Analyzing the effects of a new drug

Recently I shared excitement about tavapadon, a new dopamine agonist expected to be FDA approved in the coming months.

The data are strong; the drug improves symptoms and function, as assessed by the standard outcome measure called the MDS-UPDRS (this is the movement disorders society's modified unified Parkinson's disease rating scale).

MDS-UPDRS

The MDS-UPDRS consists of four parts that look at the disease in different but complementary ways. Part I focuses on non-motor disease manifestations, such as cognition and mood. Part II reflects the patient's view of their physical/motor function. Part III is a physical/motor evaluation by a physician. Part IV evaluates motor complications associated with the disease, which includes complications associated with disease treatments. These are four important ways to evaluate the clinical state or how severely affected a person is by the disease.

In many of the Parkinson's disease clinical trials, the studies focused primarily on a combination score, either the total of all parts of the UPDRS or a combination of Parts II and III, with the former exemplified by the landmark ELLDOPA trial published in 2004 and the latter used as an outcome measure in the TEMPO trials that evaluated tavapadon (and which are the basis for my enthusiasm about that drug).

I don't want to get deep into statistics, but the use of these combined scores bothers me, as it feels as if the data are undergoing some sort of amplification rather than being evaluated directly.

Adding two assessments makes sense when they are complementary. Looking at the questions in each section suggests to me that they feature enough redundancy that they should not be combined. I recognize the argument that because the answers are provided from complementary points of view they can be added. But I'm not convinced.

The two parts directly overlap in assessing speech, tremor, arising from seated position, walking/balance and freezing. Hard to argue these are not important aspects of the disease.

I recognize the argument that the questions are worded to provide complementary responses. Consider the need to assess freezing. The MDS-UPDRS Part II measure of freezing could be very abnormal based on a patient's experiences in crowded spaces while Part III's assessment during a brief walk in a corridor could seem near normal.

There are other areas that may seem to be different, but I believe they are the same. For example, Part II asks about handwriting as a common example of fine motor function whereas Part III assesses fine motor function by the physician directly observing the patient tap their fingers together.

Wether you agree or not that these are complementary or redundant, wouldn't you be more excited about a treatment that improves function from both perspectives?

Recall the trials with GLP-1 agonists in Parkinson's. The Phase 2 trials showed improvement on Part III and no effect on Part II. I would be more excited by both improving - because successful drugs should show improvement from both points of view. (Note that I am neither endorsing or dismissing the usefulness of the MDS-UPDRS as a tool to evaluate new therapies.)

The FDA has not published their view on combining or separating these two parts of the MDS-UPDRS. Both approaches have been reported in clinical trials. But across diseases, the FDA prioritizes evaluating a drug based on the patient's perspective of its effects rather than the physician's perspective, so reporting Part II separately makes sense.

Relevance to RB-190 and Right Brain Bio?

We completed a (near-final) review of the clinical trial protocol that we will submit to the Australian authorities as we seek permission to conduct the trial. In it, we will measure the MDS-UPDRS. And we plan to report Part II and Part III separately.

In addition, we will focus on direct measures of motor function, including tests that assess fine motor function and integrated function (movement speed + movement precision + balance + freezing). We discussed with the FDA how these direct measures are meaningful reflections of how people with Parkinson's function, which means they could serve as the primary measure to determine success or failure of RB-190.

But those questions are ones that become more important later. For now, we are focused on launching and conducting this trial - starting with our upcoming application to perform the trial - that we expect to demonstrate that people with Parkinson's can tolerate dopamine reduction. Showing this will mean that the disease is not a disease of dopamine deficiency and provide our first clinical proof of concept for RB-190 as a viable Parkinson's treatment (subject to proving so in later clinical trials).