“This NIH Funding Opportunity Announcement (FOA) invites researchers to submit applications for support of clinical studies that address critical needs for clinical trial readiness in rare neurological and neuromuscular diseases. These studies should result in clinically validated biomarkers and clinical outcome assessment measures appropriate for use in upcoming clinical trials. Through the support of trial readiness studies, NINDS and NCATS expect to enhance the quality and increase the likelihood of success of clinical trials in these rare diseases.”

The Co-Directors of the International CDKL5 Disorder Database (ICDD)- a rich natural history database collecting parent-reported and genetic data and the Directors of the eight IFCR-funded CDKL5 Centers of Excellence (COEs) – a network of clinics throughout the USA that specialize in the care of patients with CDKL5 Deficiency Disorder (CDD) actively participate in a collaborative research infrastructure, the International CDKL5 Clinical Research Network (ICCRN). This network was initiated through IFCR funding. The ICCRN seeks to answer clinically significant questions to drive improvements in the clinical care of patients with CDD. To date, IFCR support has led to 12 publications since 2017 fostered by this collaboration. Disease-modifying therapies are currently in development for CDD patients, but a mission-critical step remains unfilled prior to the FDA-approved initiation of clinical trials.

There are no measures validated for CDD and the severity of this condition renders those outcome measures that exist unsuitable.

This award provides five years of funding to (1) refine and validate appropriate clinical outcome measures (COMs) and (2) Conduct a multi-site clinical trial readiness study to assess implementation, longitudinal stability, and collect baseline COMs data. COMs will be linked to an EEG/evoked potential biomarker. The COMs of interest include:

• gross motor scale
• fine motor scale
• parent-reported measure of communication
• parent-reported measure of quality of life
• clinician and parent-reported measure of clinical severity

An External Advisory Committee will provide guidance to the development of COMs from the perspective of multiple stakeholders (industry, FDA, and global CDD patient advocacy groups) to ensure that measures will be useful in clinical trials and relevant to the patient community.

Why do we need validated standardized measures?

Validated, standardized COMs will accurately and reproducibly track meaningful changes in clinical trials, ensuring optimal testing of potential new therapeutics, including gene therapy. The COMs that the research team plans to generate, refine, and validate for the CDD population in these studies. This information will also be used to capture the range of clinical severity and quality of life to direct clinical care, complement current natural history data, generate historic baseline outcome data for future clinical trials, and will enable severity staging for clinical trial readiness in CDD. In future studies, the approach and COMs could be adaptable for disorders similar to CDD.

Under the leadership of Drs. Benke, Demarest, Leonard, Downs, and Marsh, the study will involve nine participating sites:

• Children’s Hospital Colorado/University of Colorado – Tim Benke, MD, PhD and Scott Demarest, MD
• Telethon Kids Institute- Helen Leonard, MPH and Jenny Downs, PhD
• Children’s Hospital of Pennsylvania – Eric Marsh, MD, PhD
• Boston Children’s Hospital – Heather Olson, MD
• Cleveland Clinic – Dr. Elia Pestana-Knight, MD
• St. Louis Children’s Hospital – Dr. Judy Weisenberg, MD and Dr. Robin Ryther, MD
• Texas Children’s Hospital – Dr. Bernhard Suter, MD
• NYU Langone Health Center – Dr. Dana Price, MD
• UCLA Mattel Children’s Hospital – Dr. Raj Rajaraman, MD

What does this mean to the CDD Community?

“As I stated in my Biosketch provided with the grant application: this U01 is the culmination of our clinical and clinical research efforts. We established the flag-ship (recognized by national patient advisory groups IRSF, IFCR, and Loulou Foundation) multidisciplinary Rett Clinic at Children’s Hospital Colorado (for the treatment of Rett Syndrome (RTT), CDKL5 deficiency disorder (CDD), FOXG1 disorder, and MECP2-related conditions) in 2011. We did this specifically to develop the expertise and capabilities to attract and conduct natural history and interventional clinical trials that would be disease-modifying in these developmental encephalopathies. As such, we are very honored and excited to have this opportunity to move the field forward for CDD to develop COMs and link them to biomarkers which will allow future clinical trials in CDD to be successful in providing safe and meaningful outcomes for our CDD families. I am gratified to have the opportunity to work with IFCR, the other PIs including Dr. Demarest, and the team he has organized.” Dr Tim Benke, MD, PhD, Program Director/Principal Investigator for the UO1, Professor of Pediatrics, Pharmacology, Neurology, and Otolaryngology, University of Colorado School of Medicine and Medical Director for Rett clinic and Research Director of the Neurosciences Institute at Children’s Hospital Colorado

“This is a major milestone for the CDD community. The work funded by this grant will ensure that future clinical trials accurately capture the impact of new therapeutics by identifying meaningful changes in CDD patients’ symptoms. This grant would not be possible without the infrastructure provided by the ICCRN which is the culmination of years of support by the International Foundation for CDKL5 Research. IFCRs support of both the Centers of Excellence and the International CDKL5 Disorder Database as well as our recent efforts to combine and streamline those groups into the ICCRN. The ICCRN investigators are grateful for IFCRs support and excited to advance our understanding of CDD through improved measurement of patient symptoms.” Scott Demarest, MD, Assistant Professor, Departments of Pediatrics, Neurology and Epilepsy, University of Colorado School of Medicine, Children’s Hospital Colorado and Director of the International CDKL5 Clinical Research Network (ICCRN)

“As a collaborative research community, we are honored to have the opportunity to conduct a clinical trial readiness study for CDKL5 Deficiency Disorder. Development of clinical outcome measures and biomarkers in preparation for further clinical trials including ultimately disease-modifying therapies for CDD will be critical. This work will likely impact many similar early life developmental and epileptic encephalopathies beyond CDD.” Heather Olson MD, Assistant Professor, Department of Neurology, Division of Epilepsy and Clinical Neurophysiology, Boston Children’s Hospital

“We established the International CDKL5 Disorder Database (ICCD) in 2012, housed in Australia but working closely with families from around the world. New findings have contributed strongly to clinician and family knowledge and understanding about CDD. This new grant provides an opportunity for us to establish new research that builds and validates strong and meaningful outcome measures for CDD. In doing so, we look forward to continuing our relationships with families participating in the ICCD whilst also working closely with the ICCRN. Our grant will establish outcome measures that are ready for use in clinical trials, therefore making an important contribution to how new treatments for CDD will be evaluated in clinical trials. Outcome measures that are validated for CDD could also be of value for other developmental and epileptic encephalopathies. The IFCR has supported the ICCD since inception and it is a great honor to continue and deepen this very important collaboration with the opportunities afforded by this grant.” Jenny Downs PhD, Principal Research Fellow, Program Head of Child Disability, Telethon Kids Institute, Australia

“This was only possible because of all the support and funding provided by IFCR to the International CDKL5 Database since we first established it in 2012 and equally so because of the ongoing data contributions from CDKL5 families. Your efforts on behalf of research have been amazing! Please do keep your contributions coming!” Helen Leonard MBChB, MPH for Child Health Research, University of Australia, Perth; Senior Research Fellow and Program Head of Child Disability, Telethon Kids Institute, Australia

About CDD
CDKL5 Deficiency Disorder (CDD) is a rare neurodevelopmental disorder resulting from loss-of-function mutations in the CDKL5 gene. Presenting first as infantile spasms within the first weeks of life which progresses to intractable epilepsy, CDD patients also display profound neurodevelopmental delay, with generalized hypotonia, impaired motor skills, and severely impaired speech and vision. CDD patients also have impaired sleep, gastrointestinal function, and respiratory issues. With an incidence of approximately 1 in 40,000 live births, CDD is one of the most common monogenic pediatric epilepsies, with several thousand patients estimated in the US and Europe alone. No therapies exist to treat the neurodevelopmental symptoms of CDD, and epilepsy associated with CDD is poorly managed by current anti-seizure medications.

About International Foundation for CDKL5 Research (IFCR)
IFCR is a US-based patient advocacy organization founded in 2009 by families from around the world affected by CDD. Since then, IFCR has funded groundbreaking research, including animal and cell model generation, patient-driven natural history, and a multidisciplinary clinical research network. Pioneering this network of CDKL5 Centers of Excellence across the United States has facilitated the development of a clinical research model that demands high-quality patient care. Above all, IFCR supports all CDKL5 families and caregivers by providing education, advocacy, and awareness. IFCR fosters and participates with productive partnerships with patient advocacy groups for similar rare disorders.
www.cdkl5.com

Enquiries/Media:
Heidi Grabenstatter, PhD
Science Director
T: +1 (970) 290-6257
E: hgrabenstatatter@cdkl5.com

Karen Utley, BSN
Co-Founder and President, IFCR
E: kutley@cdkl5.com
www.cdkl5.com