Short answer: No.
Longer answer: The FDA decided, on the basis of the results of an interesting clinical trial that I will describe here, that the evidence was insufficient to claim that rasagiline has a disease-modifying effect, i.e., that it slows down progression of the disease. This decision is widely viewed as being appropriate, including by me; the burden of proof should be very high to make such a claim. Among other things, there would be enormous financial implications for the company marketing rasagiline, Teva, if the FDA allowed them to claim that it slows the disease, because most patients in the Western world would take the drug. No drugs thus far have been proven, to the satisfaction of the FDA and the clinical community, to slow disease progression, although the case of levodopa itself deserves study.
But it’s worth looking at the data in more detail. I won’t go into the detail about why scientists and clinicians suspected that rasagiline (and its predecessor MAO-B inhibitor selegiline) might be neuro-protective and delay disease progression. There were a number of different studies with cells and with lab animals suggesting that this might be the case. While the briefing document prepared for the FDA provides hypotheses about how it may protect neurons from various insults, these are really just reasonable guesses; to me, it looks like a grab-bag of results from different studies.
Still, the evidence seemed strong enough, at least to Teva, to invest a huge amount of money to carry out a very interesting clinical trial to try to prove that it slows disease progression. As the ELLDOPA clinical trial fiasco highlights, a key challenge is distinguishing the effects of the drug on disease symptoms and on the disease itself. And in that respect, the “delayed start” design of the ADAGIO clinical trial is interesting. The concept is that patients were initially randomized (double blind) to take either placebo or 1 or 2 mg/day of rasagiline for the first 36 weeks. Up to this point, this is a pretty standard clinical trial, and the results were as expected, i.e., people on rasagiline had less symptoms, on average, than those on placebo. All patients, on average, showed worsening from week 12 to week 36 due to progression of the disease.
So far so good; the drug works to reduce Parkinson’s symptoms. But we already knew that. Things get more interesting after week 36. After that point, all patients take rasagiline (1 or 2 mg/day), and none take placebo. So now, at week 72, you can compare two groups of patients who are both currently taking 1 mg/day rasagiline, but half of these have been taking it for 72 weeks, whereas the other half have only taken it for the last 36 weeks. It’s an apples-to-apples comparison; the symptomatic benefit of rasagiline in both groups should be comparable. Any differences are due to the fact that one group has been taking the drug twice as long: are they better off, worse, or the same? In the 1 mg/day cohort, things looked rather nice. Patients on the drug for 72 weeks were doing better at the end of the trial than those who were only on the drug for 36 weeks. The effect was not huge, but enough to be significant, and this is exactly what you want to ‘prove’ that the drug slows disease progression.
Alas, the results in the 2 mg/day cohort muddied the waters, and ultimately killed Teva’s gambit to get rasagiline declared a ‘disease-modifying drug’. Patients who were on 2 mg/day for 72 weeks were not doing any better, on average, than patients who only took 2 mg/day for 36 weeks. This is what you would expect for a drug that has symptomatic benefit but does not slow down progression of the disease.
If the results had been the opposite, i.e., evidence of slowing the disease with 2 mg/day but not with 1 mg/day, the FDA probably would have granted the claim, because that result would make sense: more of the drug would be expected to work better than less of it. That’s the way things normally work. Taking more of a drug usually leads to a stronger effect, although it might be accompanied by worse side effects. But that’s not what happened here. There are a number of possible explanations including some that get fairly technical, and as you can imagine, Teva jumped through all sorts of hoops to try to argue away the 2 mg/day finding, to no avail.
For what it’s worth, my own view is that rasagiline probably does slow disease progression a bit. Even discounting technical explanations, or just bad luck, there are some fundamental reasons why “more” is not necessarily “better” when it comes to rasagiline. Because it binds MAO-B irreversibly (never comes off, as discussed here), it’s not a simple matter to determine the optimal dosage, and a higher dose could conceivably lead primarily to more off-target, potentially deleterious, effects. Or maybe not. Chances are, we will never know. This was a very expensive clinical trial, which can heart-breakingly close to succeeding.