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 on pricing. Here’s a key question: do we want to encourage work on diseases where effective treatments will provide the greatest benefit to the most people, or the ones that are the “easiest” to get approved and reimbursed (and just to be clear, developing treatments for any of these diseases, orphan or not, is really difficult).
Suppose that the trend continues, and some time in the next few years 39 new drugs are all approved for rare diseases. While orphan diseases are defined as having fewer than 200,000 patients at risk, many of drugs developed for these illnesses are used to treat much smaller populations. For example, Sanofi/Genzyme’s imiglucerase (Cerezyme) has been used worldwide to treat only about 5,600 type 1 Gaucher disease patients total (or about 300 patients per year) since the FDA first approved it in 1994. Imagine if each of the 39 drugs approved treated populations of less than 5,000 patients per year. The drugs would treat a total population of less than 200,000 patients in a U.S. population of more than 315 million people or about 0.06 percent of the total population. Even if each drug treated 200,000 people, this would only help about 2.5 percent of the population. Drug companies could still be quite profitable, however, by treating even these very limited patient groups with astronomically priced medicines. My fear is that a large number of biopharma companies will choose the path of least resistance and shift their primary focus to orphan diseases.
No one, including me, wants to see people with rare diseases ignored and doomed to a life without hope of a viable treatment. I think it’s great that the European Commission just committed $187 million in new funding for 26 research projects that they hope will deliver some 200 new therapies for rare diseases. Since there are about six to seven thousand of these disorders (affecting some 25 to 30 million Americans and an equal number in Europe) it will take decades, if ever, to develop effective treatments for all of them. At present there are some 420 medications that have been approved to treat about 250 of these diseases.
However, shouldn’t there be some degree of proportionality between the amount of drug development dollars being expended and the number of patients being treated? Such choices as a society are difficult. It would be wonderful if we had the resources to tackle all medical afflictions, whether they affect 500 people or 5 million per year. And even if there are effective treatments for a particular disease, a substantial problem for people without health insurance (and even for many that do who face huge co-pays) is being able to afford their treatments and medications.
This issue will only become more complicated as the financial screws get tightened on our out-of-control health care system. Medicines that are developed to treat rare diseases may go on to become mainstay drugs for larger populations. Amgen’s blockbuster drug Epogen, for example, was originally approved for an orphan indication, but was eventually used to treat much larger numbers of patients. Novartis is banking on finding expanded uses for their drug canakinumab (Ilaris), which treats a small subset of diseases affecting only 6,000 people in the world. Drugs that target particular mutations in one disease may come to be more widely used if a similar genetic defect turns up in other disorders. One thing is clear: prices for these drugs will remain breathtakingly high.
So how do we achieve the right balance here? I have previously suggested an approach that may be quite effective in tackling this “allocation of resources” dilemma. It’s time for pharma and large biotech companies to dig deep into their bulging, multi-billion dollar war chests. Working with government funded researchers, they should launch a collaborative large-scale project focused on devising a technical fix for repairing broken genes, rather than attacking individual diseases in a piecemeal fashion. I’m envisioning an effort comparable to what was undertaken for the Human Genome Project. A solution to this vexing problem could provide the clinical basis for treatments for a large number of common illnesses such as cancer and heart disease as well as a wide spectrum of genetically based rare diseases. Until that happens, though, I will try to quell my flip-flopping feelings by celebrating the successes that medical researchers have already achieved in treating both the few and the many.
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