Exploring biomarker strategies in rare disease therapeutics
Innovative biomarker strategies and regulatory flexibility from the FDA are helping to streamline rare disease therapy development, addressing patient needs more effectively.
During the 2024 AAPS PHarmSCi 360 conference in Salt Lake City, Dr. Yow-Ming Wang, associate director for biosimilars and therapeutic biologics in the Immediate Office of Clinical Pharmacology at CDER, FDA, shared insights on innovative biomarker strategies critical to developing therapeutics for rare diseases.
"Developing drugs for treating rare diseases has special challenges, such as a small patient population and disease heterogeneity," Dr. Wang revealed during her prologue presentation.
She also emphasized that biomarker strategies, regulatory flexibility and advanced bioanalytical methods are helping to overcome these challenges to deliver effective treatments for rare disease patients.
The role of biomarkers in rare disease drug development
Dr. Wang explained the central goal of drug development as "giving the right drug to the right patient at the right dose and the right time."
Biomarkers -- defined by the FDA in its BEST (Biomarkers, EndpointS, and other Tools) Resource -- are measurable indicators reflecting biological processes, responses, or conditions. They can track pharmacodynamics, disease progression and treatment efficacy, which is invaluable in rare disease trials where small patient cohorts and disease diversity make clinical assessments challenging.
"Biomarkers can play a significant role in determining the appropriate dose, treatment timing, and overall therapeutic response," Dr. Wang stated.
By incorporating biomarkers into trial designs, researchers can make more precise evaluations, helping to support robust efficacy and safety data essential for regulatory review.
Biomarkers can play a significant role in determining the appropriate dose, treatment timing, and overall therapeutic response.
Dr. Yow-Ming WangAssociate director for biosimilars and therapeutic biologics, Immediate Office of Clinical Pharmacology, CDER, FDA
Regulatory flexibility in rare disease development
Rare disease therapeutics must meet the same regulatory standards as treatments for more common conditions, but the FDA offers sponsors flexibility in fulfilling these requirements.
"In either case, sponsors need to demonstrate evidence of effectiveness in an identified population from adequate and well-controlled clinical investigations," Dr. Wang continued. "However, FDA's regulation does provide flexibility in how the regulatory standard may be met."
This flexibility is vital for rare disease research, where limited patient populations require unique considerations for clinical trial design and data analysis.
The FDA introduced the Accelerating Rare Disease Cures (ARC) program to advance these efforts in 2022. As Dr. Wang described, ARC aims "to drive scientific and regulatory innovations and engagement to accelerate the availability of treatments for patients with rare diseases."
ARC facilitates collaboration between regulatory, scientific, and patient communities, fostering innovation across clinical endpoints, biomarker usage, and trial design. Workshops held under the ARC program cover topics ranging from quantitative modeling to patient engagement, making it an essential resource for stakeholders seeking a comprehensive view of evolving FDA standards in rare disease therapeutic development.
Case studies of biomarker strategies in action
Dr. Wang highlighted several FDA-approved therapies that used biomarker strategies and innovative designs to address the challenges inherent in rare disease trials. These case studies underscore how biomarkers can streamline clinical development by providing critical data on efficacy and safety in smaller, more flexible trials.
1. Vestronidase alfa for Sly syndrome
Vestronidase alfa (Mepsevii), an enzyme replacement therapy for mucopolysaccharidosis type VII (MPS-VII), also called Sly syndrome, faced the unique challenge of a limited patient base and disease variability. Researchers employed a dose-titration approach with biomarkers to demonstrate dose-response relationships in a Phase 1/2 study to address this. According to Dr. Wang, "This innovative design provided proof of mechanism of action, showed dose-related pharmacological effects, and supported the selection of a 4 mg/kg dose for the phase 3 trial." In addition, by using pharmacodynamic (PD) biomarkers, researchers could monitor treatment effects in real time, allowing for flexible dose adjustments within the trial to optimize efficacy.
2. Velmanase alfa for enzyme deficiency
Another example is Velmanase alfa (Lamzede), which treats a rare enzyme deficiency. Researchers relied on biomarkers as a confirmatory endpoint to demonstrate the drug's effect on lung function, exercise capacity, and overall health in a small cohort of 25 patients. The study met key endpoints through a well-controlled trial, supported by strong mechanistic evidence. "The confirmatory evidence included the well-established etiology of the disease, the drug's mechanism of action and pharmacodynamic data showing statistically significant biomarker reductions," Dr. Wang described. This data was essential in building a compelling case for regulatory approval, particularly given the small patient sample and the inherent variability in clinical endpoints.
3. Pozelimab for CHAPLE disease
Pozelimab (Veopoz), used for treating CHAPLE disease, leveraged PD biomarkers to evaluate efficacy across multiple endpoints, including albumin levels and reductions in hospitalizations. With only 10 enrolled patients, the study provided a single-arm trial design that centered on measurable improvements in key biomarkers. Dr. Wang described the FDA's approach, noting, "In the setting of a very rare disease with an unmet medical need, regulatory flexibility is warranted, as it allows for meaningful data collection in a small cohort." This balanced approach allowed for a compelling regulatory case, despite the trial's limited size.
Bioanalytical methods and validation in biomarker strategy
Bioanalytical validation is a foundational component of an effective biomarker strategy, ensuring that biomarker data is robust and reliable for regulatory decision-making. The FDA's guidance on bioanalytical method validation outlines rigorous standards for assay validation, particularly when biomarkers will support a regulatory submission.
"Biomarkers are very diverse; they can be small molecules, proteins, cells or even radioligands," explained Dr. Wang.
Dr. Wang's insights at AAPS 2024 PHarmSCi 360 underscored the FDA's commitment to advancing biomarker strategies and flexible regulatory pathways, accelerating rare disease therapeutic development. Programs such as ARC and Model-Informed Drug Development create innovative approaches in a traditionally challenging field.
By fostering collaboration and applying tailored regulatory guidance, the FDA is helping to bring safe, effective treatments to rare disease patients more efficiently.
"Innovative approaches are needed to meet the complex demands of rare disease therapeutic development, and the FDA is committed to driving scientific and regulatory innovations to accelerate the availability of treatments for patients with rare diseases," Dr. Wang concluded.
Alivia Kaylor is a scientist and the senior site editor of Pharma Life Sciences.
