-voucher-programs 
20. Rare pediatric disease priority review vouchers guidance for industry. FDA. Published July 2019. Accessed January 24, 2025. https://www.fda.gov/media/90014/download 
21. Kebilidi accelerated BLA approval letter. FDA. Published November 13, 2024. Accessed January 16, 2025.  https://www.fda.gov/media/183536/download?attachment