Has The Pendulum Swung Too Far in Favor of Rare Diseases?

3/14/13

As a politician, one of the worst things you can be accused of is being a flip-flopper, a person who changes their mind on one or more issues. Another way of looking at this character trait is to say one has thoughtfully wrestled with an issue and changed one’s mind, as President Obama recently did on gay marriage. I don’t think there’s anything wrong with that. In fact, being so rigid as to preclude changing one’s opinion on any subject would be a far worse stance. Sometimes, though, we find ourselves going back and forth in support of both sides of a certain issue. As F. Scott Fitzgerald put it “The test of a first-rate intelligence is the ability to hold two opposing ideas in mind at the same time”.

My thoughts have been flip-flopping a lot lately as I struggle to fully embrace one of the “hot” trends in BioPharma: the increasing emphasis on developing drugs for orphan or rare diseases. Here’s my dilemma: while I am thrilled by recent successes in finding new medicines for these disorders, I am troubled by one of the potential consequences of this achievement. Is this movement leading to a reduction in research on diseases that affect large numbers of people but are difficult to treat, such as lung cancer or heart disease? Will the lower cost of running orphan disease clinical trials drive venture capitalists and corporate decision makers to abandon their efforts to treat Alzheimer’s, sepsis, and other disorders? Is there a fair way to apportion limited financial and scientific resources to encourage and empower both groups?

Until fairly recently, people afflicted by rare diseases grappled with the depressing realization that pharma companies would not invest their considerable resources in trying to develop new medicines for these disorders. For most of the last century people burdened with these illnesses had little hope that new drugs would become available to treat them or a loved one. It was truly heartbreaking to see people (usually children) suffer from one of these unusual illnesses, many of which were fatal and whose cause was often unknown. The desperate search for a cure for these enigmatic diseases made for such a compelling narrative that it led Hollywood to produce at least two films on the subject, Lorenzo’s Oil and Extraordinary Measures.

Everything changed in 1983 with the passage in the U.S. of the Orphan Drug Act, which was put in place to encourage drug makers to develop new medicines for rare diseases. This successful piece of Federal legislation included incentives for pharma companies in the form of exclusivity provisions and tax incentives. It increased the likelihood that companies could achieve a good financial return if they embarked on a program to come up with new drugs to treat these disorders. Similar incentives were put in place in Europe as well.

The law has been spectacularly effective. Requests to the FDA for orphan drug status from drug makers have risen from about 50 in 1984 to over 300 in 2010, although only about 25 percent of these actually get this designation. Rare diseases (defined as affecting fewer than 200,000 people) for which treatments are now available include hereditary angioedema, Pompe disease, phenylketonuria, and paroxysmal nocturnal hemoglobinemia. This past year saw the FDA approve 39 new drugs in the US. Among these were six new drugs to treat rare diseases, including homozygous familial hypercholesterolemia, Gaucher’s Disease, short bowel syndrome, and cystic fibrosis.

At first glance the drugs for rare diseases accounted for only 15 percent (6 out of 39) of newly approved medicines in 2012. However, if you dig deeper these numbers are a bit misleading. Several of these newly approved medicines aren’t actually drugs at all in the sense the term is normally used. Two of them are employed in medical imaging and one is used in preparation for colonoscopies. Doppelgangers for two of the biggest selling biotech drugs of all time were also approved last year. Teva’s tbo-filgrastim (Neutroval) is a warmed-over version of Amgen’s filgrastim (Neupogen), and Affymax/Takeda’s peginesatide (Omontys) is a longer acting substitute for Amgen’s epoetin alfa (Epogen) and darbepoetin alfa (Aranesp). Vivus’s avanafil (Stendra) is just a latecomer to the crowded erectile dysfunction drug party. GlaxoSmithKline’s raxibacumab (ABthrax) was approved to treat inhalational anthrax, but will pretty much be locked away in warehouses until and if terrorists launch a bioweapons attack on the United States. Once one focuses on the drugs that represent truly new modalities, then only 17 of the newly approved drugs are either novel agents or have new mechanisms of action, which is a similar number to what has been seen in previous years. Therefore, drugs for rare diseases actually make up about a third of all new and novel medicines.

The increasing focus on orphan diseases by pharma and biotech companies has been driven by a number of factors:

1) Clinical trials can be done with many fewer patients (and are therefore less expensive to run) because the pool of patients afflicted with the disease is much smaller.

2) FDA approval may be achievable in a much shorter time frame via its Breakthrough Therapy designation, making investments in companies developing these drugs more attractive to VC firms.

3) As a general class rare diseases may be “easier” to treat, since a significant percentage of them are caused by single gene defects, not multi-genic traits like heart disease or diabetes.

4) Payers are currently reimbursing the enormous costs of these drugs (some of which are priced up to half a million dollars per year) with little pushback since there are only a limited number of patients. This is in contrast to the recent resistance seen with the pricing of Sanofi’s colorectal cancer drug ziv-aflibercept (Zaltrap), where the company was forced to cut its price in half after doctors at Memorial Sloan-Kettering Cancer Center railed against its high cost and lack of advantage over competing medicines in a guest editorial in the New York Times.

If the trend continues, however, payers for rare disease drugs may also begin to push back … Next Page »

Stewart Lyman is Owner and Manager of Lyman BioPharma Consulting LLC in Seattle. He provides strategic advice to clients on their research programs, collaboration management issues, as well as preclinical data reviews. Follow @

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  • FDAmatters

    The supposed imbalance between investment in orphan drugs and other drugs is just that: supposed. Here’s another way to look at it: without the stimulative effect of the Orphan Drug Act and its incentives, the entire biotechnology industry would be years behind where it is today. And the result would be a loss for all patients–those with small as well as large diseases. Knowledge of biology is still more knowledge of biology than it is knowledge of small vs. large diseases.

    There are issues–not because companies disproportionately focus on orphan research, but because the evolving marketplace is supposed to be dominated (eventually) by personalized medicine. In that paradigm, almost all diseases will qualify as rare and most therapies will be orphans.

    I discuss this in an FDA Matters blog column entitled: Orphan Drugs at 30: Will Success Become Too Expensive? It can be found at: http://www.fdamatters.com/?p=2245. To check the blog out, go to http://www.fdamatters.com. Steven