Key Points of Sanfilippo Advocacy Group Response to FDA Guidance

June 4, 2020

The combined Sanfilippo Advocacy group submitted comments to the U.S. Food and Drug Administration’s (FDA) on May 5, 2020, regarding its draft guidance on drug development for Sanfilippo Syndrome for review. 

These advocacy group is working closely with the FDA on the review and hopeful revisions to the draft guidance.

The advocacy group’s entire submission (cover letter, comments, and supporting documentation) is available at:

Twenty-six Foundations working on Sanfilippo Syndrome around the world signed-on in support. 5+ Foundations and 10 expert clinicians helped with the content. The document has 39 pages and has 63 references cited.

Cover Letter Outlining Key Issues

Accompanying the 39-page comment document was a letter from collaboration leader Dr. Cara O’Neill, Chief Science Officer of Cure Sanfilippo Foundation. It outlines the many issues the advocacy groups request the FDA amend in its guidance.

May 5, 2020

Re: Docket Number: FDA-2019-D-5404

Dear Members of the FDA MPS III Draft Guidance Committee,

We wish to thank you for providing much needed focus on Sanfilippo syndrome, mucopolysaccharidosis type III (MPS III), with the creation of the MPS III Draft Guidance for Industry. This represents an important framework which we are keen to enhance through the input and incorporation of our expert-stakeholder community. We look forward to collaborating during the comment period and through direct dialog in the future.

This correspondence constitutes a formal submission to the Federal Register by Patient Advocacy Groups whose mission is to support research/scientific advances as well as the patients and caregivers with mucopolysaccharidosis type III (MPS III or Sanfilippo syndrome). Consolidated group responses to the draft guidance titled “Mucopolysaccharidosis Type III (Sanfilippo syndrome): Developing Drugs for Treatment Guidance for Industry”, are conveyed within. We are requesting a review and consideration of critical revisions and inclusion of key academic resources available for MPS III, which may not have previously been considered. This material is intended to provide additional insight for the Agency from those directly involved in the care of patients with MPS III and actively engaged in research, to include the current state of MPS III science, patient and caregiver priorities, and the realities of drug development challenges in this rare and fatal disease.

Collaboratively, Patient Advocacy Groups enlisted expertise from additional community stakeholders including academic clinical experts and patient families. Clinician feedback, supporting references and patient insights are incorporated throughout this document. In addition, the Advocacy Groups curated information from industry to foster the understanding of clinical trial experiences in MPS III drug development. We are pleased to present a consolidated scientific and patient advocacy commentary for your review and consideration.

This submission is organized in the following manner:

  • First, we will share a high-level overview of background information, disease impact and the Sanfilippo community patient voice, including identified caregiver preferences.
  • Next, we will provide detail about the many core disease manifestations; providing clarification related to the prevalence and impact of specific symptoms as they relate to quality of life, clinical trial outcomes and draft guidance.
  • Finally, we discuss other aspects of trial design and drug development which impact the path to effective and available treatments for patients. In this section, we will more broadly respond to and request clarification on the language set forth by the Agency in the current draft guidance document.

Key take away points are summarized here, though extensive detail and supportive references are provided in the larger commentary document following this letter.

  • Different endpoints are needed to conduct trials in patient cohorts relative to different stages of disease progression. For example:
    • Pre- or early symptomatic patients: cognitive/adaptive behavior endpoints may be appropriate along with other somatic and neurologic measures
    • Mid-later stage symptomatic patients: somatic, non-cognitive neurologic (ambulation, swallowing function, etc.) and behavioral endpoints are preferred
  • Somatic disease manifestations, non-cognitive neurologic symptoms, and cognitive endpoints should be viewed as equally viable paths to approval if they are in line with addressing preferred treatment targets as identified by the patient/caregiver community.
  • Multidomain endpoints are preferred to a single primary clinical outcome measure.
  • Within-patient change (patient as own control) in relevant biomarkers or functional clinical outcomes may be used to demonstrate biological activity and efficacy for rare disease populations with significant heterogeneity, such as MPS III.
  • Sufficient natural history data exists to preclude the need for concurrent control or placebo trial arms.
  • Concurrent control and placebo arms are not feasible in the MPS III community due to invasive interventions, degenerative course of disease, difficulty finding properly matched patients, and unacceptability of this type of trial to participating families.
  • Biomarkers related to primary substrate accumulation (heparan sulfate and liver volume) or enzymatic activity and brain ventricular volume or cortical gray matter volume (MRI volumetrics) should be accepted as relevant surrogate biomarkers of biologic activity as well as treatment effect in appropriate compartments relative to the treatment target.

It is our sincere and respectful request, that the information shared here will be incorporated into the final FDA guidance for MPS III. This critical step could increase the likelihood that future clinical trials will be better matched to the unique aspects of Sanfilippo syndrome, allowing for a more accurate understanding of treatment effect across the lifespan of patients affected by this devastating terminal childhood disease. We welcome your comments or questions regarding the document that we have provided and look forward to further engagement with the Agency on this important matter. We appreciate your consideration of this material and your time and attention to developing a patient-centered framework for MPS III drug development.

With sincere appreciation and thanks,
Cara O’Neill, MD FAAP
(Parent of child with MPS III; Chief Science Officer, Cure Sanfilippo Foundation)
On behalf of the Sanfilippo syndrome Patient Advocacy Groups

Contributing organizations and clinicians:

Cure Sanfilippo Foundation

Jonah’s Just Begun Foundation

National MPS Society

Sanfilippo Research Foundation- Ben’s Dream

Team Sanfilippo Foundation

Julie Eisengart, PhD, Assistant Professor of Pediatrics and Director of Neurodevelopmental Program in Rare Disease, University of Minnesota

Maria Escolar, MD MS- Professor of Pediatrics and Director of Program for the Study of Neurodevelopment in Rare Disorders, Children’s Hospital of Pittsburgh

Paul Harmatz, MD- Pediatric Gastroenterology and Nutrition, University of California- San Francisco, Benioff Children’s Hospital-Oakland

Elizabeth Jalazo, MD – Pediatrician, Medical Genetics Fellow, University of North Carolina-Chapel Hill

Simon Jones, MBChB BSc MRCPCH- Pediatrician in Inherited Metabolic Medicine – University of Manchester, UK

Heather Lau, MD MS- Assistant Professor of Neurology, Director of Lysosomal Storage Disease Program, New York University

Joseph Muenzer, MD PhD – Professor of Pediatric Genetics and Metabolism, University of North Carolina-Chapel Hill

Lynda Polgreen, MD – Assistant Professor of Pediatrics, Pediatric Endocrinology, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center; University of California – Los Angeles

Elsa Shapiro, PhD- Professor of Pediatrics and Neurology-Pediatric Behavioral Neuroscience, University of Minnesota

Chester Whitley, MD PhD – Professor of Pediatrics, Director of Advanced Therapies Program, Principal Investigator of Lysosomal Diseases Network, University of Minnesota

Additional USA organizations sign-on in support:

The Children’s Medical Research Foundation, Inc.

Abby Grace Foundation

Aislinn’s Wish Foundation

The CAM Foundation

The Isabel Jurado Foundation

Save Mickey Association

Reagan’s Hope, A Cure for Sanfilippo

Aidan’s Antics, Inc.

JLK Research Foundation

Additional International Organizations: Sign-on Support:

Sanfilippo Children’s Research Foundation (Canada)

Sanfilippo Children’s Foundation (Australia)

Stop Sanfilippo Foundation (Spain)

Fondation Sanfilippo Suisse (Switzerland)

Sanfilippo Brazil

Fundacion Sanfilippo Colombia

Associacao Sanfilippo Portugal

Sanfilippo Sud (France)

Asociacion Sanfilippo Barcelona

Le Combat De Haitem Contre Sanfilippo (France)

Fundacja Sanfilippo (Poland)

Sanfilippo Initiative e.V. (Germany)

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