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 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.
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.