For more than two years, PPMD has been leading a national effort to build a newborn screening infrastructure for Duchenne in the U.S.
Led by PPMD's Annie Kennedy, Michele Lloyd–Puryear, M.D., Ph.D., Newborn Screening Consultant for PPMD, and Jerry Mendell, MD of Nationwide Children's, the effort includes more than 50 of the worlds top newborn screening and Duchenne experts.
Over the last three months both Annie and Dr. Puryear testified on behalf of the Duchenne community to the federal Committee with oversight of conditions that are screening for in the U.S., the Advisory Committee on Heritable Disorders in Newborns and Children on behalf of the Duchenne community. Read their statements below
Date: February 11, 2016
Submitted by: Annie Kennedy, Senior Vice President – Legislation & Public Policy, Parent Project Muscular Dystrophy
On behalf of the Parent Project Muscular Dystrophy, I would like to thank the Committee for providing me with the opportunity to address you here today. My name is Annie Kennedy and I serve as PPMD’s Senior Vice President – Legislation & Public Policy and I am here on behalf of the more than 8,000 individuals estimated to be living with Duchenne muscular dystrophy in the U.S. today. But more – it is with an increasing sense of hope and urgency – that I am here today on behalf of the thousands of babies who are yet to be born with Duchenne muscular dystrophy.
Duchenne muscular dystrophy is one of the most common fatal genetic disorders diagnosed in childhood, affecting approximately 1 in every 5000 live male births. Because the Duchenne gene is found on the X-‐chromosome, it primarily affects boys; however, carriers can manifest symptoms that range in variability from mild muscle cramping – to cardiomyopathy – to young girls with the classic Duchenne phenotype.
Duchenne results in progressive loss of strength and is caused by a mutation in the gene that encodes for dystrophin. Because dystrophin is absent, the muscle cells are easily damaged. The progressive muscle weakness leads to serious and fatal medical problems, particularly issues relating to the heart and lungs. By a time young boys are typically diagnosed between the ages of 3 and 5, irreversible muscle damage has already occurred. Young men with Duchenne typically die in their early 20s.
In September of 2014, I had the opportunity to present before you and share that our Duchenne community’s research pipeline was both robust and hopeful. In light of the potentially disease modifying products that were reaching regulatory review, PPMD formally convened a national Duchenne newborn screening effort in December of 2014. Today, I am pleased today to provide you with a high-‐level update on this effort which includes a formalized national Duchenne Newborn Screening Steering Committee and 6 related Working Groups, a Duchenne Screening Test Development Project led by PerkinElmer, a project with NBSTRN, and collaborations with most federal agencies involved in newborn screening.
In January of 2015, PPMD enlisted the expertise of Dr. Michele Puryear to help lead our Duchenne newborn screening efforts. With Dr. Puryear’s guidance along with the leadership of Dr. Jerry Mendell and me, we convened a national Duchenne Newborn Screening Steering Committee. Comprised of generous and active experts from both the fields of newborn screening and Duchenne, these individuals represent a broad array of stakeholders, disciplines, and agencies. With the guidance of our Steering Committee we conducted an analysis of our current readiness for a public health program for Duchenne newborn screening and began to map out an action plan to address the gaps that had been identified. Six Work Groups were then created to address the priorities that had been identified by the action plan, with each work group led by an established newborn screening expert. In total more than 50 dedicated professionals have been involved in this effort over the last year.
The workgroup focus areas include:
- Outreach & Education – HCP and Patient/ Provider Community
- Follow-‐up and Clinical Care Considerations for Pre-‐symptomatically Identified Infants with DMD
- Laboratory Test Validation & Refinement
- NBSTRN Integration: Clinical Integration Group [CIG] and LPDR
- Bioethical and Legal Considerations • Evidence Review Workgroup
Additionally, we have been working closely with PerkinElmer on an effort to develop a refined screening test for Duchenne. This Committee is familiar with Duchenne newborn screening pilot project led by Dr. Jerry Mendell from Nationwide Children’s Hospital and Ohio State University which included the state’s 43 birthing hospitals, screened more than 40,000 babies, and identified 7 male babies who were confirmed to have Duchenne. The Ohio pilot used a an enzyme assay for creatine kinase as a first tier screening tool. DNA mutation analysis was used as a second tier test during the screening process.
We are currently working to further refine the first tier screen for creatine kinase to develop a new newborn screening test method for Duchenne. PerkinElmer is leading this project, in partnership with the California Department of Health Newborn Screening program and will be using newborn screening residual bloodspot specimens from the California Biobank. We have been working closely with PerkinElmer to coordinate outreach with 5 Duchenne Care Centers based in California that have agreed participate in the project and to assist with local IRB processes and patient informed consent from eligible families.
Our Duchenne community is also fortunate to have many well-‐developed infrastructure and registry resources including the Duchenne Certified Care Center Program supported by PPMD, the MDA Clinic network supported by MDA, MDA’s national neuromuscular registry, and PPMD’s DuchenneConnect registry which has been a part of the PCORI PCORnet network. Additionally, the DuchenneConnect data is a part of a global network of Duchenne datasets, many of which have been a part of newborn screening efforts over the years. For this reason, PPMD, MDA, and NBSTRN established an MOU to explore data integration and applicable resources available through NBSTRN.
Each of these efforts have benefited from the great expertise and generosity of experts and leaders within NIH, HRSA, FDA, CDC, ACMG, the newborn screening community, and the Duchenne community.
While Duchenne muscular dystrophy is still a 100% fatal disease, we have demonstrated that immediate identification and early clinical interventions can add years, even decades to an individual’s life span. In the last year, our landscape has changed and advanced even further.
In August of 2014, the European Commission granted marketing authorization for PTC Therapeutic’s Translarna™ for use in the European Union (EU) for the treatment of nonsense mutation Duchenne muscular dystrophy in ambulatory patients aged five years and older. It is estimated that a nonsense mutation is the cause of Duchenne in approximately 13% of patients, or approximately 2,000 patients in the United States. Translarna is anticipated to be reviewed by regulators in the U.S. in 2nd quarter 2016.
In the coming weeks, the FDA Advisory Committee review for Sarepta Therapeutics’ promising exon skipping therapy – eteplirsen -‐ could potentially benefit yet another 13% of the Duchenne population whose disease may be modified through a skipping of the targeted exon 51.
In other words, this is the dawning of a new age in Duchenne muscular dystrophy. In each instance, these therapeutic interventions will be most successful the earlier they are administered, meaning pre-‐symptomatic identification of children with Duchenne as early as possible is critical. And most importantly – we know that providing clinical interventions to children with Duchenne before they develop muscle weakness improves therapeutic outcomes and can even add years to their life spans. The Duchenne community is hopeful.
But we also know that we have an extraordinary amount of work that we must do to transform our existing national Duchenne care and support infrastructure into one that fits into the public health model for newborn screening. And we are working hard to accomplish this. We are committed to paving a path forward for Duchenne newborn screening in the United States. And with the bright hope of therapy approvals of the near horizon, we must ensure that once approved, these therapies are available to all eligible families at the earliest moment possible.
Michele Lloyd-Puryear, M.D., Ph.D.
Michele Lloyd-Puryear, M.D., Ph.D., Newborn Screening Consultant, Parent Project Muscular Dystrophy
On behalf of Parent Project Muscular Dystrophy [PPMD], I would like to thank the Committee for providing me with the opportunity to address you here today.
My name is Michele Puryear and I serve as a consultant to PPMD and I am here on behalf of the more than 8,000 individuals estimated to be living with Duchenne muscular dystrophy in the U.S. today. In addition, I am here on behalf of the thousands of babies that need to be screened for Duchenne muscular dystrophy. Ms Annie Kennedy last spoke with you in February 2016.
Duchenne muscular dystrophy (DMD) is one of the ten most severe and common pediatric genetic diseases and affects an estimated 1 in every 3,500-5000 male births. While DMD is a 100% fatal disease, in 2015 the therapeutic landscape changed and new treatments have been developed that target the different kinds of mutations causing DMD. Pending the launch of these new treatments, newborn screening of babies for DMD is critical. The current treatments are based on the various genetic mutations causing DMD and include:
- Ataluren or TranslarnaTM: It is estimated that a nonsense mutation is the cause of DMD in approximately 13% of patients, or about 2,000 patients in the USA/2,500 in the European Union [EU]. Ataluren received marketing authorization in the EU in August 2014 for the treatment of nonsense mutations for DMD in ambulatory patients aged five years and older, representing the first treatment approved for the underlying cause of the disease. Although the company developing ataluren received a “Refuse to File” letter from the FDA, the company has proceeded with clinical trials and actively is pursuing regulatory approvals for Translarna in DMD globally.
- Exon skipping therapy: There are two interventions in the regulatory pipeline that utilize exon skipping, Eteplirsen and Kyndrisa. Both benefit the same subset, or approximately 13% of the Duchenne population whose disease may be modified through a skipping of the targeted exon 51. Confirmatory trials for eteplirsen intervention are being led by Sarepta Therapeutics in the USA and an accelerated approval pathway for review commenced in 2015. After 4 years of eteplirsen treatment the six-minute walk distance was 151 m better than natural history controls and fewer treated DMD patients had lost ambulation. Data were presented to FDA by Sarepta last month and we are waiting for a final decision by FDA. Kyndrisa is being developed by Biomarin and is also currently under regulatory review in Europe.
In February 2016, we told you about our newborn screening initiative, which included the formation of a steering committee and six workgroups. The workgroups were set up to look at the existing data available for evidence review and gaps in the evidence that need to be addressed within a newborn screening pilot. In total more than 50 experts have been involved in this process. In addition, we are working in partnership with the NIH funded Newborn Screening Translational Research Network to address some of the issues and to facilitate the establishment of infrastructure needed for a pilot. The workgroups are: Outreach & Education for both health care professionals and families; Follow-up and Clinical Care considerations for pre-symptomatically identified infants with DMD; Laboratory Test Validation and Refinement; NBSTRN Integration: Clinical Integration Group and creation of a longitudinal pediatric data resource; ELSI; and finally, the Evidence Review Workgroup.
Highlights include the development of a paper to identify ELSI considerations that should be considered when conducting a newborn screening pilot. This project has become a collaborative effort with the NBSTRN-ELSI workgroup. The Follow-up and Clinical Care considerations workgroup has submitted a paper for publication. PPMD will be convening their Certified Duchenne Care Center directors and providers to develop treatment guidelines for the treatment of newborns; these will be piloted within a newborn screening pilot. This project will be in collaboration with AAP and ACMG anticipating the creation of an ACTsheet for newborns. We also have begun working with NBSTRN to create an LPDR specific to DMD. This project is in collaboration with the Muscular Dystrophy Association and will utilize our registry and the registry developed by MDA.
Additionally, we anticipate the pilot to refine the screening test for creatine kinase that we reported on at your last meeting, will begin next month. PerkinElmer is leading this project, in partnership with the California Department of Health and will be using the residual newborn screening dried blood spots from the California Biobank. PPMD has been working with Certified Duchenne Care Centers and major Duchenne clinical sites based in California that have agreed to participate in the project. IRB approval from California State and at the local institutions has been obtained.
We acknowledge the extraordinary amount of work that still remains to be done in our path toward establishing newborn screening for Duchenne muscular dystrophy.