Nancy A. Melville

October 23, 2012

MINNEAPOLIS, Minnesota — In postmenopausal women being treated for osteoporosis, an investigational oral formulation of parathyroid hormone PTH(1-31)NH2 was found to be safe and effective, according to a new study.

The results were presented here at the American Society for Bone and Mineral Research 2012 Annual Meeting.

In the 24-week randomized double-blind phase 2 clinical trial, 5 mg daily of the oral formulation (being developed by Unigene Laboratories) was compared with placebo and with open-label teriparatide (Forteo, Eli Lilly), an injectable recombinant form of PTH, in 97 postmenopausal women with osteoporosis.

The trial met its primary end point. After 24 weeks, in the oral PTH group (n = 28), bone mineral density (BMD) at the lumbar spine increased 2.2% from baseline (P = .004). In the placebo group (n = 27), BMD decreased 0.17% and in the teriparatide group (n = 30) it increased 5.1% (P < .001).

"After an initial lag, the rate of increase in BMD for oral PTH between week 12 and week 24 was comparable to teriparatide," explained study coauthor Morten Karsdal, MSc, PhD, chief executive officer of Nordic Bioscience.

The increase in total hip BMD from baseline to 24 weeks was similar in the oral PTH and teriparatide groups. "There was a significant increase at the total hip, but not as much as with the injectable," Dr. Karsdal said.

However, there were differences in biochemical markers between the 2 drugs.

At week 24, the increase from baseline in the bone resorption marker CTx-1 was lower with oral PTH than with teriparatide (12.7% vs 124.6%).

In addition, the increase from baseline in the bone formation marker P1NP at week 24 was 12% with oral PTH group (P =.09) and 225% with teriparatide (P < .001); with placebo, there was a 1.75% decrease.

Likewise, at week 24, the increase from baseline in the bone formation marker osteocalcin was 23% (P = .015) with oral PTH and 172% (P < .0001) with teriparatide; with placebo, the increase was 4.9% (P = .87).

The most common adverse events in the oral PTH and placebo groups were mild to moderate abdominal pain or distress. There were no clinically significant instances of hypercalcemia, and elevated urine calcium was more common in the teriparatide group than in the placebo and oral PTH groups.

Five patients in the oral PTH group (15%) dropped out of the study because of an on-therapy adverse event, compared with 3 (9%) in the teriparatide group and 2 (6%) in the placebo group.

"If this oral PTH is developed, it would be the first oral anabolic treatment for osteoporosis," Dr. Karsdal explained.

He noted that several obstacles have stood in the way of bringing an oral form of the popular osteoporosis treatment to market. "Many have tried and failed to make oral formulations of peptides with protease inhibitors," Dr. Karsdal said.

"To get through the gastrointestinal tract and into the system, the drug must pass through the acidic environment of the stomach and through the intestine; this makes oral formulations a complicated process," he explained.

The new PTH tablet has an enteric coating that doesn't dissolve in the stomach; instead, it dissolves at neutral pH in the small intestine. The organic acid protease inhibitor, permeability enhancers, and peptide are released, and the peptide is absorbed across the intestinal wall via paracellular transport.

According to Nelson Watts, MD, director of Mercy Health Osteoporosis and Bone Health Services in Cincinnati, Ohio, interest in an oral PTH for osteoporosis is high, but hope is tempered with caution.

"A big challenge is, of course, to get peptide hormones across the digestive system. The surest way is through injection, but this new formulation apparently does allow a mechanism for delivery," he said. "It is impressive."

Dr. Watts noted that although the "results of the study are exciting in terms of having an oral delivery system, the changes in BMD are not the same as we would see with an injectable hormone.... This is an exciting first step, but people aren't going to be able to throw away their injectables just yet."

Kong Wah Ng, MD, director of the Department of Endocrinology and Diabetes at St. Vincent's Health in Melbourne, Australia, had a similar impression.

"I suppose the authors can claim that it is an anabolic agent, and thus better than an antiresorptive. However, overall, the effect is modest, compared with teriparatide," Dr. Ng said.

They will also have to "produce evidence showing that its use will not result in an increase in osteosarcoma, which is the major limiting factor with teriparatide. At this stage, it does not look like a game-changer," he added.

Dr. Karsdal, Dr. Watts, and Dr. Ng have disclosed no relevant financial relationships.

American Society for Bone and Mineral Research (ASBMR) 2012 Annual Meeting: Abstract 1101. Presented October 14, 2012.