In Vivo Research Strategies that Reduce Risk of Failure in the Clinic

Learn practical in vivo research strategies to improve success of reaching first-in-human clinical studies

Drug development is complex, costly, and multifaceted, taking on average 10 to 15 years. No one wants to fail, particularly not in later stages when the time and costs required to pivot a strategy are even greater. Despite continued optimization of the drug development process, the failure rate remains at 90%. An analysis of clinical trials (2010-2017) showed that 40 - 50% of failures are due to the lack of clinical efficacy (Sun et al., 2022). So how can the success rate be improved?

This blog is a brief journey of early drug development, with consideration on how to optimize the late target validation stage to help reduce the risk of failure and enhance getting a great idea from concept to patients.

Validation Prior to In Vivo Studies

Drug development is a step-by-step process, starting with target and hit identification, then moving to target validation and lead optimization. The initial steps, particularly for small molecules, involve screening thousands of molecules. These steps need to use simple and rapid methodologies such as literature, in silico, and in vitro data, to filter and identify candidates that have more potential to be successful. For small molecule programs, these will include key physicochemical properties; for example, adherence to Lipinski's Rule of 5, solubility, and defined structural/functional relationship. The acceptance criteria will be adapted depending on the modality and target. These early answers cannot be found in a regulatory guideline. Rather, early drug development requires researchers to develop the best testing strategy case by case, with the aim of supporting the selection of the best candidates.

At the late target validation stage, having reduced numbers to a few key leads, the key question will be to investigate the proof of concept, i.e., "does it work?" The next best step to answer that question is often by in vivo studies. At this point in development, it is important to consider the interplay between pharmacology (how a drug works on the target), pharmacokinetics (exposure at the target site and healthy tissue), and toxicology (adverse effects versus tolerable limits). This data fits together like a jigsaw puzzle that will provide key information on exposure and margins and the management of effective and toxic dose levels. At this point, it might also be important to consider other factors in consideration of the patient that will be implicated in study designs such as ideal route of administration, frequency of dosing etc.

Setting Up the Early In Vivo Research Phase

Setting up in vivo studies in a prepared laboratory with skilled staff can save time and money. The study design should reflect the screening strategy and may depend on the number of compounds to be screened. The key question relates to the pharmacology target. For first-in-class drugs, there is an additional challenge in how to truly validate the target as a critical component of a human disease. Maximizing the set-up of early preclinical in vivo research could reduce later failure in the clinic. In addition to providing critical information on drug pharmacology and mechanism of action, adding some initial toxicology endpoints could be advantageous. These could include in-life endpoints or more in-depth analysis, such as clinical pathology or histopathology evaluation for targeted endpoints. The type of modality may also influence the toxicology profile, small molecules being more complex than a biologic in terms of cause and effect as adverse events can be pharmacology related, a secondary indirect effect or an off-target effect.

Another critical factor, sometimes overlooked early on, is understanding the exposure level of a drug at the site of the disease target organ versus normal organs. Such information can help support the selection of a successful candidate i.e., understanding the structure-tissue exposure/selectivity-activity relationship (STAR; Sun et al., 2021). Consider an oncology drug, where initially a simple effect on tumor may be enough to select a molecule. However, to derisk further, understanding the tissue exposure at the level of the tumor and healthy tissue may provide valuable information about the dose exposure relationship of efficacy and toxicology of healthy tissue. As oncology drugs can pose a risk to all cells, this information can further help clarify margins of risk and help reduce failure in the clinic.

There are other considerations around exposure. For example, if we consider the development of a drug that is targeting the central nervous system and needs to cross the blood brain barrier (BBB), it is important to understand early on that the molecule can cross the BBB. This question needs to be considered in relation to what formulation is used in these early studies. Different formulations can alter exposure profiles, and some vehicles are better at crossing the BBB, like the diluent, dimethyl sulfoxide (DMSO). If early studies are done with a formulation not suitable for use in the clinic, such as high DMSO content, studies may have to be repeated and the data may change, which could be a setback to the program and the type of formulation used. It is never too early to consider the ideal route of administration and frequency of dosing for the patient. As such, it is never too early to consider a formulation plan, which will be critical for advancing into the clinic.

Another consideration relates to drug exposure, and consideration of free drug versus bound, such as binding to serum proteins, and how this might impact exposure, availability, and function of the molecule. This is not so simple. In recent years, it is noted that the free drug hypothesis may be misleading and drug exposure in the plasma may not relate to the drug exposure in the disease-targeted tissues versus normal tissue (Risk et al., 2017; Mullet et al., 2012).

In conclusion, each stage of drug development needs to be considered in a stepwise manner and to understand the risks and how best to evaluate those risks to increase the chance of success. Learn more from this scientist-led webinar about in vivo research strategies to reduce failure risk and increase your success of reaching clinic.

References:

Mullet et al., (2012). The determination and interpretations of the therapeutic index in drug development (Nat Rev Drug Discovery 2012; 11: 751-61).

Risk et al., (2017). Importance of drug pharmacokinetics at the site of action. Clin Transci Sci 2017 10: 133-132.

Sun, D et al., (2022). Why does 90% of clinical drug development fail and how to improve it? Acta Pharmaceutica Sinica B;12(7): 3049-3062

Sarah Gould, PhD, is Director and Senior Principal Scientific Advisor at Charles River Laboratories with more than 25 years of experience working in large pharma and biotech across several distinct roles. Her expertise is in toxicology, pharmacology, and pharmacokinetics and she has a proven record of accomplishment in delivering toxicology and safety pharmacology programs, individual studies, and regulatory documents for small and large molecules, vaccines and adjuvants from Discovery to License.

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