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P221: Transformation of Drug Development for the 21st Century: Primary Disease Biomarkers

Poster Presenter

Mark Kryah

Executive Director, Program Team Leader, Program and Portfolio Management
Ultragenyx Pharmaceutical Inc.
United States

Objectives

Discuss the need for a change from treating symptoms to addressing underlying disease. Describe a precision medicine term for disease management: Primary Disease Activity Biomarker (PDAB). Describe role PDABs play in treatment of underlying causes of rare genetic, neurological, and other diseases.

Method

Many products approvals between the early 1990s and late 2010s are cited that used biomarkers as a key element of their registration packages. Many diseases are also described where a PDAB is reasonably likely to predict clinical benefit and advance on accelerated approval.

Results

The accelerated approval regulations promulgated in 1992 and later ratified in law, were a response to the AIDS crisis and the demand for more rapid and effective drug development by AIDS activists and others. At the time, many at FDA and outside pundits charged that the new Accelerated Approval (AA) regulations would destroy drug development and lead to disastrously ineffective drugs, thereby distracting patients from real drugs developed with clinical endpoints. The truth was that the exact opposite happened. The first HIV drugs that were approved and gained reimbursement with CD4 cell counts as the biomarker were later followed by better drugs based on improved and an earlier biomarker of disease activity, namely HIV viral load. During the 16 years after the 1992 regulations went into effect, 29 drugs were approved with multiple mechanisms of action against the virus, including four multiple combination drugs that led to highly active anti-retroviral therapy (HAART) and the transformation of HIV infection from a death sentence to a chronic survivable disease. If AA had not been available, the process of running clinical trials would take years with variable endpoints like rate of opportunistic infections or mortality that would be difficult to power, highly variable, imprecise, confounded, and untenable. No HAART could have been developed without AA. This is the primary example supporting use of PDABs in Accelerated Approval. The basis for this presentation is from: Molecular Genetics and Metabolism 137 (2022) 107–113: Commentary: “The transformation of drug development for the 21st century: Time for a change” by Emil D. Kakkis

Conclusion

1. The sequencing of the human genome and therapeutic technology advancements have enabled so many diseases to be diagnosed, understood, and potentially treated, but drug development has not kept pace with these advances. The requirement that a drug improves how a patient feels, functions or survives has been the standard with regulators for decades, and more recently for reimbursement. However, for diseases like progressive neurological diseases, the change in clinical symptoms occurs very late in the course of illness, leaving little room to improve the underlying disease. One precision medicine approach to address the underlying disease is to develop a class of biomarkers that are a direct measure of the core underlying primary biology or as close to it as possible. Primary Disease Activity Biomarkers (PDABs) describe a precision medicine term for disease measurement, and particularly their roles in the study of treatments for rare genetic diseases. This can be a revolution in how we think about drugs, diseases, and treatment measurement that can transform drug development, and truly open the door to treatment of the underlying cause in rare genetic, neurologic and other diseases. 2. The concept of Accelerated Approval (AA) to approve drugs first on a biomarker before confirmatory studies, often expected to be ongoing, were completed. This initially was intended to speed access to treatment by months or years, but not intended to transform drug development. Implementation of AA is now essential to making life-saving therapies available to patients around the world.