Pipelines full of orphan drugs but more work to be done

About 30 million Americans, roughly 10 percent of the population, has one of the 7,000 known rare diseases, defined as affecting fewer than 200,000 people in the U.S. And rare diseases unfortunately affect children disproportionately, making up half of all cases globally.

The drug industry has made strides, developing approved treatments for 5 percent of rare diseases. The FDA has approved more than 500 orphan drugs since the passage of the Orphan Drug Act in 1983, compared to less than 10 in the 1970s.

"The importance of the Orphan Drug Act can't be overstated," said Emma Van Hook, director of policy and research at the Pharmaceutical Research and Manufacturers of America (PhRMA). "There are several essential parts of that that have been really instrumental in driving our companies – the marketing exclusivity, tax incentives, and even things like PDUFA waivers are really important in getting companies to engage early in some of these small patient populations."

Nearly half – 47 percent – of new drug approvals in 2015 were for rare diseases, including five for pediatric patients and 11 new cancer medications.

And a new report from the PhRMA and The ALS Association shows how companies are continuing to develop medicines for rare diseases with more than 560 medicines in the pipeline.

Not surprisingly given the general trend for drug company pipelines, oncology accounts for about 40 percent of drugs for rare diseases in development, with 151 drugs for rare tumors and 82 for rare blood cancers.

There are 148 drugs being developed for diseases with genetic causes, arguably a general class as it includes diseases as diverse as cystic fibrosis and spinal muscular atrophy.

Rounding out the top five classes of rare disease drugs in development, neurological diseases, infectious diseases and autoimmune diseases had 38, 31 and 25 drugs, respectively, according to the report.

7,000 >> 560

As much as the industry has done to increase the number of treatments for rare diseases, there's arguably still more work to be done, especially considering the substantial overlap for those 560 medicines. For instance, a quick scan of the database found three drugs in development for biliary cirrhosis, which causes damage to the bile ducts in the liver; seven drugs for blood clotting disease hemophilia B; and 14 drugs being developed for glioma, a type of brain cancer.

While there's often overlap with companies working in parallel on the same diseases, Van Hook pointed out that the companies are just following where the science is leading them. "Companies are learning at the same time which genetic mutations and other factors are causing diseases," Van Hook said.

But there's clearly more that can be learned about the rest of the rare diseases that don't have drugs being developed for them, especially with the decrease in the cost of genetic sequencing increasing the amount of genomic data from patients with rare diseases.

Genomics England's 100,000 Genomes Project, for instance, should deliver data to help in that endeavor. The project plans to sequence the genomes of 50,000 people affected by rare diseases – the patient plus two blood relatives – and 50,000 genomes from cancer patients – one normal and one from the tumor.

But genetics can only get scientists so far for some diseases, Van Hook explained, "In recent years, we're learning more and more about not only how the genetics are impacting the origination and progression of rare diseases, but also how things like the proteome and the microbiome are impacting how these diseases come to fruition." She cited the example of how the environment around tumors of some rare cancers can have a tremendous impact on how the mutations in the tumor cells occur.

And once the science of the disease has been worked out, there's the issue of designing trials, which isn't always straightforward. "For many of these rare diseases, it's a little bit difficult to identify and qualify the endpoints you use in conducting studies in patients with rare diseases," Van Hook told BioWorld Insight.

Companies often don't have time to wait for long-term survival data, but surrogate endpoints can be tricky. The progression of many rare diseases is measured by subjective and qualitative measures that may not be well characterized especially given the small patient population. "There's not always a good quantifiable or measurable endpoint to show whether the disease has either advanced or responded to the treatment," Van Hook said.

Recruiting patients for clinical trials can also be difficult given the low number of patients. Even diagnosing that a patient has the disease can be tricky especially in suburban and rural areas without specialists. "Doctors may not always have the latest and greatest knowledge of what the newest identified rare diseases are," Van Hook added.

COLLABORATION KEY

Many of the issues with developing drugs for rare disease can be alleviated by companies collaborating with other entities, Van Hook said.

Given the need for very basic science on many of those rare diseases with no treatments that's often done by academic and government researchers, "engaging even more so at an early discovery and preclinical stages of research is really crucial," she said.

And patient recruitment issues, for instance, can be alleviated through working with patient advocacy groups to help find new patients for clinical trials. Those advocacy groups can also be useful source of information for identifying the most important disease symptoms and what outcomes matter to them, which can help identify potential surrogate endpoints.

And, of course, collaboration with the FDA and other regulatory bodies in establishing surrogate endpoints is paramount to gaining eventual approval. Van Hook noted, "We've been working closely with the FDA to think about how we can identify better measures of disease progression and, in turn, use that for more effective clinical trials."

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