Why and how to achieve novel outcomes in neurodegenerative gene therapy trials

Picking outcome measures for neurodegenerative gene therapy trials in rare disease is difficult. The conditions often have a lot of heterogeneity, relatively small sample sizes, and rarely disease-specific outcome measures. That is why “outside the box” thinking is necessary, and Cure Sanfilippo Foundation Chief Science Officer Cara O’Neill, MD FAAP, shared how novel outcomes could be used to expand and improve evaluation of gene therapy trials for neurodegenerative diseases at the Lysogene/Sarepta satellite symposium during SSIEM 2019 last week in Rotterdam, Netherlands.

Cara O'Neill at SSIEM 2019Most of the measures used in childhood neurodegenerative conditions are drawn from more general measures based on normal neurodevelopment and behavior patterns, rather than hallmarks of particular disease. So rare diseases are always being compared to “Normal.” But is that a fair comparison knowing that these patients have had chronic ongoing brain injury to the immature developing brain? 

“We have to do a better job of matching endpoints with the patient’s needs across the spectrum of any given disease,” urged O’Neill.

The key is meeting the patient needs, not the clinician’s needs or fulfilling assumptions that have been made in the past about patients’ need.

“We must get as close as we can to discerning what is going to make their life better, for however long that is.”

Cara O'Neill at SSIEM 2019Sharing early data from the Foundation’s MPS III Caregiver Preference Study, O’Neill noted that the more than 160 Sanfilippo caregivers across 14 different countries listed pain, communication, mobility and hyperactivity among their treatment priorities. Additionally, what caregivers prioritize changes along the course of the disease. 

O’Neill detailed how the Foundation has partnered with Aparito, Casimir Trials, and Lysogene to conduct an exploratory study of
novel outcomes for MPS IIIA running in parallel to AAV10-SGSH intracranial gene therapy trial. The study uses frequent video capture by caregivers to monitors specific disease hallmarks and priorities identified by the Caregiver Preference Study in the child’s familiar environment  to capture the child’s best ability. 

The patient-reported outcome videos study has allowed detection of subtle, but meaningful, incremental changes and appears feasible for longer term monitoring of real-world functioning and patient status, reported O’Neill.

    Insights to Help Clinicians Understand Caregiver Burden with Sanfilippo

    Caregivers for children with Sanfilippo Syndrome face a unique set of challenges because of the disease’s complex nature. There is little understanding among clinicians of the family experience of caring for patients with Sanfilippo and how a caregiver’s experiences change and evolve as patients age. The burden and impact on caregivers’ quality of life is poorly defined and best-practice guidance for clinicians is lacking.

    Chief Science Officer Cara O'NeillA group of international clinical advisors with expertise in the care of pediatric patients with Sanfilippo and lysosomal storage disorders met to begin filling this void of understanding and create best-practice guidance for clinicians. Cure Sanfilippo Foundation Chief Science Officer Cara O’Neill, MD FAAP, was among the advisors. As a mother of a child with Sanfilippo, Cara brought first-hand caregiver perspective to the collaboration in addition to scientific and medical expertise.

    The group reviewed key aspects of caregiver burden associated with Sanfilippo B by identifying and quantifying the nature and impact of the disease on patients and caregivers. They co-authored recommendations based on findings from qualitative and quantitative research, which were recently published in the Orphanet Journal of Rare Diseases.

    The article’s authors report that:
    “Providing care for patients with Sanfilippo B impinges on all aspects of family life, evolving as the patient ages and the disease progresses. Important factors contributing toward caregiver burden include sleep disturbances, impulsive and hyperactive behavior, and communication difficulties.
    Caregiver burden remained high throughout the life of the patient and, coupled with the physical burden of daily care, had a cumulative impact that generated significant psychological stress.”

    Additionally, the authors call for changing the narrative associated with Sanfilippo:

    “The panel agreed that the perceived aggressive behavior of the child may be better described as ‘physical impulsiveness’ and is often misunderstood by the general public. Importantly, the lack of intentionality of the child’s behavior is recognized and shared by parents and panel members.

    Parents may seek to protect their child from public scrutiny and avoid situations that many engender criticism of their parenting skills.”

    Read the complete article from the Orphanet Journal on Rare Diseases.

    Helping the research, clinical, and regulatory communities understand the perspectives of caregivers for Sanfilippo children is a priority for Cure Sanfilippo. The fastest path to a cure is when researchers, clinicians, regulators, and patient advocates collaborate and align. Another way to the Foundation is working to amplify the caregiver voice and project it into the industry space is with its Caregiver Preference Study. Learn more about this initiative.

    Speeding Diagnosis of Rare Diseases By Empowering Pediatricians

    First-Ever Collaboration: Pilot Program Giving Pediatricians Direct Access to Geneticists so Rare Diseases Are Diagnosed Accurately and Early

    Families need faster, accurate diagnosis so they can access clinical trial opportunities as soon as possible. A key to this happening is bridging the gap in pediatricians’ access to genetics information, especially regarding rare diseases. To help bridge this gap, Cure Sanfilippo Foundation has partnered to pilot the Genetics Access in Primary Pediatrics (GAAP) project, linking Greenwood Genetic Center’s (GCC) clinical geneticists and genetic counselors to pediatricians through the Faces2Genes app.

    Face2Gene analyzes patient photographs using machine learning and computer algorithms to help make challenging diagnoses. Through the GAPP pilot project, the Face2Gene improves patient wait times and allows a pediatrician to identify patients through a list of genetic “triggers” or features that may indicate a need for further genetic evaluation.

    If the patient’s family elects to be a part of the GAPP pilot project, the pediatrician uploads facial photos and other clinical information to Face2Gene where it can be securely shared with GGC clinicians for review. The geneticist can suggest appropriate referrals or genetic testing that can be initiated by the pediatrician in advance of the genetics appointment. Urgent referrals can be prioritized, and when the patient does come in for their genetics consultation, initial test results have already been completed, saving valuable time.

    Learn more about the Faces2Gene project and Foundation’s collaboration.

    Creation of Global Clinical Guidelines for Sanfilippo Syndrome

    Cure Sanfilippo Foundation is leading the development the first-ever Global Clinical Guidelines for the management of Sanfilippo Syndrome in partnership with the Sanfilippo Children’s Foundation (Australia).

    Best-practice guidelines for clinical care are critical for both patients and health care professionals in the management of rare diseases where lack of experience and knowledge about a condition often causes late diagnosis and less than optimal management of the condition. Such guidelines allow clinicians and other health-care professionals to make recommendations based on best-available evidence; improve consistency of diagnosis and clinical management across treatment centers; and enable affected families to make informed decisions regarding care and treatment.

    As several promising treatments move into clinical trial, the need for Global Clinical Guidelines has become increasingly important. The international  steering committee for this project includes: Dr. Simon Jones, UK (Chair); Dr. Joseph Muenzer, US; Dr. Chester Whitley, US; Dr. Nicole Muschol, Germany; Dr. Nicholas Smith, Australia; and Dr. Roberto Guigliani, Brazil.

    Experts worldwide from all of the disciplines of health professionals involved in the care of children and young adults with Sanfilippo will be invited to contribute content to the clinical management guidelines.

    These guidelines will be collated and validated by a wider pool of clinicians and the finalized Global Clinical Guidelines published in a peer-reviewed medical journal towards the end of 2019. Production of a family-friendly version of the guidelines is also planned.

    This project is supported by a grant from Global Genes and BioMarin Pharmaceutical

    Below: The team aggregated by the Foundation to lead the project.
    Global Clinical Guidelines on Sanfilippo Syndrome Steering Committee - February 2018

    Update: Read the April 2019 Foundation Update for the latest on the project.

    Caregiver Preference Study for Sanfilippo Syndrome

    Team working on Sanfilippo Syndrome caregiver preference studyCure Sanfilippo Foundation is working to publish the first-ever Caregiver Preference Study for Sanfilippo Syndrome. It will include what parents consider “meaningful benefit,” as well as an exploratory staging tool.

    The aim of the Caregiver Preference Study is to help inform the selection and development of clinical trial endpoints to reflect desired treatment benefits across the lifespan of children with Sanfilippo Syndrome. 

    Our hope is that the publication of these findings further inform key stakeholders, allowing the incorporation of patient voice into the decision making regarding the drug approval process and access. 

    Team working on Sanfilippo Syndrome caregiver preference study; Cara O'NeillOur project design for the Caregiver Preference Study incorporates these various stakeholders including industry partners, regulatory, and parents of children with Sanfilippo Syndrome. 

    More than 150 caregivers recently completed the quantitative survey and are currently being analyzed. Ongoing study results will be shared via poster presentations and manuscripts, as they become available. 

    Outcomes and interim results from our focus groups (the qualitative portion) were shared in a Platform and Poster Presentation at the World Symposium in February 2019 and 2020, and can be found here:
    presentation poster from the WORLD Symposium 2019 and poster presentation from the WORLD Symposium 2020

    In March 2020, Cure Sanfilippo Foundation presented the study’s findings to officials at the FDA’s Center for Biologics Evaluation and Research (CBER) and Center for Drug Evaluation and Research (CDER). Learn more about what was discussed at the meeting.

    Cara O'Neill presenting Caregiver Preference Study results at world conferenceThis important project has received grant support from BioMarin Pharmaceutical, Lysogene, Sobi, and Orchard Therapeutics.


    Sanfilippo Syndrome caregiver preference study poster presentation

    Collaborating on facial-recognition app to diagnose Sanfilippo Syndrome

    Cure Sanfilippo Foundation is collaborating with Face2Gene, a suite of digital resources for physicians from FDNA, to populate its Clinic app that uses facial recognition technology to assist in accurately and timely diagnoses of Sanfilippo Syndrome.

    One way to determine if different genetic syndromes have distinctly recognizable facial features is by using sophisticated facial recognition software. This distinction could, in time, lead to an earlier diagnosis by medical professionals.

    Cure Sanfilippo asked the network of Sanfilippo families that elect to operate under its umbrella to provide facial photos of their children to help create a definition of the facial features for Sanfilippo Syndrome (MPS III) and study the facial features over different ages, genders and ethnicities.

    Once sufficient numbers of photos have been submitted, FDNA will run an analysis on the different groups of photos to determine whether there are distinct gestalts and how these gestalts change over time.

    Update: In 2018, the information uploaded to Face2Gene was used to create a Natural History of Facial Features Observed in Sanfilippo Syndrome, Type B. The following poster presentations were displayed at the 2018 World Symposium. To download a PDF of the posters, click the image. 

    Sanfilippo Syndrome, Type B, (MPSIIIB) facial features observed using next-gen phenotyping tool


    Distinct facial phenotype for Sanfilippo Syndrome (MPSIII)

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