How Proof of Mechanism Studies Can Advance Clinical Drug Development

Drug development is a complex and lengthy process associated with high costs. Bringing a new medicine to the clinical practice has been estimated to cost on average over US$ 1 billion and to last more than 12 years. Moreover, there is a high attrition rate in drug development, with the vast majority of New Chemical Entities (NCEs) and Investigational Medicinal Products (IMPs) not reaching the market as approved medicines. A variety of reasons may underlie this high failure rate, with an unfavorable comparison of the benefits and risks of an NCE to already approved drugs playing a major role.

The Role of Mechanistic Evidence in Drug Development

It has been reported that a substantial subset of approved drugs does not have a known target (approximately 7%) or a clearly defined mechanism of action (up to 18%). The fact that many drugs were approved in the pre-molecular era, when the effects of drug candidates were commonly explored in whole tissues, and tissue-based responses were used to infer target identities, may have contributed to these high percentages. However, an underappreciation of the role of mechanistic evidence in drug development and approval may have also played a role.

Gaining insight into the mechanism of action of a drug candidate can help investigators make informed and timely go/no go decisions about progressing an NCE to the next stage of drug development. In addition, conducting proof of mechanism studies during the early stages instead of the late stages of clinical drug development can minimize costs and shorten timelines in the drug development process.

How Mechanistic Studies Advance Drug Development

Nowadays, the activity of a molecule on a target is typically tested early in the process of drug discovery and development. Target-based screens are commonly used to identify promising drug candidates from a small molecule library using biochemical assays. They are designed to identify molecules interacting with a particular molecular entity that has been implicated in the disease of interest. However, even now, reportedly 37% of first-in-class drugs originate from phenotypic screens, and, in some instances, their primary target may remain unknown. Phenotypic screens examine whether a small molecule exerts an intended phenotypic change in the tested biological material and may be conducted at the cellular, tissue, organ, or organismal level.

However, various types of studies throughout the course of drug development can provide mechanistic evidence. During preclinical drug development, in vitro and ex vivo experiments, involving direct manipulations, can deliver mechanistic information. Throughout clinical drug development, mechanistic data can be collected as a part of clinical trials. In addition, direct observation and simulation can also provide important mechanistic information.

Why Should Proof of Mechanism Studies be Included in Early-Phase Clinical Trials

Proof of Mechanism studies help determine whether a drug candidate reaches its target organ, interacts with its molecular target, and exerts the intended pharmacological effect. Thus, they are critical for confirming the target selectivity of a drug candidate. It is important to incorporate proof of mechanism studies in Phase 1 clinical trials in order to understand the primary molecular target and mechanism of action of a drug candidate and to inform and aid decisions regarding the drug development process.

Proof of mechanism studies conducted as a part of early-phase clinical trials provide various types of data. In particular, investigators can use them to:

•  measure the concentration of a drug candidate at its target
•       examine whether a drug candidate engages with its molecular target
•       assess whether a drug candidate exerts its expected pharmacological effect
•       examine pharmacokinetic/pharmacodynamic relationships
•       aid the selection of a suitable dose for more advanced clinical studies

Illustrations of the significance of proof of mechanism studies

The significance of proof of mechanism studies is illustrated by the findings of an analysis of decisions made by a large pharmaceutical company for 44 drug development programs in Phase 2 clinical trials between 2005 and 2009. The study found that it was not possible to determine whether the mechanism of the drug candidate was assessed properly in 43% of the analyzed programs. Moreover, “three pillars of survival” that could predict the likelihood of survival of drug candidates in Phase 2 trials were identified, and they were related to proof of mechanism studies. The pillars referred to the exposure at the target site, binding to the presumed target, and exertion of the expected pharmacological activity.

Another illustration of the benefits of proof of mechanism studies originates from the field of psychiatric drug development, which has been associated with a high attrition rate. The Fast-Fail Trials (FAST) initiative, supported by the NIMH from 2012–2015, set out to redesign psychiatric early-phase clinical trials to determine whether targeting particular biological mechanisms with drug candidates would exert the anticipated biological effects on the human brain. This approach allowed investigators to efficiently and promptly determine whether a drug candidate holds promise for successful development in further clinical studies.

Moreover, the analogs of compounds that interacted with their brain targets and affected the function of brain biomarkers could be tested to identify a molecule with optimal characteristics. Data from experiments conducted in this initiative corroborated the effect of blocking the brain kappa opioid receptor on brain circuits related to pleasure and reward. These findings supported the role of the kappa opioid receptor as a drug development target for clinical trials on drug candidates for mood and anxiety disorders. Accordingly, a study found that a robust kappa opioid receptor antagonist exerted the expected effects on neural function involved in hedonic responses (enhanced fMRI ventral striatum activation in patients with anhedonia and a mood/anxiety disorder during reward anticipation), and suggested that the compound has potential as a candidate for an anhedonia therapeutic.

Proof of Mechanism Versus Proof of Concept Studies

There is a clear distinction between proof of mechanism and proof of concept studies, as proof of concept studies provide initial data on the efficacy of an NCE by evaluating is pharmacological activity. However, proof of mechanism and proof of concept studies provide complimentary information, and their timely combined use may deliver optimal results for the selection of a dose range and patient population for later phases of drug development. Ultimately, this can help to streamline and advance the drug development process.

Proof of Mechanism Versus Proof of Principle Studies

Proof of principle studies investigate whether an NCE has a pharmacological effect on the disease of interest, including on disease biomarkers. Thus, proof of principle and proof of mechanism studies deliver complimentary information that can provide insight into the pharmacological activity of an NCE.

Challenges Associated with Proof of Mechanism Studies

• Design and validation of assays for target engagement and modulation – With the rapid technological advances in drug development, a wide range of different assay types are available for determining target engagement and modulation. The selection or design of the most appropriate assay may be challenging and requires an in-depth understanding of the target and the needs of the study. Moreover, the validation of pharmacodynamic assays may be a time-consuming and challenging process. It requires access to a state-of-the-art bioanalytical facility and the collaborative efforts of proficient bioanalytical scientists.
• Recruitment challenges – A large proportion of clinical trials, including Phase 1 clinical trials, cannot be completed in their predetermined timeframe due to recruitment challenges. This is especially true for clinical trials involving patient populations or individuals from special populations (for example with history of recreational drug use). Designing a comprehensive recruitment strategy aligned with the needs of the drug development program is crucial to streamline the recruitment process.
• Sample collection – In proof of mechanism studies, target modulation should be evaluated at the time an effect occurs. Therefore, the logistics related to sample collection, including the location, sample size, and sample processing, may be challenging.
• Data interpretation – Mechanisms identified in the course of proof of mechanism studies are often not identical to the predicted ones. Furthermore, many unknown or unexpected factors may interfere with the study observations.

Biopharma Services’ Expertise in Proof of Mechanism Studies

Working with an experienced clinical research partner can help efficiently implement proof of mechanism studies in clinical drug development. BioPharma Services is an experienced, full-service clinical research organization (CRO) that has successfully completed over 2,200 early-phase clinical trials across a variety of disease areas. Our award-winning team includes over 250 multidisciplinary experts that collaborate to design and conduct comprehensive early-phase clinical trials for our clients’ drug development programs. Our expertise in proof of mechanism studies includes:

• A multidisciplinary team of experts – Our team includes clinical pharmacologists, pharmacokinetic scientists, safety physicians, bioanalytical scientists, regulatory scientists, data managers, and biostatisticians who work together to design, conduct, and analyze the data from early-phase clinical trials, including proof of mechanism studies.
• A state-of-the-art bioanalytical laboratory – BioPharma Services has established a modern, in-house bioanalytical laboratory that is equipped with a state-of-the-art liquid chromatography with tandem mass spectrometry (LC/MS/MS) platform and has received a good laboratory practice (GLP) certification by the Standards Council of Canada (SCC). The laboratory is operated by our internal team of expert bioanalytical scientists.
• A modern clinical facility – Our state-of-the-art clinical research facility, located in Toronto, Canada, has been designed to ensure the safety of study participants and includes a Phase 1 clinical trial ICU.
• A network of external collaborators – BioPharma Services has established a network of trusted external collaborators. In cooperation with them, we can perform a wide range of clinical trials, including studies involving complex medical procedures and challenging routes of administration.
• Efficient clinical trial management – Our expertise and extensive experience in clinical research allow us to manage our clients’ clinical drug development programs in an efficient and cost-effective manner, taking into consideration the individual needs of each program.

If you would like to collaborate with an expert clinical partner that can design and conduct efficient proof of mechanism studies for your clinical drug development program, schedule a call with BioPharma Services below today.

BioPharma Services, Inc., a HEALWELL AI and clinical trial services company, is a full-service Contract Clinical Research Organization (CRO) based in Toronto, Canada, specializing in Phase 1 clinical trials 1/2a, Human Abuse Liability(HAL) and Bioequivalence clinical trials for international pharmaceutical companies worldwide. BioPharma Services conducts clinical research operations from its Canadian facility, with access to healthy volunteers and special populations.