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Early Drug Development: Progressing a Candidate Compound to the Clinics: Introductory Remarks

Fabrizio Giordanetto

D. E. Shaw Research, Department of Medicinal Chemistry, 120 W. 45th Street, New York, NY, 10036, USA

Drug discovery and development is a fascinating, challenging, and multidisciplinary process where ideas for therapeutic intervention are devised, evaluated, and translated into medicines that will ultimately benefit society as a whole. As the name implies, it consists of mainly two elements: an initial discovery phase, followed by a development phase. These two phases differ significantly from each other with respect to scope, challenges, and approaches. As an example, while discovery experiments are typically executed in a laboratory setting using isolated and approximate systems (e.g. recombinant protein, cells, animals), development experiments consist of clinical trials in hospitals with human subjects and their full pathophysiological complexity. Differences notwithstanding, discovery and development must be integrated into a coherent whole for the process to be successful. Accordingly, much thought has been devoted to ensure scientific, logistical, and organizational aspects of such integration are taken into consideration and optimized [1-4].

Thankfully, the early view (and practice) of a discovery unit tasked with the delivery of a compound, typically termed a "preclinical candidate," which is then "thrown over the fence" to the development organization responsible for its clinical progression as a candidate drug, is a memory from a (not so) distant past. Alignment of research objectives and outcomes relevant to the discovery phase with clinical imperatives relevant to the development phase and commercial viability is not always straightforward, especially in new sectors of the pharmaceutical research environment where innovative therapeutic hypotheses are speculative and not clinically validated. Nevertheless, such an alignment is absolutely required for success, and a joint understanding and ownership of the practical implications of such alignment needs to be fostered within the project teams and their organizations.

Conceptual tools to support the initial definition of discovery and development alignment at a project level, and the strengthening of this alignment as the drug hunting program evolves, have been developed and provide a useful framework [5, 6]. Unsurprisingly, early drug development is where this alignment between discovery and clinical requirements is crystallized, normally by the selection of one or more compounds that fulfill a predefined profile, that will be progressed to clinical studies.

The definition of this so-called target product profile ( [7]) affects all research activities during lead optimization, including focused compound design in order to reach the set TPP standards, and planning of a screening cascade in order to maximize the number of testing cycles on key TPP parameters. Some salient TPP properties such as toxicological risks, predicted human dosing, and pharmaceutical properties can only be effectively, and practically, assessed for the first time in a project timeline during early drug development. TPP definition and compliance have therefore far-reaching effects across the drug discovery-drug development value chain: they dictate which compounds are made in the first place, which compounds will be selected for clinical development, and ultimately which compounds will be successful at the end of the development cycle.

This book is structured around the TPP to highlight its importance as an early drug development compass. Here, we set the compound(s) of interest - one of which is destined to become the new drug substance - front and center because the experimental quantities relevant to the TPP, regardless of testing paradigms and screening technologies used, are all properties inherent to the compound itself and are set when the compound is first designed. By taking this approach, we hope to stimulate readers along three main axes: (i) achieving a clear line of sight between preclinical measures and the desired clinical outcomes; (ii) the variability, uncertainty, and realm of applicability of the data generated and the methods used; and (iii) the integration of diverse data and disciplines. These three elements are constantly pondered and discussed by early drug development scientists as part of the TPP definition and fulfillment process. They provide an evidence-based approach to defining and refining the TPP and to selecting the best possible compounds to meet the TPP requirements.

The parameters comprising a TPP are more important than the specific target values of any particular TPP parameter. To highlight this concept, an example TPP is shown in Table 1.1. TPPs are, by definition, project and time specific, and they should be viewed as living documents. Project teams should strive to define the TPP as early as possible, with the attitude to refine the TPP as more data are generated, typically when pharmacological efficacy measures or early toxicity signals are established, or in response to external stimuli such as results from competitors or clinical validation studies, to name but a few examples. Similarly, even within the same overall project, the TPP for a backup compound will very likely be different from the one used for the clinical front-runner; additional insights, knowledge, and differentiation properties gleaned during lead optimization, early drug development, and clinical development will be incorporated into the revised TPP.

Table 1.1 Target product profile (TPP) example as an essential early drug development tool.

Description Target value Comparator/standard of care Planned studies FDA's TPP template section [8] Project goal A statement that the drug is indicated for the treatment, prevention, relief, or diagnosis of a particular indication of a recognized disease or condition and their associated manifestations or symptoms alone or in conjunction with a primary mode of therapy Indication and usage Drug substance Physicochemical properties (e.g. crystallinity, thermal property, hygroscopicity) Synthetic and purification risks Estimated cost of goods Drug product Route of administration Dosage and administration Recommended usual dose (maximum absorbable dose) Dose range shown to be safe and effective Dosage intervals or titration schedule Usual duration of treatment course when treatment is not chronic Dosage form Dosage forms and strengths Dosage strength Special handling and storage conditions, chemical stability of formulation How supplied/storage and handling Pharmacokinetics and pharmacodynamics Mechanism of action: Summarize established mechanisms of action in humans at various levels (e.g. receptor membrane, tissue, organ, whole body) Clinical Pharmacology Pharmacokinetics: Describe clinically significant pharmacokinetics of a drug or active metabolites (i.e. pertinent absorption, distribution, metabolism, and excretion parameters). Document their compatibility with intended magnitude and duration of effect (e.g. include results of pharmacokinetic studies that establish the absence of an effect, including pertinent human studies and in vitro data) Pharmacodynamics: Include a description of any biochemical or physiologic or pharmacologic effects of the drug or active metabolites related to the drug's clinical effect or those related to adverse effects or toxicity. Include data on exposure-response relationship and time course of pharmacodynamics response Toxicology Results of long-term carcinogenicity studies - species identified Nonclinical toxicology Mutagenesis results Reproduction study results Include a description of clinically significant adverse reactions and potential safety hazards and limitations of use because of safety considerations, as reasonable evidence of these issues is established or suspected as from, e.g. safety pharmacology and GLP toxicological studies Warnings and precautions Describe overall...