The U.S. Food and Drug Administration has agreed to accept bone mineral density (BMD) as the primary endpoint for Entera Bio's Phase 3 trial of EB613, representing a paradigm shift in osteoporosis drug development that could accelerate the path to market for the first oral anabolic osteoporosis treatment.
In a written response to a Type A meeting request, the FDA confirmed that Entera Bio's NDA marketing application filing for EB613 would be supported by a single multinational, randomized, double-blind, placebo-controlled, 24-month Phase 3 study in women with postmenopausal osteoporosis. The study will evaluate change in total hip BMD as the primary endpoint, with incidence of new or worsening vertebral fractures as the key secondary endpoint.
Transforming Clinical Trial Economics
This regulatory milestone fundamentally alters the economics of osteoporosis drug development. Traditional osteoporosis trials have required fracture incidence as the primary endpoint, necessitating large, multi-year studies with thousands of patients that often exceed $500 million in costs. Entera Bio's Phase 3 study is projected to enroll just 400 patients over 24 months—a stark contrast to the 10,000+ patient trials typical of fracture-based studies.
The shift reduces development costs by an estimated 70% while shortening the timeline to market by 18-24 months. "This regulatory update is a major milestone for Entera and the entire osteoporosis community," said Miranda Toledano, CEO of Entera Bio. "Our alignment with the FDA reflects the strength of our data and collaborative discussions."
Scientific Foundation for BMD Endpoint
The FDA's decision is supported by robust scientific evidence from the Study to Advance BMD as a Regulatory Endpoint (SABRE) initiative. The SABRE meta-analysis of 63,000 patients across 22 trials demonstrated that a 1% increase in total hip BMD corresponds to a 12-15% reduction in fracture risk, with a correlation coefficient of R² = 0.73—significantly stronger than the blood pressure-stroke relationship (R² = 0.37) that forms the basis for antihypertensive therapy approval.
The SABRE team submitted a full qualification package to the FDA's Biomarker Division in November 2023, with a decision expected by October 2025. However, Entera Bio can proceed with its clinical development program without waiting for this formal qualification.
Addressing Unmet Medical Need
EB613 targets a significant unmet medical need in osteoporosis treatment. Over 200 million women globally are estimated to have osteoporosis, with one in two women over age 50 expected to suffer a fracture due to the condition. Despite the availability of efficacious injectable anabolic treatments, adherence rates are as low as 30% due to the requirement for daily subcutaneous injections.
"Osteoporosis afflicts more women than heart attack, stroke and breast cancer combined," noted Toledano. "No new drug for osteoporosis has been approved by FDA since 2019, and innovation has stalled for close to a decade due to the size, duration, cost and ethical constraints associated with fracture endpoint studies."
EB613 Clinical Development Progress
EB613 (oral PTH 1-34, teriparatide) completed a Phase 2, 6-month, 161-patient, placebo-controlled study that met all biomarker and BMD endpoints without significant safety concerns in women with postmenopausal osteoporosis or low BMD. The treatment produced rapid dose-proportional increases in biochemical markers of bone formation, reductions in markers of bone resorption, and increased lumbar spine, total hip, and femoral neck BMD.
The Phase 2 data showed that EB613's effects on trabecular and cortical bone using 3D-DXA demonstrated increases compared with placebo in various indices, including integral volumetric BMD and trabecular volumetric BMD, cortical thickness, and cortical surface BMD. The findings were consistent with published subcutaneous teriparatide data at the 6-month time point.
Market Implications
The regulatory breakthrough positions EB613 to potentially capture a significant share of the $2.3 billion anabolic therapy segment within the broader $4.5 billion osteoporosis treatment market. With oral therapies typically achieving adherence rates of 60% compared to 30% for injectable treatments, EB613 could address a critical barrier to effective osteoporosis management.
Substantial evidence supports the efficacy of anabolic therapies over bisphosphonates for lowering fracture risk in osteoporosis patients at high risk. However, all currently available anabolic therapies require subcutaneous injection and are used in only a minority of eligible patients. EB613 is intended to increase skeletal mass, improve bone microarchitecture and reduce the risk of fracture as the first oral, once-daily anabolic tablet treatment for osteoporosis.
