In my previous post, we briefly reviewed the results of the phase II double-blind, randomised clinical trial of Exenatide in Parkinson’s disease. The study indicates a statistically significant effect on motor symptom scores after being treated with the drug.
Over the last few days, there have been many discussions about the results, what they mean for the Parkinson’s community, and where things go from here, which have led to further questions.
In this post I would like to address several matters that have arisen which I did not discuss in the previous post, but that I believe are important.
I found out about the Exenatide announcement – via whispers online – on the afternoon of the release. And it was in a mad rush when I got home that night that I wrote up the post explaining what Exenatide is. I published the post the following evening however because I could not access the research report from home (seriously guys, biggest finding in a long time and it’s not OPEN ACCESS?!?!?) and I had to wait until I got to work the next day to actually view the publication.
I was not really happy with the rushed effort though and decided to follow up that post. In addition, there has been A LOT of discussion about the results over the weekend and I thought it might be good to bring aspects of those different discussion together here. The individual topics are listed below, in no particular order of importance:
1. Size of the effect
There are two considerations here.
Firstly, there have been many comments about the actual size of the effect in the results of the study itself. When people have taken a deeper look at the findings, they have come back with questions regarding those findings.
And second, there have also been some comments about the size of the effect that this result has already had on the Parkinson’s community, which has been considerable (and possibly disproportionate to the actual result).
The size of the effect in the results
The results of the study suggested that Exenatide had a positive effect on the motor-related symptoms of Parkinson’s over the course of the 60 week trial. This is what the published report says, it is also what all of the media headlines have said, and it sounds really great right?
The main point folks keep raising, however, is that the actual size of the positive effect is limited to just the motor features of Parkinson’s disease. If one ignores the Unified Parkinson’s Disease Rating Scale (UPDRS) motor scores and focuses on the secondary measures, there isn’t much to talk about. In fact, there were no statistically significant differences in any of the secondary outcome measures. These included:
The title of today’s post is written in jest – my job as a researcher scientist is to find a cure for Parkinson’s disease…which will ultimately make my job redundant! But all joking aside, today was a REALLY good day for the Parkinson’s community.
Last night (3rd August) at 23:30, a research report outlining the results of the Exenatide Phase II clinical trial for Parkinson’s disease was published on the Lancet website.
And the results of the study are good:while the motor symptoms of Parkinson’s disease subject taking the placebo drug proceeded to get worse over the study, the Exenatide treated individuals did not.
The study represents an important step forward for Parkinson’s disease research. In today’s post we will discuss what Exenatide is, what the results of the trial actually say, and where things go from here.
Last night, the results of the Phase II clinical trial of Exenatide in Parkinson’s disease were published on the Lancet website. In the study, 62 people with Parkinson’s disease (average time since diagnosis was approximately 6 years) were randomly assigned to one of two groups, Exenatide or placebo (32 and 30 people, respectively). The participants were given their treatment once per week for 48 weeks (in addition to their usual medication) and then followed for another 12-weeks without Exenatide (or placebo) in what is called a ‘washout period’. Neither the participants nor the researchers knew who was receiving which treatment.
At the trial was completed (60 weeks post baseline), the off-medication motor scores (as measured by MDS-UPDRS) had improved by 1·0 points in the Exenatide group and worsened by 2·1 points in the placebo group, providing a statistically significant result (p=0·0318). As you can see in the graph below, placebo group increased their UPDRS motor score over time (indicating a worsening of motor symptoms), while Exenatide group (the blue bar) demonstrated improvements (or a lowering of motor score).
Reduction in motor scores in Exenatide group. Source: Lancet
This is a tremendous result for Prof Thomas Foltynie and his team at University College London Institute of Neurology, and for the Michael J Fox Foundation for Parkinson’s Research who funded the trial. Not only do the results lay down the foundations for a novel range of future treatments for Parkinson’s disease, but they also validate the repurposing of clinically available drug for this condition.
In this post we will review what we know thus far. And to do that, let’s start at the very beginning with the obvious question:
So what is Exenatide?
The title of today’s post comes from a Rudyard Kipling poem, and it seemed appropriate as we review the results of a clinical study for Parkinson’s disease…involving bees! Much has been written about the medicinal properties of the lovely honey that bees make. The healing properties of the sweet produce of our little friends seems to cure all ailments.
Today’s post, however, is not about honey.
No, today’s post is about the other thing bees are known for: their sting!
Earlier today a group of researchers in Paris (France), published the results of a clinical trial in which they gave bee venom to people with Parkinson’s disease for 11 months.
Title: Bee Venom for the Treatment of Parkinson Disease – A Randomized Controlled Clinical Trial.
Authors: Hartmann A, Müllner J, Meier N, Hesekamp H, van Meerbeeck P, Habert MO, Kas A, Tanguy ML, Mazmanian M, Oya H, Abuaf N, Gaouar H, Salhi S, Charbonnier-Beaupel F, Fievet MH, Galanaud D, Arguillere S, Roze E, Degos B, Grabli D, Lacomblez L, Hubsch C, Vidailhet M, Bonnet AM, Corvol JC, Schüpbach M.
Journal: PLoS One. 2016 Jul 12;11(7):e0158235.
PMID: 27403743 (This study is OPEN ACCESS if you would like to read it)
No! What? Bee Venom? Really?
Yeah, I know. Weird, right? But there is actually some logic to the idea.
Bee venom has recently become in vogue for all kinds of health associated products (eg. face masks, etc – click here for more on this), but preclinical experiments have also demonstrated that it can have beneficial effects in models of Parkinson’s disease.
Bee venom (or Apitoxin as it known to the science types) contains some interesting components, one of which is called Apamin.
Apamin. Source: Wikipedia
Apamin is the only component of bees venom that can pass through the blood-brain-barrier and enter into the brain. Once inside the brain, Apamin selectively blocks structures on the membrane of cells called ‘calcium channels’.
Calcium channels allow calcium (surprise) to enter a cell, and control many physiological functions including neurotransmitter release, muscle contraction and cell survival. It has already been demonstrated in models of Parkinson’s disease that Apamin has neuroprotective properties on the dopamine neurons in the brain:
Title: Bee venom and its component apamin as neuroprotective agents in a Parkinson disease mouse model.
Authors: Alvarez-Fischer D, Noelker C, Vulinović F, Grünewald A, Chevarin C, Klein C, Oertel WH, Hirsch EC, Michel PP, Hartmann A.
Journal: PLoS One. 2013 Apr 18;8(4):e61700.
PMID: 23637888 (this article is OPEN ACCESS if you would like to read it)
The researchers in this preclinical study demonstrated that bee venom was protective in models of Parkinson’s disease. When they tested Apamin alone, however, they found that it reproduced the protective effects only partially. They concluded that other components of bee venom must be enhancing the protective action of Apamin.
So what happened in the clinical trial?
The researchers in France conducted a randomized double-blind study (meaning that nobody – researchers included – knew who was getting the bee venom or the saline control solution). They took 40 people with early stage Parkinson disease (Hoehn & Yahr stages 1.5 to 3) and assigned them to either monthly bee venom injections or equivalent injections of saline.
After 11 months of monthly injections, the researchers found that bee venom did not significantly decrease the motor features of Parkinson’s disease (as judged by UPDRS III scores during ‘off’ condition). In addition, brain imaging (DAT-scan) did not differ significantly between treatment groups over the 11 months.
The researchers did, however, see improvements in some of the cognitive measures in subjects receiving the bee venom (albeit non-significant).
In their concluding remarks, the researchers questioned whether lack of significant effect was due to the low frequency of injections (once per month). Maybe the subjects in the trial were simply receiving too little of the treatment for it to have an effect. With the support of more preclinical experimental results, they propose that a larger study is warranted with a higher administration frequency and possibly higher individual doses of bee venom.
Will this happen?
It is unclear at present.
In the study, 4 subjects had immune system responses to the bee venom, so it may be wise to firstly establish what components of bee venom are having any beneficial effect before proceeding with further clinical trials.
The banner for today’s post was sourced from modern.scot