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Experimental Drug Produces Only Modest Increases in BMD at Lumbar Spine, Actual Decrease at Total Hip: Presented at ASBMR

By John Otrompke

DENVER -- September 16, 2009 -- A trial of an experimental drug produced disappointing results in terms of increasing bone marrow density (BMD), and was terminated early due to a lack of efficacy, according to an oral presentation here at the 31st Annual Meeting of the American Society for Bone and Mineral Research (ASBMR).

The protocol for the trial was first amended, and then the trial was pulled when SB-751689, an experimental calcium-sensing receptor agonist, produced modest, but statistically significant gains according to some measures, but actually negative results according to other measures.

"We called it because of futility; there was no efficacy," explained Lorraine A. Fitzpatrick, MD, Medicine Development, GlaxoSmithKline, Collegeville, Pennsylvania, on September 13.

In the phase 2, double-blind, placebo-controlled study, 569 postmenopausal women were enrolled to open-label teriparatide or randomised to placebo, alendronate, or SB-751689 100, 200, 300, or 400 mg. All of the women participating were at least 5 years past menopause.

The trial was scheduled to last for 1 year, and an interim analysis was performed at 6 months, when the trial was terminated early.

At months 10 through 12, a modest but statistically significant increase in lumbar spine BMD was seen in the SB-751689 dose groups. The increase was from 1.4% to 1.9% in the groups receiving from 200 to 400 mg of the experimental drug. The increase in the alendronate group was 4.7%, however, and in the teriparatide group it was 9.2%.

Measured at the total hip, SB-751689 administration resulted in a decrease in total hip BMD between 0.6% and 1.2%, in contrast to increases in the alendronate and teriparatide groups.

"In terms of the total hip bone marrow density, all of them were numerically below placebo, and 1 dose was statistically significantly below placebo," said Dr. Fitzpatrick.

While in the escalated-dose arms, SB-751689 performed similarly to alendronate in the vertebral spine, performance was improved in the trabecular region, but not in the cortical region, according to Dr. Fitzpatrick.

"We think we created a sustained primary hyperthyroidism in these participants," said Dr. Fitzpatrick, who noted that that too much parathyroid hormone mimics primary hyperthyroidism, and that studies have found that hyperparathyroidism results in the preservation of the trabecular architecture.

Funding for this study was sponsored by GlaxoSmithKline.

[Presentation title: The Calcium-Sensing Receptor Antagonist, Ronacaleret (SB-751689) Causes Modest Increases in Trabecular but Not Cortical BMD by QCT in Postmenopausal Women. Abstract SA1128]

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