When Project ALS decided to move prosetin to clinical trial independently, we were newcomers to drug development. Our first task: assembling a team of experts who would steer this program forward guided by both rigorous science and the urgent need for meaningful ALS therapies. Enter Merrill Osheroff, PhD, DABT, who joined the prosetin team as the toxicologist responsible for overseeing all of prosetin’s FDA required safety studies (so-called “IND-enabling studies”) in March 2020.

Dr. Osheroff, currently President of Osheroff Consulting Services, brings nearly four decades of experience to the prosetin program, including previous roles as Director for Monsanto Safety Evaluation, Executive Director and Site Head, Worldwide Safety Sciences at Pfizer, and Senior Program Director at Battelle Memorial Institute. He holds a Ph.D. in Experimental Pathology and Laboratory Medicine from University of Wisconsin, and a B.S. in Animal Sciences from University of Maryland.

We asked Dr. Osheroff to weigh in on why IND-enabling studies are so important, how he approaches his work for a disease as serious as ALS…and how Eric and Amanda Stevens inspired him out of “semi-retirement” and onto the prosetin team.

  1. What initially attracted you to toxicology as a field of study and career?

MO:  I had always been interested in the sciences and originally entered the undergraduate pre-med program at Emory in Atlanta. After two years I decided to change disciplines and started in the pre-vet program at the University of Maryland, College Park. When a Research Assistant position in Experimental Pathology and Laboratory Medicine opened at the University of Wisconsin-Madison, I applied and entered the program. Like many other things, our experiences shape our interests and our journey through life. I enjoyed the research aspects, challenges, camaraderie and excitement of scientific research and these experiences validated my decision to dedicate myself to this career.

  1. When we asked you to join the prosetin team, we were frankly worried that you would turn us down. Was there anything about ALS and/or this effort that compelled you to get into the trenches with us?

MO: This is a terrific question because the decision to take on this project was both difficult at first and then became very easy. When Kevin [prosetin regulatory consultant Dr. Kevin Phelan] called me to discuss the program, I was transitioning into semi-retirement mode and was uncertain whether to become involved in another program or stay the course and retire. I told Kevin I needed a few days to decide. During that time of reflection, my wife and I were watching 20/20 on television and she had asked me why I would want to take on additional work at this stage. Well, on the episode of 20/20 they just so happened to be interviewing a young married couple of which the husband, a firefighter, had ALS. We have 4 children and 7 grandchildren so listening to their challenges in life since being diagnosed with ALS and knowing the prognosis for the future at this stage, my wife and I immediately choked up. So I looked over at her and through tears did the best to respond to her question by saying “that’s why.”  She just shook her head and so here I am.

  1. What is the purpose of the extensive suite of FDA-required safety and toxicity studies before any clinical trial of investigational new drugs—so-called “IND enabling studies?” 

MO: In most cases, for a New Chemical Entity (NCE) the Phase 1 study is the first opportunity to evaluate the safety of a drug in man. Because of this, we have an obligation to these exceptional people to guard their safety and do the best we can to make sure that we have characterized the pharmacology and toxicity of the drug well enough to have de-risked—as best possible—any adverse effects. Additionally, preclinical studies are our opportunity to validate potential biomarkers that provide us with early indications that one or more target organs are being affected before any obviously adverse events, and they provide us an opportunity to understand exposure as a function of dose levels. This information is important as part of the IND to inform the clinician in charge of the clinical trials about the properties of the drug and what they need to be aware of. This principle defining the transition from preclinical to clinical evaluations is seminal to the whole concept of drug development.

  1. Why is it necessary to complete this battery of safety studies even for a devastating disease like ALS, where many patients are willing to take on more risk if it means faster access to a potentially beneficial treatment? 

MO: Although there are a number of abbreviated pathways that may be followed for testing in man, without this defined pathway referred to as the IND, we would not have the opportunity to understand this drug candidate. We would not understand dose-effect and dose-response relationships, absorption and distribution, target and off-target effects, the potential for genetic effects and bioaccumulation.  Without these essential data, I’m not sure how we would effectively evaluate and characterize the drug in such a way that research on the drug could proceed and not be encumbered with effects in man that could have been controlled with background research and investigations.

My feeling is that as we sort through the ancillary data generated because we did not follow a rather well-defined IND pathway, it would cost us more time and money at the end. The patient is waiting for us to help, but I think that morally we are obligated to do this in a responsible fashion that provides us with good data for decision-making and the ability to bring forth the best candidates available.

  1. Do you think about IND enabling studies, or overall nonclinical toxicology requirements, any differently for a devastating disease like ALS vs. a condition with a lower unmet medical need? 

MO: The testing paradigm that generates the information needed to start clinical trials in man is defined by the IND requirements and guidance from the International Congress of Harmonization (ICH). Even within this set of guidance documents there are some examples of flexibility where certain study requirements may not be needed or can be postponed. An example would be the ICH S9 guidance for anticancer drugs. Another example is the September 2019 FDA Guidance for Industry: Amyotrophic Lateral Sclerosis: Developing Drugs for Treatment.  In this guidance the FDA allows some preclinical testing flexibility; however, it is imperative that we can assure—as best possible—that the drug is safe to administer. Above all, the mantra of the FDA has been “case by case” and it is incumbent for the Sponsor [Project ALS] to be able to support the testing paradigm proposed for use in the preclinical and clinical plan.