“Therapy development for ALS is challenging for many reasons,” said Michael Benatar, M.D., Ph.D., professor of neurology, the Walter Bradley Chair in ALS Research, and executive director of the ALS Center at the University of Miami. “Biomarkers with prognostic and pharmacodynamic utility have great potential to help overcome these challenges.”
Dr. Benatar and colleague Joanne Wuu, Sc.M., research associate professor, were the lead authors of the collaborative study, “Validation of Serum Neurofilaments as Prognostic and Potential Pharmacodynamic Biomarkers for ALS,” published May 8 in the American Academy of Neurology’s journal Neurology. Miller School co-authors were Lanyu Zhang, M.S., research analyst; Lily Wang, Ph.D., associate professor of public health sciences; Volkan Granit, M.D., assistant professor of neurology; and Jacob L. McCauley, Ph.D., associate professor of human genetics and pathology, and director of the John P. Hussman Institute for Human Genomics Center for Genome Technology.
In the study, detailed clinical data and biological samples were collected longitudinally from 260 patients with ALS and related disorders through the multi-center Phenotype-Genotype-Biomarker study of the Clinical Research in ALS and Related Disorders for Therapeutic Development (CReATe) Consortium. The researchers focused on two types of neurofilaments, the complex proteins found in blood or spinal fluid when neurons degenerate in diseases like ALS.
Using the serum samples, independent contract research organizations performed blinded assays for neurofilament light (NfL) and phosphorylated neurofilament heavy (pNfH) to determine if either would be useful as a biomarker with specifically defined purposes. “We found that serum NfL, but not pNfH, may be considered a clinically validated prognostic biomarker for ALS,” said Dr. Benatar. “That is, serum NfL levels may help predict prognosis.”
The study also found that levels of both types of neurofilaments were elevated but remained stable over the long term. That’s a key finding for a biomarker, because any significant reduction in NfL or pNfH in a clinical trial could thereby indicate a therapeutic effect, according to Dr. Benatar.
Looking ahead, Dr. Benatar explained that the use of neurofilament light as a pharmacodynamic biomarker in phase II clinical trials could substantially reduce the number of patients needed to enroll in order to show proof-of-concept – that the new therapies are indeed exerting the intended biological effect. Importantly, this could in turn inform a “go/no go” decision at the end of a phase II clinical trial about whether the larger (and more costly) phase III trial is warranted for the therapeutic candidate.
“Taken together,” said Dr. Benatar, “we are optimistic that these biomarker findings will accelerate the drug development process.”