Reactions to phase 2 clinical trial testing an oral antidiabetic as a treatment for Parkinson's disease

A phase 2 clinical trial in France has examined whether taking an oral anti-diabetic drug called lixisenatide - a GLP1 receptor analogue, similar to those also used for weight loss - also has an effect on the progression of Parkinson's disease. The results indicate that there is a modest but significant decrease in the progression of motor symptoms of the disease, although side effects were also observed. The results are published in the journal NEJM

03/04/2024 - 23:00 CEST
Expert reactions

José Luis Lanciego - ensayo párkinson EN

José Luis Lanciego

Senior Researcher of the Gene Therapy in Neurodegenerative Diseases Programme at the Centre for Applied Medical Research (CIMA), University of Navarra

Science Media Centre Spain

A study by French neurologists has evaluated the efficacy of a drug commonly used in the treatment of type 2 diabetes mellitus to control blood glucose levels as a potential treatment for Parkinson's disease. It is a double-blind clinical trial with lixisenatide, a GLP-1 receptor agonist drug (trade name Lyxumia). It is a 're-use' trial, i.e. a drug already approved for the treatment of another indication (type 2 diabetes mellitus) is tested for a specific disease (Parkinson's in this case), so that this type of trial already has a high level of safety from the outset. 

A total of 178 patients diagnosed with Parkinson's less than three years ago were recruited for this study and randomly assigned to either the control or placebo group. The doses of lixisenatide used were the usual doses for the treatment of diabetes, starting with an initial dose of 10 micrograms for 14 days and continuing with a maintenance dose of 20 micrograms for 12 months. The drug is self-administered by a pen injected subcutaneously into the thigh, abdomen or upper arm (the injection site is not reported in the article). 

The aim is to find out whether the administration of lixisenatide slows the progression of Parkinson's disease by comparing the scores obtained on clinical scales between the treated group and the control group. The most relevant finding is that at 12 months of treatment, the score on the motor scales is 3 points lower in the treated patients compared to the patients in the placebo group. The clinical scale used is the MDS-UPDRS III, where the higher the score, the greater the severity. 

Although the 3-point improvement is unremarkable, it is statistically significant. However, it is necessary to consider whether this improvement is of sufficient clinical benefit, as there are several side effects such as nausea, vomiting and gastro-oesophageal reflux (present in 46%, 13% and 8% of patients treated with the drug, respectively), gastrointestinal side effects commonly reported in identically treated diabetic patients. Note that side effects were considered unacceptable in approximately one-third of lixisenatide-treated patients, necessitating a reduction of their maintenance medication (20 micrograms) to the starting dose (10 micrograms). 

Among the limitations of the study, it should be noted that all patients were treated with various types of antiparkinsonian medication during the clinical trial, so it is difficult to assess whether the modest benefit obtained with lixisenatide is due to that drug or to the antiparkinsonian medication itself. It is also necessary to take into account that the follow-up time is too short (12 months) to properly assess whether or not lixisenatide has a long-term effect. Furthermore, only the dosing regimen recommended for the treatment of diabetes mellitus was used, without considering other dosing regimens. 

In conclusion, and as the authors themselves acknowledge, clinical trials with a larger number of patients and over a longer period of time will be necessary to properly determine the efficacy and safety of this potential re-use treatment for Parkinsonian patients. 

The author has declared they have no conflicts of interest

Michele Matarazzo - ensayo párkinson

Michele Matarazzo

Neurologist specialising in Parkinson's disease at the Comprehensive Neuroscience Centre HM Cinac

Science Media Centre Spain

This is a randomised, double-blind, placebo-controlled phase II clinical trial to demonstrate the neuroprotective effect of an anti-diabetic drug in Parkinson's disease. The drug in question, lixisenatide, is a GLP1 receptor agonist, used as an anti-diabetic, which has demonstrated a neuroprotective effect in preclinical models of the disease. In addition, other molecules of the same family have already been studied with the same objective, with dubious results. The study is well designed and with a sufficient patient sample to support the results and conclusions. In addition, the follow-up time is reasonable (up to one year) and the compliance rate is very high, which adds to the robustness of the study. 

Although we have very effective symptomatic treatments for Parkinson's disease, there is currently no drug that has demonstrated a net reduction in progression. Finding a molecule that can slow the progression of the disease is a major goal of research in Parkinson's disease and other neurodegenerative diseases, and this preliminary evidence provides hope for a drug that can slow the disease. This not only has a direct clinical impact (which is in fact slight), but, if the results are confirmed, it would point the way to a promising therapeutic target for further research into an effective therapy. 

There are some important limitations: 

  1. Patients were already receiving medication at the time of recruitment, and this may have some impact on the results. However, given that patients at that stage of the disease would need to be started on medication during follow-up, it is reasonable that already treated patients were included. 
  2. The main outcome assessments of the trial have been done at the so-called on stage, i.e. when the symptomatic medication previously taken by the patient is taking effect. Again, this complicates interpretation, but it is also a measure that has allowed for greater uniformity of assessments. 
  3. The trial shows a small but significant effect on the motor symptoms of the disease, but no change in the so-called non-motor symptoms (such as depression, anxiety, apathy, sleep disturbance...), which, a priori, should improve in the same way as motor symptoms, although in an early diagnosis population such as the trial it is possible that patients had so few non-motor symptoms that it was very difficult to detect a change (because of the so-called 'floor effect'). 
  4. The trial bases all its results on a clinical scale which, although the most widely used in Parkinson's disease progression, has certain limitations. Among them, there is some inter-observer variability, it does not take much account of the patient's point of view and it is not based on objective quantifiable data. Today we have objective means that can support clinical assessments, either at the neuroimaging level, or at the level of biological markers or objective motor quantification that eliminate the subjectivity of the scales. 
  5. Potentially drug-related adverse effects were more frequent in the treated group than in the placebo group. Beyond the possible implications for drug tolerability, the mere presence of these effects may have produced an unblinding bias (by presenting these adverse effects, patients are more likely to believe they are taking the drug and not the placebo, reducing the value of the double-blind and placebo comparison). 
  6. Finally, the trial shows a possible neuroprotective effect on disease progression, which would be a major revolution in the treatment of Parkinson's disease. This possible conclusion still needs to be confirmed at least (i) in another international multicentre phase III trial with a larger number of patients and (ii) after excluding more strongly that the observed effects are not due to a symptomatic impact (improvement of symptoms and not of the underlying disease), especially considering that some studies suggest that this molecule can increase dopamine levels. 
The author has not responded to our request to declare conflicts of interest
Trial of Lixisenatide in Early Parkinson’s Disease
  • Research article
  • Peer reviewed
  • Clinical trial
  • People
New England Journal of Medicine
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Meissner et al.

Study types:
  • Research article
  • Peer reviewed
  • Clinical trial
  • People
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