Operational Updates – Focus on Drug Safety

Advancing RB-190 into the clinic is a complex process. On any given day, one task or another dominates my attention – and often that changes hour to hour.

Over the past 2 months, in addition to fundraising, I’ve focused as much as possible on preparing the documents for submission to the Australian authorities that need to approve our plan. Thankfully, the chemistry and manufacturing documentation is being managed by our expert. But most of the work is mine, with the critically important input from the Right Brain team and our Australian collaborators. We’re nearing submission for permission to launch our clinical trial.

The key documents needed are: (1) the clinical trial protocol, (2) the patient informed consent form and (3) the investigator’s brochure.

The first is ready. In this trial, the second consists of two consent forms, one for trial participation and one for videorecording of the movement tests. They are ready. The third is almost ready. The investigator’s brochure consists of: (a) the description of the drug’s pharmacology and how it works, (b) the confirmation that the manufacturing is completed according to international requirements (which includes its purity, potency etc.) and (c) the evidence that the drug’s use in the trial is reasonably safe.

The first is ready. The second is ready. And the third is getting close.

Safety Assessments Required by Regulators

Regulators from countries around the world established a mechanism to develop common requirements in drug development, with that organization called “The International Conference on Harmonisation.” In 1991, they held their first meeting in Brussels which included a focus on the testing requirements before a drug could be administered to people. These are typically referred to as the “IND enabling” studies, as they are required before an IND application can be accepted by regulators — which is required before the first clinical trial can commence.

Included in these requirements are studies called chronic toxicity studies, in which animals are dosed repeatedly form months until reaching a predetermined time point and then they are sacrificed and examined.

Sacrificed and examined? It’s not nearly that simple or neat. Historically this means killing and conducting autopsies on rodents, dogs and even non-human primates. Even if you don’t have strong opinion about the use of animal testing, this type of study begs the questions of what is learned in these studies. If such studies could enable drug developers to select the right drugs to study in people and then those drugs made it to market, a strong argument could be made that such animal studies are justified. Without such data, I am one who believes strongly that such studies should not be done. And regulators are embracing the philosophy of moving away from animal studies whenever possible - referred to as replace, reduce and refine (3Rs).

The ICH conference in 1991 concluded that any new drug should undergo repeat-dose, chronic toxicity studies for 6 months in rodents and dogs and for 9 months in dogs. This became the standard practice globally.

What Do the Data Teach About Chronic Toxicity Studies?

Those who know me are not surprised that I wanted to know the answer to this question without assuming that the experts in ICH had drawn the right conclusion. Asking questions and pursuing the data to answer those questions is a foundational skill we use to properly advance RB-190 from concept to the clinic. I needed the published Proceedings from that ICH conference, as well as the 2^nd in Orlando in 1993, the 3^rd in Yokohama in 1994, the 4^th in Brussels in 1997 and the 5^th in San Diego in 2000. None are still in print. And search of used book sites and eBay were initially unsuccessful.

Eventually I found 4 of 5 and evidence that the one I still can’t find (the 4^th from 1997) did not focus on these chronic toxicity studies. After 2000, the ICH shifted its approach and published less detailed summaries on its website. These proved sufficient to show that the ICH did not reevaluate its requirements for chronic toxicity studies, and eventually finalized them in a separate document in 2009.

This meant I had access to the published transcripts of the discussions between representatives of the ICH member countries, including the FDA. Here’s what I learned.

Lessons from the ICH Meeting Transcripts

Representatives from different countries discussed what they were doing. For many, they had been requiring studies at both 6 and 12 months. As they shared their experiences, it became clear from the data that the 6-month studies were sufficient to identify relevant risks and the 12-month studies did not provide additional insight. Properly, they concluded that 12-month studies should not be required.

Then they did something puzzling. They agreed to require 9-month studies. There were no data to support that. I suppose they felt better adding that requirement just to be sure, but there was no data to support any value to that requirement. But so it came to be.

The ICH decided that before a drug could be studied in a clinical trial of up to 6 months, that drug would need to be tested in a chronic, repeat-dose toxicity studies of 6-month duration in rodents and dogs. If the plan were to conduct a trial longer than 6 months, additional repeat-dose toxicity studies were required in dogs for 9 months.

And this 9-month requirement applied for however long a drug would be used. If for under a year, the 9-month study was required. If for 5 or 10 years, the 9-month requirement was required.

Were any data presented subsequent to the 1991 ICH conference to justify 9-month trials? No. Not in an ICH conference and not in published studies in the literature.

The Relevance to RB-190

When the active ingredient in RB-190 (metyrosine) was approved by the FDA in 1979, it was intended for short term use – typically a couple of months. It was studied for up to 6 months in rats and dogs with the results satisfactory to allow for clinical use for up to 6 months. If RB-190 were a new drug, it would be expected to undergo 9-month toxicity study in dogs to permit its use beyond 6 months.

However, the FDA approved drugs for long-term use as recently at 2023 that were repurposed, originally approved for short duration therapy, for which there were no long-term repeat-dose toxicity studies – not even 6-month toxicity studies.

In our application, we are summarizing the lessons driven by data in the ICH process as well as the lessons teaching that certain requirements are not based on scientific evidence. These observations along with the reference to the FDA’s recent decisions for repurposed drugs with similar history will serve to remove these barriers from RB-190’s path.

When preparing regulatory submissions, such situations need to be considered and addressed. A developer cannot afford to assume they will get the go ahead or that others have studied the transcripts from each of these ICH Proceedings. And that’s why we will be successful as we move to the clinic.

Transparency

Whenever possible, we will share the details of our progress. And when we hit the key milestone of starting our clinical trial, we will share that information here as well as posting it on the clinical trial registries (Australia New Zealand Clinical Trials Registry at https://www.anzctr.org.au/ and in the US at https://clinicaltrials.gov).