Diabetes Drug Shows Promise in Parkinson's

Pauline Anderson

May 23, 2013

A diabetes drug looks promising for patients with Parkinson's disease (PD), according to results of a small, proof-of-concept study.

The new data showed that exenatide (Byetta, Amylin Pharmaceuticals Inc), a synthetic version of an agent in the saliva of the Gila monster (a lizard found in the Arizona desert), is tolerable and has beneficial clinical effects when added to standard PD treatments.

"We found there was a clear trend of worsening in our control group of patients who didn't get the drug, and a clear trend of improvement in the patients who were given the drug," said study author Thomas Foltynie, MRCP, PhD, Sobell Department of Motor Neurosciences, University College London Institute of Neurology, United Kingdom.

The results are enough to encourage investment in a larger randomized, placebo-controlled trial, said Dr. Foltynie. "Since we got our data, we have had discussions with both the commercial sector and some major PD research funders who are very interested in funding this and hopefully, there will be further news about this soon."

The study was published online May 20 in The Journal of Clinical Investigation.

Established Parkinson's

The synthetic version of an agonist for the glucagon-like peptide-1 (GLP-1) receptor, exenatide was approved by the US Food and Drug Administration for type 2 diabetes in 2006, and is now used by about 6 million people with diabetes around the world. The drug is also being studied in obesity.

Dr. Thomas Foltynie

The current analysis, the first of the drug in patients with PD, included 44 participants aged 45 to 70 years with PD symptoms lasting at least 5 years and receiving stable PD medication regimens. They had moderate PD with an "off-medication" Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part 3 score of greater than 15 points and at least 33% improvement in response to levodopa.

"If you recruit early PD cases, such a small study will almost certainly be contaminated by patients with essential tremor or atypical forms of Parkinson's, so we wanted to make sure that subjects had established, definite concrete Parkinson's," commented Dr. Foltynie.

The patients were randomly assigned to a control group that continued to receive conventional PD treatment (n=24) or to a group that continued these treatment but were also taught to self-administer twice-daily injections of exenatide (5 µg; n=20).

Using videotaped recordings, blinded investigators evaluated the patients off medication at baseline, 6 months, and 12 months and then after a 2-month washout period.

Mean Improvement

At 12 months, patients in the exenatide group had a mean improvement of 2.7 points on the MDS-UPDRS part 3, and controls had a mean decline of 2.2 points, for a difference of 4.9 points (95% confidence interval [CI], 0.3 - 9.4; P = .037). After the 2-month washout, the exenatide group had a mean improvement of 1.7 points and the controls a mean decline of 2.8 points, for a difference of 4.4 points (95% CI, 0.2 - 8.7; P = .042).

Adding open-label ratings of rigidity scores resulted in an improvement of 1.8 points in the treatment group at 12 months compared with a decline of 5.3 points in the control group (difference, 7.0 points; 95% CI, 1.8 - 12.2; P = .009) and an improvement of 0.8 point in the exenatide group at 14 months compared with a decline of 6.4 points in the control group (difference, 7.2 points; 95% CI, 2.1 - 12.2; P = .006).

"We noticed that there were small but sustained improvements in things like finger tapping, hand tapping, foot tapping, and the tremor and rigidity of PD" in patients receiving the drug, said Dr. Foltynie.

An analysis of MDS-UPDRS part 3 scores of patients receiving medication showed a difference that favored patients treated with exenatide compared with the control group.

As well, the treatment group had improvements at 12 and 14 months on the Mattis dementia rating scale-2. After the washout, there was a mean improvement of 2.8 points in the treatment group, while those in the control group deteriorated by a mean of 3.5 points (difference, 6.3 points; 95% CI, 2.7 - 9.9; P = .001).

Quality of Life

As measured on the Parkinson's Disease Questionnaire 39, overall quality-of-life scores didn't change, but this could be because the measurements were taken when the levodopa wore off. "The 'off' periods where the underlying PD is exposed are a minor part of the patients' day-to-day experience, but is a useful way of measuring underlying Parkinson," said Dr. Foltynie.

At baseline, conventional PD treatments did not differ between groups, but at the end of 1 year, the control group was taking about 150 mg more levodopa than the exenatide group, said Dr. Foltynie.

Weight loss was a concern in the study. There was a mean 3-kg weight loss across the exenatide group, and 2 of these patients had to have their exenatide dose reduced. One of these patients actually withdrew from the study because of excessive weight loss.

A substudy used DaTscans to evaluate dopamine in the brain of 10 exenatide recipients at baseline and 1 year. That analysis showed that all 10 patients began the study with profoundly abnormal scans, with some variation in the severity of presynaptic dopaminergic deficit. At 12 months, mean values for absolute and percentage changes in activity showed minimal change in all basal ganglia subregions.

"You would expect in PD that there would be a slow and steady decline, and we found no difference," said Dr. Foltynie.

Two of these scanned patients actually improved, which is not typically seen in PD and is encouraging, said Dr. Foltynie. However, he added, this finding can't be interpreted as showing that the drug has an advantage because the control group didn't get the same scans (as a result of funding limitations).

This result wasn't included in the published study because the authors didn't want to overemphasize it, as it was just 2 patients, but it shows that these scans could be useful in a larger study measuring outcomes, said Dr. Foltynie.

Multiple Effects

Exenatide seems to have multiple effects. It affects insulin release "in a glucose level–dependent fashion," in that it reduces higher glucose to normal but doesn't reduce normal glucose to low, said Dr. Foltynie. As well, the drug affects glucagon release, affects appetite and satiety, and slows stomach emptying, he said.

GLP-1 receptors have been identified throughout the brain, which suggests neurotrophic and neuroprotective effects. Exenatide is also being studied in Alzheimer's disease, as well as other conditions.

The current study marks a step toward sparking interest in more in-depth research. "We have shown a way of getting some data that can help reassure the commercial sector and the major Parkinson's funders," said Dr. Foltynie.

A larger, randomized, double-blind trial will probably use a new slow-release version of exenatide that needs to be injected only once a week instead of twice daily. This version, said Dr. Foltynie, could be better tolerated and improve adherence.

Innovative Approach

In a Commentary accompanying the publication, Roger A. Barker, MBBS, PhD, University of Cambridge, United Kingdom; Mark A. Stacy, MD, Duke University, Durham, North Carolina; and Patrik Brundin, MD, Van Andel Institute, Grand Rapids, Michigan, point out that translating new findings from the laboratory into patient therapies "is a slow and expensive process."

Such development in the field of neurodegenerative diseases is further complicated by the difficulty in determining whether the drug actually slows the degenerative process or just relieves symptoms, they write.

"In this issue, Aviles-Olmos et al describe a first in Parkinson's disease (PD) patient study using a drug previously approved for diabetes treatment. In addition to suggesting that the drug may indeed be disease modifying in PD, their innovative approach suggests there may be more rapid and inexpensive avenues for testing novel therapies in PD," they conclude.

The study was funded by the Cure Parkinson's Trust. The authors have disclosed no relevant financial relationships.

J Clin Invest. Published online May 20, 2013. Abstract Commentary


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