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Duchenne Report Card
What resources are in place to develop new treatments for Duchenne?
The chart above shows, graphically, where the Duchenne field is a each stage of the drug development process and what knowledge and infrastructure is already in place. Areas with a “check minus” need further development and some things are missing altogether.
Several mouse models exist for the disease, the most commonly used of which is the mdx mouse, which has a mutation that causes the dystrophin protein to stop being made prematurely. The mouse has milder symptoms of muscular dystrophy than are typically seen in humans. About 15% of those with Duchenne have a similar mutation. A mouse that lacks both dystrophin and a similar protein called utrophin is more severely affected than the mdx mouse and used to test some interventions.
Duchenne is unusual in that there is a well–studied naturally occurring Duchenne-like disease in golden retriever dogs. A large colony of these dogs are supported by an NIH core grant at the University of North Carolina and several smaller colonies are maintained at other institutions. The symptoms in the dogs more closely mimic the human version of the disease and therapies with challenging delivery issues (like gene therapy) are often tested in these dogs.
Burden of Disease
The societal burden of Duchenne is not well understood in the US and Europe, although relatively current data exists in Australia. This information is useful in calculating what insurers would be likely to pay for therapies and in advocacy efforts.
Drug Development Programs
Drug development programs do exist both in industry in large and small companies and in academic laboratories. In addition to companies focused on Duchenne specifically, many of the large pharma have programs focused on age-related (sarcopenia) and illness-related (cachexia) muscle wasting that may have applicability to Duchenne.
A regulatory path for new therapies for Duchenne is in progress through the pioneering efforts of PTC Therapeutics, the first company to attempt to get a drug approved for Duchenne, and followed now by several other companies. As soon as one drug has been successfully approved, that process should provide a road map for future submissions to regulatory agencies.
Validated Clinical Endpoints
The six minute timed walk has been used by PTC Therapeutics as the primary clinically meaningful endpoint in its recent phase IIa and phase IIb studies and seems to be acceptable to regulatory authorities in the U.S. and Europe. More work needs to be done to develop new qualified endpoints and particularly those that can be used in non-ambulatory subjects.
Clinical Research Networks
Multiple experienced clinical research networks exist in the US and Europe but the individual networks lack cohesion and there is some duplication of effort. A workshop held in conjunction with PPMD's Annual Connect Conference identified the need for an outreach mechanism to clinics with less experience in conducting trials.
The European government-funded TREAT-NMD consortium has sponsored a global patient registry that receives curated core data elements from individual Duchenne patient registries all over the world. In the US there are two Duchenne registries (including PPMD's DuchenneConnect), each with close to 2,000 individual entries, and a third is planned. Although all will feed into to the TREAT-NMD Global patient registry, the existence of multiple registries duplicates resources and causes confusion among families.
Standards of Care
PPMD successfully advocated to get funds for the US Centers of Disease Control to develop Care Considerations for Duchenne, which were finalized recently. Although useful as a minimal standard of care, room to improve on this first effort remains. Well-adopted standards of care not only help improve care, but also serve to reduce variability in clinical testing.
Another recent PPMD advocacy effort resulted in the development of a National Task Force for the Early Identification of Childhood Neuromuscular Disorders that includes advocacy organizations, government departments, medical professionals, and various professional organizations that are involved in early childhood healthcare or education.
Remaining infrastructure needs include standardized genotyping, validated biomarkers, and earlier diagnosis and identification of children in rural or inner city areas. In addition, few modifier genes for Duchenne have been identified to date, but modifiers could add additional drug targets to the pipeline.
To learn more about how PPMD will address gaps in resources, see our Programs and Priorities.
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