The Orphan Drug Act of 1983 was a game-changer for rare diseases.  A result of lobbying by patient-led groups such as NORD with bipartisan political support, its principal author was the liberal Democratic Congressman Henry Waxman and its signer was President Reagan.  The rate of FDA approval of drugs for orphan diseases increased from fewer than one per year before 1983 to an average of 13 per year over the ensuing decades.  The ODA provided drug companies 7 years of new patent protection, financial subsidies in the form of grants, a fast-track approval process and last but not least, a tax credit for 50% of the development costs.

A disorder qualifies for “orphan” designation under the ODA if its point prevalence in the US is fewer than 200,000.  PSP easily meets that criterion, with about 5,000 diagnosed cases or 20,000 if you count those who undiagnosed but potentially diagnosable.

PSP’s transition from an orphan to an object of loving care has been remarkable.  There are several reasons:

First, a drug that works for PSP may also work for other tauopathies, including Alzheimer’s disease.  Of course, a huge potential market exists in the ascendancy of AD as a major epidemiologic challenge for the Boomer Generation and beyond.

Second, the disappointing results of clinical trials of drugs addressing the beta-amyloid aggregation of AD turned the research world’s attention to tau aggregation as the key to AD prevention.

Third, PSP, as a “pure tauopathy” offers a good, clean “test bed” for anti-tau agents.  (We now know it’s not so pure, but close enough for present purposes.)

Fourth, neuroprotective trials are easier in PSP than in AD despite the recruitment difficulty arising from the disease’s rarity.  One reason is that PSP, unfortunately, progresses more quickly than AD.  (Aside: A “neuroprotective” trial attempts to reduce the rate of worsening of the disease, usually without improving the existing symptoms.  A “symptomatic” trial attempts to improve existing symptoms without regard to the long-term progression or outcome.)  Demonstrating that a drug slows a disease’s progression requires fewer patients and a shorter treatment period when the untreated disease progresses more rapidly.  This translates into cheaper development costs and less development time.

Fifth, in the absence of a proven biomarker for AD, clinical trials must rely on neurological exams and reports of daily activities by patients and caregivers.  No such clinical scale accomplishes this adequately for AD, but the PSP Rating Scale does so for PSP.  (Bragging point disguised as a disclaimer: I developed the PSPRS.)

But the House of Representatives’ version of the new tax reform bill eliminated the tax credit in the Orphan Drug Act.  The thinking was that drug companies often charge prices for those drugs far in excess of their development costs, thereby defeating the original intent of the ODA to support development of drugs without a reasonable expectation of profitability.  The drug companies can usually get away with those prices because the patients are desperate and because the insurance companies providing prescription coverage want to avoid lawsuits and public-relations disasters.  Besides, the insurors can just raise their premiums to spread the cost over their other subscribers.

The other concern in the House was that drugs developed under ODA protection may then find use against more common conditions with highly profitable results.  Some examples are Cialis (developed for pulmonary hypertension, then for erectile dysfunction), Botox (dystonia, then wrinkles) and Provigil (narcolepsy, then off-label as a cognitive enhancer) .  A PSP drug subsequently used for AD could become another example, as pointed out above.

The final tax reform law is a compromise.  It reduces the fraction of the development costs that can be taken as a tax credit from 50% to 25%, not to zero.  How will this affect the drug companies’ calculations regarding future orphan drug development?  I haven’t a clue.  But my attitude toward this complicated situation is that patients with PSP should be glad that their disease is of interest to drug companies, even if that’s only a by-product of their interest in AD or some other way to game the ODA.

Some think tank now needs to figure out just how much credit the ODA deserves for recent decades’ abundance of new drugs for orphan diseases.  Maybe it’s not an economic issue at all.  Maybe it’s just that recent basic scientific breakthroughs have created more drug targets.  Or maybe the drug companies have figured out that they can charge tens or hundreds of thousands of dollars per year for a drug and get away with it.  Either way, maybe the ODA is unnecessary or needs to be radically revised.  One can hope that if the current work on PSP results in a mega-expensive AD drug that strains our present health care model, maybe the result will be a truly universal health care system in the US.