The continued high level of interest in small molecules presents multiple opportunities to select a candidate that is ‘developable’, with subsequent rapid progression toward first-in-human (FIH) clinical testing. However, there is a high level of attrition during the pharmaceutical research and development process, which is an indicator of the vast number of potential drug substances considered for progression. Therefore, it is vital to choose molecules for pharmaceutical development very carefully. Given the plethora of new chemical entity (NCE) candidates, pharmaceutical research groups frequently face challenges when selecting the most promising candidate for development purposes. With all this in mind, how do drug developers know which strategy and approach is right for their molecule at this early stage?
Key considerations in the candidate selection stage
The first step in a drug development program is choosing the optimum molecule from a range of potential leads that have been optimized within drug discovery. At this stage, lead compounds will be ranked based on their activity in primary and secondary assays, demonstrating acceptable specificity and selectivity for the biological target that is proposed to be key for the desired therapeutic area. Best practice is to also consider the ‘developability’ of the lead compounds in conjunction with any evidence of potential in-vivo activity, by taking a holistic approach. It is important to assess each compound’s pharmacokinetic (PK) profile and to evaluate the potential toxicity using simple screens such as the Ames test and cytotoxicity assays.
At Quotient Sciences, our drug development consultants use our 30+ years of experience in clinical research outcomes to profile each new molecule that we look at. We start by using in-silico modeling of any pre-existing data associated with the lead compounds. This initial assessment helps to highlight any critical data gaps, which we can then fill with small-scale experimental work. Simple physiologically based pharmacokinetic (PBPK) modeling can also be performed at this stage, providing a holistic route to predicting the clinical performance of a molecule (or range of molecules) and allowing for maximum leverage from all data already obtained at this early stage in development. PBPK modeling integrates knowledge of a drug’s physicochemical properties (e.g., ionization status, solubility, and lipophilicity), measurements, or in-silico predictions, with physiological information like the GI tract environment (i.e. differing pH, volume, surface area, and bile salt concentrations). Using the PBPK modeling software GastroPlus®, dissolution and subsequent absorption of a compound can be predicted across the expected clinical dose range, and for potential scenarios such as food effect or in the presence of acid-reducing agents, ultimately guiding candidate selection and formulation strategy, ensuring that the selected candidate drug has a better chance for success as it enters the clinical phase.
Drug substance quantities are often limited at this stage, so we select material-sparing experiments to generate fundamental molecular-level characteristics, which helps to ensure that we choose the correct molecule. For example, to successfully develop an oral solid dosage form like a tablet, the solubility and permeability of the lead compound will have a significant impact on the speed and extent of its drug development program to become ‘clinic ready’. By associating molecular properties with in-silico absorption, distribution, metabolism, excretion, and toxicity (ADMET) models, we can significantly increase the robustness of candidate selection, which subsequently reduces the failure rate during clinical trials. Classifying the ‘developability’ of the compounds in advance and knowing how much and where a drug is likely to be absorbed in different scenarios can help avoid downstream formulation pitfalls by designing a molecule-specific pharmaceutical development plan.
Candidate selection case study: Progression of small molecule ‘developability’
Background: A US biotech company had identified nine structurally related compounds as potential candidates in an oncology discovery program. Quotient Sciences was asked to select the best candidate based on material science and oral bioavailability considerations. The quantity of each compound was limited to less than 500 mg for the assessment.
Program: Initially, the crystallinity, physical state, morphology, and salt formation for each compound were assessed. Subsequently, the inherent equilibrium solubility and pH-solubility relationships, with inclusion of biorelevant media, were investigated. The best candidate was selected for a salt screen and physical form assessment. As part of this study, high-performance liquid chromatography (HPLC) assay and related substances method development was initiated. Non-clinical formulation development was then performed across three alternative technologies guided by the Developability Classification (DCS III), including the use of permeability enhancers that were suitable for oral liquid administration. These were evaluated by the client to establish their in-vivo PK profiles.
Outcome: Quotient Sciences was able to select one suitable compound for optimization based on material science and solubility determinations. A hydrochloride salt form was selected based on the fundamental physical properties of the molecule. Non-clinical studies confirmed the most effective formulation, with subsequent progression of one molecule through Good Laboratory Practice (GLP) toxicology to a successful Phase I clinical study.
Candidate development: Bridging from candidate selection to the clinic
Having selected a lead candidate drug molecule, the next goal is to complete all of the necessary and sufficient activities that will gain regulatory approval to begin a Phase I clinical trial in humans. As well as presenting an acceptable PK profile and demonstrating in-vivo efficacy, it becomes important to show that the candidate drug has a good safety pharmacology margin with an acceptable drug-drug interaction (DDI) profile. Access to increasing quantities of drug substance becomes more critical at this stage, and it is important to consider the feasibility of Good Manufacturing Practice (GMP) suitable for early development.
At Quotient Sciences, we bridge drug substance chemistry activities with formulation and drug product development activities under a single organization, informing the candidate development program with molecular-level knowledge guided by clinical experience. We select the appropriate salt or physical form to optimize a molecule for both manufacturability and downstream product performance. In addition, we can incorporate excipients or different counter-ions as co-components to further improve product performance while facilitating formulation development. We use state-of-the-art instrumentation to probe solid-state characteristics and purity profiles of different active pharmaceutical ingredient (API) forms under specific stress conditions, which can be used predictively to further accelerate progression of the drug substance to a clinically optimal product. Again, our detailed understanding of the molecular properties and their relationship with bulk properties offers speed, novelty, and robustness with no compromise on quality. For example, as we scale up the production of the drug substance, we will look to characterize the isolated material for both amorphous and crystalline content. By recognizing a thermodynamically metastable state, we can provide enhanced product performance and mitigate the risk of conversion to an undesired, thermodynamically more stable state by establishing tight processing controls for GMP drug substance manufacture.
It is widely recognized in the industry that one of the greatest contributors to drug failure in early clinical development is poorer than expected human PK. With the emphasis on pre-clinical studies to demonstrate an acceptable safety margin by administering relatively high doses to look for in-vivo acute or chronic toxicity, it can be significantly difficult to predict human PK at the much lower, therapeutic dose. The molecular structure, physical form, salt selection, and choice of excipients in the clinical formulation are intertwined and interdependent factors that contribute to the observed human PK performance. In-depth knowledge of the drug molecule can be incredibly powerful when combined with Quotient Sciences’ unique, streamlined Translational Pharmaceutics® platform. Tightly integrating drug substance synthesis, molecular properties, analytical methods, drug product formulation, and regulatory approaches with a target product profile (TPP). Together with clinical testing in one of our clinics, utilizing our rapid ‘make-test’ cycles allows for live adaptation of the formulation to overcome unexpected PK. By integrating all these disciplines under a single organization, the unique properties of the candidate drug are matched to a highly adaptive, science-led clinical study design, which has been demonstrated to shorten development timelines by over 12 months, saving more than $100 million in R&D costs.
Science-led candidate selection and candidate development
The decision to select the right molecule at the end of the discovery phase is a critical milestone in advancing any new medicine. Candidate development involves the coordination of a number of different activities across a number of different disciplines. The speed and complexity of the subsequent candidate development journey to a FIH clinical trial is intrinsically linked to the molecular structure and the selection of the right salt, the right polymorph, the right formulation, and ultimately the design of the right product and the right clinical trial. Engaging early in the candidate selection stage with a drug development scientist with clinical experience can help provide a broader, more holistic assessment of the optimized lead molecules.
Quotient Sciences’ unique integrated approach gives customers access to expertise and capabilities that aid in selecting the optimal candidate for moving forward into development, along with the knowledge of how to holistically translate molecular-level characteristics throughout the entire development process. This approach to candidate development demonstrably reduces the overall time and cost of getting new medicines to patients in need.
Please click here to view Quotient Sciences’ latest on-demand webinar: “Navigating the Small Molecule CMC Pathway: Strategies for Avoiding Regulatory Hurdles & Early Drug Development Pitfalls”.
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