Exenatide? Again?

Despite great hope, a Phase 3 trial showed that exenatide (a GLP-1 agonist, a.k.a. Byetta and Bydureon) did not make a difference for people with Parkinson’s. The disappointment followed intriguing results in Phase 2, which showed some hope. However, as I discussed previously the results in Phase 2 were hardly clear cut yet were enough to justify the major investment in the performance of this Phase 3 trial.

Last week a new issue arose. A regulatory inspection by the UK’s MHRA reported worrisome problems at King’s College Hospital, one of 5 sites that conducted this Phase 3 trial of exenatide. On June 27, The Lancet – where the study results were published – issued an “Expression of Concern” to alert readers before the results of that original publication were accepted as published. The Lancet’s statement:

“On Feb 4, 2025, The Lancet published an Article by Nirosen Vijiaratnam and colleagues,1 which reported the efficacy and safety of exenatide once weekly as a potential disease-modifying treatment for people with Parkinson's disease in the UK.1 On May 18, 2026, The Lancet was made aware of the findings from a regulatory inspection at King's College Hospital NHS Foundation Trust, one of the clinical trial sites involved in this study, by the corresponding author of the trial. The inspection formed part of a broader review and identified department-wide concerns relating to trial conduct, oversight, and governance, including findings classified by regulators as critical and major.

“We have asked the institution of the corresponding author for an investigation into the trial. While we are awaiting the outcome of this investigation and assessments regarding the potential impact of these inspection findings on the study data and reported conclusions, we are issuing this Expression of Concern. We will update this notice as soon as we have further information.”

The media have started to report on this [here, here and here].

What are the implications of an Expression of Concern?

Consider The Lancet’s track record for Expressions of Concern (EoC). Since 2005, it has posted 13 EoCs. I’ll put aside the publications for a food supplement and a dietary treatment, leaving 11 focused on medical products. One of the 11 relates to this exenatide study and another was issued in February 2026 – for which an investigation is ongoing. Out of the other nine, eight have been retracted – meaning that the results are not reliable due to error or malfeasance. In general, The Lancet’s publication of an EoC precedes a retraction– which is the most severe penalty a Journal can render.

What would it mean if these major problems were restricted to this one site at King’s College (out of 5 sites participating in this trial)? Even if these problems were only at one site it remains a major problem. The group overseeing a trial is required to have systems in place to be certain that no sites behave improperly. And any problems should be detected and managed immediately – not a year after the study is published, as is the case here.

One could hope that analysis of the data from the four sites that conducted the trial properly could show that exenatide is beneficial. While that would be outstanding news, I believe that is extremely unlikely for several reasons. First, all the analyses of this Phase 3 trial show the same thing; the drug does not offer benefit. Second, the problems were reported in a site that contributed a relatively small amount of data relative to the other sites When studies are published, the order of the authors is typically tied to how much that site enrolled. The investigators that enroll the most people into the trial are listed first. In this authorship, the King’s College investigators were the 5^th listed of the 5 sites. Third, the database for the trial is in possession of the lead investigators and shared with the Critical Path for Parkinson’s. Both would likely have repeated the analyses without the data from the 5^th site and reported benefit if it were there. They are both silent.

The EoC is a problem; such errors in clinical trial execution and oversight are unacceptable. For the study organizers and those working at King’s College, it is irresponsible and unprofessional. It cannot be tolerated and so far, The Lancet is taking this very seriously. Hopefully the institutions involved will as well.

What can you learn if you are considering a trial?

Start by asking the investigator whether they or the site has undergone a regulatory inspection. If so, ask if there are any findings and for them to provide you with the report of the inspection. Reports are issued if any worrisome issues are identified and are a big deal. And if there are problems and they are not fully addressed promptly, it may be worth visiting a different site with different investigators before enrolling in a trial.

As an investigator, I was taught to hire an auditor to be certain my team was performing at the highest level, compliant with law and regulations. This is not required, but if a site does this then it would seem more credible to me.

My expectations?

This publication may not be retracted. The paper shows that exenatide is neither beneficial nor risky for people with Parkinson’s. That’s likely to be the same conclusion after data are eliminated from the analysis.

The industry standard is to retract when the errors or malfeasance “… compromise the reliability of the findings.” If the findings don’t change, then the EoC may be as far as this goes.

And the investigators? It’s not possible to have an opinion without access to the full reports and the responses by the investigators, their employers and those with study oversight. The failings of these individuals must be addressed and disclosed publicly to patients and the medical community. Only with such transparency do the clinical trial and medical systems maintain credibility.