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NIH, Academia and Patient Advocate Collaboration Speeds Niemann-Pick Type C1 Research

Translational Science Highlights

  • Patient-focused translational science collaboration among government and academic scientists, patients, and patients’ advocates advances a potential treatment for the rare disease Niemann-Pick type C1.

In early 2007, a group of academic scientists and an advocate for patients suffering with the rare, fatal neurological disease Niemann-Pick type C1 (NPC1) traveled internationally to advocate for NPC1 research support. The experience helped crystallize a growing idea: What if they could work in tandem to help translate the mounting scientific insights into the molecular biology of NPC1 into a singularly focused effort to develop a therapeutic? NIH and several parent-led foundations had supported earlier research leading to the discovery of the gene defect that causes the disease and how it progresses and behaves. Yet there still were no effective therapies, and they thought they could do more.

Later that same year, the group helped launch an innovative research collaborative called Support of Accelerated Research for NPC (SOAR-NPC). As described in the Orphanet Journal of Rare Diseases, SOAR-NPC is a network of parents and other patient advocates, academic scientists, and government researchers. The goal was to develop a cocktail of drugs against NPC1 for testing in patients within three to five years.

Two parent-led foundations established initial funding for SOAR-NPC, and other foundations followed with additional support. Patient advocates and scientists began meeting regularly to discuss priorities, approaches and progress. The researchers promised to openly share any resulting data among themselves, an approach that has led to an investigational NPC1 drug currently being tested in patients.

Niemann-Pick type C1 project team

Members of the collaborative Niemann-Pick type C1 project team. (Credit: NCATS)

"Since its advent, SOAR-NPC has represented a different kind of collaborative effort that is therapy-driven and distinguished by participation of patients and advocates on the research team," said NCATS Director Christopher P. Austin, M.D., one of the article's co-authors. "SOAR-NPC has the same team approach to translational science as NCATS, while demonstrating the power of an approach complementary to the usual solely scientist-driven paradigm, combining the knowledge, resources and determination of scientists, physicians, parents and other advocates."

NPC1 occurs when a faulty gene fails to remove cholesterol and other lipids from cells. The lipids accumulate in the spleen, liver and brain, impairing movement and leading to slurred speech, seizures and dementia. People with NPC1 typically die in their teens, though a late-onset form of the disease affects young adults. There are two types of NPC disease: NPC1 and Niemann-Pick type C2 (NPC2). While both cause similar effects in patients, NPC1 is much more common.

"Developing a new therapy is a lengthy and complicated process that relies on understanding the basic science and mechanism of the disease as the first step," said co-author and patient advocate Jonathan Jacoby, chair of the Hide & Seek Foundation for Lysosomal Disease Research in Long Beach, California. "There was a sense among patient advocates and scientists that the way in which science functions in an academic environment isn't always the best or only way to do science and to advance drug therapies."

Sharing ideas among scientists, parents and other advocates and working together are keys to the SOAR-NPC approach. Researchers discuss their unpublished research with each other and patient advocates. Scientists and advocates bring expertise in different fields, from pharmacology and cell biology to engineering and law, all of which can help solve a range of problems. Parents of patients bring a sense of urgency and can offer different insights into living with the disease. In addition, scientists and advocates disseminate NPC1 research information through webinars and meetings and organize events at universities to bring patients, families and researchers together.

"Parents wanted to establish a platform to generate ideas and decide together with scientists what research approaches to pursue," said NCATS senior project manager and paper co-author Elizabeth A. Ottinger, Ph.D. "As a result, parents and other advocates are regularly briefed on science, and decisions about priorities and research directions are made through discussions with scientists."

NIH's Therapeutics for Rare and Neglected Diseases (TRND) program — now overseen by NCATS — played a pivotal role in SOAR-NPC’s efforts to develop a new NPC1 therapy, helping to move a candidate drug along a translational path to clinical testing. In 2007, when SOAR-NPC was taking shape, there was a turning point in NPC1 research. Two scientists, including SOAR-NPC scientist Steven U. Walkley, D.V.M, Ph.D., independently found evidence that  2-hydroxypropyl-beta-cyclodextrin (HP-β-CD), a modified version of cyclodextrin, was effective against an NPC1 mouse model of the disease.

The drug’s development subsequently was chosen as an early TRND pilot project. Through TRND, NCATS provides expertise and drug development resources for rare diseases research by collaborations with NIH, academic scientists, foundations and pharmaceutical companies. TRND staff accepted 2-hydroxypropyl-beta-cyclodextrin as one of the first drug candidates to move through pre-clinical development and into a clinical trial. For SOAR-NPC scientists and advocates, the TRND support was a game changer.

NPC1 cells

At left, fibroblasts homozygous for mutations in NPC1 demonstrate an increased accumulation of red LysoTracker staining, indicative of the storage disease. At right, addition of cyclodextrin rescues this lysosomal storage defect. (Credit: NCATS)

TRND scientists mapped out a game plan for the types of studies required by the U.S. Food and Drug Administration (FDA), identifying the translational gaps in the drug development path. The scientists created collaborative project teams, which included NIH and SOAR-NPC investigators, bringing together expertise in chemistry, pharmacology, toxicology and other fields for drug development, to carry out the work needed to show safety and efficacy in laboratory and animal studies. The TRND-supported pre-clinical work led to a successful investigational new drug (IND) application to the FDA, a step that is required before studies in people can begin.

NPC-SOAR is more than a decade old, and as the NPC1 drug development project has progressed from basic discovery into clinical studies, the team working on NPC translation has also changed.

“Such changes are typical of the many-stage ‘relay race’ that is the translational process,” Austin said.

New collaborators joined the project team when unanticipated roadblocks were encountered. For example, cyclodextrin looked promising in cells but had difficulty getting into the brain, since it was unable to cross the blood-brain barrier, a network of blood vessels that protects the brain. The NPC team met with the FDA and others, ultimately resulting in an alternate drug delivery route to reach the brain in clinical testing. Co-author Charles H. Vite, D.V.M., Ph.D., a SOAR-NPC researcher at the University of Pennsylvania in Philadelphia, collaborated with TRND scientists on a large animal model that enabled testing of the drug delivery path and its distribution in the brain. The TRND team also worked with co-author and SOAR-NPC researcher Daniel S. Ory, M.D., at Washington University School of Medicine in St. Louis, to develop a laboratory testing system for determining the concentration and effect of the drug in the brain.

When potential hearing-associated effects from the drug were identified, collaborators from the National Institute on Deafness and Other Communication Disorders (NIDCD) stepped in to help address the problem. Specialists from NIDCD have monitored and cared for patients in the NPC1 clinical trial, including support through the NIDCD’s audiology unit.

NCATS’ role in these types of therapeutic development efforts is to progress a project to the point at which it is “de-risked” — that is, sufficiently developed so that it can be handed off to another organization, typically a biotechnology or pharmaceutical company, with the resources and expertise to complete its development and marketing.

In January 2015, Vtesse, Inc., a Gaithersburg, Maryland, biotechnology company, adopted the cyclodextrin-NPC project and moved a specific formulation of the drug, ­­now called VTS-270, into clinical testing. SOAR-NPC scientist and co-author Forbes D. Porter, M.D., Ph.D., at the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), had already begun an early-stage clinical trial of cyclodextrin at the NIH Clinical Center in 2013. Vtesse subsequently began a Phase IIB/III trial in 2015 to study VTS-270 safety and effectiveness. While VTS-270 isn’t a cure, it may delay or reduce neurological symptoms, with the potential to provide a better quality of life for NPC1 patients.

Every NCATS TRND project seeks to not only advance the development of a particular therapeutic but also provide translational science insights that can be applied to other projects. SOAR-NPC scientists continue to study NPC1 disease biology and to find new molecules as potential therapeutics that NCATS will consider adopting for development. In addition, NCATS and Vtesse are collaborating in laboratory studies to determine how cyclodextrin works in NPC cells and investigate whether cyclodextrin and a form of vitamin E may have the potential to treat other diseases similar to NPC. Researchers are still in the early stages of studies of a form of vitamin E that also appears to have potential as a treatment for NPC1.

"SOAR-NPC started with an idea, a seed that NIH helped grow and turn into a collaborative focused on the drug development process," Ottinger said.

In the past few years, SOAR-NPC has ramped up its translational science knowhow and its skills in project management. It is working with a drug development consultant, and its members better understand the complexities of the regulatory and approval process.

"Translation is a team sport, and at every step in the quest for an effective NPC1 treatment, multiple patient organizations and many public- and private-sector researchers played essential roles,” Austin said. "Together, we are making advances that offer hope for both NPC1 patients and for those with similar disorders."

Posted March 2017