Integrated Applied Clinical Pharmacology in the Advancement of Rare and Ultra-Rare Disease Therapeutics

The introduction of safe and effective rare/ultra-rare disease treatments is a focus of many biotherapeutic enterprises. Despite this increased activity, a significant unmet need remains, and the responsibility to meet this need is augmented by enhanced genomic, biologic, medical, analytical, and informatic tools. It is recognized that the development of an effective and safe rare/ultra-rare disease therapeutic faces a number of challenges with an important role noted for clinical pharmacology. Clinical pharmacology is foundationally an integrative discipline which must be embedded in and is interdependent upon understanding the pathogenic biology, clinical presentation, disease progression, and end-point assessment of the disease under study. This manuscript presents an overview and two case examples of this integrative approach, the development of C5-targeted therapeutics for the treatment of generalized myasthenia gravis and asfotase alpha for the treatment of hypophosphatasia. The two presented case examples show the usefulness of understanding the biological drivers and clinical course of a rare disease, having relevant animal models, procuring informative natural history data, importing assessment tools from relevant alternative areas, and using integrated applied clinical pharmacology to inform target engagement, dose, and the cascade of pharmacodynamic and clinical effects that follow. Learnings from these programs include the importance of assuring cross-validation of assays throughout a development program and continued commitment to understanding the relationship among the array of Pd end points and clinical outcomes. Using an integrative approach, substantive work remains to be done to meet the unmet needs of patients with rare/ultra-rare disease.