Why do Promising PD Treatments Fail?

On Tuesday, June 9th, the second day of the Movement Disorder Society International Congress in Paris, Dr. Warren Olanow, one of the world’s leading Parkinson’s specialists, gave a brilliant and authoritative talk on the subject of “What’s New in Parkinson’s Trials?"

His focus was three high-profile clinical trials that have been watched intently and anxiously by people with Parkinson’s around the world.

• One was the Ceregene trial, in which a growth factor called neurturin (CERE-120) was delivered via a gene therapy technique.
• The second was STRIDE, in which a levodopa-COMT inhibitor (Stalevo(R)) was tested for its potential impact on improving dyskinesias.
• The third was ADAGIO, designed to test the potential of rasagaline (Azilect(R)), a PD therapeutic that was approved several years ago to control symptoms of PD, for its potential to actually slow the course of the disease.

Dr. Olanow began his talk by saying that it has been an “extraordinary year …with many new trials involving drugs that offer promise to the patients we serve.” And he concluded it by saying it has been “wonderfully interesting.”

The trouble is, all three trials failed. What does this story mean for PWPs?

To this observer, it means several things:

1. The obvious one is that the intuitive perspective of many clinical scientists is simply different from that of most people with Parkinson's. Studying something, however much one may yearn for it to be successful – as Dr. Olanow does -- is just not the same thing as living with it.
2. Second, it means -- as the speaker himself pointed out in his closing minutes – that we need to do more work in the early stages of the investigative process (e.g., Phase-One trials) to provide greater assurance of efficacy before we proceed to put people living with Parkinson's through the strains and too-often dashed hopes of the much more expensive later stages (e.g., Phase-Three trials).
3. Third, of course, it means, as Ira Shoulson, M.D., another major leader of clinical research and a collaborator with the PDF on several current projects, said to me recently, “clinical research is very, very hard!” Whether it be the imperfections of animal models of Parkinson’s disease, or the data-confounding impact of the notorious placebo effect, or the impact of physician-scientist bias (after all, they too want the trials to succeed!), or simply the immense complexity of defining “end points” – that, is what the measures should be of success or failure, and whether they will be accepted by the FDA – Parkinson’s trials are indeed very hard to do.

There is of course a silver lining to this cloud: that today’s failed trial may be the basis for tomorrow’s successful one.

In at least two of the three trials that Dr. Olanow mentioned, the data have suggested a next step that could have a different outcome. In the Ceregene trial, for example, when the managers went back to see how the trial participants looked three to six months after the trial concluded, they found that some had improved – suggesting that perhaps – just perhaps – the problem was that the trial concluded too early. And in ADAGIO, there does in fact seem to be some neuroprotective effect at lower doses of the drug (though, mystifyingly, not at higher doses), giving some grounds for hope.

In my next post, I will share with you some other things that struck me as interesting about the meeting – including a bird’s eye view of potential new treatments that are currently in the pipeline.