Designing the clinical trial of RB-190

Based on feedback from Parkinson’s experts in Australia and the feedback from the meeting with scientific leadership at the Michael J. Fox Foundation, we’re carefully reviewing the clinical trial protocol. We’re reorganizing several sections to make them clearer. We’re beefing up the section on how the data will be analyzed. And we’re updating several sections to make them relevant to Australia (for example, we’re changing the listed drugs allowed and disallowed from those approved in the US to those approved in Australia).

There can be no idea, procedure or word that is not intentional. Instructions need to be written to eliminate misinterpretation. This process requires attention to all the details.

As I go through this process, which includes review of our data analysis plan, I am reminded about how many different factors need to be considered. Let me provide an example. I’ll warn you – this is going to get technical.

You may recall my dubious view of GLP-1 agonist drugs as treatment for Parkinson’s (the drugs developed to treat diabetes that are in the news as weight loss treatments).

It’s not that I disagree with the science that led people to study the effects of these drugs for Parkinson's, but rather, how the clinical trial data were interpreted. Phase 2 trials showed that the people enrolled in the study did not feel differently (this is based on the standard questionnaire study subjects complete in a clinical trial called the MDS-UPDRS-Part II), even though the doctors did see some improvement (MDS-UPDRS-Part III). That distinction is important because to use a drug, I believe it needs to improve how patients feel, lower their risk of complications or keep them alive longer. The MDS-UPDRS-Part III result represents none of those things. So I was not bullish on the therapy.

This weekend I was reading about GLP-1 agonists and learned that a consistent effect of these drugs is to slow the movement of food and drugs through the stomach and intestines. Slower transit in the intestines means that oral therapies could be absorbed slower and perhaps have more absorbed. This effect on digestion would change how levodopa is absorbed. Brain levels of levodopa - and therefore dopamine - could have lower peaks and it could take longer before the levels drop off. This could result in less side effects and not as much wearing off of the effects of the drug, both of which would be good outcomes.

While much is written about the potential benefits of GLP-1 agonists in the brain, perhaps the improvement in questionnaire scores measured during off time is a reflection of this delayed/prolonged absorption of oral levodopa caused by GLP-1 agonists slowing its movement through the stomach and intestines.

I reviewed the publication of one study's protocol (for Exenatide-PD3). It does not record food intake amount, composition or timing. The study design does not seem to include measurement of blood levels of levodopa to see if the study drug does affect levodopa as I conjecture here. If I were to get involved with a new trial of a GLP-1 agonist in Parkinson’s, I’d want to be sure it collected such information or alternatively, require subcutaneously administered levodopa instead of oral administration, which would eliminate any possible interaction between the GLP-1 agonist and levodopa.

(I realize that study design papers such as this one are not as complete as the entire study protocol, so the study could have guided investigators to consider this viewpoint. But if so, it would make sense to report about it when reporting the trial results.)

With this diversion complete, I am heading back to the details of the RB-190 trial protocol so we can continue preparing our resubmission to the Fox Foundation and to share with colleagues in Australia prior to submitting it for permission to launch the trial.