The transition of a drug from optimized medicinal chemistry lead to candidate nomination and development through clinical proof of concept has been referred to as the “Valley of Death.”1-3 It is the most consequential, high-risk period in a drug’s development. A relatively recent assessment indicates that the average success rate of development candidates in this portion of the drug development cycle is ~30%.4 During this interval, basic science knowledge needs to be translated into practical application in a clinical setting.
Translational research is the means by which the shift is made from basic to applied science. It has been stated that the “main objective of translational research is to make sure that the discoveries that advance into human trials have the highest possible chance of success in terms of both safety and efficacy in human studies.”2 This is an increasingly high bar to surmount.
Truly novel potential drugs tend to either engage a new therapeutic target, or an existing target via a new mechanism of action (MOA). The structures of these drugs, as well as their modes of action, raise significantly more fundamental questions about their safety, selectivity and efficacy than those raised for drugs that are more similar to those developed previously for a given indication. For this reason, nomination of development candidates for novel targets and/or MOAs can be protracted, due to the variety and number of studies necessary to allow a sound decision.
It is not uncommon for pharmaceutical companies, even small entrepreneurial ones, to perform this sort of in-depth “pre-preclinical” assessment of multiple leads for novel drug leads before selecting a candidate to move forward into preclinical development. These sorts of extensive assessments require more material earlier in discovery. This is further compounded if the leads in question are structurally complex and difficult to synthesize, as is frequently the case. The combination of these two trends in many classes of drug leads in recent years puts a significant additional burden on material supply even during early in vivo evaluation. Often, due to the inability to directly scale up difficult syntheses, the involvement of chemical development is required to address these issues, either on the part of the innovator company and/or their external vendors, well upstream of the point that their role has traditionally been necessary.5
The net result of the increased involvement of development functions upstream of formal candidate nomination is a blurring of the demarcation between when discovery ends and development begins. Chemical development is frequently started, de facto, by medicinal chemists, with development chemists gradually increasing their involvement until they formally take over at candidate nomination. The increased fluidity of this transition is a potential opportunity for enhancing CMC support of translational research, as long as it is tempered by the ability to systematically increase knowledge, strategize and plan. The discussion and analysis of the balance between fluidity and certainty in this article will be focused on the transition of small molecules from medicinal chemistry to chemical development and active pharmaceutical ingredient (API) manufacturing.
Medicinal Chemistry Emphasizes and Prioritizes Fluidity
Flexibility is required in the path taken to nomination of a development candidate, since there is uncertainty until a specific candidate is designated. During this period, many activities are being undertaken simultaneously, or are very aggressively overlapped. For the sake of expedience, it is often the case that a very inefficient (linear, long, low yielding, operationally cumbersome, time-consuming) route is being used for initial scale up in a medicinal chemistry group at the same time that attempts are being made to improve the chemistry for future production. In the short term, speed is prioritized, if possible, over more deliberate development efforts.
Chemical Development Depends on Certainty
Development chemists, in general, have tended to focus on certainty and granularity, for a number of reasons.
Development chemists are accustomed to taking a single molecule, rigorously characterizing it, and finding practical routes to its reproducible preparation in increasing quantities. Once a significant quantity of API is required for an early pivotal in vivo study, quality, cost and time, as it relates to the material produced, become much larger factors. In vivo toxicology and pharmacology vendors require certificates of analysis for material supplying larger, more extensive studies that are likely to impact the direction of the program, even if they are not yet IND-enabling. The sizes of the cohorts of these studies tend to be larger than for earlier studies, and the amount of material (test article) required is correspondingly larger. Ordering and reservation of animals for these studies is more costly and time-consuming, and there is usually a window in which the study can occur, without incurring a steep penalty and/or the need to reschedule the study for a later date. This requires careful planning and coordination of production and delivery of the test article, relying on some degree of predictability of yields, purity/impurity profile and reproducibility. Consistency of the purity, impurity profile and physical state of the API provided begin to take on more importance once preclinical in vivo studies increase in number and expand in size. Consistency in these attributes increases the level of confidence that effects seen in animals are primarily attributable to the drug itself, rather than impurities. Reproducibility and predictability of non-human in vivo dosage preparation recipes and protocols is also made possible by production of API batches that are more consistent.
Traditional approaches to chemical development require high granularity and certainty due to management of limited resources and scheduling the work in a way that allows timely delivery of the necessary material to the end-users. However, in situations where significant amounts of API are needed, the synthesis is difficult, and a candidate has not yet been nominated, development chemists need to be sufficiently flexible to accommodate and support material and overall program needs.
Challenges in the Transition Between Medicinal Chemistry and Chemical Development
When it is foreseen that a point of diminishing returns will be reached, regarding prioritization of speed over efficiency, a reckoning is necessary, in order to bridge the competing needs for fluidity and certainty, particularly as larger quantities of a drug candidate that is difficult and time-consuming to make are required. Based on the available knowledge and information, an approach needs to be agreed upon to develop and implement an enabling synthesis of the API, so that development requirements are met through Phase I clinical trials. Hallmarks of an enabling synthesis are that it is sufficiently practical, safe, scalable and amenable to implementation in kilo-lab equipment.
The challenge for medicinal chemists is to be able to participate in the transition of the candidate in a way that best serves their colleagues in development, regardless of whether these colleagues are permanent internal employees, consultants, and/or external CDMOs with whom the company is collaborating. This requires stretching to understand what is important for chemical development, which is often outside of the comfort zone of medicinal chemists.
Similarly, very fluid situations typically encountered and navigated effectively by medicinal chemists are outside of the comfort zone of many chemical development personnel. Historically, they may not be accustomed to accommodation of the uncertainty that is inherent to medicinal chemistry. This fluidity and uncertainty persists until formal candidate nomination, even if efforts are made to involve development chemists before this event, which is the formal beginning of development.
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How Can Medicinal Chemistry and Chemical Development Efforts Best Be Integrated, So That Net Effect is to Accelerate, Rather Than Slow the Formal Entry into Development
As has been mentioned above, significant involvement of chemical development increasingly occurs well before candidate nomination. Cimarusti and Kronenthal, in their review discussing the discovery/development transition,5 refer to this involvement as “prospective process research.” Medicinal chemists and development chemists need to work together closely upstream of the formal start of development. In previous eras of drug development, the separate functions of medicinal chemistry and chemical development were more siloed. The transfer of technology between the groups tended to be less dynamic and interactive, and more frequently “thrown over the fence.” In the current environment, that modus operandi is unsustainable. Multiple efforts need to coalesce in a way that is maximally productive –division of labor and streamlining are necessary in order to minimize or eliminate duplication of effort. This requires frequent and clear communication, and comprehensive oversight. Sharing of all relevant information is necessary in order to allow a timely assessment of the weaknesses of the medicinal chemistry synthetic route, with respect to efficiency and scalability. A strategy can then be devised to improve the route, within the constraints of time and budget, and driven by the quantities of material required for pre-nomination, preclinical and clinical supplies and milestones.
Characteristics of a good working relationship between medicinal chemistry and chemical development during the transition into preclinical development include:
- High transparency – coexistence and synergy between fluidity and certainty.
- Division of labor and data sharing to facilitate and organize multiple simultaneous eff orts.
- Timely communication of discovery stage in vivo study plans requiring significant amounts of test article, so that early scale up strategy can explicitly consider these needs.
- Judicious earmarking of material for development studies (solid state characterization, analytical development, process R&D) as soon as practically possible.
- Drafting and sharing an early CMC development plan, in order to align late discovery strategy with the transition into the preclinical development stage, to minimize delays due to lack of coordination and/or material, and remediate gaps in basic information.
- Nothing is thrown over the fence – understanding that the objective is to extract and leverage maximum knowledge, understanding and value from early synthetic and scale up work, and that this requires real time communication and follow up.
- Strong leadership, that has the perspective and experience to connect and coordinate the disparate functions that are involved in R&D and production during this stage, in which the depth and breadth of the program are expanding.
Summary
In order to have the highest impact on timing of the typical critical path CMC activities to IND fi ling and clinical proof of concept, it is necessary to skillfully and effectively navigate the interface between late medicinal chemistry and early chemical development. Focusing on the synthetic chemistry and API manufacturing aspect of CMC, there is a point in late discovery/early development at which expediency ceases to be useful in delivery of supply, and more systematic, deliberate efforts become necessary.
A key milestone in the capability to supply significant amounts of API reproducibly is the development of an enabling synthesis. It could entail as little as minor adaptations to the medicinal chemistry synthesis, or require a more involved overhaul. This underscores the need for a chemical development assessment, as soon as leads with a likelihood of being nominated as development candidates have been identified. During efforts toward this initial development goal, development chemists need to reconcile themselves to the reality that a candidate nomination process can be prolonged, and that this does not prevent the assessment and work that needs to be done in anticipation of a formal shift of the project into the realm of development. In order to facilitate the work of their development colleagues, medicinal chemists need to be as transparent as possible, provide all potentially relevant data, and remain ready and available to discuss the details. The requirement for transparency is compounded by the fact that during the pre-nomination period, transfer of this information is a very dynamic process – work is still ongoing. Understanding the capability of the medicinal chemistry synthesis is in the process of being evaluated, via attempts at scale up without modification of the synthesis. The abilities to keep the perspective of each function in mind, to value everyone’s role the process, and the recognition that fluidity and the emergence of certainty must co-exist, are crucial to a coordinated, efficient effort.
Time pressure and the technical and logistical complexity of basic and translational science continue to increase. This adds considerable challenge to the ability to provide timely test article supply, in the increasing quantities required. This has had the effect of increasing the extent of overlap of late medicinal chemistry and early chemical development. This overlap can be exploited as an opportunity to increase efficiency and contribute to success in traversing The Valley of Death, as long as the relevant participants are willing to proceed with understanding, clear communication, and collaboration.
References
- D Butler, Crossing The Valley of Death, Nature, 2008, 453, 840
- AA Seyhan, Lost in translation: the valley of death across preclinical and clinical divide – identification of problems and overcoming obstacles, Translational Medicine Commun., 2019, 4, 18
- MC Parrish, et.al., Surviving in the Valley of Death: Opportunities and Challenges in Translating Academic Drug Discoveries, Ann. Rev. Pharmacology and Toxicology, 2019, 59, 405
- A Thayer, Clinical Trials by the Numbers, Chem. Eng. News, 2016, 94(27), 26
- CM Cimarusti, DR Kronenthal, The Discovery/Development Transition, in Early Drug Development: Bringing a Preclinical Candidate to the Clinic, First Edition, Edited by Fabrizio Giordanetto, Wiley-VCH Verlag GmBH & Co, KGaA, 2018, 32