Lean Derisking: Smart Ways to Cross Drug Development’s “Valley of Death”

Moving from the preclinical to clinical stage in drug development is a costly and complex process. But there are strategic ways to streamline the process and reduce risk and costs.

In a recent webinar hosted by API, Sir Michael Houghton, Chief Scientific Officer at API and Director of the Li Ka Shing Applied Virology Institute at the University of Alberta, and API colleagues discussed how best to bridge the drug cycle’s “valley of death.”

It’s never too early for developers to consider how to translate research to the clinic, Houghton said. Taking a small molecule from discovery to first-in-human studies costs between $3-5 million, so founders must have a strategy beyond nondilutive funding, added Daren Ure, Executive Scientist, Discovery & Early Development at API.

They must consider the type of proof-of-concept data that will support this translation, Houghton said. A derisked program offers consistent mechanism-of-action evidence, potency, safety, selectivity, pharmacokinetic (PK) profile and drug interactions evaluated from biochemical binding through cells to animal models, Ure said. Evaluated from biochemical binding through cells to animal models, Ure said.

Artificial intelligence (AI) and computation tools can assist in filtering large discovery libraries into smaller, manageable sets of candidates that can move forward in trials, Ure added. Although AI has not routinely delivered a single “perfect” molecule without further experimentation, it is already improving efficiency.

Ultimately, derisking programs translate into a reduction of failure probability, said Daniel Trepanier, Executive Scientist, Preclinical Development at API. A staged approach in terms of in silico filters (considering physicochemical properties, solubility, predicted PK and toxicity), followed by in vitro ADME (absorption, distribution, metabolism and excretion), cytotoxicity and genotoxicity, then animal PK to choose a true lead therapy, he explained.

Academics should consider a SWOT analysis and map a clinical development plan at the very start, Houghton said. Launa Aspeslet, Chief Translational Officer at API agreed, adding that at initiation developers should think about how to align preclinical models with the target clinical trial population, identifying biomarkers and surrogate endpoints and ensuring scalable manufacturing and realistic formulation timelines.

API’s flexibility and agility allow it to tailor project scope and budgets instead of imposing large, fully staffed project teams or bloated proposals, Aspeslet said. API can provide either wraparound development or à la carte services.

Patent life pressure is a considerable overhang, Houghton and Trepanier said. Discovery plus preclinical and Phases 1–3 typically must fit into an approximately 10–13 year timeframe, so discovery cannot drag on continuously, Trepanier added. That said, there must be a balance between filing early enough in competitive spaces and inadvertent disclosure before and during filings. Simple, minimal early formulations to get through IND-enabling and early trials could underscore many patents, Trepanier said, while nurturing more sophisticated, patentable formulations in parallel once development advances.

Market feasibility even at this early stage is crucial, Ure said. Developers need to evaluate whether Big Pharma might license an asset and how it would fit into their portfolio.

Regulatory requirements should be considered through the translational and early clinical processes, said Aspeslet. FDA programs such as Orphan Drug Designation, Breakthrough Designation, Priority Review and Accelerated Approval can be explored. Early, ongoing dialogue with regulators is encouraged to consider mechanisms such as adaptive designs, rolling submissions and use of supportive nonclinical or external clinical data, she noted. Developers should review guidance for their specific modalities to understand the nuances, added Houghton and Ure.

All those involved should consider definitive go/no-go benchmarks in terms of trial continuation, Houghton said, and maintaining them to avoid sunk cost traps.

Even at the earliest stage, future manufacturing should be eyed, Trepanier said. He advised designing synthetic routes with scalability in mind, as that is aligned with fewer steps, higher yields, stable drug substances and accessible reagents not vulnerable to political supply shocks, before transferring to a CDMO.

CDMO selection should take a measured approach, he said. Early stage cost pressures may mean a less expensive vendor selection, but sponsors may come to realize that some shortcuts may need correcting later.

API’s global scale manufacturing allows for build-out of small molecules and RNA biologics, and is slated to be one of North America’s larger biomanufacturing facilities, Houghton said. This attraction drew him to become API’s CSO, with plans to manufacture RNA hepatitis C vaccines he is developing, through the Canadian Critical Drug Initiative, at the site.