BOSTON, Massachusetts—Using primary disease biomarkers as endpoints for drug approvals could dramatically speed and transform the development of treatments for rare diseases, keynote speaker Emil Kakkis, MD, PhD, said at the opening day of the 2022 World Orphan Drug Congress (WODC).

The presentation by Dr. Kakkis, chief executive officer and president of Ultragenyx Pharmaceutical, described biomarkers as “based on the primary genetic basis of disease” and related to “the primary biochemical process and not secondary downstream effects.”

He used the analogy of a car crash and faulty brakes. Instead of focusing on the number of crashes and how to reduce it, drug developers and regulators should focus on measuring and fixing the brake system, he said.

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“You do things that are related to the problem at hand, but not to the source. We want to get people to start focusing on the source,” he said in an interview after his talk. “That’s where we think we actually make the progress of treating diseases and where we need to go in the 21st century.”

Dr. Kakkis said increasing the use of biomarkers in the approval process would not just speed the development of specific drugs, but would revamp the entire process.

Dr. Kakkis, who has worked in the field for 30 years, argued that biomarkers are better predictors of treatment effectiveness than clinical endpoints and they facilitate an earlier start of treatment.

Drug approvals based on biomarkers may be essential for some diseases, and it is the only option for the treatment of some diseases, he said. For example, the brain is very plastic and adaptable, meaning that clinical manifestations of some diseases may not become apparent until patients have suffered substantial irreversible damage to areas such as the neuromuscular system or bones. There may not be enough reversible damage left to be treated if primary biomarkers are not used to detect disease early, he said.

He pointed to HIV treatments as an example of the value of using primary biomarkers as well as accelerated approvals. Using the CD4 count biomarker, and, later, viral load, 25 new drugs and 4 combinations were granted accelerated approvals in 16 years. That would have been impossible to do with using clinical outcome endpoints, he said.

He published an article in 2016 which reported that no products for rare genetic diseases approved based on biomarkers by the US Food and Drug Administration over a 5-year period were later found to be ineffective.

Dr. Kakkis is also a former assistant professor of pediatrics at Harbor-UCLA Medical Center in Torrance, California, and is the founder and director of the EveryLife Foundation for Rare Diseases.

The WODC, held July 11-13, 2022, in Boston, Massachusetts, was attended by about 850 people.


Keynote address: drug development in the 21st century – The use of primary disease activity biomarkers to establish efficacy. Presented at: World Orphan Drug Congress; July 12, 2022; Boston, MA.

Kakkis ED, Kowalcyk S, Bronstein MG. Accessing the accelerated approval pathway for rare disease therapeutics. Nature Biotech. 34;380-383. doi:10.1038/nbt.3530.

Senior Correspondent Larry Luxner contributed to this story.