Use of pegvaliase in the management of phenylketonuria: Case series of early experience in US clinics

Objective: To present a case series that illustrates real-world use of pegvaliase based on the initial experiences of US healthcare providers. Methods: Sixteen healthcare providers from 14 centers across the US with substantial clinical experience in treating patients with phenylketonuria (PKU) with pegvaliase in the two-plus years since FDA approval (May 2018) provided cases that exemplified important lessons from their initial experiences treating patients with pegvaliase. Key lessons from each case and takeaway points were discussed in both live and virtual meetings. Results: Fifteen cases of adults with PKU (eight males, seven females), representing a spectrum of age (18 to 53 years), previous PKU care, comorbidities, and socioeconomic situations were reviewed and discussed. Full extended case reports are included in the Supplement. The cases showed that treating patients with a daily injectable can be challenging due to a patient's financial problems, treatment challenges, and neuropsychological and psychiatric comorbidities, which can be identified before starting pegvaliase, but do not prohibit successful treatment. The authors agreed that patient education on adverse events (AEs), time to efficacy, dietary changes, and food preparation is an ongoing process that should start prior to initiating pegvaliase treatment. Treatment goals and planned dietary changes once efficacy is reached should be defined prior to treatment initiation and re-evaluated throughout the course of therapy. Each patient's titration schedule and dietary adjustments are unique, depending on occurrence of AEs and individual goals of treatment. Despite the AE profile of pegvaliase, all but two patients remained motivated to continue treatment and achieved efficacy (except one patient in whom titration was still ongoing). AEs occurring early in the treatment pathway may require prolongation of the titration phase and/or concomitant medication use, but do not seem indicative of future tolerability or eventual efficacy. Close follow-up of patients during titration and maintenance to help with dietary changes is important. Conclusion: This case series provides real-world experience on the use of pegvaliase. Until data from registries and independent research become available, the data presented herein can support appropriate management of patients receiving pegvaliase in clinical practice

Variable disease manifestations and metabolic management within a single family affected by ornithine transcarbamylase deficiency

We report on a family with ornithine transcarbamylase (OTC) deficiency, an X-linked urea cycle disorder, with variable disease severity and tailored management strategies based on each family member's biochemical profile and clinical presentation. Our primary patient is a female monozygotic twin who presented to medical care at 10 months of age with acute liver failure, gastrointestinal symptoms, altered mental status, hypoglycemia, and hyperammonemia. The patient's older brother, known to have hemizygous OTC deficiency, died at 8 months of age from cardiac arrest after complications secondary to his diagnosis. Despite her family history, manifestation of symptoms of heterozygous (partial) OTC deficiency went unrecognized by multiple providers based on misconceptions regarding a female's risk for X-linked disease. Despite barriers related to the family's low socioeconomic status, follow-up care by a multidisciplinary metabolic care team, including moderate protein restriction and nitrogen scavenger therapy, led to positive outcomes for the patient. Her twin sister and mother are also heterozygous for variants in OTC and remain controlled on moderate protein restriction. This case illustrates the importance of genotyping all individuals with genetic risk factors for OTC deficiency and the variability in disease manifestation that necessitates tailored treatment approaches for individuals with partial OTC deficiency

Development of high sustained anti-drug antibody titers and corresponding clinical decline in a late-onset Pompe disease patient after 11+ years on enzyme replacement therapy

A late-onset Pompe disease patient developed high sustained antibody titers (HSAT) of ≥51,200 after 11+ years on alglucosidase alfa and previous tolerance. There was a corresponding worsening of motor function and rise in urinary glucose tetrasaccharide (Glc4). Following immunomodulation therapy, HSAT were eliminated with improved clinical outcomes and biomarker trends. This report highlights the importance of continued surveillance of antibody titers and biomarkers, the negative impact of HSAT, and improved outcomes with immunomodulation therapy

Efficacy and safety of empagliflozin in glycogen storage disease type Ib: Data from an international questionnaire.

PURPOSE This paper aims to report collective information on safety and efficacy of empagliflozin drug repurposing in individuals with glycogen storage disease type Ib (GSD Ib). METHODS This is an international retrospective questionnaire study on the safety and efficacy of empagliflozin use for management of neutropenia/neutrophil dysfunction in patients with GSD Ib, conducted among the respective health care providers from 24 countries across the globe. RESULTS Clinical data from 112 individuals with GSD Ib were evaluated, representing a total of 94 treatment years. The median age at start of empagliflozin treatment was 10.5 years (range = 0-38 years). Empagliflozin showed positive effects on all neutrophil dysfunction-related symptoms, including oral and urogenital mucosal lesions, recurrent infections, skin abscesses, inflammatory bowel disease, and anemia. Before initiating empagliflozin, most patients with GSD Ib were on G-CSF (94/112; 84%). At the time of the survey, 49 of 89 (55%) patients previously treated with G-CSF had completely stopped G-CSF, and another 15 (17%) were able to reduce the dose. The most common adverse event during empagliflozin treatment was hypoglycemia, occurring in 18% of individuals. CONCLUSION Empagliflozin has a favorable effect on neutropenia/neutrophil dysfunction-related symptoms and safety profile in individuals with GSD Ib