Project Update (the importance of small steps)

Developing a drug is a big undertaking. And I knew that when I started (in early 20218) based on my experience helping others including from within companies and working at the FDA, first as a member of multiple advisory committees and the serving in a senior role within the FDA.

But even though I knew how hard it would be, I had no idea how hard it would be.

Fortunately I've developed so many friendships and work relationships over the years upon whom I can depend for subject matter expertise as much as emotional/intellectual support.

Typically I wake up in the morning excited for the tasks ahead. It's an amazing feeling to believe you have an opportunity to conquer a disease (and yes, reading that I wrote that feels uncomfortable - a bit self-aggrandizing - but it is how I feel).

I learned years ago, before my focus on Parkinson's, that big challenges are the right ones to take on but require a disciplined approach to avoid being overwhelmed. I need to break down the projects into small tasks. When I do it right, a task can be completed in a couple of hours or a 1/2 day. Then when looking back over several days or weeks, you can see the progress. And looking back over months, and you can see great progress.

Let me share how that looks for our manufacturing process. The goal is to have control over our drug supply and its quality. We're going to be giving this drug to people so cutting corners is not acceptable. And we needed to develop our own manufacturing even for this repurposed drug because we learned very quickly when we engaged with the companies that already make it that we could not be assured we'd get enough of their attention to be a reliable partnership. They are too big and too focused on other stuff.

When manufacturing a drug, there are two processes. First you need to make the actual drug which generally looks like a powder. That's called the drug substance (DS) or active pharmaceutical ingredient (API). Next you need to figure out how to put that powder into a form that can be stored and administered to people. For us, that was a choice between tablets and capsules. That final form is called the drug product (DP).

I've discussed before how we decided on tablets, even though capsules are easier. We thought is was possible that the highest dose administered could be high. When you make tablets, the drug is compressed into a smaller size form so any dose of a drug will be smaller in. tablet than in a capsule.

I've also discussed how fortunate I am to have an amazing person as my expert on drug chemistry, manufacturing and testing, as well as great companies making the drug substance and the drug product.

So with this big project now approaching the moment where we "press pills" - which means we'll have the drug and matching placebo in tablets - what are the steps we've recently taken to assure the project's success?

The Details Behind Drug Manufacturing

Licenses. Our manufacturer is in India, where making product starts with obtaining licenses to do so. Fortunately the manufacturer is expert in these processes and have now obtained these licenses.

Advancing to pill pressing. Before we can manufacture the pills, we need to get the ingredients delivered. There are a limited number of places that meet the requirements of regulators so that they can manufacture and sell these ingredients. And unfortunately, we are waiting on a couple to arrive.

While we wait, the manufacturer will validate their cleaning process. Since these contract manufacturers make a wide range of drugs, all the equipment needs to be cleaned as they switch from one medicine to another. It's not as simple as grabbing the windex and cleaning your window. We have a process, but we need to apply it and then prove (what we refer to as validate) that there are none of the materials left in the machines from the prior drug. This typically is a quick process, completed with a few days.

Pill pressing. For this process, we needed to match up the minimum amount of pills with the number we need of each dose for the clinical trials. The machines used to make these pills to our exacting requirements can't make a hundred at a time; they need to produce thousands. We don't want to make too many pills of any particular dose since that could be a waste of our limited supply of API.

And for the trial, we don't need many of the 40 mg tablets since they will be needed for only the first couple of weeks. We need more of the 160 mg and 320 mg tablets because those are the ones people in the study will be taking for several months. We spent a lot of time considering all different scenarios, such as the possibility that in some cases, people in the study may need to be on the same dose for 2 weeks instead of 1 and that some people may get to a high dose and not feel well and need to have their dose reduced. Finally we matched the numbers from these two calculations.

Bottling. In general, we plan to provide a bottle of pills for each week, which means 21 pills. But there could be bad weather or a family emergency that requires us to postpone an appointment, so we need more than 21 per bottle. Typically we think of a bottle of 30, but that could mean we'd end up having almost a third of the drug supplied being wasted. We compromised at 25 which seems to provide some cushion but not too much of a cushion that it is wasteful.

The list goes on. We need to create a standard way to label the bottles so we know what drug level it is, for example "level 3" would be 160mg or matched placebo. We need to have codes on the bottle that can be used to track which ones are RB-190 and which are placebo, and match that information to each patient properly. We cannot afford to mix that up. And that code needs to be listed with its actual composition (RB-190 or placebo) in a secure place that only 2 or 3 people know about. That's how we make sure that no one knows during the study who is receiving active drug or placebo. We need to store the drug product in its bottles, after we've tested the tables to prove they are made properly with the right ingredients and no contaminants. And the pills need to undergo testing to define their shelf-life - how long we have before they cannot be used. And of course, we need to set up the protocol for shipping the drug from the manufacturer to the clinical trial sites - after the necessary regulatory processes are completed. We've completed most of the work in this paragraph and have plans in place to manage the rest.

I've left out a ton of work but hope you get a sense of our work, the progress and how we are getting closer to starting this clinical trial of RB-190.

The Next Big Challenges

In parallel with the manufacturing, our two biggest tasks are to complete our fund raising and to secure regulatory permission to start the trial. And in parallel, we are engaging with experts in Parkinson's disease to get the clinical trial protocol more refined. We're starting to focus in on the clinical trial sites tht would be the best match for our development program.

In the context of years of failures to develop therapeutics and the dogma that Parkinson's is a disease of dopamine deficiency, we are looking at the disease from the perspective of dopaminergic neurons which allowed us to find this unique and promising path. And we are working with a singular goal in mind; to conquer the disease.