Exenatide disappointment.

We learned ~3 weeks ago that the GLP-1 agonist exenatide failed to impact the disease in its Phase 3 clinical trial (EXENATIDE-PD3). It seems the details are being withheld until the full results are published in a medical journal, which could be months from now. Exenatide is a GLP-1 agonist, which is the kind of medicine increasingly used for weight loss (in addition to its benefits for diabetics and people with cardiac disease).

Let's review some of the reasons the community was so excited about the possible impact of exenatide on Parkinson's disease and then consider its failure in the context of the Right Brain Bio approach. I'll ask, should we be more or less optimistic about RB-190, or alternatively, if these are completely independent matters.

The hope.

In 2017, Foltynie and colleagues (publication here) published the results of a randomized, placebo-controlled, double-blind, Phase 2 clinical trial testing exenatide in 62 people with Parkinson's (moderate disease already on dopaminergic drug therapy). Therapy improved the motor examination after a year of weekly treatments.

Yes, my description of the primary finding of this trial does seem awkwardly written. What do I mean by the motor examination? In clinical trials and in clinical practice, the most common way to measure symptoms in PD is by using a questionnaire called the Unified Parkinson's Disease Rating Scale (UPDRS) (publication here). Part 3 of this scale is where the doctor grades the severity of the disease focusing on motor function. This is very much related to - but different from - how a person with Parkinson's feels. Part 2 of this scale is a series of questions the person with PD answers, reflecting the way they feel.

In this particular trial, the Parkinson's experts (who did not know which people were receiving exenatide and which placebo) used Part 3 of the UPDRS to conclude that exenatide significantly improved disease severity compared to placebo after a year of treatment. But those same patients reported their symptoms - how they felt and functioned using Part 2 of the UPDRS - was not different between the placebo and the exenatide treatment.

A trial can produce these kinds of different results between the doctors' and patients' views, and of course one would be more confident interpreting a study when both change in the same direction.

My initial sense of this trial was that it showed great promise. To determine whether this promise could be proven, bigger studies were planned.

The excitement.

Once adequate funding secured, a Phase 3 trial (publication here) was launched in 2019 in the UK to evaluated further the effect of exenatide over 2 years of treatment. The primary assessment is the physician rated effect of the drug (Part 3 of the UPDRS) with wide range of other measurements to provide additional insight into the effects and utility of exenatide.

In parallel, a Phase 2 clinical trial of lixisenatide (publication here) was launched in France in 2018 with the same primary assessment - Part 3 of the UPDRS.

As with the excitement about GLP-1 agonists for diabetes, cardiovascular risk and weight loss, there was palpable excitement about the potential benefits of these drugs for Parkinson's.

The disappointment.

Unfortunately, the trial with lixisenatide showed the dichotomy between how the doctors and the patients assessed the effect of the drug on movement. The doctors were convinced that patients did better on the drug, but the patients did not feel any difference between the drug and placebo.

About 3 weeks ago, top line results were disclosed for the Phase 3 study of exenatide and they were disappointing. The drug did not appear to benefit the people with PD in the study, neither by doctors' or their own assessments. We are still waiting for the full results to be reported, at which time we'll be much more sophisticated and rigorous with our assessments.

The implications.

Let's consider what we know about these GLP-1 agonist drugs. They do cross the blood-brain barrier, which means that when given by injection and absorbed into the body, they can get into the brain. We don't know fully what they do once they get to the brain but laboratory studies suggest that GLP-1 agonists could preserve mitochondria, dopaminergic neurons and enhance neurotransmission (publication here), which are each very important ways to reverse the disease. However, the results of these studies suggest that these drugs do more - and that one or more additional mechanisms could be causing adverse effects sufficient to "cancel out" these expected benefits.

From the literature it's hard to conclude with confidence what harmful mechanisms could be activated by GLP-1 agonists. One paper (publication here) that suggests GLP-1 stimulation could increase activity of tyrosine hydroxylase (which is the opposite effect to RB-190). With increased tyrosine hydroxylase activity more dopamine is synthesized, which would make GLP-1 agonists dopaminergic therapies akin to levodopa and dopamine agonists. This feels speculative to me until further data are published to confirm this finding. If that were proven to be the case, then it would make sense that these drugs improve UPDRS-Part 3 but do not affect the underlying disease. That's what other dopaminergic drugs do.

Hopefully the publication of final results from the Phase 3 trial of exenatide will provide the insight needed to determine whether there is hope for these agents - and if not, provide clues for other approaches. And perhaps we'll learn enough so that the disappointing results can be offset partially by the benefits of the knowledge gained. But that wouldn't fully address my frustration of another therapy failing to conquer the disease. And so I carry on; convinced PD can be conquered by RB-190.