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  • Dessi McEntee

A Series: Nonclinical Safety Strategies in Drug Development

Small Molecule Therapeutics


New medicines or drugs, in their most basic forms of development, stand to answer two main questions: does it work and is it safe? The latter relies heavily on animal data from early-stage development to late-stage clinical development and even post-marketing. In fact, determination of the human starting dose of a new drug is based entirely on one, single animal study. I will cover why this is in later posts, but for today we will take a closer look at how nonclinical safety strategies drive the progression of new medicines. Note, the information that follows is by no means an exhaustive list of how drug safety is conducted but does give some insights as to the processes and approaches.


The easiest way to outline how animal studies are used to support drug safety assessments is to look at the type of therapeutic being developed. Today we will focus on small molecules, but I will cover other molecule types in future posts.


Overview

Small molecule therapeutics are exactly what you may think: “small” molecules, in that they have low molecular weights. Aside from that, they are synthetically made or created in a powder form and are dosed orally. This isn’t absolute for all small molecules, some are injected or applied dermally, and some may have characteristics that differ from those aforementioned. In general, though, you can think of small molecule therapeutics as the tablet of ibuprofen you took this morning.


When it comes to the safety of small molecules, most strategies are driven by ICH guidelines with some tweaks here or there based on historical regulatory-accepted tests/studies. For this article, we will use strategies employed to support a new drug submission to the FDA.


Preclinical Development

The first step after drug discovery and creating many new drugs is to pick one of these to move forward, and assessing early safety is a big yet very difficult part. Many in vitro assays are done to try to understand the on-target and off-target toxicity potential of new drugs, however they are only assays and are less than perfect at predicting what will happen in an animal let alone a patient. The main objective of these assays is to look at trends and patterns – what is happening with Target A when Compounds X, Y and Z are applied and then comparing X, Y and Z against each other. In vivo efficacy studies, or studies done in animal disease models to test if the drug works, also start happening at this stage and can be used to some extent to understand the safety. The drawback of using these studies at face value though is definitive toxicology studies are done in healthy animals and typically in different species than the efficacy studies.


Nonclinical Development: DC-enabling Stage

Once a compound is chosen to move forward, it enters the Development Candidate-enabling stage, or the DC-enabling stage. This stage is where studies are run to enable a compound to be nominated as a Development Candidate to progress development of the compound. Every company has different criteria for endpoints a compound must hit to be nominated as a Development Candidate, but we can outline some basic safety endpoints here. Typically, DC-enabling toxicology studies include Maximum Tolerated Dose (MTD) studies or Dose Range Finding (DRF) studies of 1-14 days in length. Dosing route, regimen, frequency, etc. all depend on the intended clinical scheme but the objective is the same: evaluate safety for the first time in animals at high doses in short duration, evaluate the associated toxicity of the compound and evaluate the associated toxicokinetics of that toxicity. Taken together, these data will provide a basis for a DC nomination and inform doses for the next set of animal studies.


Nonclinical Development: IND-enabling Stage

Once a compound is nominated and approved as a Development Candidate, it then moves to the Investigational New Drug-enabling stage, or the IND-enabling stage. This stage is where definitive toxicology studies are run to enable a compound to be nominated as an Investigational New Drug and be submitted in an IND application to the FDA. Typically, the IND-enabling stage consists of Safety Pharmacology studies and Good Laboratory Practices (GLP) studies, or the regulated studies that the FDA definitively uses to determine the safety of new drugs. Safety Pharm studies usually consist of a cardiovascular Latin Square study to determine any acute toxicity on the cardiovascular system, looking closely at effects on the heart and blood pressure. The GLP studies are usually 28 days long, are conducted at the highest quality, include various toxicology and safety pharmacology endpoints, determine a No-Observed-Adverse-Effect-Level (NOAEL), and provide safety margins to the anticipated human dose. One of the most critical aspects of these studies is the NOAEL, or the dose level used in the study that did not produce any compound-related adverse effects. For the most part, the NOAEL, through various calculations, is directly used to establish the starting dose in First In Human (FIH) clinical trials. Mischaracterization of the animal data within these studies can lead to a misinterpretation of the NOAEL leading to a miscalculation of the starting human dose. Imagine the fallout if done incorrectly.


Clinical Development

Once a compound is nominated and approved as an IND, an IND application is submitted and hopefully the compound moves into clinical trials. From here, further nonclinical safety studies are performed to support clinical development including genotoxicity, reproductive toxicity, chronic toxicity and carcinogenicity. It is important to note that most of these toxicology studies are run in two different species, a rodent and a nonrodent. For small molecules, these are usually the rat and the dog but some programs may differ from this based on scientific justification.


Conclusion

Overall, how a company decides to assess the safety of its drug is a combination of what has worked in the past, what needs to be done from a regulatory standpoint, and what custom tweaks need to be made based on the molecule and how it works. Nonclinical safety and development is an art in this way, requiring the ability to perfectly integrate all of these components. In addition, there are further sides of the coin in that there requires a balance of the scientific and business objectives. Drug development is timely and costly, and a fact of the industry is scientific strategy must also include business strategy. Focusing on one without the other is not recommended.


This overall approach towards nonclinical safety for small molecules has been the typical approach for most small molecules for the last 20-30 years. Not much has changed, and not much innovation has been incorporated or even attempted. Think of the changes in the world that have happened in the past 20-30 years and how impactful those have been, yet we still antiquely operate in the nonclinical safety space. We think it’s time for change, don’t you?



Dessi McEntee, MS, DABT is a board-certified toxicologist with an MS in Pharmacology and Toxicology and a BS in Animal Science. Dessi has over a decade of extensive experience in nonclinical toxicology in the pharmaceutical industry and has overseen drug development strategies across startup, small and big pharmaceutical and biotech companies. Dessi is currently the Founder & CEO of Mimicry Solutions, working to reinvent drug safety by turning animal predictions into human predictions through ARTEMIS™. More information can be found at www.mimicrysolutions.com.

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