Romosozumab Tops Teriparatide in Phase 3 Osteoporosis Study

Miriam E Tucker

April 02, 2016

Boston — The investigational agent romosozumab significantly promoted bone-mineral density (BMD) at the hip and spine compared with teriparatide (Forteo, Lilly), a parathyroid hormone (PTH) 1-34 replacement therapy, in postmenopausal women with osteoporosis who were transitioning from bisphosphonate therapy, a new open-label phase 3 study shows.

Data from Amgen and UCB Pharma's STRUCTURE trial were presented here at ENDO 2016 by Bente Langdahl, MD, PhD, professor at the department of endocrinology and internal medicine at Aarhus University Hospital, Denmark.

Romosozumab, which is administered subcutaneously once a month, is a novel investigational humanized monoclonal antibody that inhibits sclerosin, an osteocyte-derived inhibitor of osteoblast activity. The drug has the dual effect of promoting bone formation and inhibiting resorption. In the current study, "romosozumab provided significant improvements in hip bone strength in a population that remained at high risk of fracture despite bisphosphonate therapy," Dr Langdahl said.

Patients transitioning from oral bisphosphonates to romosozumab showed "consistent and significant gains in bone mass and estimated strength over teriparatide. At the hip, patients transitioning to teriparatide showed either no gains or significant decreases in these parameters," she reported.

Asked to comment, session moderator Sundeep Khosla, MD, of the Mayo Clinic, Rochester, Minnesota, told Medscape Medical News, "I think [romosozumab] is a very promising drug. Sclerostin is relatively specific for osteocytes in the bone, so the off-target effects should be low."

In a previous phase 2 multicenter, randomized, placebo-controlled study published in the New England Journal of Medicine and reported by Medscape, romosozumab increased BMD and bone formation and reduced bone resorption in postmenopausal women with low BMD. An accompanying editorial deemed the agent "a potential breakthrough in osteoporosis therapeutics" (N Engl J Med. 2014;370:476-477).

And in February 2016, the two companies announced top-line results from their large, ongoing phase 3 Fracture Study in Postmenopausal Women With Osteoporosis (FRAME), showing that romosozumab met the primary end point of reducing the incidence of new vertebral fractures and a secondary end point of reducing the incidence of clinical fractures, although it failed to meet another secondary end point of reducing the incidence of nonvertebral fractures through months 12 and 24.

Significant BMD Gains at Hip and Spine

In STRUCTURE, 436 women with postmenopausal osteoporosis (mean age 72 years) who had taken an oral bisphosphonate for at least 3 years prior to screening and alendronate in the year prior to screening were enrolled. They had BMD T-scores of –2.5 or below at the total hip, lumbar spine, or femoral neck and also had a history of fracture (vertebral or nonvertebral) after age 50.

They received daily calcium and vitamin D and were randomized to 210-mg subcutaneous romosozumab once monthly or 20-μg teriparatide once daily.

At baseline, the participants' mean T-scores were –2.2 for total hip, –2.9 at the lumbar spine, and –2.5 at the femoral neck.

The mean percent change from baseline in the primary end point, BMD at the total hip as measured by dual-energy X-ray absorptiometry through month 12 was 2.6% with romosozumab compared with –0.6% with teriparatide (P < .0001 between groups).

And at the lumbar spine, the changes at 1 year were 9.8% vs 5.4% for romosozumab vs teriparatide, respectively (P < .0001).

Quantitative computed tomography (QCT) revealed significantly greater gains in integral and cortical BMD with romosozumab compared with teriparatide at 12 months (P < .0001), and estimated hip strength gains were also significantly larger with romosozumab (P < .0001).

Some Concerns but a Promising Therapy

In all, adverse events occurred in 75.2% of patients treated with romosozumab compared with 69.2% with teriparatide, and serious adverse events occurred in 7.8% vs 10.7%, respectively. Arthralgia and nasopharyngitis were reported in 10% or more patients with romosozumab, and injection-site reactions were reported in 7.8%.

Three patients in the romosozumab group developed hypocalcemia, compared with none with teriparatide. In response to an audience member's question about the possible mechanism, Dr Langdahl pointed out that the levels were only slightly below the normal range and only one patient reported symptoms. "We can only speculate....We'll get much more data from the [ongoing] phase 3 trial."

Dr Khosla told Medscape Medical News that romosozumab would likely be indicated for use for only a year, after which women would be transitioned to an antiresorptive agent. "It's such a potent stimulator of bone formation, you don't want to overshoot," he said, noting that there have been concerns that bone growth in the vertebrae could cause nerve compression.

Nonetheless, he said, "It's a very promising therapy and I think as clinicians we're really awaiting its clinical availability. I have many patients who ask about it."

Dr Langdahl is a speaker for Amgen, Eli Lilly, Merck, Eli Lilly, and Orkla, and an advisor to Amgen, Eli Lilly, Merck, and UCB Pharma; disclosures for the coauthors are listed in the abstract. Dr Khosla had no relevant financial relationships.

ENDO 2016: The Endocrine Society Annual Meeting. Boston, Massachusetts; April 1, 2016. Abstract OR01-1

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