Novel Osteoporosis Drug Promising in Early Study

Promising but did not prove to be effective.....

Novel Osteoporosis Drug Promising in Early Study
By John Gever, Senior Editor, MedPage Today
Published: September 17, 2009
Reviewed by Dori F. Zaleznik, MD; Associate Clinical Professor of Medicine, Harvard Medical School, Boston


Action Points
--------------------------------------------------------------------------- â– Explain to interested patients that bone is alive, with new bone continuously formed and old bone resorbed. Explain that parathyroid hormone is an important regulator of new bone formation and is therefore a target for osteoporosis drug development.

â– Explain JTT-305 is not FDA-approved for any purpose and is available only in a clinical setting.

â– Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered preliminary until published in a peer-reviewed journal.

DENVER -- Another calcium sensing receptor (CaSR) antagonist has shown promise as an osteoporosis treatment in an early clinical study, but skeptics wondered whether it will ultimately succeed where an earlier effort in this direction failed.

JTT-305, under development by Japan Tobacco, significantly increased lumbar spine bone density in a 12-week trial while showing favorable effects on markers of bone formation and resorption, according to Seiji Fukumoto, MD, of the University of Tokyo.

Fukumoto reported the findings here at the American Society for Bone and Mineral Research's annual meeting.

But Lorraine Fitzpatrick, MD, a researcher at a competing firm who led clinical development of a CaSR antagonist that failed in phase II testing, said the results suggested JTT-305 might have its own problems.

The CaSR mediates release of parathyroid hormone, a critical player in bone dynamics. One current drug, teriparatide (Forteo), mimics the effects of parathyroid hormone to increase bone formation and density directly, while most other osteoporosis drugs, such as bisphosphonates, work by inhibiting resorption.

Some researchers believe that inhibiting the CaSR will increase natural parathyroid hormone output to achieve the same effect as teriparatide. Where teriparatide is a recombinant peptide that requires a daily injection, the CaSR can be antagonized with orally active small molecules -- including JTT-305.

Fukumoto's study tested two doses of the drug against placebo for 12 weeks in 154 postmenopausal women with osteoporosis, average age 66, in a randomized, single-blind fashion.

Baseline lumbar spine T scores ranged from -3.1 to -3.2 among the three treatment groups.

The marquee result was that lumbar bone mineral density (BMD) increased 2.35% in the patients taking 10 mg/day of JTT-305, a major improvement in just three months of treatment.

Patients in the placebo group saw an increase of 0.90% (P<0.05). A 20-mg dose of the drug led to a mean lumbar BMD increase of 1.80% (not significant versus placebo).

The study did not measure fracture rates or effects on BMD at other sites such as the hip or wrist.

Biomarkers of bone turnover, including collagen-associated peptides (NTX in urine and CTX and PINP in serum) as well as osteocalcin, indicated significant favorable effects for JTT-305 relative to placebo and to baseline.

Unlike the lumbar BMD results, though, the higher dose generally had the more powerful impact on these markers.

The downside for JTT-305 was that it led to significant, dose-dependent increases in corrected serum calcium relative to placebo.

At week 12, mean corrected calcium levels were about 10.5 mg/dL in the 20-mg group and 10.1 mg/dL with the 10-mg dose. Calcium levels in the placebo group remained steady at 9.4 mg/dL. The normal range for serum calcium is 8.4 to 10.2 mg/dL.

An earlier study in healthy postmenopausal women had shown that marked increases in parathyroid hormone seen after dosing persisted for about six hours, creating a "shoulder" in the concentration-time curve.

Such a profile, along with the heightened serum calcium, suggested mild hyperparathyroidism, said Fitzpatrick, a senior researcher at GlaxoSmithKline.

Fitzpatrick led clinical studies of a CaSR antagonist called ronacaleret, co-developed by GlaxoSmithKline and NPS Pharmaceuticals, for which favorable early-stage results were reported at ASBMR's 2008 meeting. (See ASBMR: Old Idea for Keeping Osteoporosis in Check Gets New Airing)

But two weeks later after those presentations, the company said it was terminating an ongoing phase II study and cancelling further development of the drug, citing lack of efficacy.

Fitzpatrick provided a postmortem on ronacaleret in two presentations here preceding Fukumoto's.

The drug had shown modest but significant efficacy in increasing lumbar spine BMD, but total hip BMD decreased, she said. Serum calcium levels had also increased, and parathyroid hormone was persistently elevated, similar to what Fukumoto reported for JTT-305.

The combination of mild hyperparathyroidism and limited efficacy killed the drug, she said.

In an interview after the presentations, Fitzpatrick said a narrow therapeutic index was probably a class effect for CaSR antagonists.

"The question is, can they get the dose low enough to miss [the parathyroid hormone shoulder], to get the anabolic effect or not?"

Noting that osteoporosis is not directly life-threatening and that other drugs are available, she said it could be difficult for products with a narrow therapeutic index to gain approval.

The challenge for Japan Tobacco, she added, is to "tweak the drug to make it behave just the way they want it to."

Fukumoto characterized the results as "promising," adding that "further study is necessary to prove the long-term efficacy," both for BMD and for reducing fracture rates.

The JTT-305 study was funded by Japan Tobacco.

Fukumoto reported a consulting relationship with Japan Tobacco. Other researchers on the study were Japan Tobacco employees.

Fitzpatrick is an employee of GlaxoSmithKline.


Primary source: American Society for Bone and Mineral Research
Source reference:
Fukumoto S, et al "Randomized, single-blinded placebo-controlled study of a novel calcilytic, JTT-305, in patients with postmenopausal osteoporosis" ASBMR 2009; Abstract 1131.