Repurposing drugs helps patients with rare diseases

Developing new uses for drugs takes a massive amount of research, but what happens when there’s no profit motive for pharma?

Dr. Nicolas Sireau knows the frustration of watching his own children suffer from a rare debilitating disease. He also knows that a cure for alkaptonuria is not a priority for pharmaceutical companies. That is why he founded the UK nonprofit Findacure. At Elsevier, we’re working with Findacure to enable the study of rare disease mechanisms, pairing information and analytics to assess the biological make-up of disease and shortlist the most promising potential treatments that could be repurposed safely and effectively.

William Bateson, the father of modern genetics, once said we must “treasure our exceptions,” but not surprisingly, cures for rare diseases are not often a priority for pharmaceutical companies when the return on R&D investment is difficult to achieve for a small number of patients. In some cases, however, repurposing generic drugs as therapies for rare diseases can be a pragmatic and life-changing solution to this problem.

Nicolas Sireau, PhD, co-founder of FindacureThis possibility inspired Dr. Nicolas Sireau of Cambridge in the UK. Dr. Sireau has two children with a congenital disorder, alkaptonuria, a chronic debilitating disease that causes severe, degenerative arthritis. At an R&D Forum at the pharma company GSK, he talked about the frustrations of watching the disease take its toll, knowing that finding a cure was not on any pharmaceutical company’s priority list. Those frustrations had compelled him to team up with a physician in Cambridge to found Findacure, a UK-based nonprofit organization that drives research and develop treatments for rare diseases.

Findacure is building cost-of-illness models for specific rare diseases, quantifying the current cost to the UK’s National Health Service (NHS) – and revealing potential savings through the of use repurposed drugs as treatments. In the process, it is bringing hope to patients and the potential to save lives.

Finding a new use for an immunosuppressant

Empowering Knowledge UnimpededElsevier is celebrating the unsung, the unseen and the as yet unknown. We are proud to support collaboration and innovation every day through information and smart tools and in special ways, like this collaboration between Findacure and Elsevier. For more stories about the people and projects empowered by knowledge, we invite you to visit Empowering Knowledge.

To realize its goal, Findacure aims to do a proof-of-concept study demonstrating that a particular generic drug could benefit a particular patient population, that the drug’s mechanism of action is understood, and that the drug could reduce the cost of healthcare, particularly to the NHS. Ten diseases are targeted, the first of which is congenital hyperinsulinism (CHI).

CHI is an extremely rare disease that causes newborns to have a permanently excessive level of insulin in the blood, which can lead to brain injury or death if not caught quickly. For the most severe cases of CHI, the only currently viable treatment is removal of the pancreas (near total pancreatectomy), consigning the patient to a lifetime of diabetes.

The generic immunosuppressant sirolimus shows promise as an off-label treatment that can help patients regulate their own blood sugar and keep their pancreas. But before the drug can be prescribed routinely for CHI, it must be tested in clinical trials. And before that can happen, Findacure needs a robust body of evidence demonstrating that sirolimus can and should be progressed to a proof-of-concept phase II study.

Compelled to help

Tim Hoctor, VP of Professional Services at Elsevier

Tim Hoctor, VP of Professional Services for Corporate R&D at Elsevier, was in the audience listening to Dr. Sireau that day when he thought of a way to help. Findacure was focusing on CHI for its first proof-of-concept study, he recalled, “and I knew our extensive access to data, and our ability to harmonize and analyze it, would be useful. We have access to data from published research (from regulatory drug filings) at the click of a button, and the ability to analyze it to find patterns and relationships not always clear or available to researchers.”

Hoctor brought the idea of helping to his team at Elsevier, and they were enthusiastic. Some have been researchers in the life sciences themselves, so this presented an opportunity for them to stay connected with the field and use their pharma expertise to provide meaningful contributions to this project.

Findacure accepted the offer, expecting to receive some relevant journal articles. But they are receiving much more.

Rick Thompson, PhD, Scientific Officer for FindacureDr. Rick Thompson, Scientific Officer for Findacure, said:

To be perfectly honest, we didn’t fully appreciate the scope of services Elsevier was offering. I was well aware of Elsevier’s role in publishing. But I didn’t know about the professional services side and all the data mining, analyses and research they could do. When we fully understood the kind of support being offered to our small charity, it blew us away.

Acceleration through informatics

By analyzing the disease’s biological pathways and structure, and by text mining the published literature for further insights into the disease, Elsevier is providing a summary of the literature describing the use of sirolimus in CHI and any associated adverse events; a summary of the literature discussing the increase in insulin sensitivity associated with the use of sirolimus; and a structured list of papers about CHI (e.g., separate folders for reviews, research papers, clinical paper, cases, side effects) to help inform researchers and educate clinicians. In addition, Elsevier is helping Findacure understand the research landscape and affiliations for CHI, enabling Findacure to further build its network of authors and institutions.

Maria Shkrob, PhD, Project Manager for Elsevier professional Services

One of employees doing this work is Dr. Maria Shkrob, Project Manager for Elsevier Professional Services. With a PhD in molecular biology, she has spent seven years working in the development of bioinformatics software solutions and databases and their application. For Findacure, Dr. Shkrob used Elsevier’s text mining tools to make a list of proteins, chemicals, diseases, and cell processes associated with CHI in literature. She then used this information to build a disease model for CHI and the sirolimus mechanism of action by using Elsevier’s Pathway Studio, which enables the study and visualization of disease mechanisms, gene expression, and proteomics and metabolomics data.

“Many if not most people come to the biomedical domain driven by the desire to participate in research that helps real patients and makes somebody’s life better,” she said. “Working on this project and seeing the dedication of Findacure’s team, my own team, and other Findacure collaborators has made me feel like I am doing exactly what I always wanted to do.”

Matthew Clark, PhD, Consultant for Elsevier R&D Solutions

Another employee active in the project is Dr. Matthew Clark, Life Sciences R&D Solutions Consultant. With a PhD in chemistry, Dr. Clark has had an extensive career in pharmaceutical R&D and discovery informatics.  For Findacure, Matthew combined the data from several Elsevier products via their APIs to connect pathways (the sequence of molecular interactions responsible for causing the disease) to compounds known to inhibit members of those pathways. This analysis identified a number of molecules that could be tested to treat the disease. In addition, these analyses provided networks of researchers who are working on the disease.

In a later stage of the collaboration, once sirolimus is ready for testing, Elsevier will use tools such as Pathway Studio to assess CHI’s biological make-up in depth, and then shortlist additional promising potential treatments that could be repurposed safely and effectively.

This work is part of a formal collaboration that began in September. Elsevier is providing pro bono informatics expertise and advice, as well as access to published literature through its online tools, for three years.

“Collaboration is a critical factor in life science, as we all seek to move the needle in extending and improving quality of life,” Hoctor said. “But collaboration is more than a business need; collaboration is a privilege for those who, by working together, are able to truly make an impact.”

What are the anticipated outcomes?

Dr. Thompson said the collaboration could have a broad impact:

Providing strong evidence that the generic drug sirolimus could benefit people with CHI would enable Findacure to more easily raise funding for clinical trials. Building a stronger network over the next few years should also facilitate the clinical trial process by enabling the recruitment of a larger patient population, as well as clinicians and researchers committed to trying a cost-effective treatment. If successful, the approach developed in partnership with Elsevier could be replicated for other rare diseases.

Hoctor said Elsevier plans to expand its collaborations in the life science community. “I’m particularly eager to expand on our work alongside dedicated life science researchers to make a demonstrable impact. Our team at Elsevier is energized by this collaboration, which clearly shows the power of data and the transformation from information to insights.”

Read more about Elsevier’s R&D Solutions for Pharma & Life Sciences or check out Elsevier's Pharma R&D Today blog.

Elsevier Connect Contributor

Marilynn LarkinMarilynn Larkin (@MarilynnL) is an award-winning science writer and editor who develops content for medical, scientific and consumer audiences. She was a contributing editor to The Lancet and its affiliated medical journals for more than 10 years and a regular contributor to the New York Academy of Sciences' publications and Reuters Health's professional newsfeed. She also launched and served as editor of Caring for the Ages, an official publication of the American Medical Directors Association. Larkin's articles also have appeared in Consumer Reports, Vogue, Woman's Day and many other consumer publications, and she is the author of five consumer health books.

As a consultant on postural awareness and confidence building, Larkin has presented to corporations and nonprofits and at regional and national meetings of, among others, the American Society on Aging and National Council on Aging, the American College of Sports Medicine, and New Jersey Dietetic Association.

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