Glycogen storage disease type III: a mixed-methods study to assess the burden of disease.

Background: Glycogen storage disease type III (GSD III) is a rare inherited disorder that results from a glycogen debranching enzyme deficiency. Objectives: The purpose of this research was to collect data on the signs, symptoms, and impacts of GSD III from the perspective of adult patients and caregivers of individuals with GSD III. Design: Online survey and qualitative interviews. Methods: Following institutional review board approval, adult patients and caregivers of children with GSD III were recruited through advocacy networks and clinical sites. If eligible, participants were consented, screened, and sent a survey and/or participated in a 60-min interview. The survey and interview included questions about family history, diagnosis, signs and symptoms, impacts, and management of GSD III. Conceptual models were developed following the analysis of results. Results: In all, 29 adults and 46 caregivers completed the online survey and/or the interviews with 73 survey and 19 interview respondents. Adults and caregivers reported digestive, musculoskeletal, growth and physical appearance, and cardiac signs and symptoms. Liver conditions were reported by most respondents (83%). Adults and caregivers frequently reported impacts such as difficulty keeping up with peers (77%) and difficulty exercising/difficulty with physical activity (53%). Hypoglycemia was frequently reported in both adults and children, with more than half reporting hospitalizations due to hypoglycemia. Caregivers focused on hypoglycemia when reporting signs/symptoms that most interfere with their child's life and prevention of hypoglycemia as a desired outcome for an effective therapy. Adults most often reported muscle weakness as a top interfering symptom and the most important goal of a potential therapy. Impacts were also reported in activities of daily living, cognitive, emotional, work/school, and sleep domains. Conclusion: Individuals with GSD III experience a broad spectrum of symptoms and disease impacts. There is an unmet need for therapies that improve metabolic control, reduce the burden of dietary management, reduce fatigue and liver problems, and improve muscle strength and function.

Burosumab Improves Patient-Reported Outcomes in Adults With Tumor-Induced Osteomalacia: Mixed-Methods Analysis.

Tumor-induced osteomalacia (TIO) is an ultra-rare disease caused by tumors that secrete fibroblast growth factor 23, leading to chronic hypophosphatemia, poor skeletal health, and impaired physical function. In a phase 2 trial (UX023T-CL201; NCT02304367; n = 14), 48 weeks of burosumab treatment restored phosphate homeostasis, with improvements in skeletal health, functional mobility, and patient-reported pain, fatigue, and health-related quality of life (HRQL) (SF-36 v2). Here, we report an exploratory mixed-methods analysis of change from baseline after 144 weeks of burosumab treatment alongside qualitative data from exit interviews with 8 of 14 trial participants to evaluate meaningful treatment effects from a patient perspective. The interview subset (n = 8) reported pain and fatigue and compromised HRQL at baseline. In the interviews, participants reported that compromised HRQL and pain were the most important aspects of the disease to treat; both were considered more bothersome than fatigue and compromised physical function and activities of daily living. Improvements in pain and fatigue after treatment were reported, some of which achieved statistically and/or clinically meaningful thresholds. Furthermore, improvements in SF-36 v2 scores were most pronounced in the Physical Component Score and its Physical Function and Bodily Pain domains. Overall, the interview subset provided descriptions of symptomatic improvement and its clinical meaningfulness, including physical function, participation in activities of daily living, and mental well-being. Thus, this exploratory mixed-methods analysis provides deeper understanding of patients' perception of clinical meaningfulness beyond that articulated in validated patient-reported outcome instruments. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

The efficacy and safety of burosumab in two patients with cutaneous skeletal hypophosphatemia syndrome.

Cutaneous skeletal hypophosphatemia syndrome (CSHS) is an ultra-rare mosaic disorder manifesting as skeletal dysplasia and FGF23-mediated hypophosphatemia, with some experiencing extra-osseous/extra-cutaneous manifestations, including both benign and malignant neoplasms. Like other disorders of FGF23-mediated hypophosphatemia including X-linked hypophosphatemia (XLH) and tumor-induced osteomalacia (TIO), patients with CSHS have low serum phosphorus and active 1,25-dihydroxyvitamin D levels. Current treatment options for patients with CSHS include multiple daily doses of oral phosphorus and one or more daily doses of active vitamin D analog to correct the deficits. Recently, the fully human monoclonal antibody against FGF23 burosumab received US approval for the treatment of XLH and TIO, two rare diseases characterized by FGF23-mediated hypophosphatemia leading to rickets and osteomalacia. Given the similarities between the pathobiologies of these disorders and CSHS, we investigated the impact of burosumab on two patients, one pediatric and one adult, with CSHS who participated in separate, but similarly designed trials. In both the pediatric and adult patients, burosumab therapy was well-tolerated and contributed to clinically meaningful improvements in disease outcomes including normalization of phosphorus metabolism and markers of bone health, and improvements in skeletal abnormalities, fractures, and physical function. Reported adverse events were minimal, with only mild injection site reactions attributed to burosumab therapy. Together, these findings suggest that burosumab therapy is a promising therapeutic option for patients with CSHS.

Qualitative evaluation of the symptoms and quality of life impacts of long-chain fatty acid oxidation disorders.

BACKGROUND: Long-chain fatty acid oxidation disorders (LC-FAOD) are a group of rare autosomal-recessive genetic disorders characterized by metabolic deficiencies in which the body is unable to convert long-chain fatty acids into energy. To date, however, there is limited understanding of the patient experience of LC-FAOD. METHODS: The symptoms, observable signs, and quality of life (QoL) impacts associated with LC-FAOD were explored via a focus group (n = 8) and semi-structured interviews (n = 6) with patients and caregivers of patients with LC-FAOD, and interviews (n = 4) with expert clinicians. Data were analyzed via thematic analysis and summarized in a conceptual model. RESULTS: Participants reported a wide range of signs and symptoms associated with LC-FAOD, broadly categorized as musculoskeletal, endocrine/nutritional/metabolic, neurological, gastrointestinal/digestive, sensory, cardiovascular, respiratory, urological, and constitutional. LC-FAOD were reported to have a significant impact on various aspects of patients' lives including physical functioning, participation in daily activities, emotional/psychological wellbeing, and social functioning. Lifestyle modifications (such as diet and exercise restrictions) were necessary because of the condition. Symptoms were typically episodic in presentation often arising or exacerbated during catabolic conditions such as prolonged exercise, fasting, physiological stress, and illness/infection. Symptoms were also commonly reported to lead to emergency room visits, hospitalization, and clinical complications. CONCLUSION: LC-FAOD have a considerable impact on patients' lives. There is a high degree of concordance in the signs, symptoms, and impacts of LC-FAOD reported by patients, caregivers, and clinicians; however, there were many symptoms and impacts that were only reported by patients and caregivers, thus demonstrating that insights from patient/caregiver experience data are integral for informing medical product development and facilitating patient-centered care.

Burosumab for the Treatment of Tumor-Induced Osteomalacia.

Tumor-induced osteomalacia (TIO) is caused by phosphaturic mesenchymal tumors producing fibroblast growth factor 23 (FGF23) and is characterized by impaired phosphate metabolism, skeletal health, and quality of life. UX023T-CL201 is an ongoing, open-label, phase 2 study investigating the safety and efficacy of burosumab, a fully human monoclonal antibody that inhibits FGF23, in adults with TIO or cutaneous skeletal hypophosphatemia syndrome (CSHS). Key endpoints were changes in serum phosphorus and osteomalacia assessed by transiliac bone biopsies at week 48. This report focuses on 14 patients with TIO, excluding two diagnosed with X-linked hypophosphatemia post-enrollment and one with CSHS. Serum phosphorus increased from baseline (0.52 mmol/L) and was maintained after dose titration from week 22 (0.91 mmol/L) to week 144 (0.82 mmol/L, p < 0.0001). Most measures of osteomalacia were improved at week 48: osteoid volume/bone, osteoid thickness, and mineralization lag time decreased; osteoid surface/bone surface showed no change. Of 249 fractures/pseudofractures detected across 14 patients at baseline, 33% were fully healed and 13% were partially healed at week 144. Patients reported a reduction in pain and fatigue and an increase in physical health. Two patients discontinued: one to treat an adverse event (AE) of neoplasm progression and one failed to meet dosing criteria (receiving minimal burosumab). Sixteen serious AEs occurred in seven patients, and there was one death; all serious AEs were considered unrelated to treatment. Nine patients had 16 treatment-related AEs; all were mild to moderate in severity. In adults with TIO, burosumab exhibited an acceptable safety profile and was associated with improvements in phosphate metabolism and osteomalacia. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research..

The long-term safety and efficacy of vestronidase alfa, rhGUS enzyme replacement therapy, in subjects with mucopolysaccharidosis VII.

Vestronidase alfa (recombinant human beta-glucuronidase) is an enzyme replacement therapy (ERT) for Mucopolysaccharidosis (MPS) VII, a highly heterogeneous, ultra-rare disease. Twelve subjects, ages 8-25 years, completed a Phase 3, randomized, placebo-controlled, blind-start, single crossover study (UX003-CL301; NCT02377921), receiving 24-48 weeks of vestronidase alfa 4 mg/kg IV. All 12 subjects completed the blind-start study, which showed significantly reduced urinary glycosaminoglycans (GAG) and clinical improvement in a multi-domain responder index, and enrolled in a long-term, open-label, extension study (UX003-CL202; NCT02432144). Here, we report the final results of the extension study, up to an additional 144 weeks after completion of the blind-start study. Three subjects (25%) completed all 144 weeks of study, eight subjects (67%) ended study participation before Week 144 to switch to commercially available vestronidase alfa, and one subject discontinued due to non-compliance after receiving one infusion of vestronidase alfa in the extension study. The safety profile of vestronidase alfa in the extension study was consistent with observations in the preceding blind-start study, with most adverse events mild to moderate in severity. There were no treatment or study discontinuations due to AEs and no noteworthy changes in a standard safety chemistry panel. Out of the eleven subjects who tested positive for anti-drug antibodies at any time during the blind-start or extension study, including the baseline assessment in the blind-start study, seven subjects tested positive for neutralizing antibodies and all seven continued to demonstrate a reduction in urinary GAG levels. There was no association between antibody formation and infusion associated reactions. Subjects receiving continuous vestronidase alfa treatment showed a sustained urinary GAG reduction and clinical response evaluated using a multi-domain responder index that includes assessments in pulmonary function, motor function, range of motion, mobility, and visual acuity. Reduction in fatigue was also maintained in the overall population. As ERT is not expected to cross the blood brain barrier, limiting the impact on neurological signs of disease, and not all subjects presented with neurological symptoms, outcomes related to central nervous system pathology are not focused on in this report. Results from this study show the long-term safety and durability of clinical efficacy in subjects with MPS VII with long-term vestronidase alfa treatment.

Individual heat map assessments demonstrate vestronidase alfa treatment response in a highly heterogeneous mucopolysaccharidosis VII study population.

Mucopolysaccharidosis (MPS) VII is an ultra-rare, progressively debilitating, life-threatening lysosomal disease caused by deficiency of the enzyme, ß-glucuronidase. Vestronidase alfa is an approved enzyme replacement therapy for MPS VII. UX003-CL301 was a phase 3, randomized, placebo-controlled, blind-start study examining the efficacy and safety of vestronidase alfa 4 mg/kg intravenously administered every 2 weeks to 12 patients with MPS VII. Due to the rarity of disease, broad eligibility criteria resulted in a highly heterogeneous population with variable symptoms. For an integrated view of the diverse data, the changes from baseline (or randomization for the placebo period) in clinical endpoints were grouped into three functional domains (mobility, fatigue, and fine motor + self-care) and analyzed post-hoc as subject-level heat maps. Mobility assessments included the 6-minute walk test, 3-minute stair climb test, Bruininks-Oseretsky test (BOT-2) gross motor function subtests, and patient-reported outcome assessments (PROs) related to movement, pain, and ambulation. Fatigue assessments included the Pediatric Quality of Life Multidimensional Fatigue Scale and other fatigue-related PROs. Fine motor + self-care assessments included BOT-2 fine motor function subtests and PROs for eating, dressing, hygiene, and caregiver assistance. Most subjects showed improvement in at least one domain. Two subjects improved in two or more domains and two subjects did not show clear improvement in any domain. Both severely and mildly affected subjects improved with vestronidase alfa in clinical assessments, PRO results, or both. Heat map analysis demonstrates how subjects responded to treatment across multiple domains, providing a useful visual tool for studying rare diseases with variable symptoms.

Content validity and electronic PRO (ePRO) usability of the Lung Cancer Symptom Scale-Mesothelioma (LCSS-Meso) in mesothelioma patients.

PURPOSE: Obtaining qualitative data directly from the patient perspective enhances the content validity of patient-reported outcome (PRO) instruments. The objective of this qualitative study was to evaluate the content validity of the Lung Cancer Symptom Scale for Mesothelioma (LCSS-Meso) and its usability on an electronic device. METHODS: A cross-sectional methodological study, using a qualitative approach, was conducted among patients recruited from four clinical sites. The primary target population included patients with pleural mesothelioma; data were also collected from patients with peritoneal mesothelioma on an exploratory basis. Semi-structured interviews were conducted consisting of concept elicitation, cognitive interviewing, and evaluation of electronic patient-reported outcome (ePRO) usability. RESULTS: Participants (n = 21) were interviewed in person (n = 9) or by telephone (n = 12); 71% were male with a mean age of 69 years (SD = 14). The most common signs and symptoms experienced by participants with pleural mesothelioma (n = 18) were shortness of breath, fluid build-up, pain, fatigue, coughing, and appetite loss. The most commonly described symptoms for those with peritoneal mesothelioma (n = 4) were bloating, changes in appetite, fatigue, fluid build-up, shortness of breath, and pain. Participants with pleural mesothelioma commonly described symptoms assessed by the LCSS-Meso in language consistent with the questionnaire and a majority understood and easily completed each of the items. The ePRO version was easy to use, and there was no evidence that the electronic formatting changed the way participants responded to the questions. CONCLUSIONS: Results support the content validity of the LCSS-Meso and the usability of the electronic format for use in assessing symptoms among patients with pleural mesothelioma.

Content validity and ePRO usability of the BPI-sf and "worst pain" item with pleural and peritoneal mesothelioma.

BACKGROUND: The Brief Pain Inventory-short form (BPI-sf) is widely used in self-reported pain assessment, incorporates pain numeric rating scales (NRS) and is commonly utilized in electronic format in clinical trials, however, there is no published information about its usability as an electronic patient-reported outcome (ePRO) measure. The objective of this qualitative study was threefold: 1) to better understand pain experiences among patients with pleural or peritoneal mesothelioma; 2) to assess the interpretability of the instructions, item stem, recall period, and response option of the "worst pain" item of the BPI-sf; and 3) to examine the usability of the TrialMax Touch™ (CRF Health, Inc., Plymouth Meeting, PA) screen-based handheld device and the electronic format of the BPI-sf in a sub-sample of pleural mesothelioma patients. METHODS: A cross-sectional qualitative study was conducted among participants with pleural and peritoneal mesothelioma recruited from 4 clinical sites in the US. Semi-structured telephone or in-person interviews were conducted consisting of concept elicitation, cognitive interviewing of the 11-item BPI-sf, and in-person interview evaluation of ePRO assessment usability in pleural mesothelioma patients. RESULTS: Twenty-one participants recruited from 4 clinical sites in the US were interviewed in-person (n = 9) and by telephone (n = 12); 71% male; mean age 68.7 ± 13.6 years. Pleural and peritoneal patients described pain as ranging from discomfort to intense pain and reported being able to distinguish tumor pain from treatment pain. The BPI-sf "worst pain" item was relevant to, and easily understood by, study participants with pleural and peritoneal mesothelioma. The ePRO version was found to be easy to use, but readability of small font may be an issue. Participants reported minimal differences between their responses on the paper and ePRO version for all of the pain severity and pain interference items. CONCLUSIONS: Results support the relevance and ease of understanding of the "worst pain" item and provide support for its content validity in patients with pleural and peritoneal mesothelioma. Usability of the ePRO format of the BPI-sf was confirmed for use in clinical trials among patients with pleural mesothelioma.