Not-For-Profits Fill The R&D Gap For Underserved Diseases

By Fred Olds, contributing editor

Some say there is market dysfunction in drug discovery and development. Large patient populations in third-world countries and patients with rare diseases are left without effective medications or therapies. Economics, regulatory oversight, and stockholder demands chain pharma to the blockbuster. But perhaps the market is working as it should. Desperation impels action. Frustrated parents, patients, and relief organizations have formed advocacy groups to support R&D in diseases where big pharma cannot. They have the advantage of focus, ingenuity, and immediacy that only limited resources and desperation can give. The sense of urgency in the nonprofit-industry business model focuses efforts on translational research and bringing cures to market.

What changes for R&D in this relationship is the goal. Advocacy and relief groups seek products, not profits. Removing the criterion of profitability from compound selection can speed the entry of candidates into research. With their increasing sophistication and financial resources, advocacy groups have the ability to partner with researchers directly to speed the discovery and commercialization of therapies.

The Nonprofit In Big Science
Rafick-Pierre Sékaly, Ph.D., co-director and scientific director at VGTI-Florida, says that nonprofits now play an increasing role in drug development, focusing on the early stages of discovery and preclinical development. As an example, he points to the work of large foundations like the Wellcome Trust or the Gates Foundation. They have the resources to put together projects of scale with multiple players and moving parts, and set the guidelines with stringent milestones, timelines, and rules regarding intellectual property. They regularly ask for research proposals to solve specific challenges. The Gates Foundation supports global health projects that can help large populations in underdeveloped nations. One of its main programs is developing treatments for AIDS/HIV, an area of expertise for VGTI.

VGTI has been a player in two international consortia funded by the Gates Foundation. One was aimed at developing novel assays to measure protective immune responses, while the second was focused on developing novel viral vectors as vaccines for HIV. Sékaly says projects that have targets of such importance require multiple institutions that bring different expertise to the table. “You can no longer work alone; the tasks are too many and the scope too big.” Sékaly describes this as, “The idea of big science. You work alongside researchers you would have considered competitors 10 years ago.”  He says, however, that these are the kinds of projects that will make a huge difference to humanity.

Advocacy Adding Incentive to R&D In The Third World
At the end of the last century, more than one million people died annually from malaria. Most of these were children under 5 and pregnant women. The medicines used to fight the parasite were losing potency and there were few new drugs in development. It was a huge potential market, but poverty in the endemic areas was so great that there was no incentive to conduct R&D. It was the kind of helpless situation that drives some to action.

Dr. David Reddy, CEO of Medicines for Malaria Ventures (MMV), says, “A handful of individuals representing WHO, World Bank, IFPMA (International Federation of Pharmaceutical Manufacturers & Associations), the United Kingdom, and Switzerland recognized  something had to be done and looked for a way to share risk.”  The result was MMV, a public-private partnership to support the development of antimalarial drugs and therapies. Reddy says MMV-supported research has brought four new compounds to market, entered more than 65 projects in development, and identified about 2,500 compounds that have activity against the parasite.

Reddy explains that the key was creating incentives for research and development through the Product Development Partnership (PDP). MMV is supported by grants from public and private organizations and gifts and in-kind donations of expertise, personnel, and facilities from researchers and manufacturers. It uses these philanthropic donations to support the R&D of effective and affordable antimalarials, which reduces the organization’s development costs to almost a quarter of the industry average.

MMV attracts research through an annual call for proposals. Reddy says, “We look for drug candidates that are truly differentiated and targeted.” He explains that being very selective reduces costs, prevents overlapping efforts, and concentrates research on a small group of promising compounds rather than diluting resources over many.

Keeping manufacturing costs low is a high priority. The agreement with pharmaceutical partners is to price the medicines at marginally more than the cost of manufacturing. This keeps the price of medications low enough for underdeveloped countries and patients to afford. “We expect rigor from the manufacturer to reduce costs,” says Reddy. “Industry estimates for clinical development of an anti-infective drug are $180 million. For one of our more recent antimalarials, Pyramax, developed with Shin Poong, the figure was $43 million. The numbers speak to the efficacy of the model.”

RARE Diseases — Patient Advocacy Aggregating Numbers For Leverage
On the other end of the spectrum are parents who have a child with unusual symptoms that no physician seems able to put a name to. But when they do, it’s a diagnosis that is as foreign as the name is to say. There are nearly 7,000 rare diseases and fewer than 50% have an advocacy group. Nonprofits play an important role in this area because few pharma companies will invest in development of therapies for such small numbers.

Nicole Boice is organizing the RARE Project, a nonprofit platform to aggregate their numbers. There are roughly 30 million Americans with a rare disease, making it one of the largest patient groups in the United States, but one with a fractured voice. RARE plans to link patients, information, and resources in numbers sufficient to make legislators and the public take notice.

A major objective of that effort is to increase R&D for rare diseases. Boice identifies patient activism and lobbying for legislative and regulatory reform as important steps to speed up the delivery of drugs. Currently she favors reauthorization of PDUFA (Prescription Drug User Fee Act) and passage of new orphan drug legislation, which she feels will increase incentives for R&D in rare diseases. Additionally, Boice says, “We are launching a corporate alliance with biotech and pharma to move the needle on reimbursement and physician education on rare disease.”

A problem with rare diseases research is that the patients are rare as well. This poses a problem for researchers when they try to register enough patients to show significance in clinical trials. RARE has contracted with Patients Like Me to use its technology to start an open registry for rare diseases. This gives patients an opportunity to share their medical information with professionals. For researchers, the registry provides a source for recruitment and information about patients with the disease.

Research Finds A Home And Backward Engineering
Success at promoting research requires skill. Paul and Debra Miller founded CureDuchenne when their 5-year-old son was diagnosed with Duchenne muscular dystrophy. She says, “Starting a 501(c) is easy and relatively inexpensive. Getting results is not.”  She says an advantage she and her husband had was the business background to organize and push activities forward. Their goal was to find a cure for Duchenne in their son’s lifetime and put themselves out of business in 10 years.

Usually nonprofits find research to support, but occasionally the research finds the nonprofit. Shortly after setting up office, Debra Miller was approached by Prosensa, a Dutch company that had promising research to moderate the effects of the disease through exon skipping. She committed to supporting their research with $1.3 million, and worked arrangements to get the money. Prosensa conducted the research, and seven years later Prosensa received a commitment of up to a $650 million investment for their Duchenne programs.

Since then, CureDuchenne has supported seven projects that are now in human trials. They are the result of a science advisory board that has taken a backward engineering view of the disease. Miller and the advisory board imagine what a cure would look like. Then they work backward and imagine what research they would need to get there. Reviewing the stack of research proposals they receive, the board attempts to find a project that fits their view of the cure. “If we don’t find one,” Miller says, “We set out to create the project. We will put scientists together who have similar research. Other times we will push scientists along even if they don’t think they’re ready.”

Focus On Translational Research And Reimbursement
Parents often become the force behind nonprofits searching for cures. They provide family support and information and back basic research. What they don’t often do is look for more immediate results through translational research. FasterCures, a nonprofit working toward accelerated access to new therapies, calls this the valley of death, the area between promising basic research and commercialization and the space where good ideas die because few organizations will take the risk to back them.

This was the case for Beth Anne Baber when her son was diagnosed with a neuroblastoma, the most common form of solid tumors in children. As a bench researcher in cancer herself, she was shocked to find that the current standard of care for pediatric cancer was massive doses of drugs designed for adults years ago. She found many nonprofits providing family support or backing basic research, but fewer groups were going after actual pediatric therapies. So Baber founded the Nicholas Conor Institute (TNCI) to find and support translational research in childhood cancers.

She located companies developing promising products in diagnostics and theranostics that were looking for backing. Their partnerships faced an unexpected obstacle. They found childhood cancers are somewhat in-between categories. They are clearly rare diseases and just as clearly cancer. However, when Baber sought support from larger pharmaceutical companies that work with rare diseases, she was told they didn’t work with cancer. When she went to cancer-oriented pharma companies, she was told they didn’t work with rare diseases.

This posed a problem because it would be difficult to find backing, sell, and get reimbursement for diagnostics and therapeutics designed for children. The institute decided to expand diagnostic panels to be applicable to adult patient populations as well. This made both scientific and economic sense because there were a number of mutual targets for both adult and pediatric oncology.

Baber points out it’s equally important to work with insurance companies to get coverage for the diagnostic panel. The partnership has to demonstrate the value equation of the test to payors. She says this is not something that can wait until the test has been validated and ready for clinical use. Without coverage, they may not be able to have the test ordered by the treating oncologists.

To fund the translational development research, Baber uses what she calls “hybrid” venture philanthropy. It involves forming a consortium of charities, businesses, and other interested entities that pool funding for a project. The result is shared rights to the IP and licensing, and reduces risks since the investment is split among several members of the consortium. The added benefit for investors is being able to claim they support the development of an actual product that is in clinical use.

New Opportunities For Innovation
Probably no one wakes up and says, “I think I’ll start a foundation today.” Patient advocacy and relief organizations are the children of tragedy and frustration. In the information age, their frustration has formed communities that seek to reform regulatory bottlenecks and promote drug research and development. Their focus on solutions rather than profits has opened opportunities for researchers and biotechs to find funding to cure rare diseases and epidemics. This partnership is filling the void for neglected diseases and is an opportunity to innovate.