Adverse events of pegvaliase in the treatment of phenylketonuria: A pharmacovigilance study based on the FAERS database

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Adverse events of pegvaliase in the treatment of phenylketonuria: A pharmacovigilance study based on the FAERS database

https://doi.org/10.21203/rs.3.rs-4650740/v1

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Pegvaliase was approved by the FDA in 2018 for the treatment of phenylketonuria(PKU).However, the long-term safety of pegvaliase in a large sample population is unclear. The purpose of this study was to investigate the adverse events associated with pegvaliase in the real world by mining data from the FAERS database. We extract adverse event data on pegvaliase from the FAERS database and perform a disproportionality analysis utilizing ROR，PRR，BCPNN and MGPS. A total of 82 preferred terms (PTs) simultaneously met the criteria of all four algorithms. Common PTs include reactions at the injection site，joint pain, sensitivity reactions, headaches, skin reactions, injection site pruritus, and rash pruritic, corresponding to adverse events reported in clinical trials. Unexpected significant adverse events were identified, such as amino acid level decreased or increased, panic attacks, self-injurious ideation, disturbances in attention, tunnel vision, and so on. The median onset time for adverse events to pegvaliase is 15 days(IQR = 9-42 days), with the majority occurring within 30 days (n=509, 67.78%). The top three drugs most commonly prescribed in conjunction with pegvaliase are famotidine, cetirizine, and sapropterin. When pegvaliase is used in combination with these drugs, it is associated with an increase or decrease in the risk of certain adverse events. Our study provides crucial insights for the safer and more effective use of pegvaliase.

Biological sciences/Drug discovery

Biological sciences/Genetics

Health sciences/Medical research

pegvaliase

adverse event

FAERS

pharmacovigilance

data mining

Phenylketonuria is an autosomal recessive disorder. The global prevalence of phenylketonuria is about 1 in 24, 000. The prevalence of phenylketonuria varies among different ethnicities, with the highest prevalence observed in white or East Asian populations. Disparities also exist in prevalence across regions, with the highest prevalence occurring in European and Middle Eastern countries. Among Asian countries, excluding China, the prevalence is comparatively lower¹. Phenylalanine is a necessary amino acid that cannot be produced by the human body and must be acquired through the diet. It undergoes metabolism in the liver. Phenylalanine is converted to tyrosine through the concerted action of phenylalanine hydroxylase and various cofactors such as BH4, molecular oxygen, iron, and DNAJC12 protein^2,3. Tyrosine, under the catalysis of different enzymes through different metabolic pathways, can synthesize various hormones including dopamine, norepinephrine, epinephrine, thyroid hormones, melanin and so on. It is fully metabolized into acetoacetate and fumarate to generate energy^2–4.

Deficiency in phenylalanine hydroxylase or its cofactors leads to obstruction in the phenylalanine metabolic pathway. As a result, phenylalanine is unable to be converted to tyrosine, leading to an accumulation of phenylalanine and a deficiency of tyrosine in the body. Uncontrolled phenylketonuria typically leads to irreversible intellectual disability, epilepsy, psychiatric and behavioral problems, as well as mild hyperpigmentation of the skin and hair, eczema, and musty odor^5,6.

Untreated hyperphenylalaninemia is categorized by blood phenylalanine levels into mild hyperphenylalaninemia(phenylalanine concentrations of 120–360 µmol/l, no treatment necessary) and phenylketonuria(Phe concentrations > 360 µmol/l). Depending on the effectiveness of BH4 treatment, phenylketonuria can be categorized as BH4-responsive phenylketonuria and BH4-unresponsive phenylketonuria.The duration of treatment for untreated phenylketonuria varies depending on the levels of phenylalanine⁶. The current treatment options aim to reduce blood phenylalanine concentrations, including dietary management, pharmacotherapy (with sapropterin and Polyethylene glycolated phenylalanine ammonia lyase), and gene therapy^4,7,8.

Polyethylene glycolated phenylalanine ammonia lyase (PEG-PAL), extracted from the Anabaena variabilis, primarily acts in the liver and kidneys, degrading phenylalanine into ammonia and trans-cinnamic acid. The metabolic waste products are eliminated via urine^9–11. Pegvaliase is the inaugural polyethylene glycolated PAL enzyme that has been sanctioned by the US Food and Drug Administration(FDA) for the management of phenylketonuria. All medications, during the treatment process, may lead to more or less, or severe or mild adverse events. Pegvaliase treatment for phenylketonuria can also result in adverse events. Common adverse events to pegvaliase include injection site reactions, fatigue, arthralgia, allergic reactions, dizziness, headache, generalized skin reactions, nausea, abdominal pain, diarrhea, vomiting, cough, oropharyngeal pain, pruritus, anxiety, as well as nasal congestion^12,13. These adverse events not only affect the effectiveness of treatment but may also result in more severe consequences.

The FDA Adverse Event Reporting System(FAERS) collects drug-related adverse events and other associated information, providing the potential for utilizing large-scale data to explore drug adverse events. This study aims to explore the adverse events of pegvaliase by conducting disproportionality analysis on the data related to pegvaliase within the FAERS database.

This study conducted pharmacovigilance analysis using data extracted from the FAERS database, which is dedicated to collecting adverse event data of post-market drugs. The FAERS database encompasses seven categories of data: demographics(DEMO), drug information(DRUG), therapy duration(THER), outcomes(OUTC), adverse event coding(REAC), report sources(RPSR), and drug indications for administration(INDI). In the FAERS database, adverse events are encoded using PTs from the Medical Dictionary of Regulatory Activities(MedDRA)(version 26.1), where one PT may correspond to one or multiple higher-level group terms(HLGT), higher-level terms(HLT), and system organ classes(SOC) within MedDRA.

This study retrospectively searched data submitted to the FDA from Q2 2018 through Q4 2023, and the raw data were rigorously cleaned using software R4.3.3, including the removal of duplicate reports, PTs related to pegvaliase indications, and PTs that were clearly unrelated to the drug, in order to obtain the target data. In this study, we conducted disproportionality analyses, including Reporting Odds Ratios(ROR), Proportional Reporting Ratios(PRR), Bayesian Confidence Propagation Neural Network(BCPNN), and Multiple Gamma Poisson Shrinker(MGPS), to comprehensively analyze the safety and potential risks of pegvaliase. The parameters required for the four algorithms are calculated based on the 2 × 2 contingency table, which is provided specifically in Table 1. The precise formulas and signal detection criteria for the four algorithms are detailed in Table 2.

General characteristics

A total of 5372 AE cases and 13010 AE reports related to pegvaliase were included in this study, and baseline information on patients using pegvaliase is presented in Table 3. Out of the reporters, the majority were consumers, with 4500 cases, making up 83.8% of the total.The United States had the highest number of reports, with 5, 269 cases, making up 98.1% of the total. The number of reported adverse events fluctuated between 2018 and 2023, with 2021 being the most reported year(n = 1137, 21.17%). The least reported year was 2018(n = 145, 2.7%). In terms of clinical outcomes, the most common event resulting in hospitalization or prolonged hospitalization was observed in 165 cases(3.0%), excluding instances of unknown outcomes and other unspecified serious adverse events.

Signal detection

Signal strengths and reports of pegvaliase at the SOC level are described in Table 4. Statistically, pegvaliase-associated AEs occurrence targeted 26 SOCs. According to the ROR method, the top three ranked SOCs are immune system disorders, musculoskeletal and connective tissue disorders, and general disorders and administration site conditions. As shown in Fig. 1, a total of 89 PTs meeting all four algorithms simultaneously were identified. After excluding PTs related to pegvaliase indications and those clearly unrelated to pegvaliase, 82 PTs meeting all four algorithms simultaneously were identified, as shown in Table 5. The top 10 PTs with the highest report counts are shown in Fig. 2. By comparing the study results with the prescribing information for pegvaliase, it was found that 37 PTs were consistent with the product labeling and warnings. These may include reactions at the injection site, joint pain, sensitivity reactions, headaches, skin reactions, and rash pruritic. At the same time, new valuable potential adverse events were identified, such as amino acid level decreased or increased, panic attacks, self-injurious ideation, disturbances in attention, tunnel vision, as well as various adverse events belonging to the respiratory, thoracic, and mediastinal disorders, ear and labyrinth disorders, immune system disorders, gastrointestinal disorders, investigations, infections and infestations, vascular disorders, blood and lymphatic system disorders, injury, poisoning and procedural complications, musculoskeletal and connective tissue disorders, psychiatric disorders, eye disorders.

Time-to-onset analysis

In total, 751 reports of AE associated with Pegvaliase provided the time of onset, with a median onset time of 15 days (IQR 9–42 days). As shown in Fig. 3, the results of the study indicated that the majority of AE cases occurred within 30 days (n = 509, 67.78%). However, AEs may still occur one year later after Pegvaliase initiation. (n = 28, 3.73%).

Subgroup analyses

This study demonstrated that the top three drugs most commonly used in combination with pegvaliase are famotidine (773 cases), cetirizine (479 cases), and Sapropterin (340 cases). When pegvaliase is combined with famotidine, the signal strengths and reports at the SOC level are shown in Supplementary Table S1. A total of 50 PTs meeting all four algorithms simultaneously were identified, as shown in Supplementary Table S2. In the group of pegvanlise combined with cetirizine, the signal strengths and reports at the SOC level are shown in Supplementary Table S3. A total of 53 PTs meeting all four algorithms simultaneously were identified, as shown in Supplementary Table S4. In the pegvanlise combined with Sapropterin group, the signal strengths and reports at the SOC level are shown in Supplementary Table S5. A total of 32 PTs meeting all four algorithms simultaneously were identified, as shown in Supplementary Table S6.

FAERS, a spontaneous reporting system used to investigate drug safety after market approval, has been extensively utilized to identify adverse events that may not be listed on drug labels. This study conducted a comprehensive post-market pharmacovigilance analysis of pegvaliase-related adverse events using the FAERS database, with the aim of providing clinical pharmacotherapy reference. Excluding cases with missing age data, most of the adverse events related to pegvaliase occurred in adults.There are several reasons for this phenomenon the bulk of pegvaliase case reports come from the United States, where pegvaliase is mainly authorized for phenylketonuria patients aged 18 and above, pegvaliase was introduced to the market earlier in the United States, and there is typically a greater inclination to report adverse events in the United States. Excluding cases with unknown gender, the incidence of adverse events related to pegvaliase was higher in females than in males, suggesting a potential gender-related association with pegvaliase adverse events. It's worth noting that gender-related information was missing in 35.1% of patients, which could lead to biased results. Among all the reported years, the number of cases reported in 2018 was the lowest.One possible reason for this is that pegvaliase was approved for phenylketonuria treatment in May 2018.

The most common AEs associated with Pegvaliase include arthralgia, hypersensitivity reactions, headache, skin reactions, pruritic rash, and injection site reactions. Our research indicates that more than half of these common AEs are related to injection site reactions. In clinical practice, to prevent injection site reactions, patients are encouraged to rotate their injection sites. If multiple injections are required for a single dose, the injection sites should be at least 2 inches apart¹⁴. Following the occurrence of injection site reactions, treatment with H1 receptor antagonists, topical steroids, cold compresses or discontinuation of pegvaliase is recommended¹⁵.

Researchs suggest that higher and more frequent doses of pegvaliase can lead to a significant initial decreasein blood phenylalanine levels but may also increase the frequency of hypersensitivity adverse events. This could prompt a reduction or interruption in pegvaliase dosage, resulting in elevated blood phenylalanine levels. On the other hand, with the escalation in pegvaliase dosage and treatment duration, there is a trend towards a decrease and stabilization in the frequency of hypersensitivity adverse events, alongside a notable and consistent reduction in blood phenylalanine levels^12,15,16. Patients with phenylketonuria may experience psychological and neurological disorders such as fear, self-harm, vision loss, attention deficit, and others^17–21. Therefore, the occurrence of panic attacks, self-injurious ideation, tunnel vision, and attention disturbances could either be complications of phenylketonuria or adverse events resulting from the use of pegvaliase, requiring further exploration.

The study results indicate that the median onset time for adverse events was 15 days, with most adverse events occurring within 30 days. Nevertheless, negative incidents may still happen even a year later. Therefore, clinical practitioners should closely monitor adverse events in users of pegvaliase, especially within the first 30 days. Additionally, longer-term follow-up is warranted for patients receiving pegvaliase treatment.

The top three drugs most commonly prescribed in conjunction with pegvaliase are famotidine, cetirizine, and sapropterin. Famotidine is an H2 receptor antagonist commonly used to treat gastrointestinal disorders. At the SOC level, based on signal strength ranked by MGPS method, the signal intensity of gastrointestinal disorders with pegvaliase, whether used alone or in combination with other drugs, is stronger than when pegvaliase is combined with famotidine, suggesting that combining famotidine with pegvaliase is associated with a reduced risk of gastrointestinal disorders.

Antihistamines are commonly utilized in the management of both allergic and non-allergic conditions.There are four subtypes of histamine receptors, with H1-antihistamines being the largest category of drugs used for allergic diseases. Cetirizine is a second-generation H1-antihistamines with strong efficacy in allergic rhinitis, allergic conjunctivitis, and urticaria^22–26. When pegvaliase is used alone or in combination with other drugs, it is possible to detect signs of allergic rhinitis(ROR = 5.36) and urticaria(ROR = 10.59). However, when pegvaliase is used in combination with cetirizine, only a signal for urticaria(ROR = 10.10) is identified, indicating that the combination of pegvaliase and cetirizine is associated with a reduced risk of allergic rhinitis and urticaria.

Tetrahydrobiopterin(BH4) serves as a cofactor for various enzymes and is involved in the breakdown of phenylalanine in individuals with BH4-responsive phenylketonuria, leading to a decrease in blood phenylalanine levels. The first synthetic form of BH4 appeared in the 1970s, namely sapropterin, which was approved for the treatment of phenylketonuria in 2007. Common adverse events in patients using sapropterin include headache, rhinorrhea, pharyngitis, vomiting, diarrhea, nasal congestion, cough, and abrasions^27–32. However, little is currently known about the adverse events of pegvaliase in combination with sapropterin. Disproportionality analysis indicates that whether pegvaliase is used alone or in combination with other drugs, compared to when combined with sapropterin, the top three adverse events at the SOC level are immune system disorders, musculoskeletal and connective tissue disorders, and general disorders and administration site conditions. Furthermore, the signal intensity derived from the combination of pegvaliase and sapropterin is stronger than that from pegvaliase used alone or in combination with other drugs. This indicates that the co-administration of pegvaliase with sapropterin increases the risk of certain adverse events. Therefore, clinicians should exercise heightened vigilance regarding the occurrence of such adverse events in clinical practice.

This real-world observational study, despite having a large sample of data, has limitations.The research primarily relied on the FAERS database, which is a spontaneous reporting system. This may lead to incomplete and inaccurate data collection due to variations in reporting practices across different countries and individuals, posing risks of data bias. Since all data are voluntarily reported by relevant individuals, data gaps are inevitable, potentially leading to biases in analysis. The study lacks the total population receiving pegvaliase treatment, thus making it impossible to precisely calculate the true incidence of each adverse event. The analysis of adverse events only provides estimates of signal strength without quantifying risks or inferring causality.Hence, additional clinical trials will be required in the future to establish causal relationships between drug usage and negative effects. Further mechanistic studies are needed to better understand the clinical significance of the newly identified adverse events and to develop appropriate interventions. Although it has certain limitations, the FAERS database continues to be a distinctive and crucial tool for monitoring the safety of approved drugs in the post-market phase.

Conclusively, although many clinical trials have confirmed the efficacy and safety of pegavarase in the treatment of phenylketonuria, previous studies have been limited by small sample sizes, and the exploration of adverse events of pegavarase has become particularly urgent as its use continues to increase. This study provides a comprehensive and systematic analysis of drug vigilance in the FAERS database, revealing the safety profile of pegvaliase.Our research offers valuable evidence for further investigation and clinical practice involving pegvaliase.

Acknowledgements

We appreciate the FAERS open policy and the provided data, as well as all participants in this study.

Author contributions

Junfa Liu: Writing – original draft, Methodology, Investigation, Formal analysis, Data curation, Conceptualization. Zhe Chen : Investigation, Formal analysis, Data curation. Xiongfei Liu: Methodology, Investigation. Xiangyang Li: Supervision, Investigation, Conceptualization. Zhitao Dong: Writing – review & editing, Writing – original draft, Supervision, Investigation, Conceptualization.

Funding

The authors declare that no financial support was received for the research.

Data availability

The publicly available datasets used in the analysis of this study can be found online at: https://www.fda.gov/. Dataset generated in this study are available from the corresponding author on reasonable request.

Competing interests

The authors declare no competing interests.

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Tables 1 to 5 are available in the Supplementary Files section

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Adverse events of pegvaliase in the treatment of phenylketonuria: A pharmacovigilance study based on the FAERS database

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