Uncommon disorders in the spotlight

NIH and FDA celebrate Rare Disease Day


Recent events held by the National Institutes of Health (NIH) and the Food and Drug Administration (FDA) highlighted the agencies' efforts at developing and making available therapies for rare diseases, many of which are genetic.

The meetings were part of the agencies' celebration of Rare Disease Day, an international event during which rare disease patients, advocates, researchers, clinicians, and government agencies meet to discuss their successes and shared concerns, says Mary Dunkle, Vice President for Communication at the National Organization for Rare Diseases (NORD). NORD and the Genetic Alliance were on the planning committees for both the NIH and FDA events, she said. NIH's second annual Rare Disease Day event was held February 29 in Bethesda, Maryland, while FDA's companion event followed on March 1 in Silver Spring, Maryland.

An estimated 6% of Americans are affected by one of more than 7,000 rare diseases, which the federal government defines as disorders affecting less than 200,000 people, Stephen Groft, PharmD, Director of NIH's Office of Rare Disease Research, told the NIH audience, which included many patient advocates.

Emphasizing the disproportionately great role rare diseases play in medical discoveries, Timothy Coté, MD, MPH, NORD's Chief Medical Officer, told participants at the NIH event to “remember that because so much information comes from people with rare diseases, we have obligations to these people who have taught us so much.”

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Rare Disease Day is an annual awareness-raising event that takes place internationally.

Genetic Alliance CEO Sharon Terry urged disease advocacy groups and researchers gathered at NIH to work together to promote research, legislative, and regulatory changes that can help them all. A particular disease community's thinking of itself as part of a larger group of people concerned with rare diseases is in keeping with medical researchers' new view of many conditions as “parts of pathways rather than single diseases by name,” she said.

Ivafactor: A Success Story

Only 4,000 rare diseases have an identified molecular cause, and just 250 of these disorders have a treatment, illustrating an “enormous gap in what we know and what we can do about it,” said NIH Director Francis Collins, MD.

For cystic fibrosis patients with rare mutation, patient advocates, researchers, government agencies, and industry recently bridged that gap with FDA approval of ivafactor, which targets the G551D mutation and is marketed by Vertex Pharmaceuticals as Kalydeco. Both NIH and FDA officials repeatedly held up the drug as an example of what can be accomplished when these groups work together.

The FDA approved the drug in less than four months, which is lightning speed for the agency. One reason for this is that the FDA has made rare diseases a top focus, spurred by the 1983 Orphan Drugs Act, FDA Commissioner Margaret Hamburg, MD, said during her agency's event. The legislation takes aim at the roadblocks to development and FDA approval of therapies and devices for rare diseases, said Gayatri Rao, MD, JD, who heads FDA's Office of Orphan Products Development. As a group, these disorders' natural histories aren't well known and are very different from one another and occur in small groups, making patient enrollment and effective design for trials difficult, she explained.

Another reason for the quick ivafactor approval was the Cystic Fibrosis Foundation's support of collaborative, research-ready clinical networks that “were ready for the big one when it happened,” said Deputy FDA Commissioner Stephen Spielberg, MD, PhD. “The science was all there. That's why the review time at FDA was just three months,” Dr. Spielberg explained. “It took collaboration. That's a message you all know so well,” he told an audience with numerous patient advocates.

Dr. Collins, who headed the team that discovered the cystic fibrosis gene, noted the journey from that finding to approval of ivafactor took 21 years. The process is quicker today. Dr. Collins gave as an example his own study of Hutchinson-Gilford progeria syndrome, which involves dramatic aging in children. The responsible genetic mutation was identified in 2003, and an NIH trial led by Dr. Collins of a repurposed cancer drug, rapamycin, began in 2007. That trial has had promising results, he said.

FDA Focus on Rare Disease Therapeutics

FDA approved 26 drugs and other products for rare diseases in 2011, including some repurposed products, said Dr. Hamburg, adding that FDA also approved six medical devices for rare conditions under the Humanitarian Device Exemption program in 2011. About one-third of all new molecular entities approved by the agency were for rare diseases, she said.

Dr. Hamburg pointed to a recent study that shows her agency's long-term attention to rare diseases. Researchers from FDA and the Keck Graduate Institute of Applied Life Sciences report that from 2000 to 2009, FDA designated 1,138 orphan drugs and approved 148, including 38 for pediatric diseases. The proportion of approvals for pediatric products increased from 17.5% in the first half of the decade to nearly a third, 30.8%, in the second [Thorat et al., 2012].

Research on Rare Disease

During the NIH event, officials and researchers highlighted the agency's commitment to rare disease programs and research aimed at developing and delivering new tests and therapies. Among them are the following initiatives:

  • NIH's Genetic Testing Registry (GTR), to which laboratories voluntarily submit information on specific assays at ncbi.nlm.nih.gov/gtr. That information includes test characteristics and information on analytic and clinical validity, Dr. Collins said in his announcement about the new website. It allows searches by test, condition, phenotype, and lab and syndromes. GTR also links to information from the American College of Medical Genetics on how to find genetics professionals.

  • NIH's National Center for Advancing Translational Science (NCATS), which aims to re-engineer the process of translating scientific discoveries into new drugs, diagnostics, and devices. Working closely with the regulatory, academic, nonprofit, and private sectors, NCATS will try to identify and remove bottlenecks that slow the development of effective treatments and cures, Dr. Groft said.

  • Funding to the Mendelian Disorders Genome Centers at Yale University, University of Washington, Johns Hopkins University, and Baylor College of Medicine. Richard Lifton, MD, Phd, Chair of Genetics at Yale University, said the consortium will identify diseases and their underlying molecular basis. Noting several published studies that used new technologies to determine genetic causes of ichthyosis with confetti and certain cases of severe hypertension, Dr. Lifton said he hoped the new effort would apply these technologies more broadly.

  • A translational effort called Vascular Interventions/InnovationsandTherapeutic Advances (VITA). The project will provide funding for early-stage translational development of new diagnostics and therapies for vascular disorders, thrombotic diseases, and pulmonary hypertension that are commonly neglected by industry, said Zorina Galis, PhD, Chief of the Vascular Biology and Hypertension Branch at the National Heart, Lung, and Blood Institute. VITA will “address ideas that need proof of principle and those that have it but require more study before a company can apply for FDA approval,” she said.

Benefits Beyond Rare Disease

Many researchers noted rare diseases drive findings that add to the understanding of more widespread disorders. Among them are inflammatory diseases, said Raphaela Golbach-Manksy, MD, Acting Section Head of the Translational Autoinflammatory Disease Section of the National Institute of Arthritis and Musculoskeletal and Skin Diseases. She described studies of serious disorders involving fevers, rashes, and organs, including the skin, eyes, ears, brain, and gut, which led to the discovery of disease-causing genes, key inflammatory pathways, and novel treatments that have significantly improved lives of patients who suffer from rare autoinflammatory diseases.

Discovery of the IL-1β activating inflammasome through study of neonatal onset multisystem inflammatory disorder (NOMID), deficiency of the IL-1 receptor antagonist (DIRA), and chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperatures (CANDLE) has provided new understanding of inflammation in patients with common diseases like diabetes, gout, obesity, and coronary artery disease and has led to novel targets for therapeutic interventions, Dr. Goldbach-Mansky said.

Leslie Biesecker, MD, Chief of the Genetic Disease Research Branch at the National Human Genome Research Institute, said at the NIH meeting that he envisions a day when new technologies like whole genome sequencing and exome sequencing enable a new way of diagnosing disease and diminish the diagnostic odysseys so many patients with rare diseases face. Findings from the NIH ClinSeq study, which is looking at extensive genomic data from 900 adults, and similar genomic research could upend the usual clinical steps of taking medical histories, performing examinations, considering differential diagnoses, and applying clinical tests and then interpreting them, he said.

Instead of “chasing tests based on symptoms,” patients would first get a genomic test, Dr. Biesecket said. Afterwards, clinicians would focus evaluations on phenotypes associated with particular genetic variations. “The rare disease community is the best place to develop this model,” he added.

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