New strategies are positioning MDA's research program for success
by Amy Labbe
The fast pace of scientific progress in this first decade of the 21st century, coupled with expanding knowledge about human genetics and disease, has led to significant changes in the way MDA approaches research.
For the past 50 years, MDA’s basic laboratory research program has uncovered critical information about the genetic defects underlying neuromuscular diseases. This information has opened the possibility of developing drug therapies aimed at specific genetic targets.
To translate this possibility into reality, in 2004 MDA initiated its translational research program, with the goal of fast-tracking promising findings from the lab to clinical trials.
“The research program is evolving to take advantage of the strengths of everyone involved in the search for cures, from investigators and research teams to investors, to pharmaceutical and biotechnology companies large and small, to other health organizations and to those with neuromuscular diseases,” says MDA Vice President of Translational Research Sharon Hesterlee.
A big part of that evolution has been the translational program. It doesn’t replace but complements the basic research model already in place, putting more methods at MDA’s disposal for finding treatments and cures. The Basics and Beyond
The difference between MDA’s translational and basic research programs is the difference between “top-down” and “bottom-up” approaches to research.
The bottom-up approach fuels discovery in the basic research program, where projects advancing basic science and generating ideas for potential drug therapies are initiated by the researchers themselves. These applications are reviewed by MDA’s Scientific or Medical Advisory Committees (SAC or MAC), and then approved by MDA’s Board of Directors.
“In the basic research program, the goal is to fund the best research and the best ideas out there without dictating where they come from,” Hesterlee says. “There’s merit in that strategy — with its less-directed approach, we’ve fielded good ideas from unpredictable places.”
In contrast, the translational top-down model allows MDA to exert more control as it capitalizes on all the successful research it has funded over the years and pursues the most promising avenues in drug development research.
“‘Top-down’ means we decide what areas we’re interested in and what we want to study,” Hesterlee says. “We can’t be passive — good ideas come from unsolicited proposals, but with drug development, you want more control.”
Translational Grants
The translational research program awards four types of grants to help overcome obstacles hindering preclinical therapy development and early-phase clinical research for new drugs (or new applications for existing drugs).
Infrastructure grants fund the development of tools, techniques and services, such as animal facilities or collections of immune-system proteins, that benefit neuromuscular disease research and that typically aren’t eligible for funding from other sources.
Clinical research training grants address the need for clinicians with the proper training and experience to plan and run effective clinical trials.
“It was clear there was a lack of trained clinical investigators who could do clinical trials,” Hesterlee explains. “Clinicians have to have a lot of experience in areas such as statistics, and U.S. Food and Drug Administration and university regulations, and they need to know how to design a trial and run it efficiently.”
The clinical research training grant satisfies that need by funding a two-year program in which physicians take courses in areas such as epidemiology, clinical statistics and trial design for one year, followed by participation in a clinical research project the second year.
Investigational new drug (IND) planning grants fund academic research on potential therapies at the point where they look promising in an animal model and are ready to be developed into a drug. (An IND is a drug that has never been tested in humans before.) IND planning grants fund all the steps required before the FDA will approve testing in humans: toxicology, manufacturing, some optimization (finding the best formulation for a compound), and scale-up (increasing production from laboratory scale to the levels needed for clinical development).
Corporate grants are used to fund companies directly. Contracts govern the arrangements and typically include royalty-sharing agreements. Projects also are “milestone-driven” — if goals aren’t achieved as stipulated in the contract, MDA is not obligated to pay.
“We want to make sure there is an increased level of accountability now for these projects,” says Cristina Csimma, principal at Clarus Ventures, a venture capital firm with a focus on life sciences in Cambridge, Mass.
Csimma, a member of MDA’s Translational Research Advisory Committee (TRAC) since August 2006, observes that funding projects that don’t reach conclusion “takes away resources from a project that could have been funded.”
All translational grant applications are reviewed by two experts in the field, and then passed along to the TRAC, which asks applicants to make personal presentations. The TRAC makes funding recommendations to MDA’s Board of Directors, which makes the final decision.
From top to bottom
There are real advantages to having both kinds of research programs.
“We’re kind of hedging our bets,” says Hesterlee. In translational research, “we’re taking advantage of the ability to direct some aspects of our program, but at the same time [in basic science research] we’re casting a wide net, and looking for unexpected things we might not know about otherwise.”
Hesterlee notes that MDA’s goal is “not just to fund research and get the drug fairy to make drugs — we have to be actively involved in that process, managing it from beginning to end to make sure nothing falls through the cracks.
“We don’t want anything to stall because there’s not a hand-off to the next stage. We want to make sure we see the whole thing through. What people and their families want to know is, who’s in charge of curing my disease? And at MDA that’s our mission. Our goal is to cure diseases.”
To learn more about the strategies the translational research program is utilizing, see “Strategic Choices in ALS” (below), “Collaborating with Companies” and “Joining Forces with Other Organizations.”
Strategic Choices in ALS
| The ALS TDI collaboration is a prime example of the translational research program’s top-down style of selecting and directing research projects. |
In January 2007, MDA, through its Augie’s Quest research initiative, entered into a collaboration with the ALS Therapy Development Institute (ALS TDI), launching the largest ALS drug discovery project in history. The three-year, $36-million project aims to identify biochemical targets and find drug therapies for ALS (amyotrophic lateral sclerosis, or Lou Gehrig’s disease).
The ALS TDI collaboration is a prime example of the translational research program’s top-down style of selecting and directing research projects, says Sharon Hesterlee, MDA vice president of translational research.
“We’ve become more strategic and goal-driven about how we spend our money,” she adds. “It’s a matter of choosing the most promising avenues of research and then going after them, not just taking what comes our way.”
The necessity for an active, often aggressive approach to the early stages of drug development can not be underestimated, especially when dealing with “orphan” or extremely rare diseases.
It’s important to actively support projects that have the most potential to result in therapies, says Cristina Csimma of Clarus Ventures. MDA must “focus on those with the most ‘big-picture’ potential,” she says, in order to increase the Association’s visibility within the biopharmaceuticals industry and attract investors to drug development programs.
Collaborating with Companies
| MDA helped fund clinical trial sites for Genzyme’s laboratory-engineered form of the acid maltase enzyme, Myozyme, approved by the U.S. Food and Drug Administration as a treatment for Pompe disease. |
“If there are no companies involved, there will be no drugs,” notes MDA’s Sharon Hesterlee, vice president of translational research.
As a means to moving preferred drug development programs forward, MDA has entered into collaborations with biopharmaceutical companies such as Genzyme in Cambridge, Mass., PTC Therapeutics in South Plainfield, N.J., and Wyeth Pharmaceuticals in Madison, N.J.
“Building relationships with companies and understanding how they work and what motivates them is critical, because drugs don’t make it through phase 3 testing and marketing approval in an academic lab,” says Hesterlee.
There are a number of ways, in addition to direct funding, that MDA helps companies pursue drugs of mutual interest; the idea is to figure out what it is the company can’t do for itself and fill the need.
The Association can help facilitate connections to experts and subcontractors; provide funding to clinical trial sites to help cover associated medical expenses or travel and housing (things companies aren’t allowed to pay for directly); help companies and industry leaders understand the needs of the people MDA serves; provide data or help in planning trials; and fund early high-risk ventures.
In short, the research program helps “de-risk” and make the diseases MDA covers attractive to industry and venture capital firms that play a critical role in drug development.
MDA helped fund clinical trial sites for Genzyme’s laboratory-engineered form of the acid maltase enzyme, Myozyme, approved by the U.S. Food and Drug Administration in April 2006 as a treatment for Pompe disease.
In 2005, the Association gave PTC Therapeutics $1.5 million for the development of PTC124, an experimental compound that forces cells to ignore a specific error in genetic coding and construct normal proteins. The drug is in trial now for Duchenne muscular dystrophy and cystic fibrosis.
MDA provided sites for a Wyeth Pharmaceuticals clinical trial of MYO-029 in adults with Becker, limb-girdle and facioscapulohumeral muscular dystrophies. The laboratory-developed, immune-system protein is designed to hinder myostatin, a natural protein that limits skeletal muscle formation.
“In recent years, there has been a real trend toward health organizations very actively funding research by biotechs in disease areas of interest to them,” says Diane Goetz, director of patient and professional advocacy at PTC Therapeutics. She notes that patients and families also view these relationships positively. “MDA is in the forefront of health organizations who understand the importance of these grants to ultimately helping the patients they serve.”
Hesterlee says results from these sorts of partnerships can be measured in the rising number of companies getting involved with rare diseases, and also in the number of drugs that are either in the preclinical phases or moving into phase 1 or phase 2 testing.
Working with companies is “highly beneficial for MDA,” notes Christina Csimma of Clarus Ventures, because it enables the Association to get a good feel for current trends and areas of interest in the industry, and essentially have “its finger on the pulse of research.”
Joining Forces with Other Organizations
| “Combined efforts eliminate having to reinvent the wheel, and they lead to faster results, which is what everyone wants.” |
MDA has made a point to collaborate with other health organizations in recent years, forging both formal and informal, national and international alliances.
“MDA covers a lot of different disorders, and because of that we have a lot of strengths,” says Sharon Hesterlee, MDA vice president of translational research. “But it really helps us leverage our resources if we can work with some of the groups that are focused on a single disease.”
Cooperation brings about faster results through information sharing, broader range of expertise, combined funding and complementary efforts.
In January 2007, MDA formed the Duchenne Research Collaborative International (DRCI) with the Association Francaise contre les Myopathies (AFM) of France, Parent Project Muscular Dystrophy (PPMD) in the United States, and United Parent Project Muscular Dystrophy (UPPMD) headquartered in the Netherlands. The organizations pool knowledge and resources to accelerate development of therapies for Duchenne muscular dystrophy.
In spinal muscular atrophy (SMA), the Patient Advisory Group (PAG) of the International Coordinating Committee for Spinal Muscular Atrophy Clinical Trials, formed in 2004, includes MDA, Families of SMA, Fight SMA and the SMA Foundation. Together, the groups set research priorities, combine resources and contribute funding to move projects forward.
In June 2006, MDA teamed up with the Friedreich’s Ataxia Research Alliance (FARA) to combat this neuromuscular disease. The two organizations compare notes on promising research and combine efforts to get companies interested in early phase drug-development work.
“The synergy between two groups working together is cause for excitement,” says Nick Johnson, of Watertown, Mass., who serves both on MDA’s National Task Force on Public Awareness and on the executive committee and board of directors for FARA. “Combined efforts eliminate having to reinvent the wheel, and they lead to faster results, which is what everyone wants.”
Johnson, a mechanical engineer, has Friedreich’s ataxia and was the recipient of the 2004 MDA National Personal Achievement Award.
“The idea is to share information and make sure both groups are operating on the same track,” he says. “We don’t want one plus one to equal two — we want it to equal 10.”
Hesterlee agrees. “If collaborating with other organizations is going to get us there faster, that’s what we need to do.” |
