Biomarkers are a major interest for myotonic dystrophy (DM), but understanding of their utility (Context of Use) in clinical trials can be elusive. The ‘flavors’ of biomarkers relate to the ways they are utilized: diagnostic, prognostic, predictive, pharmacodynamics (PD) and pharmacokinetic (PK). The right biomarkers are invaluable in selecting/stratifying patients, determining on-target activity, and dosing and assessing efficacy and safety of candidate therapies. Arriving at the “right” biomarkers to minimize uncertainty and aid decision-making is essential, but nontrivial, as experiences in Duchenne have so clearly shown.
A simplistic view is that a molecular endpoint identified in a laboratory study can be a panacea in accelerating drug approval. The reality is that, in moving beyond the discovery phase, a range of questions, from methodological to interpretive, must be answered before a biomarker has validity.
Given the high bar for regulatory qualification, biomarker studies ultimately must reside within collaborative networks that recognize that no one gets to the solution alone. A key barrier to overcome is that biomarker qualification is uncharted territory for most academic researchers.
Two recent initiatives, the BEST Resource (Biomarkers, EndpointS, and other Tools) and the Framework for Defining Evidentiary Criteria for Biomarker Qualification, are aimed at clarifying terminology and process with all stakeholders, and thereby accelerating qualification and use of biomarkers in therapy development programs.
The FDA-NIH Joint Leadership Council, dedicated to improving regulatory science, developed the BEST Resource. BEST initially focused on harmonizing the terminology of translational science and biomedical project development. The intent is to provide clarity and consistency in communications among all stakeholders. The BEST glossary is an invaluable resource, going well beyond biomarker and endpoint terminology to provide a wealth of examples and informational links.
The Framework for Defining Evidentiary Criteria for Biomarker Qualification, a partnership led by the Foundation for the NIH that includes NIH, FDA, PhRMA, the Critical Path Institute and pharmaceutical companies, provides “a general framework to assist the development of biomarkers for qualification, to improve upon the quality of submissions to the FDA and to clarify the evidentiary criteria needed to support the biomarker’s "Context Of Use" (pdf). The ready availability of these criteria increases transparency of the qualification process and thereby facilitates interactions between biomarker developers and FDA.
What opportunities exist to exploit these new tools in biomarker development for DM? In a recent DM Research News, MDF highlighted the potential for FDA biomarker qualification of a panel of splicing events identified with the Myotonic Dystrophy Clinical Research Network (DMCRN). The recent clarification of evidentiary standards will markedly aid this effort. In addition, the Wyck Foundation and MDF recently funded Dr. Thurman Wheeler (Massachusetts General Hospital) to explore miRNAs in serum and urine as DM1 biomarkers. While this is a discovery-phase project, it’s important that the new qualification guidance is taken into account even by studies at such an early stage.
A recent publication by Ms. Alessandra Perfetti, Dr. Fabio Martelli and colleagues (IRCCS Policlinico San Donato) piloted circulating miRNAs as putative biomarkers for DM1. Dysregulated miRNAs included miR-1, miR-27b, miR-133a/-133b, miR-140-3p, miR-206, miR-454 and miR-574. Elevated miRNAs correlated with impaired muscle strength and elevated MCK, and could readily distinguish DM1 (103 subjects) from controls (111). Some of the miRNAs identified in DM1 patient samples are non-specific in that they also are dysregulated in Duchenne (miR-1, mIR-206 and miR-133a/-133b), but that does not preclude their potential value as prognostic, predictive, PD or PK biomarkers in DM1. Before a biomarker can be qualified, more extensive studies must assess how this miRNA profile links to pathogenic or regenerative processes across multiple organ systems, and show if these miRNAs are suitable in tracking disease progression and/or drug efficacy.
To achieve qualified DM biomarkers, we all must speak the same “BEST” language and assimilate, rather than silo, lessons learned from each study. But most of all, the DM research community must adopt a highly collaborative culture (valuing community needs over individual publications), since validated, quantitative assays, well-powered and phenotypically rich data sets and inter-site validation are essential in navigating the pathway to effective drug development tools.
BEST (Biomarkers, EndpointS, and other Tools) Resource
FDA-NIH Biomarker Working Group.
Validation of Plasma MicroRNAs as Biomarkers for Myotonic Dystrophy Type 1.
Perfetti A, Greco S, Cardani R, Fossati B, Cuomo G, Valaperta R, Ambrogi F, Cortese A, Botta A, Mignarri A, Santoro M, Gaetano C, Costa E, Dotti MT, Silvestri G, Massa R, Meola G, Martelli F. Sci Rep. 2016 Dec 1;6:38174. doi: 10.1038/srep38174.