Today – 27th February, 2019 – the long-awaited results of the Phase II GDNF clinical trial were published.
GDNF (or glial cell line-derived neurotrophic factor) is a protein that our bodies naturally produce to nurture and support cells. Extensive preclinical research suggested that this protein was particularly supportive of dopamine neurons – a group of cells in the brain that are affected by Parkinson’s.
The results of the Phase II clinical trial suggest that the treatment was having an effect in the brain (based on imaging data), but the clinic-based methods of assessment indicated no significant effect between the treatment and placebo groups.
In today’s post we will look at what GDNF is, review the previous research on the protein, discuss the results of the latest study, and look at what happens next.
And be warned this is going to be a long post!
Boulder, Colorado. Source: Rps
It all began way back in 1991.
George H. W. Bush was half way into his presidency, a rock band called Nirvana released their second album (‘Nevermind’), Michael Jordan and the Chicago Bulls rolled over the LA Lakers to win the NBA championship, and Arnold Schwarzenegger’s ‘Terminator 2’ was the top grossing movie of the year.
But in the city of Boulder (Colorado), a discovery was being made that would change Parkinson’s research forever.
In 1991, Dr Leu-Fen Lin and Dr Frank Collins – both research scientists at a small biotech company called Synergen, isolated a protein that they called glial cell-derived neurotrophic factor, or GDNF.
And in 1993, they shared their discovery with the world in this publication:
Title: GDNF: a glial cell line-derived neurotrophic factor for midbrain dopaminergic neurons.
Authors: Lin LF, Doherty DH, Lile JD, Bektesh S, Collins F.
Journal: Science, 1993 May 21;260(5111):1130-2.
For the uninitiated among you, when future historians write the full history of Parkinson’s, there will be no greater saga than GDNF.
In fact, in the full history of medicine, there are few experimental treatments that people get more excited, divided, impassioned and evangelical than GDNF.
This ‘wonder drug’ has been on a rollercoaster ride of a journey.
What exactly is GDNF?
In previous posts, we have discussed some of the potential benefits of knowing your genetic status with regards to Parkinson’s. For example, knowing if you have a certain genetic risk factor could make eligible for taking part in a particular clinical trial.
There may, however, also be some benefits in NOT knowing your genetic status.
New research suggests that simply learning of a genetic risk can alter one’s physiology.
In today’s post, we will review the results of this new research and discuss what it could mean for the Parkinson’s community.
When I was a kid, I thought I was superman.
Then one of the adult figures in my life told me that I wasn’t.
And all of a sudden I lost my ability to fly.
Many years have gone by now, and its only recently that I’ve discovered that that person was actually wrong: I am Superman.
But curiously my powers of levitation have not (yet) returned…
The power of suggestion has always amazed me. Whether it is based on what others tell us, or on what we tell ourselves, it is truly wonderous the enormous impact some of the information we are given has on our lives. We seemingly get told something and quite often it is just accepted as gospel.
But as we take in that information, there can also be consequences (perceived or otherwise) resulting from that knowledge. And this can have important implications for us and how we interact with the world. In fact, some information that we absorb can affect our very physiology.
Can you give me an example?
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?
In October 2015, researchers from Georgetown University announced the results of a small clinical trial that got the Parkinson’s community very excited. The study involved a cancer drug called Nilotinib, and the results were rather spectacular.
What happened next, however, was a bizarre sequence of disagreements over exactly what should happen next and who should be taking the drug forward. This caused delays to subsequent clinical trials and confusion for the entire Parkinson’s community who were so keenly awaiting fresh news about the drug.
Earlier this year, Georgetown University announced their own follow up phase II clinical trial and this week a second phase II clinical trial funded by a group led by the Michael J Fox foundation was initiated.
In todays post we will look at what Nilotinib is, how it apparently works for Parkinson’s disease, what is planned with the new trial, and how it differs from the ongoing Georgetown Phase II trial.
The FDA. Source: Vaporb2b
This week the U.S. Food and Drug Administration (FDA) has given approval for a multi-centre, double-blind, randomised, placebo-controlled Phase IIa clinical trial to be conducted, testing the safety and tolerability of Nilotinib (Tasigna) in Parkinson’s disease.
This is exciting and welcomed news.
What is Nilotinib?
Nilotinib (pronounced ‘nil-ot-in-ib’ and also known by its brand name Tasigna) is a small-molecule tyrosine kinase inhibitor, that has been approved for the treatment of imatinib-resistant chronic myelogenous leukemia (CML).
What does any that mean?
Basically, it is the drug that is used to treat a type of blood cancer (leukemia) when the other drugs have failed. It was approved for treating this cancer by the FDA in 2007.
The contents of today’s post may not be appropriate for all readers. An illegal and potentially damaging drug is discussed. Please proceed with caution.
3,4-Methylenedioxymethamphetamine (or MDMA) is more commonly known as Ecstasy, ‘Molly’ or simply ‘E’. It is a controlled Class A, synthetic, psychoactive drug that was very popular with the New York and London club scene of the 1980-90s.
It is chemically similar to both stimulants and hallucinogens, producing a feeling of increased energy, pleasure, emotional warmth, but also distorted sensory perception.
Another curious effect of the drug: it has the ability to reduce dyskinesias – the involuntary movements associated with long-term Levodopa treatment.
In today’s post, we will (try not to get ourselves into trouble by) discussing the biology of MDMA, the research that has been done on it with regards to Parkinson’s disease, and what that may tell us about dyskinesias.
Good times. Source: Carwash
You may have heard this story before.
It is about a stuntman.
His name is Tim Lawrence, and in 1994 – at 34 years of age – he was diagnosed with Parkinson’s disease.
Tim Lawrence. Source: BBC
Following the diagnosis, Tim was placed on the standard treatment for Parkinson’s disease: Levodopa. But after just a few years of taking this treatment, he began to develop dyskinesias.
Dyskinesias are involuntary movements that can develop after regular long-term use of Levodopa. There are currently few clinically approved medications for treating this debilitating side effect of Levodopa treatment. I have previously discussed dyskinesias (Click here and here for more of an explanation about them).
As his dyskinesias progressively got worse, Tim was offered and turned down deep brain stimulation as a treatment option. But by 1997, Tim says that he spent most of his waking hours with “twitching, spasmodic, involuntary, sometimes violent movements of the body’s muscles, over which the brain has absolutely no control“.
And the dyskinesias continued to get worse…
…until one night while he was out at a night club, something amazing happened:
“Standing in the club with thumping music claiming the air, I was suddenly aware that I was totally still. I felt and looked completely normal. No big deal for you, perhaps, but, for me, it was a revelation” he said.
His dyskinesias had stopped.
According to our friends at Wikipedia:
A placebo (/pləˈsiboʊ/ plə-see-boh; Latin placēbō, “I shall please” from placeō, “I please”) is a simulated or otherwise medically ineffectual treatment for a disease or other medical condition intended to deceive the recipient. Sometimes patients given a placebo treatment will have a perceived or actual improvement in a medical condition, a phenomenon commonly called the placebo effect or placebo response.
In our previous post we wrote about cell transplantation and we cited the two double-blind clinical studies that found little positive effect resulting from the procedure.
In both of those studies, half the participants were given a sham surgery – that is, they were put into the surgery room, anesthetized, an incision was made in their scalps, but nothing was injected into their brains. They (and their assessing investigators) were not told if they were in the transplant group or the sham/control group and they were left in this ‘blind’ state for 12-18 months.
Time is a funny thing.
After a couple of weeks of wondering which group they were in and self assessing their abilities since the surgery, some of the individuals in those studies may have started to think that you are in one group or the other. This is a very human thing to do.
The effect is VERY strong. And it can mess with a clinical study in terrible ways.
In one of the double-blind clinical studies discussed in the last post (Freed et at, 2001), one of the patients had described herself as ‘not being physically active for several years’ before her surgery. Shortly after her surgery, she found that she was able to hike and ice skate again. A miraculous change in situations.
Twelve months after the surgery, however, she found out that she’d had been in the sham/control surgery group. Nothing had been injected into her brain. She had received NO treatment.
Her response was solely due to the placebo effect.
The Placebo effect in Parkinson’s disease
Early last year there was an interesting study conducted that looked at the placebo effect and Parkinson’s disease.
Title: Placebo effect of medication cost in Parkinson disease: a randomized double-blind study.
Author: Espay AJ, Norris MM, Eliassen JC, Dwivedi A, Smith MS, Banks C, Allendorfer JB, Lang AE, Fleck DE, Linke MJ, Szaflarski JP.
Journal: Neurology. 2015 Feb 24;84(8):794-802.
The investigators conducted a double-blind study involving 12 patients with moderate-severe Parkinson disease (average age of the subjects was 62.4 ± 7.9 years; and their average time since diagnosis was 11 ± 6 years). The study involved two visits to the clinic – the first visit involved a clinical assessment while the subjects were both ‘off’ and ‘on’ their standard medication. The assessment also involved a brain scan (fMRI). This was done to determine the magnitude of the dopaminergic benefit of their standard medication.
During the second visit, the subjects were told that they would be given two formulations – a “cheap” and “expensive” – of a “novel injectable dopamine agonist”. Both of these solutions were simply the same saline (medical salt water) solution. Four hours after being give the first injection, the subjects were given the other solution. In this manner, the subjects were exposed to both the ‘cheap’ and ‘expensive’ solutions. During visit 2, the subjects were clinically assessed and brain scanned 3 times, once before the first solution was injected, once after the first solution, and once after the second solution was given.
Below is a flowchart illustrating the structure study:
The results were interesting:
- Both of the placebos improved motor function when compared with the baseline (no medication state)
- The expensive placebo had more effect than the cheap placebo (remember: they were the same solution!)
- The benefits were greater when patients were randomized first to expensive placebo followed by the cheap.
- There was a significant difference in the level of improvement between the cheap and expensive placebos (UPDRS-III), with the expensive placebo giving better benefits
- Brain imaging demonstrated that activation was greater when the cheap placebo was given first.
The authors concluded that the “expensive placebo significantly improved motor function and decreased brain activation in a direction and magnitude comparable to, albeit less than, levodopa. Perceptions of cost are capable of altering the placebo response in clinical studies“.
The authors also wrote a summary of the debriefing that followed the study, where the subjects were informed about the true nature of the study. They told the subjects that rather than being injected with a novel dopamine agonist, they were simply given a saline solution – the same solution for both ‘cheap’ and ‘expensive’. They reported that “responses ranged from disbelief to amazement regarding changes experienced“. It must have been rather bewildering to have been told that the positive benefits you experienced were ‘all in your head’ and not based on any pharmacological effect.
While extremely unethical, we here at the SoPD can’t help but wonder about long this placebo effect could last. Would the difference between the cheap and expensive solutions still exist in 12 months time if the subjects were left blinded and continued to take them?
So how might this work?
We know that the placebo effect in Parkinson’s disease is controlled by the release of dopamine – one of the chemicals in the brain that is affected by Parkinson’s disease. Importantly, we know that it the endogenous dopamine that is causing the effect – that is the dopamine our brains are producing naturally as opposed to the L-dopa treatment.
The dopamine that helps to control our motor movements is also involved with positive anticipation, motivation, and response to novelty. Thus when the placebo solution was given to subjects in this study, they believed that they were receiving an active drug and demonstrated an “expectation of reward” response. And the more expensive solution simply heightened the expectation and positive anticipation, therefore increasing the amount of dopamine produced/released.
Given that dopamine is involved with both the features of Parkinson’s disease AND with the mechanisms of anticipation/expectation, you can begin to understand why the placebo effect is such an enormous problem for clinicians undertaking clinical trials.
It would be nice, however, to have a better understanding of the placebo effect and try to harness its positive benefits while also treating Parkinson’s with diseasing slowing/halting therapies.