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Short-Term Administration of Mycophenolate Is Well-Tolerated in CLN3 Disease (Juvenile Neuronal Ceroid Lipofuscinosis)

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JIMD Reports, Volume 43

Part of the book series: JIMD Reports ((JIMD,volume 43))

Abstract

Mycophenolate, an immunosuppressant, is commonly used off-label for autoimmune neurological conditions. In CLN3 disease, a neurodegenerative disorder of childhood, preclinical and clinical data suggest secondary autoimmunity and inflammation throughout the central nervous system are key components of pathogenesis. We tested the short-term tolerability of mycophenolate in individuals with CLN3 disease, in preparation for possible long-term efficacy trials of this drug. We conducted a randomized, double-blind, placebo-controlled, crossover study of mycophenolate in 19 ambulatory individuals with CLN3 disease to determine the safety and tolerability of short-term administration (NCT01399047). The study included two 8-week treatment periods with a 4-week intervening washout. Mycophenolate was well tolerated. 89.5% of participants completed the mycophenolate arm, on the assigned study dose (95% CI: 66.9–98.7%), and there were no significant differences in tolerability rates between mycophenolate and placebo arms (10.5%; 95% CI: −3.3–24.3%, p = 0.21). All reported adverse events were mild in severity; the most common adverse events on mycophenolate were vomiting (31.6%; 95% CI: 12.6–56.6%), diarrhea (15.8%; 95% CI: 3.4–39.6%), and cough (15.8%; 95% CI: 3.4–39.6%). These did not occur at a significantly increased frequency above placebo. There were no definite effects on measured autoimmunity or clinical outcomes in the setting of short-term administration. Study of long-term exposure is needed to test the impact of mycophenolate on key clinical features and CLN3 disease trajectory.

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References

  • Adams HR, Mink JW (2013) Neurobehavioral features and natural history of juvenile neuronal ceroid lipofuscinosis (Batten disease). J Child Neurol 28(9):1128–1136. https://doi.org/10.1177/0883073813494813

    Article  PubMed  PubMed Central  Google Scholar 

  • Augustine EF, Mink JW (2016) Juvenile NCL (CLN3 disease): emerging disease-modifying therapeutic strategies. Pediatr Endocrinol Rev 13(Suppl 1):655–662

    PubMed  Google Scholar 

  • Augustine E, Newhouse N, Adams H, Vierhile A, Kwon J, Marshall F, Mink J (2012) Epilepsy in juvenile neuronal ceroid lipofuscinosis is usually characterized by well-controlled generalized tonic-clonic seizures. Mol Genet Metab 105(2):S18–S19. https://doi.org/10.1016/j.ymgme.2011.11.021

    Article  Google Scholar 

  • Augustine EF, Adams HR, Mink JW (2013) Clinical trials in rare disease: challenges and opportunities. J Child Neurol 28(9):1142–1150. https://doi.org/10.1177/0883073813495959

    Article  PubMed  PubMed Central  Google Scholar 

  • Byron Jones MGK (2003) Design and analysis of cross-over trials, 2nd edn. Chapman and Hall/CRC, Boca Raton

    Google Scholar 

  • Castaneda JA, Pearce DA (2008) Identification of alpha-fetoprotein as an autoantigen in juvenile Batten disease. Neurobiol Dis 29:92–102

    Article  CAS  Google Scholar 

  • Chattopadhyay S, Ito M, Cooper JD, Brooks AI, Curran TM, Powers JM, Pearce DA (2002a) An autoantibody inhibitory to glutamic acid decarboxylase in the neurodegenerative disorder Batten disease. Hum Mol Genet 11(12):1421–1431

    Article  CAS  Google Scholar 

  • Chattopadhyay S, Kriscenski-Perry E, Wenger DA, Pearce DA (2002b) An autoantibody to GAD65 in sera of patients with juvenile neuronal ceroid lipofuscinoses. Neurology 59(11):1816–1817

    Article  Google Scholar 

  • Cialone J, Adams H, Augustine EF, Marshall FJ, Kwon JM, Newhouse N et al (2012) Females experience a more severe disease course in Batten disease. J Inherit Metab Dis 35(3):549–555. https://doi.org/10.1007/s10545-011-9421-6

    Article  PubMed  Google Scholar 

  • de Blieck EA, Augustine EF, Marshall FJ, Adams H, Cialone J, Dure L et al (2013) Methodology of clinical research in rare diseases: development of a research program in juvenile neuronal ceroid lipofuscinosis (JNCL) via creation of a patient registry and collaboration with patient advocates. Contemp Clin Trials 35(2):48–54. https://doi.org/10.1016/j.cct.2013.04.004

    Article  PubMed  PubMed Central  Google Scholar 

  • Downing HJ, Pirmohamed M, Beresford MW, Smyth RL (2013) Paediatric use of mycophenolate mofetil. Br J Clin Pharmacol 75(1):45–59. https://doi.org/10.1111/j.1365-2125.2012.04305.x

    Article  CAS  PubMed  Google Scholar 

  • Drack A, Augustine E, Grider T, Pearce D, Mullins R (2012) Anti-retinal antibodies in Juvenile Neuronal Ceroid Lipofuscinosis (JNCL). In: Paper presented at the 13th international congress on neuronal ceroid lipofuscinoses, London

    Google Scholar 

  • Hatonen T, Kirveskari E, Heiskala H, Sainio K, Laakso ML, Santavuori P (1999) Melatonin ineffective in neuronal ceroid lipofuscinosis patients with fragmented or normal motor activity rhythms recorded by wrist actigraphy. Mol Genet Metab 66(4):401–406. https://doi.org/10.1006/mgme.1999.2815

    Article  CAS  PubMed  Google Scholar 

  • Hee SW, Willis A, Tudur Smith C, Day S, Miller F, Madan J et al (2017) Does the low prevalence affect the sample size of interventional clinical trials of rare diseases? An analysis of data from the aggregate analysis of clinicaltrials.gov. Orphanet J Rare Dis 12:44. https://doi.org/10.1186/s13023-017-0597-1

    Article  PubMed  PubMed Central  Google Scholar 

  • Kwon JM, Adams H, Rothberg PG, Augustine EF, Marshall FJ, Deblieck EA et al (2011) Quantifying physical decline in juvenile neuronal ceroid lipofuscinosis (Batten disease). Neurology 77:1801–1807

    Article  CAS  Google Scholar 

  • Lerner TJ, Boustany R-MN, Anderson JW, D’Arigo KL, Schlumpf K, Buckler AJ et al (1995) Isolation of a novel gene underlying batten disease, CLN3. Cell 82(6):949–957. https://doi.org/10.1016/0092-8674(95)90274-0

    Article  Google Scholar 

  • Lim MJ, Beake J, Bible E, Curran TM, Ramirez-Montealegre D, Pearce DA, Cooper JD (2006) Distinct patterns of serum immunoreactivity as evidence for multiple brain-directed autoantibodies in juvenile neuronal ceroid lipofuscinosis. Neuropathol Appl Neurobiol 32:469–482

    Article  CAS  Google Scholar 

  • Lim MJ, Alexander N, Benedict JW, Chattopadhyay S, Shemilt SJ, Guerin CJ et al (2007) IgG entry and deposition are components of the neuroimmune response in Batten disease. Neurobiol Dis 25:239–251

    Article  CAS  Google Scholar 

  • Marshall FJ, de Blieck EA, Mink JW, Dure L, Adams H, Messing S et al (2005) A clinical rating scale for Batten disease: reliable and relevant for clinical trials. Neurology 65:275–279

    Article  CAS  Google Scholar 

  • Montcuquet A, Collongues N, Papeix C, Zephir H, Audoin B, Laplaud D et al (2017) Effectiveness of mycophenolate mofetil as first-line therapy in AQP4-IgG, MOG-IgG, and seronegative neuromyelitis optica spectrum disorders. Mult Scler 23(10):1377–1384. https://doi.org/10.1177/1352458516678474

    Article  CAS  PubMed  Google Scholar 

  • Ostergaard JR, Rasmussen TB, Molgaard H (2011) Cardiac involvement in juvenile neuronal ceroid lipofuscinosis (Batten disease). Neurology 76:1245–1251

    Article  CAS  Google Scholar 

  • Pearce DA, Atkinson M, Tagle DA (2004) Glutamic acid decarboxylase autoimmunity in Batten disease and other disorders. Neurology 63:2001–2005

    Article  CAS  Google Scholar 

  • Prescott RJ (1981) The comparison of success rates in cross-over trials in the presence of an order effect. J R Stat Soc Ser C (Appl Stat) 30(1):9–15. https://doi.org/10.2307/2346652

    Article  Google Scholar 

  • Ramirez-Montealegre D, Chattopadhyay S, Curran TM, Wasserfall C, Pritchard L, Schatz D et al (2005) Autoimmunity to glutamic acid decarboxylase in the neurodegenerative disorder Batten disease. Neurology 64(4):743–745. https://doi.org/10.1212/01.wnl.0000151973.08426.7e

    Article  CAS  PubMed  Google Scholar 

  • Santavuori P, Moren R (1977) Experience of antioxidant treatment in neuronal ceroid-lipofuscinosis of Spielmeyer-Sjogren type. Neuropadiatrie 8(4):333–344. https://doi.org/10.1055/s-0028-1091529

    Article  CAS  PubMed  Google Scholar 

  • Santavuori P, Westermarck T, Rapola J, Pohja P, Moren R, Lappi M, Vuonnala U (1985) Antioxidant treatment in Spielmeyer-Sjogren’s disease. Acta Neurol Scand 71(2):136–145

    Article  CAS  Google Scholar 

  • Santavuori P, Heiskala H, Autti T, Johansson E, Westermarck T (1989) Comparison of the clinical courses in patients with juvenile neuronal ceroid lipofuscinosis receiving antioxidant treatment and those without antioxidant treatment. Adv Exp Med Biol 266:273–282

    CAS  PubMed  Google Scholar 

  • Sato S, Murakami A, Kuwajima A, Takehara K, Mimori T, Kawakami A et al (2016) Clinical utility of an enzyme-linked immunosorbent assay for detecting anti-melanoma differentiation-associated gene 5 autoantibodies. PLoS One 11(4):e0154285. https://doi.org/10.1371/journal.pone.0154285

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Seehafer SS, Ramirez-Montealegre D, Wong AM, Chan CH, Castaneda J, Horak M et al (2011) Immunosuppression alters disease severity in juvenile Batten disease mice. J Neuroimmunol 230:169–172 Netherlands: 2010 Elsevier B.V.

    Article  CAS  Google Scholar 

  • Senn S (2002) Cross-over trials in clinical research, 2nd edn. Wiley, New York

    Book  Google Scholar 

  • Staropoli JF, Haliw L, Biswas S, Garrett L, Holter SM, Becker L et al (2012) Large-scale phenotyping of an accurate genetic mouse model of JNCL identifies novel early pathology outside the central nervous system. PLoS One 7(6):e38310. https://doi.org/10.1371/journal.pone.0038310

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vermersch P, Stojkovic T, de Seze J (2005) Mycophenolate mofetil and neurological diseases. Lupus 14(Suppl 1):s42–s45

    Article  CAS  Google Scholar 

  • Zweije-Hofman IL, van der Zee HJ, van Nieuwenhuizen O (1982) Anti-parkinson drugs in the Batten-Spielmeyer-Vogt syndrome; a pilot trial. Clin Neurol Neurosurg 84(2):101–105

    Article  CAS  Google Scholar 

Download references

Acknowledgments

The trial was supported by research grants from the Batten Disease Support and Research Association and the Food and Drug Administration (#FD003908). We thank the study participants and their families for graciously sharing their time and support for the study. We also acknowledge the study contributions of the site investigators, medical monitors, and data safety monitoring committee.

Site Investigators

Kirk Agerson, MD; Angela Black, MD; Tom Byrne, MD; David Callahan, MD; Emily de los Reyes, MD; Greg Guerriero, DO; John Gunderman, MD; Donna Heffernan, MD; Raymond Hubbard, MD; Randa Jarrar, MD; Marian Kummer, MD; Dawn Marie Minyon-Sarver, DO; Young Oliver, MD; Wilfred Raine, MD; Katherine Sims, MD; Ayame Takahashi, MD; Sharmell Wilson, MD.

Medical Monitors

Jennifer Kwon, MD, University of Rochester Medical Center, Rochester, NY.

Laurie Seltzer, DO, University of Rochester Medical Center, Rochester, NY.

Data and Safety Monitoring Committee

Leon Dure, MD, University of Alabama, Birmingham, AL.

Marc Lande, MD, MPH, University of Rochester Medical Center, Rochester, NY.

Michael McDermott, PhD, University of Rochester Medical Center, Rochester, NY.

Author information

Authors and Affiliations

  1. Department of Neurology, University of Rochester Medical Center, Rochester, NY, USA

    Erika F. Augustine, Heather R. Adams, Amy Vierhile, Jonathan W. Mink & Frederick J. Marshall

  2. Department of Pediatrics, University of Rochester Medical Center, Rochester, NY, USA

    Erika F. Augustine, Heather R. Adams, Amy Vierhile & Jonathan W. Mink

  3. Center for Health + Technology, University of Rochester Medical Center, Rochester, NY, USA

    Erika F. Augustine

  4. Department of Biostatistics and Computational Biology, University of Rochester Medical Center, Rochester, NY, USA

    Christopher A. Beck

  5. Pharmaceutical Product Development (PPD), Charlotte, NC, USA

    Sara Defendorf

  6. Pediatrics and Rare Diseases Group, Sanford Research, Sioux Falls, SD, USA

    Derek Timm & Jill M. Weimer

  7. Department of Neuroscience, University of Rochester Medical Center, Rochester, NY, USA

    Jonathan W. Mink

Authors
  1. Erika F. Augustine
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  2. Christopher A. Beck
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  3. Heather R. Adams
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  4. Sara Defendorf
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  5. Amy Vierhile
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  6. Derek Timm
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  7. Jill M. Weimer
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  8. Jonathan W. Mink
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  9. Frederick J. Marshall
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Corresponding author

Correspondence to Erika F. Augustine .

Editor information

Editors and Affiliations

  1. Tulane University Medical School, New Orleans, LA, USA

    Eva Morava

  2. Division of Metabolism & Children’s Research Centre, University Children’s Hospital Zürich, Zürich, Switzerland

    Matthias Baumgartner

  3. Division of Child and Adolescent Neurology, Mayo Clinic, Rochester, MN, USA

    Marc Patterson

  4. Clinical and Molecular Genetics Unit, UCL Institute of Child Health, London, UK

    Shamima Rahman

  5. Division of Human Genetics, Medical University Innsbruck, Innsbruck, Austria

    Johannes Zschocke

  6. Center for Child and Adolescent Medicine, Heidelberg University Hospital, Heidelberg, Germany

    Verena Peters

Additional information

Communicated by: Verena Peters

Appendices

Synopsis

Short-term administration of mycophenolate was well tolerated in an ambulatory sample of individuals with juvenile neuronal ceroid lipofuscinosis, a monogenic disorder with secondary autoimmunity.

Corresponding Author

Erika F. Augustine, MD, MS.

Compliance with Ethics Guidelines

Conflict of Interest

EF Augustine, HR Adams, and JW Mink have received research support from Abeona Therapeutics. JW Mink has received consulting fees from Sumitomo, Inc. CA Beck, S Defendorf, A Vierhile, D Timm, JM Weimer, and FJ Marshall declare that they have no conflicts of interest.

Funding

The trial was supported by research grants from the Batten Disease Support and Research Association and the Food and Drug Administration (#FD003908). The authors confirm independence from the sponsors; the content of the article has not been influenced by the sponsors.

Informed Consent

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. The trial was reviewed and approved by the University of Rochester Research Subjects Review Board (#33940) and was registered at Clinicaltrials.gov (NCT01399047). Parent permission was obtained for the enrollment of each study participant.

Contributions of Individual Authors

EF Augustine:

Conceptualization of the study, conducting the study, interpretation of the data, drafting and revising the manuscript

CA Beck:

Conceptualization of the study, analysis and interpretation of the data, revising the manuscript

HR Adams:

Conceptualization of the study, conducting the study, interpretation of the data, revising the manuscript

S Defendorf:

Conducting the study, revising the manuscript

A Vierhile:

Conducting the study, revising the manuscript

D Timm:

Specimen analysis, revising the manuscript

JM Weimer:

Specimen analysis, revising the manuscript

JW Mink:

Conceptualization of the study, conducting the study, interpretation of the data, revising the manuscript

FJ Marshall:

Conceptualization of the study, conducting the study, interpretation of the data, revising the manuscript

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© 2018 Society for the Study of Inborn Errors of Metabolism (SSIEM)

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Augustine, E.F. et al. (2018). Short-Term Administration of Mycophenolate Is Well-Tolerated in CLN3 Disease (Juvenile Neuronal Ceroid Lipofuscinosis). In: Morava, E., Baumgartner, M., Patterson, M., Rahman, S., Zschocke, J., Peters, V. (eds) JIMD Reports, Volume 43. JIMD Reports, vol 43. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2018_113

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  • DOI: https://doi.org/10.1007/8904_2018_113

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  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-662-58613-6

  • Online ISBN: 978-3-662-58614-3

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