Iclepertin was Boehringer’s first-in-class asset for treating Cognitive Impairment Associated with Schizophrenia (CIAS) and was the most advanced new chemical entity in BI’s pipeline, reaching Phase III with breakthrough designation (BTD) granted by US FDA and China CDE. Iclepertin has challenging physiochemical and material properties with low solubility and a tendency to amorphize and agglomerate under mechanical stress, leading to reduced bioavailability for patients. The R&D team faced difficulties in producing DS batches with consistent particle size and establishing CMC control for DS and DP quality, posing significant challenges and risk for clinical supply and regulatory filing due to the tendency of Iclepertin to form polymorphs that were hard to characterize by traditional methods.
This presentation illustrates how a DS-DP Interface team rose to the challenge and found the root cause while demonstrating similarity in properties and justified a proposal with the agency at the End of Phase II meeting, which gave better flexibility for DS control and supply. We also devised a suitable isolation process for DS to mitigate agglomeration issues, ensuring DS supply and transfer to Operation, and established the Critical Quality Attribute (CQA) for DS, allowing good control of DP for clinical supply. The team's approach and learning set an example and were later applied in several other programs. By moving away from functional thinking and adopting a scientifically driven, deliverable-focused approach to solving development challenges, the team set a precedent for other teams to follow.
