DDT-BMQ-000054: Planning for biomarker qualification, implementation and dissemination for BMD as a surrogate biomarker in future osteoporosis treatment trials: the SABRE project

PROJECT SUMMARY Currently approved therapies for osteoporosis can reduce spine fracture risk by 50-75% and hip fracture risk by up to 50%. However, due to fears about very rare side effects, use of osteoporosis medications has declined by 50% since 2008. Therefore, there is a strong need for new therapies that have a strong safety

profile, perhaps with greater efficacy and convenience for the patient. However, new trials require fracture endpoints and must be very large: as long as 5-years with > 16,000 patients making the development of new medications extremely expensive and no longer feasible. The FNIH-ASBMR-SABRE (Study to Advanced BMD as a Regulatory Endpoint) began in 2013 with a primary

goal of qualifying the treatment-related change in bone mineral density (BMD) as a surrogate endpoint in future trials of new anti-osteoporosis therapies. Successful completion of this goal would prompt innovation and facilitate new drug development. To this end, we have collected individual patient data from >150,000 patients

in >50 randomized trials and used this unique resource to perform analyses to determine a strong relationship between larger BMD increase and greater fracture reductions in those trials. Starting in 2016, we began work with the FDA to obtain formal qualification of change in BMD as a surrogate endpoint for fracture in future trials. To date, our Letter of Intent and Qualification Plan have been approved by

the FDA and we submitted our Final Qualification Package in August 2023. FDA issued a Reviewability Memorandum in March 2024, agreeing to complete review by January 2025. The current proposal will fund our continued work on this project including responding to any questions during or following the review. If approved, change in BMD would be the first surrogate biomarker qualified by FDA.

Therefore, as part of this proposal, we will also address a number of unique questions regarding the practical implementation of this, the first FDA qualified, surrogate biomarker. For this project, we expect to be meeting with FDA to respond to the suggestions in the review of the FQP and after to advise on the implementation of this surrogate.

The qualification of BMD change as a surrogate endpoint for fracture in future trials of antiosteoporosis therapies would be a breakthrough in the field that would lead to expedited development of new medications and enormous benefits for osteoporosis patients and public health.