Tuesday, June 23, 2009

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.

7 comments:

Dan said...

I am so pleased that you have started this blog and are allowing patients and caregivers to interact within this format. I am a patient with a diagnosis of Parkinson's Plus, probable MSA, and I have been writing a blog for over two years that evolved into a book called, "I Will Go On: Living with a Movement Disorder." This book is available under this title at Amazon.com. I plan to read your blog and respond as appropriate in the future. I am involved in support groups at the local level and have many patient and caregiver contacts. Thank you again, Dan

Carolyn said...

Wonderful Blog Robin! I have subscribed to my Google Reader and look forward to more posts.

As a "treated" participant in the CERE-120 Trial, it was particularly disappointing to see Phase II trail. But as my PD-mentor says, in truth "There are no failed trials. Something is always learned"

LindaH said...

Thank you for explaining and illustrating so well the dfifering viewpoints of researchers and patients on what they consider “promising” or “interesting” Parkinson’s research. PWP largely support scientists’ efforts and understand their need to communicate research findings at conferences, and in academic journals, and also the importance of learning from “failed” trials. We also underestand how crucial it is for PWP to partcipate in clinical trials, and many are willing to accept considerable risks. But in addition to advancing science and benefiting future generations, we are also seeking better treatments that will treat our symptoms today and someday bring us a cure.

Those of us who have been battling PD for 10 or 15 years or more,have all heard the “a cure in 5 years” speech when we were diagnosed. It’s been a long “5 years”

Two days after your blog post, there was another failed trial reported at the MDS conference – Spheramine. http://www.mdvu.org/emove/article.asp?ID=1192

Actually, the phase II trial’s failure had been “unofficially” reported last year by a Bayer(the sponsor) press release. Either way, we can be sure that spheramine will be joining the other “failed” treatments on the shelf.

A good friend was a participant in the phase I Spheramine trial and believes she benefited from the unilateral implant of retinal cells for many years afterward. The sponsor will probably claim this was due to the strong placebo effect in PD, just as the GDNF infusion clinical successes were explained away, and that treatment shelved 5 years ago.

Can a placebo effect last for 9 years? Five years? One year? We need to know the answer to this question and questions about other trial design issues tht may be confounding trial results.

Yes, many PWP are frustrated with the current drrug development and clinical trial system and lack of long term effective treatment for advanced PD. We want to be involved in finding the answers. Thanks for welcoming our viewpoints in this blog.
linda

Dean Provost said...

Robin: I think it is great that you have started this blog. With your perspective on PD research I look forward to future articles.

One thing puzzles me: I cannot find any reports of "failure" related to Rasagaline(Azilect). Can you direct me?

Peggy said...

I continue to be very concerned about the "failed" Parkinson's trials that have been reported recently. I am a post Phase I Spheramine trial participant who had the experimental implanting of dopamine-producing retinal cells from a donar eye nearly a decade ago and experienced considerable improvement of symptoms. And an unofficial article posted at wemove.org explained that the Phase II double-blind placebo-controlled phase had failed, after only reviewing data from 12 months. What frightens me was this statement: "The study failed to show efficacy of cellular implants of human retinal pigmented epithelial cells beyond a remarkable placebo effect . . . Preliminary long-term results in part of the study patients suggests that the placebo effect persists even longer than 12 months."

Why was this article, which has not been peer-reviewed, put out there before being closely scrutinized by ALL stakeholders, to include trial participants? Doesn't doing so bias future publications about the results? I am sure the expense of continuation of a Phase II trial is a major factor in this decision. But are we losing promising potential treatments in shutting the door too soon or making unproven suggested explanations for unexpected results(such as an extended placebo effect)?

I have lots of questions, and even more topics I would like to see discussed regarding this frequently-occurring dilemma of following Phase I and animal studies for a number of years, then what appears to be "throwing in the towel" after only 12 months follow-up for Phase II trials.

Phase II and later studies deserve as much if not more time for review, especially if done with the risk of participants who consented to placebo-controlled sham surgery.

Robin Elliott said...

Thank you to everyone for your comments.

Dean, in response to your question, my reference was not to the original trials of Azilect as a therapeutic agent for Parkinson's -this was established some years ago and the treatment is of course is now in wide use around the world - but to the recent trial, known as ADAGIO, in which the treatment was being tested for its potential as a disease-modifying agent - in other words, to see whether it has the capacity to slow down the progression of Parkinson's. When tested for this, the trial was reported to have "failed to meet its end-point" for the 2 mg dose, but not the 1 mg dose - that is, the data did not prove that Azilect at the higher concentration slows Parkinson's. As I said in my original blog posting, this was a mystifying result. Clearly, this finding warrants the close scrutiny of peer-review before drawing any conclusions.

The announcement was originally made during the summer of 2008 but it has not yet been published, which is perhaps why you have not seen anything.

Having said all this, there is still hope that Azilect may be found to be neuroprotective, but this will require additional investigation.

Thanks for writing, and for your comments!

Robin Elliott

Anonymous said...

Thank you for your interesting, informative blog. Two comments: Two movement disorder specialists I have seen (one of whom participated in the ADAGIO study, I believe) are convinced that Azilect at low doses does slow the progression of PD. How soon will the next trial phase begin?

Regarding health insurance reform: Please don't minimize the financial issues. Those of us with PD who aren't yet old enough for Medicare and who are currently out of work cannot obtain private insurance for ANY amount of money, because PD is a pre-existing condition that automatically disqualifies us. Changing this fact alone would be a vast improvement in the present system.