By Deb Borfitz
August 16, 2010 | Interest in orphan drug research has picked up noticeably in recent months, with both Pfizer and GSK opening up R&D units devoted to rare diseases earlier this year. The biggest impetus may well be expiring patents on more commonly used drugs and no potential blockbusters in the pipeline, theorizes Peter Saltonstall, president and CEO of the National Organization for Rare Disorders (NORD). Possibly, drugs developed for a rare disease can also be “leveraged” to treat more typical conditions.
Financial incentives to develop novel drugs for rare diseases include, most notably, a seven-year market exclusivity period via the Orphan Drug Act (ODA) of 1983 upon approval of the niche product. The ODA further bestows a tax credit on half of clinical trial expenses, the opportunity to apply for an Orphan Drug grant under a $14 million per year research grant program, and waiver of Food and Drug Administration (FDA) filing fees. Thanks largely to the ODA, orphan drugs now represent nearly 40% of all new products approved by the FDA, and seven of ten biological products approved last year, says Timothy Coté, MD, PhD, director of the FDA’s Office of Orphan Products Development (OOPD). Still, only 359 orphan drugs, covering 150 rare diseases, have been approved by the agency.
More than 8,000 rare diseases are known to exist, but as few as 10% of these diseases have approved treatments in use worldwide, says Marc Dunoyer, head of GSK’s rare diseases unit. “In the U.S., less than half of the 25 million patients with rare diseases benefit from orphan drugs developed and approved specifically for their disease. In Europe, approximately 94% of patients go untreated.” The proportion of treatments is smaller yet in the developing world.
As defined by the ODA, a rare disorder is found in fewer than 200,000 Americans in any given year. Many such diseases have fewer than 10,000 sufferers, Saltonstall says, with the majority occurring even less frequently. Natural histories are generally ill-defined, making it hard to design studies and select a target for intervention.
Many companies have nonetheless turned out rare disease products and some have been quietly doing so for years. A small group of companies are fully dedicated to novel treatments, but only a fraction of those have more than a single product. Large pharmaceutical firms have yet to prove themselves as active actors in orphan drug development, says Coté, noting that his yardsticks are orphan status designation (granted by OOPD) and subsequent drug approvals. “I’m not ready to applaud yet.”
GSK has the most orphan drug designations granted in the US among pharmaceutical manufacturers—14 in total compared to 11 for Novartis and 10 for Roche/Genentech, says Dunoyer. The rare diseases unit works closely with JCR Pharmaceuticals and Prosensa and seeks to collaborate with other companies and institutions.
Plenty of Positives
Among the upsides of rare disease research are highly motivated and organized patient populations, a collaborative and close-knit research community, wider availability of biomarkers, the potential for high per-patient revenues, and the opportunity to partner with small biotechs that up to now have been responsible for most of the breakthroughs. Some of these niche therapies have a “transformative…Lazarus-like effect” on afflicted patients, says Coté, and so they are also uniquely satisfying to produce.
“The risks associated with product discovery and early development in rare diseases…is generally lower than other disease areas, as disease definitions are very clear and clinical trials tend to be small with robust endpoints,” says Dunoyer. “In fact, it’s estimated that the probability of R&D success is relatively higher [20%] in rare diseases compared with other disease areas [10%]. In most cases, the molecular target is known, making it easier for specialized physicians to diagnose patients.”
Another plus is wider availability of genetic testing for orphan conditions, reports Florham Park, NJ-based consultancy Defined Health. Also, approval rates for drugs with orphan indications are typically higher. Worldwide sales of orphan drugs escalated to well over $60 billion last year, nearly on par with the oncology market. France, Germany, Spain, Holland, and Sweden are among the European countries that systematically reimburse for orphan drugs. But the potential for public and political backlash over prices, especially for “ultra-orphan drugs,” remains a concern. Orphan drugs can cost tens or even hundreds of thousands of dollars per patient per year and industry-supported patient assistance programs are failing to meet escalating demand.
Most of the challenges of rare disease research occur during late-stage development, including a narrow pool of available patients, limited clinical expertise for both regulatory and clinical research purposes, and the difficulty in achieving a balance between the need for scientific rigor and flexible trial design, says Saltonstall.
All Hands on Deck
The FDA has shown flexibility when it comes to the review of orphan drug products, in some cases basing approvals on trials involving fewer than 20 patients, says Coté. But typically, at least one adequate and well-controlled clinical trial is required.
A report forthcoming from the FDA’s newly formed Rare Disease Review Group will identify ways to optimize the FDA approval process for orphan drugs as well as enhance guidance. The FDA and National Institutes of Health (NIH) are also cooperatively developing tools, regulations, and strategies to stimulate new rare disease drug programs. Independently, the NIH has been lobbying Congress for a half-billion-dollar fund, aimed at start-up biotechs, to jump-start clinical trials for new drugs that treat neglected diseases. Meanwhile, the Senate is eying a bill that would extend priority vouchers from neglected diseases to pediatric rare disease therapies.
The FDA last year issued 160 orphan-drug designations and the OOPD hopes to improve that figure with a series of hands-on workshops to “de-mystify” the application process, says Coté. The OOPD also recently established a Rare Disease Repurposing Database identifying products that have received orphan status designation and are already market-approved for the treatment of some other diseases. Since 1983, only 358 of 2,200 drugs granted orphan designation have become approved products. But in the absence of legislative safeguards, Satonstall warns, some companies may be reticent to utilize it because new rounds of studies might uncover safety issues that could put a star product at risk.
Coordination, Dialogue Needed
NORD-sponsored focus groups suggest orphan product developers often face “unexpected hoops” in the regulatory process, including differing country requirements. “This is probably the single biggest issue faced by developers/sponsors,” says Dunoyer. “The need for several clinical trials can make recruitment of patients a real challenge.”
Greater industry collaboration with academia could help unclog the orphan drug pipeline, says Synegeva BioPharma CEO Sanj Patel. His company has intentionally positioned itself to reach “forgotten” patients, supported by a management team with first-hand experience in rare diseases on both the clinical and commercial side. It also has the capability to scale up manufacturing of protein therapeutics, one of the key challenges in developing orphan medications. Synageva’s tactics include innovative trial design, collaboration with rare disease patient communities, equipping genetics counselors with screening and recruitment tools, and working with physicians to decipher patients’ diagnostic path. Five products are under development.