Collaborations Needed To Speed Orphan Drug Development

WASHINGTON, DC -Large pharmaceutical companies have little financial incentive to underwrite new drug development for rare neurological diseases. Most are looking for a blockbuster drug that can be prescribed for millions of patients. But that doesn't mean it is a lost cause, said industry and academic investigators here at the Seventh Annual Meeting of the American Society of Experimental Neurotherapeutics (ASENT) last month.

Inroads in orphan drug development can be made through partnerships among investigators in academic, industry, and government laboratories - as well as with support from patient advocacy groups and private philanthropic organizations, they said at a symposium sponsored by the Dystonia Medical Research Foundation (DMRF).

Drug development from basic research to the clinic is a long and precarious uphill course, said Mahlon DeLong, MD, Chairman of Neurology at Emory University School of Medicine and Chair of the Scientific Advisory Board of the DMRF.

There's an enormous need for better drugs for dystonia, said Dr. DeLong, who noted that dystonia affects about 300,000 people in the US. Although botulinum toxin for focal dystonia has been a godsend, he said, many of the drugs used for dystonia have been in use for 10 to 15 years. This, he said, is frustrating.

OBSTACLES TO DEVELOPMENT

The costs of pharmaceutical research and development have mushroomed and failures are so expensive that many companies will develop only drugs with a huge potential market, said ASENT President Kathleen Clarence-Smith, MD, PhD, CEO of Prestwick Pharmaceuticals, Inc., in Washington, DC.

Furthermore, she said, drug development today is hampered by a worldwide shortage of medicinal chemists. There is an urgent need to make the process of drug development more efficient, especially for diseases that affect five million people or fewer, she said. She noted that today it takes $802 million to develop a new drug whereas it may have cost $231 million to do so 10 years ago.

Figure. Dr. Mahlon D...

Venture capitalists will no longer invest in early drug discovery, said Dr. Clarence-Smith. They want drugs that have been shown to work in people. She said that many promising investigational drugs fail because of toxicity when they go from animal testing to the first human study, or they fail because they do not work in humans as expected. But she also noted that trial design is critically important. Many drugs are lost because the wrong trial is done, she said.

Despite these obstacles, I am absolutely sure that it can be solved, said Dr. Clarence-Smith of the problem of orphan drug development. Some of this may just be charity … you've got to go to the right place, she said. Often we go to the wrong group for money. For some scientists, the right place may be a US company that specializes in orphan drug development or a grant from the FDA Office of Orphan Products Development. (See Targeting Drug Development.)

HOPE WITH SMALLER COMPANIES

One hope for orphan drug development lies with smaller drug companies, those whose leaders think that a $30 million to $50 million product is a great asset, said Roger J. Porter, MD, a consultant to the pharmaceutical industry (primarily in the area of antiepileptic drugs). Dr. Porter, who previously spent 20 years at the NIH, including a stint as Deputy Director of NINDS, is an Adjunct Professor of Neurology at the University of Pennsylvania in Philadelphia and an Adjunct Professor of Pharmacology at the Uniformed Services University of the Health Sciences (USUHS) in Bethesda, MD.

Dr. Porter said he can remember teary-eyed researchers at a drug company when their drug was voted down because the patient population for it was not big enough. Unfortunately, he said, when a drug is dropped, it is typically dropped totally - and rarely out-licensed to another firm. This situation arose not only from liability issues, but also because, if the out-licensed drug ultimately made money for some other company, the directors of the first company would be deemed incompetent.

We have to control development costs, said Mark H.N. Corrigan, MD, Executive Vice President of Research and Development at Sepracor, Inc., of Marlborough, MA. Mid-sized companies can target market opportunities of less than $500 million, he said.

But Dr. Corrigan noted that Merck & Company's voluntary withdrawal of the blockbuster COX-2 painkiller Vioxx (rofecoxib) last September had an overall chilling effect. He also noted that some drugs that a company intended to be blockbusters eventually turn out to have a smaller market than expected. For example, he cited the oncology drug imatinib mesylate (Gleevec), which was first used for breast cancer but is now prescribed for much fewer patients with chronic myelogenous leukemia or those with gastrointestinal stromal tumors.

LOWER COST FOR DEVELOPMENT

On the upside, Dr. Corrigan noted that developing a drug for a rare disease generally costs about 25 percent of what it would take to develop a drug for high blood pressure, for example. He also noted that interactions between companies working on orphan drugs and the FDA tend to be more collegial than the usual arms-length approach, due in part to the fact that FDA has a special office for orphan drug development.

As examples of efforts to stimulate orphan drug development, Robert W. Baughman, PhD - Associate Director for Technology Development at the NINDS - cited that institute's translational research initiative, which seeks to speed new neurological drugs from bench to bedside. He also cited the anticonvulsant-screening project, through which pharmaceutical companies can have their compounds screened at NINDS cost and receive confidential results.

The NINDS budget is about $1.7 billion per year, noted Dr. Baughman, so NINDS cannot participate in the development of new drugs in the way large pharmaceutical companies can. On the other hand, he said, only a few neurological diseases will ever really interest large companies. It's got to be partnerships, Dr. Baughman concluded of drug development for rare neurological diseases.

EXAMPLES OF PARTNERSHIPS

Bernard Ravina, MD, NINDS Program Director for the Clinical Trials cluster and an investigator in the Neurogenetics Branch, described his experience collaborating with pharmaceutical companies on developing neuroprotective drugs for Parkinson disease. NINDS designs the protocol and funds a trial, and the company does the actual development and retains intellectual property rights.

It's a good example of the kinds of things we can do working together, said Dr. Ravina. Perceived negatives for the company in any NIH-industry collaboration, he said, are a loss of control and potential loss of trade secrets. But, he noted, one intriguing approach in such a collaboration - which he called the pull approach - is to create a market where a new drug is needed with specific incentives. He compared this approach to the Gates Foundation's setting up a large pool of money to stimulate development of a malaria vaccine.

Figure. Dr. Roger Po...

Giovanna M. Spinella, MD, Director of the NIH Extramural Research Program in the Office of Rare Diseases, said that the development of drugs for rare diseases may hold benefits beyond treatment for an orphan disease in terms of increased understanding of normal and abnormal physiology. Her office, legislated by the Rare Diseases Act of 2002, establishes clinical research centers with an emphasis on rare diseases; trains scientists; participates in collaborative research programs; is part of the trans-NIH working group on rare diseases research; and supports a rare diseases clinical research network.

ROLE FOR PATIENT ADVOCACY

Finally, symposium speakers emphasized the critical importance of patient advocacy groups in the development of orphan drugs for rare diseases. The patient support organizations are really the glue, said Dr. Spinella. It's up to the community to make a case for an orphan drug.

Rosalie Lewis, an ASENT board member and former President of the Dystonia Medical Research Foundation - whose four sons carry the DYT1 gene that causes early torsion dystonia - said patient advocates bring needed, persuasive passion to fundraising for orphan drug development.

We live disease: either ourselves or our children, she said. Ms. Lewis has frequently appeared on Capitol Hill to ask for more funding for dystonia research, and in 2001 she was instrumental in ensuring that language about the need for more dystonia research was added to the House Appropriations legislation that authorized the NIH budget for that year.

Ms. Lewis noted that the dystonia foundation is proactively reaching out to pharmaceutical companies to foster interest in dystonia therapies: either through new indications for existing drugs or through the development of new drugs specifically for dystonia.

TARGETING ORPHAN DRUG DEVELOPMENT

Large pharmaceutical companies may shun small-market drugs in favor of blockbusters, but developing a drug with a small market is exactly what Orphan Medical, Inc., in Minnetonka, MN, sees as its mission.

Symposium attendee Russell Katz, MD - Director of the FDA Division of Neuropharmacological Drug Products - cited Orphan Medical's drug Xyrem (sodium oxybate) as a drug that was approved for a narrow indication for a small population.

We approved the drug for one symptom of narcolepsy, he said in an interview. The drug is approved for patients with narcolepsy who suffer from cataplexy, sudden loss of muscle tone. About 100,000 to 140,000 Americans have narcolepsy, and of these 60- to 90-percent have cataplexy, according to the company.

The company takes advantage of incentives in the Orphan Drug Act of 1983 - including tax credits and extended marketing exclusivity - focusing on products in phase II or phase III trials for CNS disorders, sleep disorders, and pain management.

In the government sector, Dr. Katz noted that the FDA Office of Orphan Products Development publishes requests for applications for its grants program as part of its mission to enhance drug development for rare diseases. For FDA purposes, a rare disease is considered to be one that affects less than 200,000 people.

ARTICLE IN BRIEF

✓ Speakers at the ASENT meeting discuss the challenges and opportunities for developing orphan drugs.