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Case Study

Using MBMA to run virtual “head-to-head trials”

Osteoporosis is common in post-menopausal women. The long-term sequelae of osteoporosis include bone fractures, particularly of the hip and vertebrae. Bone mineral density (BMD) of the lumbar spine (LS) and total hip (TH) are the canonical biomarkers for measuring the efficacy of osteoporosis drugs.

The sponsor had achieved regulatory approval in several countries for denosumab to treat this condition. Denosumab is a humanized monoclonal antibody that inhibits osteoclast-mediated bone absorption resulting in increased bone mass, volume, and strength.1 Treatment with denosumab significantly decreased the risk of bone fracture in women with postmenopausal osteoporosis.2

The challenge

The osteoporosis drug landscape is crowded with many competitors. A year-long clinical trial comparing denosumab and alendronate in postmenopausal women with low bone mass suggested that denosumab treatment significantly increased LS and TH BMD compared to alendronate.3 Denosumab has not been compared in clinical trials to other approved osteoporosis treatments.

The solution

Model-based meta-analysis (MBMA) was used to compare denosumab to the competition.4 The primary goal was comparing the time course of LS and TH BMD changes during treatment with denosumab or other osteoporosis drugs to gain insight into the effect of dose, dose frequency, and route of administration.

The MBMA used data from 142 clinical trials for preventing or treating postmenopausal osteoporosis. The drugs were grouped according to their MOA: bisphosphonates, selective estrogen receptor modulators (SERMs), parathyroid hormone (PTH), RANKL (denosumab), and calcitonin.

The MBMA analysis provided insight into how denosumab compares to other drugs approved for this indication without having to spend the time and money on running head-to-head clinical trials.

References

1. Kostenuik, P.J., et al. Denosumab, a fully human monoclonal antibody to RANKL, inhibits bone resorption and increases BMD in knock-in mice that express chimeric (murine/human) RANKL. J. Bone Miner. Res. 24, 182-195 (2009).

2. Cummings, S.R., et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N. Engl. J. Med. 361, 756-765 (2009).

3. Brown, J.P., et al. Comparison of the effect of denosumab and alendronate on BMD and biochemical markers of bone turnover in postmenopausal women with low bone mass: a randomized, blinded, phase 3 trial. J. Bone Miner. Res. 24, 153-161 (2009).

4. Mandema, J.W., Zheng, J., Libanati, C. & Perez Ruixo, J.J. Time course of bone mineral density changes with denosumab compared with other drugs in postmenopausal osteoporosis: a dose-response-based meta-analysis. J. Clin. Endocrinol. Metab. 99, 3746-3755 (2014).

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