Preclinical Development – Biomolecular
2019 PharmSci 360
Recent FDA Guidance on Immunogenicity (January 2019) requests for a summary of risk assessment to be provided as part of the Investigative New Drug (IND) Application. The summary is considered a living document that gets updated through the course of development as new information emerges from clinical trial experience as well as later stage process development. Such risk assessments rely on both product and patient specific factors. The liabilities can be proactively identified by specialized algorithms optimized using mined data as well as outputs from ex vivo human immune cell-based assays. A proactive evaluation of such risks can help in reducing/limiting the liabilities associated with structure/sequence and process (like hot spots in a sequence or propensity to aggregate or deamidate, excipient and device), as well as patient specific risks (diseased state, standard care, genetic background and demographics), hence improving the likelihood of such biologics to be safe and efficacious in clinic. Such a risk assessment strategy is in place within Merck and is being included with current IND submissions.
With the success of first-generation biologics like monoclonal antibodies, recombinant proteins and growth factors as well as targeted therapies, there has been an increased interest in second generation platforms, that can be as dramatically impactful on patient care. The desirable characteristics include superiority to first generation with respect to specificity to multiple targets at a time, treat more than one aspect of a disease simultaneously, improved expression and potency, other positive quality attributes, including better and cheaper production processes and a cleaner safety profile. To ensure success of novel innovative biologics on next generation innovative platforms, a strong understanding of risks and mitigating them during developability will need to be implemented.