Browsing by Author "Lah, Melissa"

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    7519 Withdrawal of DCCR (Diazoxide Choline) Extended-Release Tablets Worsens Hyperphagia and Increases Weight and BMI in a 16-week Double-blind, Placebo-controlled, Randomized Withdrawal Period in Patients with Prader Willi Syndrome
    (Oxford University Press, 2024-10-05) Gevers, Evelien F.; Miller, Jennifer Lynne; Bridges, Nicola Anne; Felner, Eric Ian; Salehi, Parisa; Stevenson, David; Yanovski, Jack; Bird, Lynne; Kimonis, Virginia; Hall Shoemaker, Ashley; Stephens Obrynba, Kathryn; Lah, Melissa; Littlejohn, Elizabeth; Cowen, Neil; Yen, Kristen; Ballal, Shaila; Hirano, Patricia; Huang, Michael; Bhatnagar, Anish; Medical and Molecular Genetics, School of Medicine
    Background: Prader-Willi syndrome (PWS) is a rare genetic neurobehavioral-metabolic disease characterized by hyperphagia, endocrinopathies, weight gain, hypotonia, behavioral problems, and an increased risk of mortality and reduced life expectancy. There are currently no approved treatments for hyperphagia in PWS. Diazoxide choline extended-release (DCCR) is a novel, once daily oral therapy being developed for the treatment of PWS. Herein, we present results of the Randomized Withdrawal Period (RWP) of Clinical Study C602, a long-term treatment study of DCCR in people with PWS. Objectives and Methods: This was a 16-week multi-center, double-blind, placebo-controlled RWP that enrolled participants ≥4 years of age who were actively enrolled in the open label period of Clinical Study C602 and had received 2-4 years of DCCR treatment (target dose: ≥3.3 mg/kg; optimal range: 4.2-5.8 mg/kg) at the time of RWP entry. RWP-eligible participants were randomized 1:1 to continue DCCR or withdraw from DCCR and receive Placebo. The primary objective was to evaluate the effect of continued DCCR administration versus Placebo on hyperphagia based on the change in Hyperphagia Questionnaire for Clinical Trials (HQ-CT) Total Score from Baseline to Week 16. Additional endpoints included: the Clinical Global Impression of Severity (CGI-S) and Clinical Global Impression of Improvement (CGI-I) at Week 16; changes in body composition (weight, BMI, and BMI z-scores) at Week 16; and the safety profile of DCCR. Results: DCCR (n=38) and Placebo (n=39) groups were generally balanced for demographic and baseline characteristics. At Week 16, a statistically significant difference in change from baseline in HQ-CT Total Score was observed between DCCR and Placebo groups with HQ-CT Total Scores increasing markedly (indicating worsening hyperphagia) in the Placebo group compared to the DCCR group (LSMean difference [SE] -5.0 [1.57], p=0.002). CGI-S and CGI-I showed trends towards worsening in the Placebo group versus the DCCR group (p=0.079 and 0.092, respectively). The Placebo group also experienced significantly greater increases in weight, BMI, and BMI z-scores (p=0.035, 0.034, and 0.023, respectively) than the DCCR group. DCCR was well-tolerated, with no new or unexpected safety signals, and no serious adverse events or discontinuations due to adverse events in the DCCR group. Conclusions: In this 16-week RWP, the Placebo group experienced significant worsening in hyperphagia and increases in body weight, BMI, and BMI z-scores, along with worsening trends for the CGI-S and CGI-I, compared to the DCCR group. DCCR was well tolerated, with a safety profile that was consistent with prior experience. These data suggest treatment with DCCR may lead to clinical benefits in people with PWS by reducing hyperphagia and improving body composition.
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    Comparison of willingness and preference for genetic counseling via telemedicine: before vs. during the COVID-19 pandemic
    (Springer, 2022) Allison, Camille O.; Prucka, Sandra K.; Fitzgerald‑Butt, Sara M.; Helm, Benjamin M.; Lah, Melissa; Wetherill, Leah; Baud, Rebecca E.; Medical and Molecular Genetics, School of Medicine
    The COVID-19 pandemic required genetic counseling services, like most outpatient healthcare, to rapidly adopt a telemedicine model. Understanding the trends in patients' preferences for telemedicine relative to in-person service delivery both before and after the advent of the COVID-19 pandemic may aid in navigating how best to integrate telemedicine in a post-COVID-19 era. Our study explored how respondents' willingness to use, and preference for, telemedicine differed from before to after the onset of the COVID-19 pandemic. Respondents included patients, or their parent/guardian, seen in a general medical genetics clinic in 2018, prior to the COVID-19 pandemic, and in 2021, during the COVID-19 pandemic. Respondents were surveyed regarding their willingness to use telemedicine, preference for telemedicine relative to in-person care, and the influence of various factors. Among 69 pre-COVID-19 and 40 current-COVID-19 respondents, there was no shift in willingness to use, or preference for, telemedicine across these time periods. About half of respondents (50.6%) preferred telemedicine visits for the future. Of the 49.4% who preferred in-person visits, 79.1% were still willing to have visits via telemedicine. Predictors of these preferences included comfort with technology and prioritization of convenience of location. This study suggests that a hybrid care model, utilizing telemedicine and in-person service delivery, may be most appropriate to meet the needs of the diverse patients served. Concern for COVID-19 was not found to predict willingness or preference, suggesting that our findings may be generalizable in post-pandemic contexts.
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    Diazoxide Choline Extended-Release Tablet in People With Prader-Willi Syndrome: A Double-Blind, Placebo-Controlled Trial
    (Oxford University Press, 2023) Miller, Jennifer L.; Gevers, Evelien; Bridges, Nicola; Yanovski, Jack A.; Salehi, Parisa; Obrynba, Kathryn S.; Felner, Eric I.; Bird, Lynne M.; Shoemaker, Ashley H.; Angulo, Moris; Butler, Merlin G.; Stevenson, David; Abuzzahab, Jennifer; Barrett, Timothy; Lah, Melissa; Littlejohn, Elizabeth; Mathew, Verghese; Cowen, Neil M.; Bhatnagar, Anish; DESTINY PWS Investigators; Medical and Molecular Genetics, School of Medicine
    Context: Prader-Willi syndrome (PWS) is a rare neurobehavioral-metabolic disease caused by the lack of paternally expressed genes in the chromosome 15q11-q13 region, characterized by hypotonia, neurocognitive problems, behavioral difficulties, endocrinopathies, and hyperphagia resulting in severe obesity if not controlled. Objective: The primary end point was change from baseline in hyperphagia using the Hyperphagia Questionnaire for Clinical Trials (HQ-CT). Other end points included Global Impression Scores, and changes in body composition, behaviors, and hormones. Methods: In DESTINY PWS, a 13-week, randomized, double-blind, placebo-controlled, phase 3 trial, 127 participants with PWS aged 4 years and older with hyperphagia were randomly assigned 2:1 to diazoxide choline extended-release tablet (DCCR) or placebo. Results: DCCR did not significantly improve hyperphagia (HQ-CT least-square mean (LSmean) [SE] -5.94 [0.879] vs -4.27 [1.145]; P = .198), but did so in participants with severe hyperphagia (LSmean [SE] -9.67 [1.429] vs -4.26 [1.896]; P = .012). Two of 3 secondary end points were improved (Clinical Global Impression of Improvement [CGI-I]; P = .029; fat mass; P = .023). In an analysis of results generated pre-COVID, the primary (HQ-CT; P = .037) and secondary end points were all improved (CGI-I; P = .015; Caregiver Global Impression of Change; P = .031; fat mass; P = .003). In general, DCCR was well tolerated with 83.3% in the DCCR group experiencing a treatment-emergent adverse event and 73.8% in the placebo group (not significant). Conclusion: DCCR did not significantly improve hyperphagia in the primary analysis but did in participants with severe baseline hyperphagia and in the pre-COVID analysis. DCCR treatment was associated with significant improvements in body composition and clinician-reported outcomes.
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    A distinct X-linked syndrome involving joint contractures, keloids, large optic cup-to-disc ratio, and renal stones results from a filamin A (FLNA) mutation
    (Wiley, 2016-04-01) Lah, Melissa; Niranjan, Tejasvi; Srikanth, Sujata; Holloway, Lynda; Schwartz, Charles E.; Wang, Tao; Weaver, David D.; Medical and Molecular Genetics, School of Medicine
    We further evaluated a previously reported family with an apparently undescribed X-linked syndrome involving joint contractures, keloids, an increased optic cup-to-disc ratio, and renal stones to elucidate the genetic cause. To do this, we obtained medical histories and performed physical examination on 14 individuals in the family, five of whom are affected males and three are obligate carrier females. Linkage analysis was performed on all but one individual and chromosome X-exome sequencing was done on two affected males. The analysis localized the putative gene to Xq27-qter and chromosome X-exome sequencing revealed a mutation in exon 28 (c.4726G>A) of the filamin A (FLNA) gene, predicting that a conserved glycine had been replaced by arginine at amino acid 1576 (p.G1576R). Segregation analysis demonstrated that all known carrier females tested were heterozygous (G/A), all affected males were hemizygous for the mutation (A allele) and all normal males were hemizygous for the normal G allele. The data and the bioinformatic analysis indicate that the G1576R mutation in the FLNA gene is very likely pathogenic in this family. The syndrome affecting the family shares phenotypic overlap with other syndromes caused by FLNA mutations, but appears to be a distinct phenotype, likely representing a unique genetic syndrome. © 2016 Wiley Periodicals, Inc.
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    Real-world treatment, dosing, and discontinuation patterns among patients treated with pegvaliase for phenylketonuria: Evidence from dispensing data
    (Elsevier, 2022-09-25) Lah, Melissa; Cook, Keziah; Gomes, Dumingu Aparna; Liu, Stephanie; Tabatabaeepour, Nadia; Kirson, Noam; Chen, Er; Lindstrom, Kristin; Bulloch Whitehall, Kaleigh; Van Backle, Joost; Burton, Barbara K.; Medical and Molecular Genetics, School of Medicine
    Background: Phenylketonuria (PKU) is an inborn metabolic error characterized by a deficiency of the enzyme required for the metabolism of phenylalanine, an essential amino acid found in most protein-containing foods. Pegvaliase (Palynziq®) is an enzyme substitution therapy approved for adults with PKU who have inadequate blood phenylalanine control (≥600 μmol/L) on existing management. Objective: To characterize the treatment, discontinuation, and dosing patterns in patients treated with pegvaliase in real-world practice settings in the United States following commercial availability in 2018. Study design: Retrospective cohort study using BioMarin's proprietary drug dispense database associated with the pegvaliase REMS program. Methods: Sample construction identified all patients who properly initiated pegvaliase in real world settings ('full cohort') and a subset of patients ('extended follow-up cohort') with ≥12 months between first dispense of maximum dose and last pegvaliase dispense. Key outcomes were quantified across patients in both cohorts: maximum daily dose; time to maximum daily dose; maximum daily syringes; and dose escalation over time. The overall dose at discontinuation and time to discontinuation were calculated. Patients who subsequently reinitiated therapy were identified. For the extended follow-up cohort, 12-month changes in dose and syringes and dispensing gaps during the 12 months after maximum dose were quantified across all patients and were further stratified by maximum dose. Results: Overall, 1596 patients associated with 33,814 dispenses were reflected in the pegvaliase dispense dataset during the study period from July 9, 2018, through December 31, 2021; 1280 patients associated with 25,973 dispenses met inclusion criteria for the full cohort, with 19.9 dispenses each on average. Of these patients, 483 patients associated with 15,149 dispenses also met the extended follow-up criteria, with an average of 31.4 dispenses.Average treatment duration in the full cohort was 82.2 weeks, including 50.8 weeks after maximum daily dose was achieved. The average maximum daily dose was 30 mg with an average time to maximum dose of 31.8 weeks: 43.0% of patients had a maximum dose of 20 mg, 31.3% a maximum dose of 40 mg, and 12.0% a maximum dose of 60 mg. At data cut-off, 289 patients (22.6%) had discontinued; within this group, 126 patients (43.6%) discontinued within the first 6 months after reaching maximum dose.The overall average treatment duration for patients in the extended follow up cohort at data cut off was 131.2 weeks, including 98.6 weeks after maximum dose was achieved. The average maximum daily dose across the cohort was 32.9 mg: 42.4% of patients had a maximum dose of 20 mg, 41.0% a maximum dose of 40 mg, and 11.2% a maximum dose of 60 mg. At 12 months after achieving maximum dose, 35% of patients had down-dosed, with a 46.8% decrease (on average) from their maximum dose. Conclusions: Real-world use of pegvaliase reflects longer titration periods than in the dosing schedule based on trial experience. Over time, a substantial number of patients are able to reduce their daily dose by titrating down from their maximum dose, a finding of great interest to clinicians and patients alike.
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    Relationship satisfaction in adults with phenylketonuria is positively associated with following recommended treatment, having a partner involved in management, and maintaining good health
    (Springer, 2023) Sundstrom, Rachel; Wetherill, Leah; Sapp, Katie; McPheron, Molly; Lah, Melissa; Medical and Molecular Genetics, School of Medicine
    Rationale: Phenylketonuria (PKU) is a metabolic condition that requires treatment for life. There is increasing evidence that chronic illnesses put strain on relationships and marriages. However, no studies have examined the unique factors that metabolic conditions have on affected individuals and their relationship satisfaction. We surveyed a population of adult patients with PKU and assessed how management, treatment, and lifestyle factors impact their relationship satisfaction. Purpose: The purpose of our study was to explore whether factors such as involvement of partner in PKU management, impact of challenges unique to PKU (e.g., diet, family planning, mood disturbances), and PKU treatment types were associated with the degree of relationship satisfaction. Method: We surveyed adult patients with PKU (n = 82) who were either currently in or had previously been in a long-term relationship. We developed a 78-question survey that included unique questions regarding lifestyle, treatment, and management of their PKU in addition to a validated Relationship Assessment Score. Questions included single choice, multiple choice, and 3 open-ended questions. Results: We found that higher relationship satisfaction was associated with increased partner involvement, increased health, and adherence to recommended PKU treatments. Participants utilizing both diet and pharmaceutical treatment had the highest relationship satisfaction. Finally, participants who reported that their PKU did not contribute to the ending of a previous relationship reported higher relationship satisfaction scores. Conclusion: This study suggests that involvement of partners in the management and treatment of a chronic illness and adherence to recommended treatments can significantly improve relationship satisfaction.
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    Use of pegvaliase in the management of phenylketonuria: Case series of early experience in US clinics
    (Elsevier, 2021-08-14) Adams, Darius; Andersson, Hans C.; Bausell, Heather; Crivelly, Kea; Eggerding, Caroline; Lah, Melissa; Lilienstein, Joshua; Lindstrom, Kristin; McNutt, Markey; Ray, Joseph W.; Saavedra, Heather; Sacharow, Stephanie; Starin, Danielle; Tiffany-Amaro, Jennifer; Thomas, Janet; Vucko, Erika; Wessenberg, Leah B.; Whitehall, Kaleigh; Medical and Molecular Genetics, School of Medicine
    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.