Published: Ability change across multiple domains in mucopolysaccharidosis (Sanfilippo syndrome) type IIIA

E.G. Shapiro, J.B. Eisengart, D. Whiteman, et al., Ability change across multiple domains in mucopolysaccharidosis (Sanfilippo syndrome) type IIIA, Molecular Genetics and Metabolism (2023),https://doi.org/10.1016/j.ymgme.2023.108110

Abstract

The objective of this paper is 1) to expand the scope of the domains previously published in a natural history study of Mucopolysaccharidosis IIIA (Sanfilippo syndrome type A) (MPS IIIA) and 2) to present evidence regarding the capacity of a new metric, Growth Scale Values (GSVs), in comparison with traditional metrics, to show changes in skills as assessed by the Bayley Scales of Infant Development -III (BSID-III) and the Vineland Adaptive Behavior Scales, Second Edition (VABS-II). We re-analyzed a cohort of 25 children, 20 with rapid progressing disease and 5 with slow progression, who had been followed over two years using the BSID-III, and the VABS-II. Previously findings were reported using age equivalent scores; now we are also presenting findings with GSVs. For the re-analysis, Language and Motor scores were added to the Cognitive scale on the BSID-III, and Domain- and Subdomain-level scores added to the Total VABS-II score (i.e., ABC Composite). We evaluated raw scores, age equivalent scores, and GSVs (and standard scores for the VABS-II only). Individual patient data can be found in the appendices to this publication.

Results indicate that 1) Cognition as measured by GSVs was the most sensitive to decline; 2) GSVs showed significant decline in the range of 4 to 6 years of age; 3) For children under 4 years of age, positive growth occurs on most scales and most metrics, with the exception of language which slows somewhat earlier; 4) Other than the Cognitive scale, Receptive Language on the BSID-III and Receptive Communication on the VABS-II showed the most sensitivity to change; 5) Gross Motor skills showed the least decline over time and appeared to lack sensitivity to MPS IIIA motor concerns; and 6) No evidence for sensitivity to change for any metric was found in time intervals less than one year.

We conclude that GSVs are a precise measurement of change to detect decline in function, and they are a valuable method for future clinical trials in MPS IIIA. Evidence continues to support cognition as a primary endpoint. Additional work is needed to identify sensitive measures of meaningful endpoints to families.

Major MPS Natural History Study Review Paper Published

Authored by Elsa Shapiro, PhD and Julie Eisengart, PhD, this review substantially documents MPS Natural History

The natural history of neurocognition in MPS disorders: A review

Abstract:

MPS disorders are associated with a wide spectrum of neurocognitive effects, from mild problems with attention and executive functions to progressive and degenerative neuronopathic disease. Studies of the natural history of neurocognition are necessary to determine the profile of abnormality and the rates of change, which are crucial to select endpoints for clinical trials of brain treatments and to make clinical recommendations for interventions to improve patients’ quality of life. The goal of this paper is to review neurocognitive natural history studies to determine the current state of knowledge and assist in directing future research in all MPS disorders. There are seven different types of MPS diseases, each resulting from a specific enzyme deficiency and each having a separate natural history. MPS IX, will not be discussed as there are only 4 cases reported in the literature without cognitive abnormality.

For MPS IH, hematopoietic cell transplant (HCT) is standard of care and many studies have documented the relationship between age at treatment and neurocognitive outcome, and to a lesser extent, neurocognitive status at baseline. However, the mortality and morbidity associated with the transplant process and residual long-term problems after transplant, have led to renewed efforts to find better treatments. Rather than natural history, new trials will likely need to use the developmental trajectories of the patients with HCT as a comparators. The literature has extensive data regarding developmental trajectories post-HCT. For attenuated MPS I, significant neurocognitive deficits have been documented, but more longitudinal data are needed in order to support a treatment directed at their attention and executive function abnormalities.

The neuronopathic form of MPS II has been a challenge due to the variability of the trajectory of the disease with differences in timing of slowing of development and decline. Finding predictors of the course of the disease has only been partially successful, using mutation type and family history. Because of lack of systematic data and clinical trials that precede a thorough understanding of the disease, there is need for a major effort to gather natural history data on the entire spectrum of MPS II. Even in the attenuated disease, attention and executive function abnormalities need documentation.

Lengthy detailed longitudinal studies are needed to encompass the wide variability in MPS II.

In MPS IIIA, the existence of three good natural history studies allowed a quasi-meta-analysis. In patients with a rapid form of the disease, neurocognitive development slowed up until 42 to 47 months, halted up to about 54 months, then declined rapidly thereafter, with a leveling off at an extremely low age equivalent score below 22 months starting at about chronological age of 6. Those with slower or attenuated forms have been more variable and difficult to characterize. Because of the plethora of studies in IIIA, it has been recommended that data be combined from natural history studies to minimize the burden on parents and patients. Sufficient data exists to understand the natural history of cognition in MPS IIIA. MPS IIIB is quite similar to IIIA, but more attenuated patients in that phenotype have been reported. MPS IIIC and D, because they are so rare, have little documentation of natural history despite the prospects of treatments.

MPS IV and VI are the least well documented of the MPS disorders with respect to their neurocognitive natural history. Because, like attenuated MPS I and II, they do not show progression of neurocognitive abnormality and most patients function in the range of normality, their behavioral, attentional, and executive function abnormalities have been ignored to the detriment of their quality of life. A peripheral treatment for MPS VII, extremely rare even among MPS types, has recently been approved with a post-approval monitoring system to provide neurocognitive natural history data in the future.

More natural history studies in the MPS forms with milder cognitive deficits (MPS I, II, IV, and VI) are recommended with the goal of improving these patients’ quality of life with and without new brain treatments, beyond the benefits of available peripheral enzyme replacement therapy. Recommendations are offered at-a-glance with respect to what areas most urgently need attention to clarify neurocognitive function in all MPS types.

Full paper: https://www.sciencedirect.com/science/article/pii/S1096719221000585?via%3Dihub#s0015

Industry Collaboration Webinar Recording Available

This webinar was designed for clinical specialists, investigators, and pharmaceutical representatives who work in therapy development.

View the webinar


Rare disease drug development is made possible through strong industry partnerships with academic and medical experts. When diseases involve the central nervous system, trial design is even more complex. It requires partnering with experts who have specific disease experience, who understand measurements, and who are familiar with the complexities of clinical trials.

Elsa Shapiro, PhD and Paul Harmatz, MD, present an informative conversation on the unique role of the consulting psychologist, building partnerships within the greater trial ecosystem, and considerations for protocol development.

Paul Harmatz, MD: Dr. Harmatz is Professor in Residence at UCSF Benioff Children’s Hospital Oakland, California. He completed his Pediatric internship and residency training at Harbor-UCLA Medical Center. Following a research fellowship in Pediatric Gastroenterology and Nutrition at Massachusetts General Hospital, he remained in Boston until 1992 as faculty in Pediatrics at Harvard Medical School. During the last 15 years, Dr. Harmatz has participated in clinical trials with MPS I, MPS II, IVA, VI, and VII and has managed clinical care for MPS patients living in northern California.

MPS Cognitive Master Class

Shapiro Neuropsychology Consulting was proud to organize a Master Class in the MPS disorders with Dr. Elsa Shapiro, directing the program as lead faculty.

Organized with the The University of Minnesota Division of Clinical Behavioral Neuroscience, and the National MPS Society, this expert Master Class in Neurocognitive and Neurobehavioral Measurement In Mucopolysaccharidosis (MPS) took place in November, 2020. Attendees, doctorate level psychologists and psychometrists, are participated from more than 40 international sites. The goal of the Master Class was to disseminate expertise in response to the growth in the number of MPS trials and new therapy developments. Thanks to generous industry sponsorship, this class was offered at no cost to qualified psychologists at clinical trial sites who see, or will see, patients with Mucopolysaccharidosis (MPS) in clinical trials. The recordings of the MasterClass live on with the National MPS Society.

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Satellite Session at the WorldSymposium, 2018

Cognitive impairment in patients with MPS II: From disease burden to cognitive testing, a satellite symposium supported by Shire took place February 2018 at the WORLDSymposium for Lysosomal Storage Diseases. 

Dr. Elsa Shapiro and Dr. Christina Lampe presented on topics including an investigation of challenges in assessing cognition and behavior in patients with MPS II and the burden of cognitive impairment as it relates to daily activity.  During a case study session the audience had the opportunity to vote their responses in an interactive quiz format.

 

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Consensus Papers Posted

In December, 2016 experts from around the globe convened in London for the International Conference for Cognitive Endpoints in MPS. A consensus panel, led by Dr. Hanneke van der Lee, met to address cognitive endpoints in MPS I,  MPS II and MPS III. The resulting literature review and paper now are published and are open access. 

Cognitive and adaptive measurement endpoints for clinical trials in mucopolysaccharidoses types I, II, and III: A review of the literature:

http://www.mgmjournal.com/article/S1096-7192(17)30209-3/fulltext

Cognitive endpoints for therapy development for neuronopathic mucopolysaccharidoses: Results of a consensus procedure:

http://www.mgmjournal.com/article/S1096-7192(17)30211-1/fulltext

Thank you to the National MPS Society, the MPS Society of the UK and to all our our industry partners for support in making this endevour possible. 

Thank you and Best Wishes to Kate Delaney

While Shapiro & Delaney as a consultancy formed in the past several years, Kate Delaney and Elsa Shapiro have been working together in the rare disease space for more than 20 years. On May 1 we wish Kate well as she takes the next steps in her efforts to help children with rare diseases, leaving the consultancy to make her mark in a new role in industry. 

Everyone who has worked with Kate can attest to her warmth, professionalism, expertise and dedication. We know that Kate will be continue to make a strong impact and further the mission of bringing new and effective treatment to the children who need it. 

Elsa Shapiro will continue to offer expert perspective under the new business name, Shapiro Neuropsychology Consulting. 

 

 

EMA Slide Share- Presentation Given at Consensus Conference

Dr. Caroline Auriche, Head of Scientific Advices for the European Medicines Agency (EMA), presented to physicians, clinicians and industry professionals working in Mucopolysaccharidosis (MPS) research at the International MPS Consensus Conference for Cognitive Endpoints.  Slides from this presentation are posted below. 

Slides and Audio: 

 

Slides (click through as pictures):

Update- A Successful Consensus Conference.

In partnership with the National MPS Society (U.S.) and UK MPS Society, Shapiro & Delaney organized a successful consensus conference to discuss neurocognitive and related endpoints in clinical trials for the mucopolysaccharidoses.

Held in London in the beginning December, this conference drew 80 invited international experts as well as representatives from 18 pharmaceutical companies. Parents and patient advocates were also represented.

Both FDA and EMA representatives attended and presented.

The conference format consisted of large group presentation of current literature by Dr. Darren Janzen and discussion by experts and audience, followed by a second day of Delphi consensus panel deliberations that were open for observation. 

Workshop sessions were also held on the second day. Overseen by Kate Delaney and Dr. Brian Bigger, presented pertinent topics and brought experts from around the world together with industry for open and productive discussion. Sessions included:

  • MPS Disorders: Clinical Manifestations in MPS I, II and III- Dr. Maureen Cleary
  • MPS disorders: Genotype-Phenotype Correspondence- Dr. Chester Whitley
  • New Treatment Options and Ongoing Clinical Trials- Dr. Brian Bigger
  • Patient/Parent Reported Outcomes- Dr. Julie Eisengart, Dr. Kendra Bjoraker, Dr. Kelly King
  • Newborn Screening and Early Identification; Challenges for Treatment and Assessment – Dr. Paul Orchard, Kate Delaney
  • The Basics of Reliable Cognitive Assessment Kathleen Delaney, -J.P. Marchal
  • Neurological, Neuroimaging and Biochemical Markers and their Relationship to Cognition-  Dr. Igor Nestrasil, Dr. Hernan Amartino, Dr. Patricia Dickson

Workshop presentation videos will be released for viewing beginning in mid-January.

Consensus proceedings, overseen by Dr. Hanneke van der Lee at the University of Rotterdam, resulted in a list of recommendations and assessment guidelines. Papers describing the results will be submitted to journals in the first quarter of 2017 and will be touched on in Dr. Elsa Shapiro's keynote addess at the WORLDSymposia in February 2017.

 

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Elsa Shapiro Announced as Keynote Speaker at WORLDSymposium

WORLDSymposium announces Elsa Shapiro, PhD, Professor of Pediatrics and Neurology in the Division of Pediatric Behavioral Neuroscience at the University of Minnesota, as the 2017 Keynote Speaker. Dr. Shapiro's address: Understanding and Measuring Neurodegeneration in Childhood Onset Lysosomal Diseases.

The goal of WORLDSymposium is to provide an interdisciplinary forum to explore and discuss specific areas of interest, research and clinical applicability related to lysosomal diseases. Each year, WORLDSymposium hosts a scientific meeting presenting the latest information from basic science, translational research, and clinical trials for lysosomal diseases. This symposium is designed to help researchers and clinicians to better manage and understand diagnostic options for patients with lysosomal diseases, identify areas requiring additional basic and clinical research, public policy and regulatory attention, and identify the latest findings in the natural history of lysosomal diseases. 

Dr. Shapiro will be speaking on Wednesday, February 15, 2017. 

Learn more: www.worldsymposia.org/about

Shapiro & Delaney form partnership with National MPS Society (U.S.) and UK MPS Society to organize an international consensus conference.

Shapiro & Delaney, together with the National MPS Society and the UK MPS Society, are organizing an international consensus conference on neurocognitive and related endpoints in clinical trials for the mucopolysaccharidoses. 

Across the spectrum of MPS disorders, differing endpoints in natural history studies and clinical trials lead to lack of comparability of results, which handicaps the identification of effective treatments. With the development of new treatments, it is crucial to develop a guide for future studies.

To be held Dec 2 and 3 in the UK, with more than 70 invited international experts attending, this consensus conference will address cognitive endpoints in MPS I, II and III. Results from the conference Delphi proceedings, as well as a Literature review and industry survey will be compiled and published. In addition to Consensus Panel proceedings, the conference will serve as a key touch-point for industry representatives and invited attendees with Kate Delaney leading panel discussions in pertinent topics such as: obstacles to accurate neurocognitive assessments, early developmental assessments of infants and regulatory considerations when using neurocognitive endpoints in clinical trials.

Conference Steering Committee:

Elsa Shapiro, PhD, Shapiro & Delaney, LLC, & University of Minnesota, USA; Mark Dant, US National MPS Society; Kathleen Delaney, Shapiro & Delaney LLC; Christine Lavery, UK Society for Mucopolysaccharide Diseases; Brian Bigger, PhD, University of Manchester, UK; Patricia Dickson, MD, Harbor-UCLA Pediatrics, Los Angeles, CA, USA; Maria L Escolar, MD. MS. University of Pittsburgh, PA, USA; Roberto Giugliani,MD, PhD,  Federal University of Rio Grande do Sul, Porto Alegre, Brazil; Paul Harmatz, MD, UCSF Benioff Children's Hospital Oakland, CA, USA; Simon Jones, M.D., St. Mary’s Hospital, Central Manchester University Hospitals, University of Manchester, UK; Shauna Kearney,  Ph.D., Birmingham Children's Hospital, UK; Joseph Muenzer, MD, PhD, University of North Carolina at Chapel Hill, USA; Igor Nestrasil, MD, PhD, University of Minnesota, USA; Maurizio Scarpa, MD, Horst Schmidt Clinic, Wiesbaden, Germany; Frits Wijburg, MD, PHD Academic Medical Center, U of Amsterdam, Netherlands; Hernan Amartino, MD.  Hospital Universitario Austral, Buenos aires, Argentina; Simon Jones, MD, Central Manchester University Hospitals, University of Manchester, UK; Lorne Clark, MD, University of British Columbia, Canada; Stewart Rust, PHD, Royal Manchester Children's Hospital, UK

This conference is possible through the generous support of eighteen pharmaceutical industry sponsors. 

Contact jennifer.greenberg@shapiroanddelaney.com for more information or with media inquiries. 

Involvement

FDA Workshop
Held April 16 and 17, this FDA workshop focused on cognitive endpoints in rare inborn errors of metabolism and common diseases. These presentations (video, transcripts, and slides) are now on-line.

UK Mucopolysaccharidosis Society Workshop
The UK Mucopolysaccharidosis Society had an important recent workshop regarding natural history studies and clinical trials in Sanfilippo syndrome (Mucopolysaccharidosis Type III) that included academia, industry, and advocacy groups.  This workshop concluded that common natural history databases and standard protocols were necessary to ensure that patients obtain the best services.