Biologic therapeutics (biologics) are isolated from living organisms whether they be human, animal, or microorganism. Examples of biologics include proteins, nucleic acids, viruses, or cells. Biologics also vary in size and complexity and exert their therapeutic effects through an array of mechanisms. Regardless of their complexity or size, all therapeutics must achieve certain development milestones to ensure the optimal candidates progress while the less optimal do not. The only way that this selection process can occur is through informed decision making. In this blog, I’ll describe some important strategic considerations for successful development of these challenging therapeutics.
The Biologics Roadmap from NME to IND
A few of the primary preclinical development milestones are new molecular entity (NME) declaration, lead selection, meeting with health authorities at the pre- investigational new drug application (IND) phase, and then filing an IND. Meeting these milestones requires answering multiple questions:
- What data are required to move in vivo therapeutics through these milestones?
- How are you going to collect that data?
- When do you need that data?
While there isn’t a single correct method to carry a complex biologics program through pre-clinical development into first-in-human studies, the necessary considerations will be consistent. These include determining the target product profile (TPP), the starting dose, the dose interval and range, and the optimal biological dose.
What is a TPP?
A TPP is a dynamic resource that serves to guide development decisions across functional areas by creating alignment around a product’s attributes and outcomes. It should include plans around the geographies that you plan to seek marketing authorization in (US, Europe, Japan, etc.) as well as the indication and patient population that you want to be approved in the drug label. The TPP should also consider the commercial landscape, and how this new drug will fit into it.
The format of this document varies between organizations, molecules, and therapeutic areas. Be sure to include all relevant information in your TPP. The TPP is a living document and needs to integrate data as it becomes available.
How to Choose the First-in-human (FIH) Starting Dose
Selecting the FIH starting dose is a difficult aspect of pre-clinical development for several reasons. Complex biologics, especially those that modulate the immune system, can have exaggerated and unexpected pharmacology. Another common challenge is that pre-clinical models often fail to predict the potential for human toxicity or beneficial immune modulation.
In light of these challenges, how do we provide dosing guidance for molecules with high risk characteristics or minimal translatable data? Start by defining the molecule’s level of risk. The risk associated with the safety of a therapeutic will impact the dose level and method by which it is selected. In general, higher risk molecules usually have lower starting doses than lower risk molecules. When you’ve assessed the level of risk, try to define the dose- or exposure-response relationship using the relevant pharmacodynamic or even toxicology parameters depending on the level of risk.
Dose Selection Methods
Understanding the dose- or exposure-response relationship will help you select an appropriate FIH dose. The dose selection method (minimum anticipated biological effect level- MABEL; minimal pharmacologically active dose- MPAD; no anticipated adverse effect level- NOAEL, among others) you use depends on the molecule’s risk. Use more than one method to calculate multiple potential starting doses and be clear about your rationale for choosing these methods.
Biomarkers and Pharmacodynamics (PD)
Often you have to make important clinical development decisions in the absence of clear-cut guidance. Biomarker and PD readouts can inform those decisions, but this is only possible if you ask the right questions during pre-clinical development. If you don’t ask the right questions, you risk gathering unclear biomarker or PD data that you don’t know what to do with. So, consider what decisions you need to make. What data will inform those decisions? Which specific biomarkers provide that data, and at what point in dose escalation will you observe changes in those biomarkers?
A Robust Clinical Pharmacology Roadmap is Key to Success with Complex Biologics
In summary, biologics are growing in complexity, and many applications are currently in oncology. Key milestones have to be carefully considered in pre-IND early development. These include the TPP, evaluating risk, and selecting a FIH study dose. Attaining these milestones is more complex for complex biologics than for small molecules or simple biologics.
The clinical pharmacology roadmap for complex biologics is centered on the predicted relationship between dose or PK and PD, safety or response in any of the above relationships and also identifying sources of population variability.
Using this roadmap, we can attain marketing authorization and provide new drugs that can help patients. To learn more about strategic considerations for successfully developing complex biologics, watch this webinar.