Et Tu Nilotinib?: Understanding Headlines about an Anti-Cancer Drug for PD

jbeck.jpgThe Society for Neuroscience annual meeting, which took place last week in Chicago, IL, is a place where the latest preliminary data in neuroscience is presented. True to form, there was an interesting abstract presented by Fernando Pagan, M.D. and colleagues from Georgetown University Hospital which suggested a potential treatment for those with Parkinson’s disease (PD). At the heart of the presentation, Dr. Pagan and colleagues reported that in a small trial, an anti-cancer drug called nilotinib was able to reverse both the movement symptoms and cognitive decline of people with PD involved in the study.

First, the potential is incredibly exciting. We all know that the PD community urgently needs better treatments and certainly, the idea of repurposing drugs (as we have discussed before) might be the quickest way to find those drugs and get them in the hands of those who need them.

MedicineBut it is also a good point to slowdown. Why? It is very early days. As others have pointed out, the study was a “non-randomized, non-blinded, non–placebo-controlled study that looked at [only] 12 patients.” Additionally, the full data has not been published, meaning there is not yet a way for the PDF team to review and analyze it. In absence of hard data, keeping in mind how powerful the placebo effect can be in PD and the desire by all to see the drug be successful, these claims deserve caution.

The good news is that there is compelling evidence from the lab suggesting that nilotinib could impact Parkinson’s disease – at least in a mouse (see our 2013 write-up here). The other good news is that nilotinib, despite being a drug with nasty side effects such as heart attacks and sudden death all listed in its black box warning, did not cause harm in the 12 participants who took it.

That said, we need to know more about its impact in Parkinson’s disease in larger studies. But the road is long even for this already FDA-approved drug. For example, dosing could be an issue. The doses Dr. Pagan and colleagues provided to people with PD in the study were only about 25 percent of a typical dose for a cancer patient. But in the initial animal studies mentioned above, the doses were significantly higher. If doses are increased, there is concern about adverse events (like those described above), which not only present pitfalls for people with PD, but also can make larger studies more difficult.

At PDF, we await the published results of this study, and remain hopeful about its future. But ours is a cautious hope because we have seen this excitement before (see examples, here, herehere and here) when potentially promising therapies have been heralded to the rafters yet have crumbled when more rigorously examined.

Don’t get me wrong – we all should hold out hope that nilotinib will prove to be effective. But it is important to remember the disappointment of past miracle drugs and wait until the evidence has been gathered, lest we feel double-crossed before we do the double-blind.

My fingers are crossed.

17 thoughts on “Et Tu Nilotinib?: Understanding Headlines about an Anti-Cancer Drug for PD

  1. Jim Wong

    Great perspective on this latest flash in the pan, Jim. Somewhere in that placebo effect there’s a brain that can anticipate and adapt, taking input from body sensors and combining its’ experiences to create expectations that impact symptoms. How can we discern where biochemistry ends and imagination begins? We understand so little about our brains.

    Reply
  2. Thomas A. Shiftan

    Jim, I have to disagree with you that this is just another underpowered trial trial raising false hopes. I agree with you that such was the case with CoQ10 and creatine; however the initial studies for these drugs were underwhelming and these drugs never were expected to show patient impprovement but rather delayed progression. The nilotinib study was based on clearing neurotoxic proteins. In vitro as well as animal studies showed dramatic results consistant with the findings in theee Pagan trial. A control group is important but since we are reminded by evry article written on PD that nothing reverses the process, we should be very impressed with a study that showed “improvement” in the 11 patients that completed the study. Moreover we have extensive safety data from patients with Chronic Myelogenous Leukemia, GIST tumors, and a few other conditions which indicate that the drug is safe at higher doses, at least as safe as DBS. This is the first development in PD that i have witnessed that deserves an active approach. One way or the other, I think we need to get this drug to those who are past their honeymoon with Sinemet. A risk is that you are right and nilotinib too is a flash in the pan. A bigger risk is that those of us with PD continue to lose function while there is a safe drug on the shelf gathering dust that may well make a diffence.

    Reply
    1. James Beck, Ph.D., Vice President, Scientific Affairs Post author

      Tom, I do not believe this study is raising false hopes, but the potential of false hopes. It is important to remember that this is simply an abstract presented at a national meeting….it is not peer reviewed and the data has not been made publicly available. Until we know more about this trial and its results, it is important not to jump to conclusions in either direction.

      Reply
      1. Thomas A. Shiftan MD

        JIm, I agree that we need to see the data; however, I believe the nilotinib data that we have seen suggests that it is safe and possibly/probably somewhat effective in reversing PD related signs and symptoms. The fact that we’re having the national call today is indicative of the interest this drug is stirring and I commend PDF for moving quickly on this issue. Nilotinib is also different because it is already approved for use. Neurologists may not be familiar with its use but they will easily become so. There are unlikely to be surprises with unexpected side effects that haven’t shown up thus far. I suspect many physicians would be trying it off label for their more advanced PD patients if it wasn’t for the 800 lb gorilla in the room, namely the cost.

        Reply
  3. David L. Keller, MD

    The mouse study used high doses of nilotinib that would have been risky in humans because its purpose was to demonstrate efficacy in principle, not safety. Nobody cries or sues over a dead mouse. The benefits of disease reversal were evident in the uncontrolled human trial at low doses of nilotinib which are undoubtedly lower & safer than the anti-cancer human doses, which themselves are safe enough for humans if care is taken. Death from torsade is highly correlated with QT prolongation, which in turn is a stable quantity on a given dose and easily measured on ECG. The magnitude of the anecdotal benefits seen vastly exceed the magnitude of any conceivable placebo effect, and grew with time, rather than diminishing with time as expectation effects do. Add in the serum and CSF findings of improvement in biomarkers and it becomes inexcusable for any foe of Parkinson’s to continue to sit back and watch Moussa’s group inch along on their meager funding. I am putting my money where my mouth is and I call on PDF to do likewise. Even a skeptic cannot justify delaying a futility study at this point.

    Reply
    1. James Beck, Ph.D., Vice President, Scientific Affairs Post author

      Dr. Keller, It is important to remember that this is a brief report of the outcome of a small trial. We all await more information on how the trial was conducted and access to the data underlying the results. In regard to your comment that mice may not sue, the issue of dose is a serious concern, not only for the reasons raised regarding human safety but also because there is a legitimate scientific disagreement over whether low doses of nilotinib sufficiently engage the c-abl enzyme. Lest we fall pray to buying a bill of goods, it is simple prudence to wait to see the data that underlies this study. I hope for the best.

      Reply
  4. Scott Roberts

    I disagree with the minor complaints above. This article’s perspective and wording is “perfect” from my point of view. Other things to consider is that there is a patent behind the originators of the research, and I had read 2 of the 12 patients were providing funding at least a part of the study. The two before and after videos they provided did not provide any evidence of the claims made in the audio. Coming out with such strong statements for a safety trial that has not even been published is ironically a case for and against hope, depending on how much you trust the researchers. The patent and something like a $40,000/year price tag for the high dose group (300 mg per day, 1/2 of a leukemia patient’s low dose schedule 600 mg/day) should be a cause of great skepticism. Also, there is a lot more research on compounds that “break up” misfolded a-Syn than people realize. GM1 completed phase 3 long ago and the 38 patients that took it for 2 years remained in better condition than when they started for as long as they took it. By the evidence, it stopped PD for as long as they took it. It seems already permitted by FDA regulations for off-label use. But it is animal-derived and a physician and his family are having trouble getting people interested in his sheep farm for producing it. Rapamycin is another with off-label potential, but no work in humans. “Finally, rotenone-induced alpha-syn aggregates were cleared following rapamycin stimulation of autophagy.” (150 pubmed articles containing rapamycin and Parkinson’s). I found 12 plant compounds that are pretty good at breaking up or preventing a-Syn misfolding, 1 of which is associated with decreased PD in epidemiological work (gallic acid in black tea, although that was a Singapore study where mercury in fish food is also associated with PD and black tea is known to prevent its absorption). BTW, the highest “PD” incidence in the world, Iraq, may actually be latent mercury poisoning from their 1971 grain disaster (possibly 100,000 acquired measurable brain damage at the time).

    Reply
  5. Bruce Wong MD, MSc, FRACP

    These are incredible findings in a small number of patients, preceded by thoughtful science, a well structured mouse study and biological plausibility. The effect size as reported is large and dramatic and would not be eliminated by inclusion of controls or be the result of a random effect. The only potential error would come from some sort of fraud within the trial – highly unlikely for well respected investigators from Georgetown – not withstanding potential financial implications for the author that submitted a “use patent”. It is unhelpful calling this a phase I study as this study is not in the usual sequence of drug development – the drug is already approved for CML. Phase I would describe a dose ranging study in normal patients. This study is more a “proof on concept” study in Parkinsons patients and it is what it is.

    So Parkinson’s disease patients now have a choice with this data, elect to wait for better data – while suffering the symptoms of the disease and its’ inexorable course to neuronal cell loss. Take the drug at risk that the results are not true or a fraud. Any physician can prescribe the drug, no insurance company will likely pay for it. I have seen patients that are at the end of available therapies try drugs which much less information.

    Nilotinib at low dose is relatively safe – all of the labelled toxicities are dose related. So the potential individual harm is the low risk of side effects of the low dose and the money that the drug will cost you – I have seen it 112 x 150mg tablets for around $4,000, which is the low dose the Georgetown investigators used – that would be about 4 months of therapy.

    I would discount the comment that the effect goes away after you stop the drug – they started the drug in 12 patients, stopped the drug in fewer, as they continue on an expanded access program, and the stopping that they did see was likely after only 6 months of therapy – the duration of the primary study. So not enough data on this point.

    An additional item is that Nilotinib is reported to have about 1.5% crossing the blood brain barrier but because of low CSF protein more of the drug remain ‘free’ and effective. A related drug, Dasatinib, which has the same mechanism of action is actually more potent at inhibiting Tyrosine Kinase, and 5% crosses the blood brain barrier – in CML it is the treatment of choice for brain leukemia because of this.

    Reply
    1. Earl Graham

      Based on the comments above, and the fact that nilotinib CAN NOW be prescribed off label, it is reasonable to assume that some physicians currently are a using it in selected patients with advanced PD.
      What is it their feedback?

      Reply
    2. James Beck, Ph.D., Vice President, Scientific Affairs Post author

      Though not clear what prompted the about comment about the trial stage (maybe the listing on clinical trials.gov?), the clarification regarding “proof of concept” and Phase I trials is useful edification. I would simply add that this trial would be a Phase IIa.

      Regarding your other comments, it is really difficult to make any other judgments about the trial absent an actual scientific report, where the details are laid out for all to study. I am confident that you, and our PDF community, agree that science-by-press release is not a helpful way to advance PD therapies.

      Reply
  6. Earl Graham

    Based on the comments above, and the fact that nilotinib CAN NOW be prescribed off label, it is reasonable to assume that some physicians currently are a using it in selected patients with advanced PD.
    What is it their feedback?

    Reply
  7. James Beck, Ph.D., Vice President, Scientific Affairs Post author

    We do not know, but PDF will certainly update this post and provide our interpretation when it is available.

    Reply
    1. Jane

      Still waiting for the official study report for phase I Nilotinib.. any update on that? Is it normal to take so long for an official report?

      Reply
      1. James Beck, Ph.D., Vice President, Scientific Affairs Post author

        Yes, it can easily take 3-6 months for research to vetted by peer review and published…longer if the reviewers request revisions made to the paper, e.g., requesting new or different analysis of the data.

        Reply
  8. Ann Smith

    Months have passed. Have the data and documentation pertaining to the Phase I Trial been published or otherwise made available to the scientific community and/or the public? Is there any information available about the “expanded access study” mentioned in the October 17,2015 Georgetown University press release? Is there any indication when a Phase II Trial will begin? Time is of the essence for many of us. Thank you.

    Reply
  9. Thomas A. Shiftan

    The article has been published in the Journal of Parkinson’s Disease. Unfortunately, though there are interesting biochemical changes which will require further study, much of the hype from the original press release is gone and for good reason. Jim Beck was right on target with his words of caution. The drug did seem to be reasonably safe but it’s going to take a lot more subjective or even better objective improvement than less constipation for nilotinib to find a role in the management of PD.

    Reply

Leave a Reply

Your email address will not be published. Required fields are marked *