Abstract
Patient registries for rare diseases enable systematic data collection and can also be used to facilitate postauthorization safety studies (PASS) for orphan drugs. This study evaluates the PASS for betaine anhydrous (Cystadane), conducted as public private partnership (PPP) between the European network and registry for homocystinurias and methylation defects and the marketing authorization holder (MAH). Data were prospectively collected, 2013–2016, in a noninterventional, international, multicenter, registry study. Putative adverse and severe adverse events were reported to the MAH's pharmacovigilance. In total, 130 individuals with vitamin B6 nonresponsive (N = 54) and partially responsive (N = 7) cystathionine beta-synthase (CBS) deficiency, as well as 5,10-methylenetetrahydrofolate reductase (MTHFR; N = 21) deficiency and cobalamin C (N = 48) disease were included. Median (range) duration of treatment with betaine anhydrous was 6.8 (0–9.8) years. The prescribed betaine dose exceeded the recommended maximum (6 g/day) in 49% of individuals older than 10 years because of continued dose adaptation to weight; however, with disease-specific differences (minimum: 31% in B6 nonresponsive CBS deficiency, maximum: 67% in MTHFR deficiency). Despite dose escalation no new or potential risk was identified. Combined disease-specific treatment decreased mean ± SD total plasma homocysteine concentrations from 203 ± 116 to 81 ± 51 μmol/L (p < 0.0001), except in MTHFR deficiency. Recommendations for betaine anhydrous dosage were revised for individuals ≥ 10 years. PPPs between MAH and international scientific consortia can be considered a reliable model for implementing a PASS, reutilizing well-established structures and avoiding data duplication and fragmentation.
| Original language | English |
|---|---|
| Pages (from-to) | 719-733 |
| Number of pages | 15 |
| Journal | Journal of Inherited Metabolic Disease |
| Volume | 45 |
| Issue number | 4 |
| Early online date | 31 Mar 2022 |
| DOIs | |
| Publication status | Published - Jul 2022 |
Bibliographical note
Funding Information:information Czech Health Research Council, Grant/Award Number: NV19-01-00307; Czech Ministry of Health, Grant/Award Number: RVO VFN 64165; European Union, Grant/Award Number: CHAFEA agreement no. 2012 12 02; Medizinischen Fakultat Heidelberg, Universitat Heidelberg, Grant/Award Number: F.206852; Orphan Europe SARLThe authors are indebted to all patients and their parents who participated in this study by sharing their experience of daily practice and life with homocystinurias for their motivation and trust. The authors thank Collette Stainforth, Bradford Teaching Hospitals NHS Foundation Trust, Bradford, UK, for providing data sets from her site. The Cystadane Surveillance Protocol (CSP) was funded by Orphan Europe SARL (currently Recordati Rare Diseases SARL being part of Recordati S.P.A.). The European Network and Registry for Homocystinurias and Methylation Defects (E-HOD) was funded by the European Union, in the framework of the Health Programme 2008–2013 (CHAFEA agreement no. 2012 12 02). Ulrike Mütze was supported by Olympia Morata research fellowship of the Medical Faculty of the Ruprecht Karl University of Heidelberg (grant number F.206852). Viktor Kožich and Pavel Ješina received institutional support from the Ministry of Health (General University Hospital in Prague- RVO VFN 64165) and from the Czech Health Research Council (grant NV19-01-00307). The authors confirm independence from the sponsor; the content of the article has not been influenced by the sponsor.
Funding Information:
Czech Health Research Council, Grant/Award Number: NV19‐01‐00307; Czech Ministry of Health, Grant/Award Number: RVO VFN 64165; European Union, Grant/Award Number: CHAFEA agreement no. 2012 12 02; Medizinischen Fakultat Heidelberg, Universitat Heidelberg, Grant/Award Number: F.206852; Orphan Europe SARL Funding information
Funding Information:
The CSP was funded by Orphan Europe SARL (currently Recordati Rare Diseases SARL being part of Recordati S.P.A.) and data entry of the study sites was reimbursed. Celine Plisson is a Recordati Rare Diseases employee. Carlo Dionisi‐Vici received honoraria for educational activity by Orphan Europe/Recordati Rare Diseases. Luis Aldámiz‐Echevarría declares payment for lectures from Mead‐Johnson Nutrition, Takeda Pharma, Nutricia Metabolics, and Sanofi Genzyme, payment for expert testimonies on urea cycle defects and support for attending meetings by Nutricia Metabolics and Amicus Therapeutics. Matthias R. Baumgartner declares research funds from Nutricia Metabolics and participation on advisory boards for Hemoshear Therapeutics and Moderna and participation on a data safety monitoring board for Lysogene. Saikat Santra declares benefitting from travel and educational grants payed by Recordati Rare Diseases to his institutional charity fund. Karine Mention declares payments for lectures by Sanofi Genzyme and Chiesi. Andrew Morris declares having received an honorarium from the Recordati Rare Disease Foundation for lecturing on their Inherited disorders of glucose homeostasis course. Manuel Schiff declares having received an honorarium from the Recordati Rare Disease Foundation for lecturing on their webinar on homocystinurias and lecturing for the Recordati Rare Disease Foundation on mitochondrial diseases and metabolic cardiomyopathies free of charge. Helen Mundy declares having received fees for lectures from the British Dietetic Association, consulting fees form Ultragenyx for GSD gene therapy safety monitoring and support for attending the SSIEM from Vitaflo. Silvia Meavilla Olivas declares support for attending meetings by Nutricia Metabolics, Nestlé and Mead‐Johnson Nutrition. Isidro Vitoria Miñana declares having received honoraria for lectures from Vitaflo, PIAM Farmaceutici, Nutricia Metabolics and Recordati Rare Diseases. The other authors declare no conflicts of interest.
Funding Information:
The authors are indebted to all patients and their parents who participated in this study by sharing their experience of daily practice and life with homocystinurias for their motivation and trust. The authors thank Collette Stainforth, Bradford Teaching Hospitals NHS Foundation Trust, Bradford, UK, for providing data sets from her site. The Cystadane Surveillance Protocol (CSP) was funded by Orphan Europe SARL (currently Recordati Rare Diseases SARL being part of Recordati S.P.A.). The European Network and Registry for Homocystinurias and Methylation Defects (E‐HOD) was funded by the European Union, in the framework of the Health Programme 2008–2013 (CHAFEA agreement no. 2012 12 02). Ulrike Mütze was supported by Olympia Morata research fellowship of the Medical Faculty of the Ruprecht Karl University of Heidelberg (grant number F.206852). Viktor Kožich and Pavel Ješina received institutional support from the Ministry of Health (General University Hospital in Prague‐ RVO VFN 64165) and from the Czech Health Research Council (grant NV19‐01‐00307). The authors confirm independence from the sponsor; the content of the article has not been influenced by the sponsor.
Publisher Copyright:
© 2022 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.