Sapropterin

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Barbara K Burton - One of the best experts on this subject based on the ideXlab platform.

  • long term preservation of intellectual functioning in Sapropterin treated infants and young children with phenylketonuria a seven year analysis
    Molecular Genetics and Metabolism, 2021
    Co-Authors: Susan E Waisbren, Barbara K Burton, Annette Feigenbaum, Amarilis Sanchezvalle, Laura Konczal, Joshua Lilienstein, Shawn E Mccandless, Richard Rowell, Kaleigh Whitehall, Nicola Longo
    Abstract:

    Abstract Sapropterin dihydrochloride has been approved for the treatment of hyperphenylalaninemia in infants and young children with phenylketonuria (PKU). Sapropterin can reduce phenylalanine (Phe) levels in tetrahydrobiopterin (BH4)-responsive patients, potentially preventing the intellectual impairment caused by elevated Phe levels. The long-term effect of Sapropterin on intellectual functioning was assessed using the Full-Scale Intelligence Quotient (FSIQ) in 62 children who began treatment before the age of 6 years. Over each 2-year interval, the estimate of mean change in FSIQ was −0.5768 with a lower limit of the 95% confidence interval (CI) of −1.60. At the end of the follow-up period (Year 7), the least squares mean estimate of the change in FSIQ from baseline was 1.14 with a lower limit of the 95% CI of −3.53. These lower limits were both within the clinically expected variation of 5 points. During the whole study period, mean blood Phe levels remained within the American College of Medical Genetics (ACMG) target range of 120–360 μmol/L. In addition, height, weight, and head circumference were maintained within normal ranges throughout follow-up, as defined by growth charts from the World Health Organization (WHO) and Centers for Disease Control and Prevention (CDC) for children below and above the age of 24 months, respectively. All patients (n = 65) enrolled in this study experienced at least one adverse event, as expected from previous studies. In conclusion, long-term use of Sapropterin in individuals with PKU helps to control blood Phe, preserve intellectual functioning, and maintain normal growth in BH4-responsive children who initiated treatment between the ages of 0 to 6 years.

  • long term developmental progression in infants and young children taking Sapropterin for phenylketonuria a two year analysis of safety and efficacy
    Genetics in Medicine, 2015
    Co-Authors: Nicola Longo, Elaina Jurecki, Barbara K Burton, Annette Feigenbaum, Susan E Waisbren, Komudi Siriwardena, David Dimmock, Sylvia Stockler, William Lang, Charlie Zhang
    Abstract:

    Long-term developmental progression in infants and young children taking Sapropterin for phenylketonuria: a two-year analysis of safety and efficacy

  • a randomized placebo controlled double blind study of Sapropterin to treat adhd symptoms and executive function impairment in children and adults with Sapropterin responsive phenylketonuria
    Molecular Genetics and Metabolism, 2015
    Co-Authors: Barbara K Burton, Mitzie Grant, Annette Feigenbaum, Rani H Singh, Robert L Hendren, K Siriwardena, John A Phillips, Amarilis Sanchezvalle, Susan E Waisbren, J Gillis
    Abstract:

    Symptoms of attention deficit-hyperactivity disorder (ADHD), particularly inattention, and impairments in executive functioning have been reported in early and continuously treated children, adolescents, and adults with phenylketonuria (PKU). In addition, higher blood phenylalanine (Phe) levels have been correlated with the presence of ADHD symptoms and executive functioning impairment. The placebo-controlled PKU ASCEND study evaluated the effects of Sapropterin therapy on PKU-associated symptoms of ADHD and executive and global functioning in individuals who had a therapeutic blood Phe response to Sapropterin therapy. The presence of ADHD inattentive symptoms and executive functioning deficits was confirmed in this large cohort of 206 children and adults with PKU, of whom 118 responded to Sapropterin therapy. In the 38 individuals with Sapropterin-responsive PKU and ADHD symptoms at baseline, Sapropterin therapy resulted in a significant improvement in ADHD inattentive symptoms in the first 4 weeks of treatment, and improvements were maintained throughout the 26 weeks of treatment. Sapropterin was well-tolerated with a favorable safety profile. The improvements in ADHD inattentive symptoms and aspects of executive functioning in response to Sapropterin therapy noted in a large cohort of individuals with PKU indicate that these symptoms are potentially reversible when blood Phe levels are reduced.

  • Sapropterin dihydrochloride use in pregnant women with phenylketonuria an interim report of the pku moms sub registry
    Molecular Genetics and Metabolism, 2014
    Co-Authors: Dorothy K Grange, John J Mahoney, Barbara K Burton, Richard Hillman, Shoji Yano, Jerry Vockley, C T Fong, Joellen Hunt, Jessica L Cohenpfeffer
    Abstract:

    For pregnant women with phenylketonuria (PKU), maintaining blood phenylalanine (Phe) 360μmol/L. Severe adverse events identified by the investigators as possibly related to Sapropterin use were premature labor (N=1) and spontaneous abortion (N=1) for the women and hypophagia for the offspring [premature birth (35w4d), N=1]. One congenital malformation (cleft palate) of unknown etiology was reported as unrelated to Sapropterin. Although there is limited information regarding the use of Sapropterin during pregnancy, these sub-registry data show that Sapropterin was generally well-tolerated and its use during pregnancy was associated with lower mean blood Phe. Because the teratogenicity of elevated maternal blood Phe is without question, Sapropterin should be considered as a treatment option in pregnant women with PKU who cannot achieve recommended ranges of blood Phe with dietary therapy alone.

  • safety of extended treatment with Sapropterin dihydrochloride in patients with phenylketonuria results of a phase 3b study
    Molecular Genetics and Metabolism, 2011
    Co-Authors: Barbara K Burton, Maria Nowacka, Julia B Hennermann, Mark Lipson, Dorothy K Grange, Anupam Chakrapani, Friedrich K Trefz, Alex Dorenbaum, Michael Imperiale, Sun Sook Kim
    Abstract:

    Abstract Background Phenylketonuria (PKU) results from impaired breakdown of phenylalanine (Phe) due to deficient phenylalanine hydroxylase (PAH) activity. Sapropterin dihydrochloride (Sapropterin, Kuvan®) is the only US- and EU-approved pharmaceutical version of naturally occurring 6R-BH 4 , the cofactor required for PAH activity. Sapropterin enhances residual PAH activity in Sapropterin-responsive PKU patients and, in conjunction with dietary management, helps reduce blood Phe concentrations for optimal control. Approval was based on the positive safety and efficacy results of four international clinical studies, the longest of which was 22 weeks in duration. Objective To evaluate the safety of long-term treatment with Sapropterin in PKU subjects who participated in previous Phase 3 Sapropterin trials. Methods PKU-008 was designed as a Phase 3b, multicenter, multinational, open-label, 3-year extension trial to evaluate the long-term safety of Sapropterin in patients with PKU who were classified as Sapropterin responders and participated in prior Phase 3 Sapropterin studies: 111 subjects aged 4–50 years completed prior studies and were subsequently enrolled in study PKU-008. Routine safety monitoring was performed at 3-month intervals and included adverse event reporting, blood Phe monitoring, clinical laboratory evaluations, physical examinations and vital sign measurements. Results Average exposure during PKU-008 was 658.7 ± 221.3 days (range, 56–953; median, 595). The average total duration of participation in multiple studies (PKU-001, PKU-003, PKU-004, and PKU-008; or PKU-006 and PKU-008) was 799.0 ± 237.5 days (range, 135-1151). The mean Sapropterin dose was 16.2 ± 4.7 mg/kg/day. Most adverse events were considered unrelated to treatment, were mild or moderate in severity, and were consistent with prior studies of Sapropterin. No age-specific differences were observed in adverse event reporting. Three subjects discontinued treatment due to adverse events that were considered possibly or probably related to study treatment (one each of difficulty concentrating, decreased platelet count, and intermittent diarrhea). No deaths were reported. Of seven reported serious adverse events, one was considered possibly related to study treatment (gastroesophageal reflux). There were no laboratory or physical examination abnormalities requiring medical interventions. For most subjects, blood Phe concentrations were consistently within target range, confirming the durability of response in subjects undergoing extended treatment with Sapropterin. Conclusion Sapropterin treatment was found to be safe and well tolerated at doses of 5 to 20 mg/kg/day for an average exposure of 659 days. This study supports the safety and tolerability of Sapropterin as long-term treatment for patients with PKU.

Ania C Muntau - One of the best experts on this subject based on the ideXlab platform.

  • long term efficacy and safety of Sapropterin in patients who initiated Sapropterin at 4 years of age with phenylketonuria results of the 3 year extension of the spark open label multicentre randomised phase iiib trial
    Orphanet Journal of Rare Diseases, 2021
    Co-Authors: Ania C Muntau, Vincenzo Leuzzi, Alberto Burlina, Francois Eyskens, Peter Freisinger, Hatice Serap Sivri, Gwendolyn Gramer, Renata Pazdirkova, Maureen Cleary, Amelia S Lotzhavla
    Abstract:

    During the initial 26-week SPARK (Safety Paediatric efficAcy phaRmacokinetic with Kuvan®) study, addition of Sapropterin dihydrochloride (Kuvan®; a synthetic formulation of the natural cofactor for phenylalanine hydroxylase, tetrahydrobiopterin; BH4), to a phenylalanine (Phe)-restricted diet, led to a significant improvement in Phe tolerance versus a Phe-restricted diet alone in patients aged 0–4 years with BH4-responsive phenylketonuria (PKU) or mild hyperphenylalaninaemia (HPA). Based on these results, the approved indication for Sapropterin in Europe was expanded to include patients < 4 years of age. Herein, we present results of the SPARK extension study (NCT01376908), evaluating the long-term safety, dietary Phe tolerance, blood Phe concentrations and neurodevelopmental outcomes in patients < 4 years of age at randomisation, over an additional 36 months of treatment with Sapropterin. All 51 patients who completed the 26-week SPARK study period entered the extension period. Patients who were previously treated with a Phe-restricted diet only (‘Sapropterin extension’ group; n = 26), were initiated on Sapropterin at 10 mg/kg/day, which could be increased up to 20 mg/kg/day. Patients previously treated with Sapropterin plus Phe-restricted diet, remained on this regimen in the extension period (‘Sapropterin continuous’ group; n = 25). Dietary Phe tolerance increased significantly at the end of the study versus baseline (week 0), by 38.7 mg/kg/day in the ‘Sapropterin continuous’ group (95% CI 28.9, 48.6; p < 0.0001). In the ‘Sapropterin extension’ group, a less pronounced effect was observed, with significant differences versus baseline (week 27) only observed between months 9 and 21; dietary Phe tolerance at the end of study increased by 5.5 mg/kg/day versus baseline (95% CI − 2.8, 13.8; p = 0.1929). Patients in both groups had normal neuromotor development and growth parameters. Long-term treatment with Sapropterin plus a Phe-restricted diet in patients who initiated Sapropterin at < 4 years of age with BH4-responsive PKU or mild HPA maintained improvements in dietary Phe tolerance over 3.5 years. These results continue to support the favourable risk/benefit profile for Sapropterin in paediatric patients (< 4 years of age) with BH4-responsive PKU. Frequent monitoring of blood Phe levels and careful titration of dietary Phe intake to ensure adequate levels of protein intake is necessary to optimise the benefits of Sapropterin treatment. Trial registration ClinicalTrials.gov, NCT01376908. Registered 17 June 2011, https://clinicaltrials.gov/ct2/show/NCT01376908 .

  • international best practice for the evaluation of responsiveness to Sapropterin dihydrochloride in patients with phenylketonuria
    Molecular Genetics and Metabolism, 2019
    Co-Authors: Ania C Muntau, R Cerone, Turgay Coskun, Amaya Belangerquintana, Darius J Adams, Tatiana V Bushueva, Yinhsiu Chien, Ana Chiesa, Javier De Las Heras, Francois Feillet
    Abstract:

    Abstract Phenylketonuria (PKU) is an inherited metabolic disease caused by phenylalanine hydroxylase (PAH) deficiency. As the resulting high blood phenylalanine (Phe) concentration can have detrimental effects on brain development and function, international guidelines recommend lifelong control of blood Phe concentration with dietary and/or medical therapy. Sapropterin dihydrochloride is a synthetic preparation of tetrahydrobiopterin (6R-BH4), the naturally occurring cofactor of PAH. It acts as a pharmacological chaperone, reducing blood Phe concentration and increasing dietary Phe tolerance in BH4-responsive patients with PAH deficiency. Protocols to establish responsiveness to Sapropterin dihydrochloride vary widely. Two meetings were held with an international panel of clinical experts in PKU management to develop recommendations for Sapropterin dihydrochloride response testing. At the first meeting, regional differences and similarities in testing practices were discussed based on guidelines, a literature review, outcomes of a global physician survey, and case reports. Statements developed based on the discussions were sent to all participants for consensus (>70% of participants) evaluation using a 7-level rating system, and further discussed during the second meeting. The experts recommend Sapropterin dihydrochloride response testing in patients with untreated blood Phe concentrations of 360–2000 μmol/L, except in those with two null mutations. For neonates, a 24-h Sapropterin dihydrochloride loading test is recommended; responsiveness is defined as a decrease in blood Phe ≥30%. For older infants, children, adolescents, and adults, a test duration of ≥48 h or a 4-week trial is recommended. The main endpoint for a 48-h to 7-day trial is a decrease in blood Phe, while improved Phe tolerance is the endpoint to be assessed during a longer trial. Longer trials may not be feasible in some locations due to lack of reimbursement for hospitalization, while a 4-week trial may not be possible due to limited access to Sapropterin dihydrochloride or public health regulation. A 48-h response test should be considered in pregnant patients who cannot achieve blood Phe ≤360 μmol/L with a Phe-restricted diet. Durability of response and clinical benefits of Sapropterin dihydrochloride should be assessed over the long term. Harmonization of protocols is expected to improve identification of responders and comparability of test results worldwide.

  • diagnostic and therapeutic recommendations for the treatment of hyperphenylalaninemia in patients 0 4 years of age
    Orphanet Journal of Rare Diseases, 2018
    Co-Authors: Ania C Muntau, Marcel Du Moulin, Francois Feillet
    Abstract:

    Treatment of phenylketonuria (PKU) with Sapropterin dihydrochloride in responsive patients from an early age can have many advantages for the patient over dietary restriction alone. Accordingly, approval of Sapropterin in the European Union was extended in 2015 to include patients aged 0–4 years, bringing the treatment age range in line with that in the USA and providing an additional treatment option for those patients with PKU who are responsive or partially responsive to treatment with Sapropterin. Subsequently, European guidelines have been published on the diagnosis and management of patients with PKU. However, testing for PKU can be demanding and requires particular expertise. We have compiled experience-based, real-world guidance in an algorithmic format to complement the published guidelines, with the overall aim to achieve optimized and individualized care for patients with PKU. Our guidance covers aspects such as how to perform, monitor and interpret appropriate biochemical measures to achieve effective patient management and desired outcomes, how to perform a tetrahydrobiopterin (BH4) loading test to assess responsiveness in newborns, and how to initiate Sapropterin treatment in patients from birth. We also provide our expert opinion on starting pharmacotherapy in patients who were previously managed by diet alone. Real-world-based guidance is particularly important in managing therapeutic strategies in newborns with PKU to achieve optimal long-term outcomes and will serve as a complement to the other published guidelines.

  • Diagnostic and therapeutic recommendations for the treatment of hyperphenylalaninemia in patients 0–4 years of age
    'Springer Science and Business Media LLC', 2018
    Co-Authors: Ania C Muntau, Marcel Du Moulin, Francois Feillet
    Abstract:

    Abstract Background Treatment of phenylketonuria (PKU) with Sapropterin dihydrochloride in responsive patients from an early age can have many advantages for the patient over dietary restriction alone. Accordingly, approval of Sapropterin in the European Union was extended in 2015 to include patients aged 0–4 years, bringing the treatment age range in line with that in the USA and providing an additional treatment option for those patients with PKU who are responsive or partially responsive to treatment with Sapropterin. Subsequently, European guidelines have been published on the diagnosis and management of patients with PKU. However, testing for PKU can be demanding and requires particular expertise. We have compiled experience-based, real-world guidance in an algorithmic format to complement the published guidelines, with the overall aim to achieve optimized and individualized care for patients with PKU. Results Our guidance covers aspects such as how to perform, monitor and interpret appropriate biochemical measures to achieve effective patient management and desired outcomes, how to perform a tetrahydrobiopterin (BH4) loading test to assess responsiveness in newborns, and how to initiate Sapropterin treatment in patients from birth. We also provide our expert opinion on starting pharmacotherapy in patients who were previously managed by diet alone. Conclusions Real-world-based guidance is particularly important in managing therapeutic strategies in newborns with PKU to achieve optimal long-term outcomes and will serve as a complement to the other published guidelines

  • efficacy safety and population pharmacokinetics of Sapropterin in pku patients 4 years results from the spark open label multicentre randomized phase iiib trial
    Orphanet Journal of Rare Diseases, 2017
    Co-Authors: Ania C Muntau, Vincenzo Leuzzi, Alberto Burlina, Francois Eyskens, Peter Freisinger, Corinne De Laet, Frank Rutsch, Serap H Sivri, Suresh Vijay, Milva Orquidea Bal
    Abstract:

    Sapropterin dihydrochloride, a synthetic formulation of BH4, the cofactor for phenylalanine hydroxylase (PAH, EC 1.14.16.1), was initially approved in Europe only for patients ≥4 years with BH4-responsive phenylketonuria. The aim of the SPARK (Safety Paediatric efficAcy phaRmacokinetic with Kuvan®) trial was to assess the efficacy (improvement in daily phenylalanine tolerance, neuromotor development and growth parameters), safety and pharmacokinetics of Sapropterin dihydrochloride in children <4 years. In total, 109 male or female children <4 years with confirmed BH4-responsive phenylketonuria or mild hyperphenylalaninemia and good adherence to dietary treatment were screened. 56 patients were randomly assigned (1:1) to 10 mg/kg/day oral Sapropterin plus a phenylalanine-restricted diet or to only a phenylalanine-restricted diet for 26 weeks (27 to the Sapropterin and diet group and 29 to the diet-only group; intention-to-treat population). Of these, 52 patients with ≥1 pharmacokinetic sample were included in the pharmacokinetic analysis, and 54 patients were included in the safety analysis. At week 26 in the Sapropterin plus diet group, mean phenylalanine tolerance was 30.5 (95% confidence interval 18.7–42.3) mg/kg/day higher than in the diet-only group (p < 0.001). The safety profile of Sapropterin, measured monthly, was acceptable and consistent with that seen in studies of older children. Using non-linear mixed effect modelling, a one-compartment model with flip-flop pharmacokinetic behaviour, in which the effect of weight was substantial, best described the pharmacokinetic profile. Patients in both groups had normal neuromotor development and stable growth parameters. The addition of Sapropterin to a phenylalanine-restricted diet was well tolerated and led to a significant improvement in phenylalanine tolerance in children <4 years with BH4-responsive phenylketonuria or mild hyperphenylalaninemia. The pharmacokinetic model favours once per day dosing with adjustment for weight. Based on the SPARK trial results, Sapropterin has received EU approval to treat patients <4 years with BH4-responsive phenylketonuria. ClinicalTrials.gov, NCT01376908 . Registered June 17, 2011.

Francois Feillet - One of the best experts on this subject based on the ideXlab platform.

  • international best practice for the evaluation of responsiveness to Sapropterin dihydrochloride in patients with phenylketonuria
    Molecular Genetics and Metabolism, 2019
    Co-Authors: Ania C Muntau, R Cerone, Turgay Coskun, Amaya Belangerquintana, Darius J Adams, Tatiana V Bushueva, Yinhsiu Chien, Ana Chiesa, Javier De Las Heras, Francois Feillet
    Abstract:

    Abstract Phenylketonuria (PKU) is an inherited metabolic disease caused by phenylalanine hydroxylase (PAH) deficiency. As the resulting high blood phenylalanine (Phe) concentration can have detrimental effects on brain development and function, international guidelines recommend lifelong control of blood Phe concentration with dietary and/or medical therapy. Sapropterin dihydrochloride is a synthetic preparation of tetrahydrobiopterin (6R-BH4), the naturally occurring cofactor of PAH. It acts as a pharmacological chaperone, reducing blood Phe concentration and increasing dietary Phe tolerance in BH4-responsive patients with PAH deficiency. Protocols to establish responsiveness to Sapropterin dihydrochloride vary widely. Two meetings were held with an international panel of clinical experts in PKU management to develop recommendations for Sapropterin dihydrochloride response testing. At the first meeting, regional differences and similarities in testing practices were discussed based on guidelines, a literature review, outcomes of a global physician survey, and case reports. Statements developed based on the discussions were sent to all participants for consensus (>70% of participants) evaluation using a 7-level rating system, and further discussed during the second meeting. The experts recommend Sapropterin dihydrochloride response testing in patients with untreated blood Phe concentrations of 360–2000 μmol/L, except in those with two null mutations. For neonates, a 24-h Sapropterin dihydrochloride loading test is recommended; responsiveness is defined as a decrease in blood Phe ≥30%. For older infants, children, adolescents, and adults, a test duration of ≥48 h or a 4-week trial is recommended. The main endpoint for a 48-h to 7-day trial is a decrease in blood Phe, while improved Phe tolerance is the endpoint to be assessed during a longer trial. Longer trials may not be feasible in some locations due to lack of reimbursement for hospitalization, while a 4-week trial may not be possible due to limited access to Sapropterin dihydrochloride or public health regulation. A 48-h response test should be considered in pregnant patients who cannot achieve blood Phe ≤360 μmol/L with a Phe-restricted diet. Durability of response and clinical benefits of Sapropterin dihydrochloride should be assessed over the long term. Harmonization of protocols is expected to improve identification of responders and comparability of test results worldwide.

  • diagnostic and therapeutic recommendations for the treatment of hyperphenylalaninemia in patients 0 4 years of age
    Orphanet Journal of Rare Diseases, 2018
    Co-Authors: Ania C Muntau, Marcel Du Moulin, Francois Feillet
    Abstract:

    Treatment of phenylketonuria (PKU) with Sapropterin dihydrochloride in responsive patients from an early age can have many advantages for the patient over dietary restriction alone. Accordingly, approval of Sapropterin in the European Union was extended in 2015 to include patients aged 0–4 years, bringing the treatment age range in line with that in the USA and providing an additional treatment option for those patients with PKU who are responsive or partially responsive to treatment with Sapropterin. Subsequently, European guidelines have been published on the diagnosis and management of patients with PKU. However, testing for PKU can be demanding and requires particular expertise. We have compiled experience-based, real-world guidance in an algorithmic format to complement the published guidelines, with the overall aim to achieve optimized and individualized care for patients with PKU. Our guidance covers aspects such as how to perform, monitor and interpret appropriate biochemical measures to achieve effective patient management and desired outcomes, how to perform a tetrahydrobiopterin (BH4) loading test to assess responsiveness in newborns, and how to initiate Sapropterin treatment in patients from birth. We also provide our expert opinion on starting pharmacotherapy in patients who were previously managed by diet alone. Real-world-based guidance is particularly important in managing therapeutic strategies in newborns with PKU to achieve optimal long-term outcomes and will serve as a complement to the other published guidelines.

  • Diagnostic and therapeutic recommendations for the treatment of hyperphenylalaninemia in patients 0–4 years of age
    'Springer Science and Business Media LLC', 2018
    Co-Authors: Ania C Muntau, Marcel Du Moulin, Francois Feillet
    Abstract:

    Abstract Background Treatment of phenylketonuria (PKU) with Sapropterin dihydrochloride in responsive patients from an early age can have many advantages for the patient over dietary restriction alone. Accordingly, approval of Sapropterin in the European Union was extended in 2015 to include patients aged 0–4 years, bringing the treatment age range in line with that in the USA and providing an additional treatment option for those patients with PKU who are responsive or partially responsive to treatment with Sapropterin. Subsequently, European guidelines have been published on the diagnosis and management of patients with PKU. However, testing for PKU can be demanding and requires particular expertise. We have compiled experience-based, real-world guidance in an algorithmic format to complement the published guidelines, with the overall aim to achieve optimized and individualized care for patients with PKU. Results Our guidance covers aspects such as how to perform, monitor and interpret appropriate biochemical measures to achieve effective patient management and desired outcomes, how to perform a tetrahydrobiopterin (BH4) loading test to assess responsiveness in newborns, and how to initiate Sapropterin treatment in patients from birth. We also provide our expert opinion on starting pharmacotherapy in patients who were previously managed by diet alone. Conclusions Real-world-based guidance is particularly important in managing therapeutic strategies in newborns with PKU to achieve optimal long-term outcomes and will serve as a complement to the other published guidelines

  • Additional file 1: of Diagnostic and therapeutic recommendations for the treatment of hyperphenylalaninemia in patients 0–4 years of age
    2018
    Co-Authors: Ania Muntau, Marcel Du Moulin, Francois Feillet
    Abstract:

    Dose dependent dissolution recommendation for Sapropterin according to the guidance for water dilution. This table shows the number of tablets and the quantity of diluent required according to the weight of each child. (PDF 181 kb

  • the kuvan adult maternal paediatric european registry kamper multinational observational study baseline and 1 year data in phenylketonuria patients responsive to Sapropterin
    JIMD reports, 2015
    Co-Authors: Friedrich K Trefz, Alberto Burlina, Ania C Muntau, Amaya Belangerquintana, Frank Rutsch, Florian B Lagler, Flavie Moreau, J Alm, Francois Feillet
    Abstract:

    Introduction: Sapropterin dihydrochloride (Kuvan®), a synthetic 6R-diastereoisomer of tetrahydrobiopterin (BH4), is approved in Europe for the treatment of patients aged ≥4 years with hyperphenylalaninaemia (HPA) due to BH4-responsive phenylalanine hydroxylase (PAH) deficiency, in conjunction with a phenylalanine-restricted diet, and also for the treatment of patients with BH4 deficiency.

Alberto Burlina - One of the best experts on this subject based on the ideXlab platform.

  • long term efficacy and safety of Sapropterin in patients who initiated Sapropterin at 4 years of age with phenylketonuria results of the 3 year extension of the spark open label multicentre randomised phase iiib trial
    Orphanet Journal of Rare Diseases, 2021
    Co-Authors: Ania C Muntau, Vincenzo Leuzzi, Alberto Burlina, Francois Eyskens, Peter Freisinger, Hatice Serap Sivri, Gwendolyn Gramer, Renata Pazdirkova, Maureen Cleary, Amelia S Lotzhavla
    Abstract:

    During the initial 26-week SPARK (Safety Paediatric efficAcy phaRmacokinetic with Kuvan®) study, addition of Sapropterin dihydrochloride (Kuvan®; a synthetic formulation of the natural cofactor for phenylalanine hydroxylase, tetrahydrobiopterin; BH4), to a phenylalanine (Phe)-restricted diet, led to a significant improvement in Phe tolerance versus a Phe-restricted diet alone in patients aged 0–4 years with BH4-responsive phenylketonuria (PKU) or mild hyperphenylalaninaemia (HPA). Based on these results, the approved indication for Sapropterin in Europe was expanded to include patients < 4 years of age. Herein, we present results of the SPARK extension study (NCT01376908), evaluating the long-term safety, dietary Phe tolerance, blood Phe concentrations and neurodevelopmental outcomes in patients < 4 years of age at randomisation, over an additional 36 months of treatment with Sapropterin. All 51 patients who completed the 26-week SPARK study period entered the extension period. Patients who were previously treated with a Phe-restricted diet only (‘Sapropterin extension’ group; n = 26), were initiated on Sapropterin at 10 mg/kg/day, which could be increased up to 20 mg/kg/day. Patients previously treated with Sapropterin plus Phe-restricted diet, remained on this regimen in the extension period (‘Sapropterin continuous’ group; n = 25). Dietary Phe tolerance increased significantly at the end of the study versus baseline (week 0), by 38.7 mg/kg/day in the ‘Sapropterin continuous’ group (95% CI 28.9, 48.6; p < 0.0001). In the ‘Sapropterin extension’ group, a less pronounced effect was observed, with significant differences versus baseline (week 27) only observed between months 9 and 21; dietary Phe tolerance at the end of study increased by 5.5 mg/kg/day versus baseline (95% CI − 2.8, 13.8; p = 0.1929). Patients in both groups had normal neuromotor development and growth parameters. Long-term treatment with Sapropterin plus a Phe-restricted diet in patients who initiated Sapropterin at < 4 years of age with BH4-responsive PKU or mild HPA maintained improvements in dietary Phe tolerance over 3.5 years. These results continue to support the favourable risk/benefit profile for Sapropterin in paediatric patients (< 4 years of age) with BH4-responsive PKU. Frequent monitoring of blood Phe levels and careful titration of dietary Phe intake to ensure adequate levels of protein intake is necessary to optimise the benefits of Sapropterin treatment. Trial registration ClinicalTrials.gov, NCT01376908. Registered 17 June 2011, https://clinicaltrials.gov/ct2/show/NCT01376908 .

  • efficacy safety and population pharmacokinetics of Sapropterin in pku patients 4 years results from the spark open label multicentre randomized phase iiib trial
    Orphanet Journal of Rare Diseases, 2017
    Co-Authors: Ania C Muntau, Vincenzo Leuzzi, Alberto Burlina, Francois Eyskens, Peter Freisinger, Corinne De Laet, Frank Rutsch, Serap H Sivri, Suresh Vijay, Milva Orquidea Bal
    Abstract:

    Sapropterin dihydrochloride, a synthetic formulation of BH4, the cofactor for phenylalanine hydroxylase (PAH, EC 1.14.16.1), was initially approved in Europe only for patients ≥4 years with BH4-responsive phenylketonuria. The aim of the SPARK (Safety Paediatric efficAcy phaRmacokinetic with Kuvan®) trial was to assess the efficacy (improvement in daily phenylalanine tolerance, neuromotor development and growth parameters), safety and pharmacokinetics of Sapropterin dihydrochloride in children <4 years. In total, 109 male or female children <4 years with confirmed BH4-responsive phenylketonuria or mild hyperphenylalaninemia and good adherence to dietary treatment were screened. 56 patients were randomly assigned (1:1) to 10 mg/kg/day oral Sapropterin plus a phenylalanine-restricted diet or to only a phenylalanine-restricted diet for 26 weeks (27 to the Sapropterin and diet group and 29 to the diet-only group; intention-to-treat population). Of these, 52 patients with ≥1 pharmacokinetic sample were included in the pharmacokinetic analysis, and 54 patients were included in the safety analysis. At week 26 in the Sapropterin plus diet group, mean phenylalanine tolerance was 30.5 (95% confidence interval 18.7–42.3) mg/kg/day higher than in the diet-only group (p < 0.001). The safety profile of Sapropterin, measured monthly, was acceptable and consistent with that seen in studies of older children. Using non-linear mixed effect modelling, a one-compartment model with flip-flop pharmacokinetic behaviour, in which the effect of weight was substantial, best described the pharmacokinetic profile. Patients in both groups had normal neuromotor development and stable growth parameters. The addition of Sapropterin to a phenylalanine-restricted diet was well tolerated and led to a significant improvement in phenylalanine tolerance in children <4 years with BH4-responsive phenylketonuria or mild hyperphenylalaninemia. The pharmacokinetic model favours once per day dosing with adjustment for weight. Based on the SPARK trial results, Sapropterin has received EU approval to treat patients <4 years with BH4-responsive phenylketonuria. ClinicalTrials.gov, NCT01376908 . Registered June 17, 2011.

  • Efficacy, safety and population pharmacokinetics of Sapropterin in PKU patients
    Orphanet Journal of Rare Diseases, 2017
    Co-Authors: Ania C Muntau, Vincenzo Leuzzi, Alberto Burlina, Francois Eyskens, Peter Freisinger, Corinne De Laet, Frank Rutsch, Suresh Vijay, H. Serap Sivri, Milva Orquidea Bal
    Abstract:

    Background Sapropterin dihydrochloride, a synthetic formulation of BH_4, the cofactor for phenylalanine hydroxylase (PAH, EC 1.14.16.1), was initially approved in Europe only for patients ≥4 years with BH_4-responsive phenylketonuria. The aim of the SPARK (Safety Paediatric efficAcy phaRmacokinetic with Kuvan®) trial was to assess the efficacy (improvement in daily phenylalanine tolerance, neuromotor development and growth parameters), safety and pharmacokinetics of Sapropterin dihydrochloride in children

  • Additional file 1: Figure S1. of Efficacy, safety and population pharmacokinetics of Sapropterin in PKU patients
    2017
    Co-Authors: Ania Muntau, Vincenzo Leuzzi, Alberto Burlina, Francois Eyskens, Peter Freisinger, Corinne De Laet, Frank Rutsch, Suresh Vijay, H. Serap Sivri, Milva Bal
    Abstract:

    Summary of neuromotor developmental milestones – ITT population. Data show (a) the proportion of patients with normal development in the area of assessment at baseline, (b) Week 12, and (c) Week 26 treated with Sapropterin plus the Phe-restricted diet, or Phe-restricted diet alone. P-values show comparison of results between treatment groups at Week 26 using the chi-squared test. Table S1. PAH genotypes of Sapropterin responders (n=37). (DOCX 180 kb

  • the kuvan adult maternal paediatric european registry kamper multinational observational study baseline and 1 year data in phenylketonuria patients responsive to Sapropterin
    JIMD reports, 2015
    Co-Authors: Friedrich K Trefz, Alberto Burlina, Ania C Muntau, Amaya Belangerquintana, Frank Rutsch, Florian B Lagler, Flavie Moreau, J Alm, Francois Feillet
    Abstract:

    Introduction: Sapropterin dihydrochloride (Kuvan®), a synthetic 6R-diastereoisomer of tetrahydrobiopterin (BH4), is approved in Europe for the treatment of patients aged ≥4 years with hyperphenylalaninaemia (HPA) due to BH4-responsive phenylalanine hydroxylase (PAH) deficiency, in conjunction with a phenylalanine-restricted diet, and also for the treatment of patients with BH4 deficiency.

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  • safety of extended treatment with Sapropterin dihydrochloride in patients with phenylketonuria results of a phase 3b study
    Molecular Genetics and Metabolism, 2011
    Co-Authors: Barbara K Burton, Maria Nowacka, Julia B Hennermann, Mark Lipson, Dorothy K Grange, Anupam Chakrapani, Friedrich K Trefz, Alex Dorenbaum, Michael Imperiale, Sun Sook Kim
    Abstract:

    Abstract Background Phenylketonuria (PKU) results from impaired breakdown of phenylalanine (Phe) due to deficient phenylalanine hydroxylase (PAH) activity. Sapropterin dihydrochloride (Sapropterin, Kuvan®) is the only US- and EU-approved pharmaceutical version of naturally occurring 6R-BH 4 , the cofactor required for PAH activity. Sapropterin enhances residual PAH activity in Sapropterin-responsive PKU patients and, in conjunction with dietary management, helps reduce blood Phe concentrations for optimal control. Approval was based on the positive safety and efficacy results of four international clinical studies, the longest of which was 22 weeks in duration. Objective To evaluate the safety of long-term treatment with Sapropterin in PKU subjects who participated in previous Phase 3 Sapropterin trials. Methods PKU-008 was designed as a Phase 3b, multicenter, multinational, open-label, 3-year extension trial to evaluate the long-term safety of Sapropterin in patients with PKU who were classified as Sapropterin responders and participated in prior Phase 3 Sapropterin studies: 111 subjects aged 4–50 years completed prior studies and were subsequently enrolled in study PKU-008. Routine safety monitoring was performed at 3-month intervals and included adverse event reporting, blood Phe monitoring, clinical laboratory evaluations, physical examinations and vital sign measurements. Results Average exposure during PKU-008 was 658.7 ± 221.3 days (range, 56–953; median, 595). The average total duration of participation in multiple studies (PKU-001, PKU-003, PKU-004, and PKU-008; or PKU-006 and PKU-008) was 799.0 ± 237.5 days (range, 135-1151). The mean Sapropterin dose was 16.2 ± 4.7 mg/kg/day. Most adverse events were considered unrelated to treatment, were mild or moderate in severity, and were consistent with prior studies of Sapropterin. No age-specific differences were observed in adverse event reporting. Three subjects discontinued treatment due to adverse events that were considered possibly or probably related to study treatment (one each of difficulty concentrating, decreased platelet count, and intermittent diarrhea). No deaths were reported. Of seven reported serious adverse events, one was considered possibly related to study treatment (gastroesophageal reflux). There were no laboratory or physical examination abnormalities requiring medical interventions. For most subjects, blood Phe concentrations were consistently within target range, confirming the durability of response in subjects undergoing extended treatment with Sapropterin. Conclusion Sapropterin treatment was found to be safe and well tolerated at doses of 5 to 20 mg/kg/day for an average exposure of 659 days. This study supports the safety and tolerability of Sapropterin as long-term treatment for patients with PKU.

  • relative bioavailability of Sapropterin from intact and dissolved Sapropterin dihydrochloride tablets and the effects of food a randomized open label crossover study in healthy adults
    Clinical Therapeutics, 2010
    Co-Authors: Donald G Musson, Carl S Hornfeldt, Sun Sook Kim, William G Kramer, Erik Foehr, Frederick A Bieberdorf, Alex Dorenbaum
    Abstract:

    Abstract Background: Phenylketonuria (PKU) is an autosomal recessive metabolic disorder characterized by hyperphenylalaninemia in association with neurocognitive and neuromotor impairment. Sapropterin dihydrochloride (hereafter referred to as Sapropterin ) administered orally as dissolved tablets is approved by the US Food and Drug Administration for hyperphenylalaninemia in patients with tetrahydrobiopterinresponsive PKU. Objectives: This study compared the relative oral bioavailability of Sapropterin when administered as intact and dissolved tablets. It also assessed the effect of food on the oral bioavailability of Sapropterin administered as intact tablets. Methods: This was a randomized, open-label, 3-treatment, 6-sequence, 3-period crossover study in healthy male and female subjects. Subjects were randomized to receive single oral 10-mg/kg doses of Sapropterin administered as dissolved tablets after a fast; as intact tablets after a fast; and as intact tablets with a high-calorie, high-fat meal. The 3 dosing periods were separated by a washout period of at least 7 days. In each dosing period, blood samples were obtained within 40 minutes before and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 18, and 24 hours after dosing. A follow-up assessment was performed 5 to 7 days after the last dosing period. The relative bioavailability of Sapropterin from the 3 dosing regimens was assessed based on C max , AUC 0−t , and AUC 0−∞ , estimated from calculated plasma tetrahydrobiopterin concentrations using a noncompartmental model. Safety assessments included physical examinations, clinical laboratory tests, and ECGs at the beginning and end of the study. Vital signs were monitored periodically during each treatment period. Results: The study enrolled 32 healthy subjects (16 men, 16 women) with a mean (SD) age of 29.2 (9.0) years, height of 172.7 (10.0) cm, weight of 73.0 (13.9) kg, and body mass index ranging from 18 to 30 kg/m 2 . Twenty-three were white, 5 African American, 2 Asian/Pacific Islander, 1 Hispanic, and 1 Native American. The estimated geometric mean ratio of AUC 0−t for intact compared with dissolved tablets under fasting conditions was 141.24% (90% CI, 122.05–163.43), and the geometric mean ratio of AUC 0−t for intact tablets under fed compared with fasting conditions was 143.46% (90% CI, 124.22–165.69). Nine subjects (28.1%) reported a total of 20 treatment-emergent adverse events (AEs). The most frequently reported AEs were gastrointestinal disorders (6 subjects [18.8%]) and central nervous system disorders (4 [12.5%]). Eight AEs considered possibly or probably related to Sapropterin were reported by 4 subjects (12.5%); these were of mild severity and gastrointestinal in nature. No severe or serious AEs or discontinuations due to AEs occurred during the study. Conclusions: Administration of Sapropterin as intact tablets and with a high-calorie, high-fat meal was associated with increased drug exposure. Oral administration of Sapropterin 10 mg/kg as intact tablets with or without food was generally well tolerated.

  • efficacy of Sapropterin dihydrochloride in increasing phenylalanine tolerance in children with phenylketonuria a phase iii randomized double blind placebo controlled study
    The Journal of Pediatrics, 2009
    Co-Authors: Friedrich K Trefz, Barbara K Burton, Dorothy K Grange, Alex Dorenbaum, Nicola Longo, Mercedes Martinez Pardo Casanova, Daniel Gruskin, Emil D Kakkis, Eric Crombez, Paul Harmatz
    Abstract:

    Objective To evaluate the ability of Sapropterin dihydrochloride (pharmaceutical preparation of tetrahydrobiopterin) to increase phenylalanine (Phe) tolerance while maintaining adequate blood Phe control in 4- to 12-year-old children with phenylketonuria (PKU). Study design This international, double-blind, randomized, placebo-controlled study screened for Sapropterin response among 90 enrolled subjects in Part 1. In Part 2, 46 responsive subjects with PKU were randomized (3:1) to Sapropterin, 20 mg/kg/d, or placebo for 10 weeks while continuing on a Phe-restricted diet. After 3 weeks, a dietary Phe supplement was added every 2 weeks if Phe control was adequate. Results The mean (±SD) Phe supplement tolerated by the Sapropterin group had increased significantly from the pretreatment amount (0 mg/kg/d) to 20.9 (±15.4) mg/kg/d ( P P Conclusions Sapropterin is effective in increasing Phe tolerance while maintaining blood Phe control and has an acceptable safety profile in this population of children with PKU.

  • safety and efficacy of 22 weeks of treatment with Sapropterin dihydrochloride in patients with phenylketonuria
    American Journal of Medical Genetics Part A, 2008
    Co-Authors: Phillip Lee, Alex Dorenbaum, Eric Crombez, Judith Bebchuk, Eileen P Treacy, Melissa P Wasserstein, Lewis Waber, Jon A Wolff, Udo Wendel, Heidi Christschmidt
    Abstract:

    Phenylketonuria (PKU) is an inherited metabolic disease characterized by phenylalanine (Phe) accumulation, which can lead to neurocognitive and neuromotor impairment. Sapropterin dihydrochloride, an FDA-approved synthetic formulation of tetrahydrobiopterin (6R-BH4, herein referred to as Sapropterin) is effective in reducing plasma Phe concentrations in patients with hyperphenylalaninemia due to tetrahydrobiopterin (BH4)-responsive PKU, offering potential for improved metabolic control. Eighty patients, ≥8 years old, who had participated in a 6-week, randomized, placebo-controlled study of Sapropterin, were enrolled in this 22-week, multicenter, open-label extension study comprising a 6-week forced dose-titration phase (5, 20, and 10 mg/kg/day of study drug consecutively for 2 weeks each), a 4-week dose-analysis phase (10 mg/kg/day), and a 12-week fixed-dose phase (patients received doses of 5, 10, or 20 mg/kg/day based on their plasma Phe concentrations during the dose titration). Dose-dependent reductions in plasma Phe concentrations were observed in the forced dose-titration phase. Mean (SD) plasma Phe concentration decreased from 844.0 (398.0) µmol/L (week 0) to 645.2 (393.4) µmol/L (week 10); the mean was maintained at this level during the study's final 12 weeks (652.2 [382.5] µmol/L at week 22). Sixty-eight (85%) patients had at least one adverse event (AE). All AEs, except one, were mild or moderate in severity. Neither the severe AE nor any of the three serious AEs was considered related to Sapropterin. No AE led to treatment discontinuation. Sapropterin is effective in reducing plasma Phe concentrations in a dose-dependent manner and is well tolerated at doses of 5–20 mg/kg/day over 22 weeks in BH4-responsive patients with PKU. © 2008 Wiley-Liss, Inc.

  • pharmacokinetics of Sapropterin in patients with phenylketonuria
    Clinical Pharmacokinectics, 2008
    Co-Authors: Francois Feillet, Mark Lipson, Alex Dorenbaum, Paul Harmatz, Diane R Mould, Lorne A Clarke, Concetta Meli, A A M Morris, Bruce Green, M Giovannini
    Abstract:

    impairment, which result from elevated blood phenylalanine concentrations. To date, the recommended management of phenylketonuria has been the use of a protein-restricted diet and the inclusion of phenylalaninefree protein supplements; however, this approach is often associated with poor compliance and a suboptimal clinical outcome. Sapropterin dihydrochloride, herein referred to as Sapropterin, a synthetic formulation of 6Rtetrahydrobiopterin (6R-BH4), has been shown to be effective in reducing blood phenylalanine concentrations in patients with phenylketonuria. The objective of the current study was to characterize the pharmacokinetics and pharmacokinetic variability of Sapropterin and to identify the characteristics that influence this variability. Patients and methods: This was a 12-week, fixed-dose phase of an open-label extension study. The study was conducted at 26 centres in North America and Europe.

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