August brought some welcome news for the Parkinson’s community: results from a Phase 2 clinical trial suggested the diabetes drug exenatide halted the worsening of motor problems in people in moderate stages of the disease. As reported in the Lancet on August 3, motor symptoms slightly improved in those taking the drug for nearly a year, while the placebo group declined. Notably, a portion of the benefits of exenatide, aka Bydureon, persisted for 12 weeks after participants had stopped taking the drug. The results come with caveats–as the trial included only 62 patients, all from a single center. Some commentators were not convinced the results point to modification of the disease, as patients had the greatest motor improvements at the beginning of the trial. However, even as the authors and commentators stressed that the findings must be replicated in larger trials, optimism was in the air. Thomas Foltynie of University College London headed the trial.
“I think it is an exciting new era in PD treatment,” commented Ted Dawson of John Hopkins University School of Medicine in Baltimore. “Naturally the trial needs to be replicated in a larger cohort of de-novo patients. This should prime the pump for development of this class of drugs for the treatment of PD and related neurodegenerative disease.”
Nigel Greig of the National Institutes of Health in Bethesda, a co-author on the paper, called the findings highly promising. “This approved type 2 diabetes mellitus drug holds potential to impact the course of the disease itself, and not merely the symptoms of PD,” he wrote to Alzforum.
Telling Slopes? Motor scores worsened (increased) in the placebo group (red), and slightly improved in the exenatide group (blue), whose scores were worse at baseline. Left shows absolute scores, right shows change. [Courtesy of Athauda et al., The Lancet, 2017].
Paul Aisen of the University of Southern California in San Diego did not think the data support a disease modifying mechanism. “In general, the results look typical for symptomatic therapy: rapid improvement followed by a trajectory that parallels the placebo curve,” he wrote to Alzforum. “A larger study with a longer wash-out period and a pre-defined delayed start analysis plan would be necessary to address the question of disease-modification.”
As a glucagon-like peptide-1 (GLP-1) receptor agonist, exenatide triggers insulin secretion and boosts glucose metabolism. The drug and others in its class are approved for diabetes treatment, but have also assembled a portfolio of neuroprotective benefits in experimental models (for review, see Li et al., 2016). Among them, GLP-1 receptor agonists boost neurogenesis, quell neuroinflammation, and protect dopaminergic neurons from damage inflicted by mitochondrial toxins in animal models of PD (Bertilson et al., 2008 , Cao et al., 2016, and Jan 2009 news). This preclinical data motivated researchers to test exenatide in a small, open-label study beginning in 2010. Motor symptoms improved in people with moderate PD who took the drug for a year. This continued two months after exenatide treatment stopped, while patients who took only L-Dopa continued to decline (Jun 2013 news ). This proof-of-concept trial lacked a proper placebo group, which the researchers rectified with the current randomized, double-blind, placebo-controlled trial.
First author Dilan Athauda and colleagues conducted the trial at the Leonard Wolfson Experimental Neuroscience Center at University College London. All of the 62 patients had been on dopaminergic treatment, and were starting to experience wearing-off effects of the therapy. Protocol algorithms randomized the volunteers 1:1 to take placebo or 2 mg exenatide, which was self-administered via subcutaneous injection once weekly for 48 weeks. A 12-week wash-out period, without treatment, followed.
The trial’s primary outcome was a change in scores on part 3 of the Movement Disorders Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) at 60 weeks, following the 12 week wash-out. Measurements for this outcome—which were taken every 12 weeks in addition to baseline and 60 weeks—were recorded in the early morning in the “off-medication state,” when patients had not taken their dopaminergic therapy for at least eight hours. Part 3 of the MDS-UPDRS tests motor symptoms, such as tremor, bradykinesia, and gait disturbances. In addition, the researchers measured a number of secondary outcomes, including cognition, quality of life, and mood, when patients were on their normal medications. The researchers also conducted several exploratory measurements, including DaTscan PET to assess dopamine transporter activity, and timed motor tests conducted in both on- and off-medication states. They measured concentrations of the drug in blood and urine every 12 weeks, and checked cerebrospinal fluid for exenatide at 12 and 48 weeks.
Randomization of small trials can produce unbalanced groups by chance, and that was indeed the case with this one. Compared to the 30 participants assigned to the placebo group, the 32 patients randomized to take exenatide were on average four years older, had higher MDS-UPDRS part 3 scores at baseline, and were taking lower doses of dopaminergic treatment. In this scale, higher scores mean worse motor function.
At 48 weeks, off-medication scores in MDS-UPDRS part 3 had worsened by 1.7 points in the placebo group, while participants taking exenatide had improved by 2.3 points compared to baseline. At 60 weeks, the placebo group had declined by 2.1 points, while volunteers taking exenatide maintained an improvement of 1 point better than baseline. Therefore, while the placebo group steadily declined throughout the course of the trial, the exenatide group got better, and maintained a portion of that benefit even after 12 weeks without the drug. While the exenatide group outperformed their baseline scores at 60 weeks, their scores did slip after stopping treatment.
Notably, in keeping with the worse baseline motor performance in the exenatide group, the placebo group outperformed the treatment group throughout the trial. Athauda emphasized to Alzforum that a change in scores, rather than a difference in absolute scores between groups, was the predefined primary outcome measure. Other commentators agreed that the worse average scores in the treatment group did not detract from the study’s main finding: that motor scores actually improved in people taking exenatide.
“Changing the slope of that curve is the holy grail of PD research,” commented Patrik Brundin of the Van Andel Institute in Grand Rapids, Michigan. He added that because both the exenatide and placebo groups started the trial 6.4 years after their PD diagnosis, the poorer baseline motor scores of the exenatide group suggest they had a more rapidly progressing disease. This makes their improvement all the more impressive and convincing, he said.
Though participants taking exenatide clocked a net improvement in motor scores between baseline and 60 weeks, most of the gain occurred during the first twelve weeks, and waned as the trial went on. Brundin speculated that acute pharmacological effects, such as enhanced dopamine production, could be responsible for this initial burst of improvement. He added that other effects of the drug, such as neuronal repair, neuroprotection, and quenching damaging neuroinflammation, may exert benefits more gradually.
According to Christian Hölscher of Lancaster University in England, the finding that exenatide’s benefits outlasted the 12-week washout period suggests the trial achieved the ultimate of outcomes: disease modification. “This is proof that exenatide makes a long-term impact, as opposed to just patching up symptoms,” he told Alzforum. “We’ve finally struck gold.”
Not everyone was convinced. Suzanne Craft of Wake Forest School of Medicine in Winston-Salem, North Carolina, took a more cautious tone, pointing out that motor scores started to deteriorate after treatment stopped. “A longer follow-up period would be helpful in determining whether there is a rebound effect, or whether there is truly some persistent benefit to exenatide treatment that might support a disease modifying mechanism,” she wrote to Alzforum.
David Standaert of the University of Alabama at Birmingham felt there could be other explanations as well. “While the improvement in ‘off-medication’ state could be a disease-modifying effect, it could also be a long-lasting symptomatic effect, or an effect on the pharmacodynamics of the other medications.”
The authors themselves were also conservative in their interpretation of the results. “It might be tempting to view persistent benefits detectable after the washout period as evidence of disease modification,” they wrote in the paper’s discussion. However, they noted that 12 weeks may have been insufficient time to eliminate unexpected long-lasting symptomatic effects. For example, symptomatic relief may promote participants to take up or maintain healthy behaviors such as exercise, which could have long-term benefits.
Despite improvements on the MDS-UPDRS part 3, no significant changes on secondary outcome measures were noted, including quality of life. This is not entirely surprising, Brundin said, given the short duration of the trial, small motor improvements, and relatively moderate symptoms the participants started out with. He and Hölscher speculated that more noticeable benefits could emerge in longer trials.
Exenatide also did not boost motor performance in participants while they were under the influence of dopaminergic treatment. The failure of this exploratory measure indicates that exenatide only effects symptoms when participants are in an “artificial state,” namely when they are not taking their usual medications, Standaert pointed out.
As another exploratory outcome, the researchers measured dopamine transporter activity via DaTscan at baseline and 60 weeks. They found that while activity in dopaminergic regions declined in both groups, it did significantly less so in the exenatide group. In a separate commentary co-authored with Brundin and Richard Wyse of Cure Parkinson’s Trust in London, the authors cautioned against over interpretation of these imaging results, pointing out that they were not adjusted for multiple comparisons (Athauda et al., 2017).
Exenatide seemed well-tolerated. Adverse events—including gastrointestinal symptoms, weight loss, nausea, and loss of appetite—occurred with similar frequency in the treatment and placebo groups. People in the exenatide group lost more weight on average than those in the placebo group, but the researchers observed no significant correlation between the degree of weight loss and primary outcome. Of the eight serious adverse events that occurred throughout the trial, six were in the exenatide group, though the authors state that none were considered related to treatment. One person had to discontinue exenatide due to elevation in the pancreatic enzyme amylase at 12 weeks. Hyperamylasemia has been documented in diabetics taking the drug, but caused no symptoms in the patient in this trial.
Regardless of their interpretation of the results, all authors and commentators Alzforum consulted called for a longer, multi-center Phase 3 trial of the drug in PD patients. The source of funding for such an expensive trial is up uncertain, especially given that AstraZeneca’s patent on exenatide recently expired. The Michael J Fox Foundation sponsored the present trial. Because this drug and others in its class are already approved for diabetes treatment, it is possible that some doctors could prescribe them off-label to people with PD. However, Brundin and other commentators emphasized that most physicians would be appropriately unwilling to do so without further proof of the drug’s effects on the disease.
Standaert, a clinician, agreed, pointing to the need for larger trials. “Outside of a clinical trial, I would not recommend treatment with exenatide to any of my patients with PD at this time. The benefits are uncertain at best, and there are clearly risks of therapy.” – Jessica Shugart
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- Li Y, Li L, Hölscher C. Incretin-based therapy for type 2 diabetes mellitus is promising for treating neurodegenerative diseases.Rev Neurosci. 2016 Oct 1;27(7):689-711. PubMed.
- Bertilsson G, Patrone C, Zachrisson O, Andersson A, Dannaeus K, Heidrich J, Kortesmaa J, Mercer A, Nielsen E, Rönnholm H, Wikström L. Peptide hormone exendin-4 stimulates subventricular zone neurogenesis in the adult rodent brain and induces recovery in an animal model of Parkinson’s disease. J Neurosci Res. 2008 Feb 1;86(2):326-38. PubMed.
- Cao L, Li D, Feng P, Li L, Xue GF, Li G, Hölscher C. A novel dual GLP-1 and GIP incretin receptor agonist is neuroprotective in a mouse model of Parkinson’s disease by reducing chronic inflammation in the brain. Neuroreport. 2016 Apr 13;27(6):384-91. PubMed.
- Athauda D, Wyse R, Brundin P, Foltynie T. Is Exenatide a Treatment for Parkinson’s Disease?. J Parkinsons Dis. 2017;7(3):451-458. PubMed.