Osteoporosis Clinical Trials, Not for the Faint-Hearted

Fifteen years. That is the time it took from when Amgen accidentally discovered via big mice an "essential pathway that regulates bone metabolism" to the FDA's approval last month of Prolia for the treatment of osteoporosis in postmenopausal women at high risk for fracture. Amgen is currently recruiting in Phase III trials for the same treatment and indication in men. NCT00980174 is the http://clinicaltrials.gov identifier for that ADAMO trial.

Prolia, or denosumab, is unique in that it is the first and only RANK Ligand inhibitor approved for this indication. In addition, denosumab is the first biotechnology product to be approved for osteoporosis. As an anabolic, it builds up organs and tissues using naturally occurring metabolic pathways, or in this case, the RANK ligand inhibitor blocks the bone loss imbalance caused by the RANK ligand and allows denosumab to mimic bone-protecting effects of a specific protein.

Colin G. Miller, PhD, Senior Vice President of Medical Affairs at BioClinica (Newtown, PA), spoke to Applied Clinical Trials about Prolia and osteoporosis clinical trials in general. "Anabolic compounds actually change the bone metabolism rather than bisphosphonates, which stick in the bone to prevent or reduce osteoclastic resporption," explained Miller. Because of this mechanism of action, Prolia is considered superior to the bisphosophonates.

Therapeutic corner

The most popularly known bisphosphonate is Fosamax (Merck), which fell off the patent cliff February 2008, is generic, and grouped with Boniva (Roche and GlaxoSmithKline) and Actonel (Warner-Chilcott and Sanofi-Aventis). These are the oral formulations and are associated mostly with gastrointestinal (GI) side effects. These tablets can be taken once a day, once a week or once a month. Considering that the patient is recommended to stand for at least 30 minutes after dosing, the once a month option is probably better for lifestyle issues. Novartis' bisphosphonate Reclast is a once-a-year injection, so it bypasses the GI issue.

However, Prolia is a twice-yearly injection, which as far as formulation and lifestyles go, is a good thing toward compliance. Here's a negative for compliance: the ability to pay. Prolia will cost approximately $850 per injection.

While shares of Amgen rose on the news of its back-to-back U.S. and European approvals, and positive feelings based on the first biotech approval in this area with success after a long clinical trial process, the current payment atmosphere is not so glowing.

Here are some basic facts on osteoporosis, according to the International Osteoporosis Foundation:

• One in three women over 50 will experience osteoporotic fractures, as will one in five men.

• Osteoporosis affects an estimated 75 million people in Europe, the United States, and Japan.

• By 2050, the worldwide incidence of hip fracture in men is projected to increase by 310% and 240% in women.

• Nearly 75% of hip, spine, and distal forearm fractures occur among patients 65 years old or over.

• The peak number of hip fractures occur at 75 to 79 years of age for both sexes.

All these statistics sound like a positive for the pharmaceutical industry as far as potential sales go. In fact, the global osteoporosis market has been forecast by Research and Markets to be worth between $8 billion to $10 billion this year and nearly $14 billion by 2014.

According to Miller, the picture becomes a bit cloudy on the post-fracture outlook. After a hip fracture, the typical prognosis for the 75+ is approximately 20% will go on to fracture the second hip, about 20% are likely to have increased morbidity, and 20% will die. Therein lies the problem for prescribing medication after the diagnosis. The disease has already progressed too far and now spills into the cost benefit and quality-of-life issue spectrum.

Most 75 to 80-year-olds in the United States have their drugs paid by Medicare. With the likelihood that Medicare would prefer to pay the generic prices of a bisphosphonate vs. the injection of a superior anabolic at a higher price point, Amgen may be facing longer-term struggles toward the success of Prolia, which has projected sales of $1 billion a year by 2012. In fact, Amgen is evaluating Prolia in metastatic bone disease in the United States so that it will be able to take advantage of the bone loss issue caused by over-expression of Rank Ligand in some cancers, where analysts predict it may actually make more money. The European Commission approved Prolia—in addition to the osteoporosis in postmenopausal women indication—for bone loss associated with hormone ablation in men with prostate cancer at increased risk of fractures. GSK will co-market the drug in Europe and the rest of the world.

Biomarker research

Oncology indication aside, in order to find the people who would most benefit from a preventive drug before the disease progresses, a strong biomarker would be needed.

"Four years ago, we were approached by Novartis to help find a better biomarker to predict spine fracture, and help enrich the population used in trials," Miller said. In fact, at press time, BioClinica and collaborators, Novartis and Optasia Medical (Manchester, UK) were finalizing their joint press release on their results, which have appeared in the medical journal Spine.

Those results are now being used in a five-year epidemiological study to see if the process can accurately predict spine fracture as the potential process has shown. This process is using modeling or simulation software that can read x-rays to identify vertebral deformities or abnormalities that it models based on an initial development and placement of 88,000 discrete points taken on lateral spine X-ray films from 150 subjects.

Miller said there were other biomarkers in development, which could help spur the current stasis of the osteoporosis clinical trials market, including fractal analysis and finite element analysis. While not the most robust of therapeutic areas, there are osteoporosis drugs in development on hold out there in Phase II and Phase III. And these are more likely to be smaller companies that are waiting on funding. This would include Radius Health's PTH BA058 (parathyroid hormone), which also builds bone and concluded Phase II trials successfully in August 2009. It has a http://clinicaltrials.gov identifier of NCT00542425.

And funding is not easy to come by for biotechs these days, or osteoporosis trials for that matter. Miller says osteoporosis is one of the most expensive therapeutic areas in which to conduct a Phase III trial. Miller listed the factors, including: a high number of patients to power the trial, between 3000 and 4000, who then need a DEXA test, spine films, and blood draws that are all centrally read, as well as visits every three months. The trials run for a minimum of 18 months and go to at least three years.

Factor in that the average price for the cost per patient for Phase III trial, without the multiple criteria stated above is $26,000. Factor in that for every patient enrolled, five are screened. The Prolia Phase III trial, NCT00089791, consisted of 7808 subjects. "A pharmaceutical company could develop two analgesics for one osteoporosis drug," said Miller, by way of comparison.

But for those companies willing to continue to tackle the hurdles of osteoporosis drug development, the way may be paved with biomarker development. Drugs in development include different drug deliveries or formulations (i.e., a nasal spray). Some are reformulations of calcitonin, which has been available for quite some time and is a hormone that affects blood concentrations and calcium. Another compound based on PTH is in development by Novartis, following on Forteo from Lilly, which was the first approved PTH and is delivered daily via pen injection.

FRAX Tool PORTED to iPHONE

FRAX, or the fracture risk assessment tool, is a free online fracture-risk calculator that was developed by the World Health Organization Collaborating Center for Metabolic Bone Diseases at the University of Sheffield, UK. The online tool itself can be accessed at http://www.shef.ac.uk/FRAX. However, the future is calling and the FRAX developers have made the tool available for the Apple iPhone.

Courtesy of Apple

The FRAX algorithms give a 10-year probability of fracture. The model was developed from information on fracture risk factors from 12 prospectively studied population-based groups in diverse geographic regions, including North America, Europe, Asia, and Australia. As mentioned, the tool is available online as well as for the iPhone (but not for iPhone 4.0 yet), and as a downloadable one-page, two-sided questionnaire in PDF format.

The iPhone application was launched this past May in Florence, Italy, during the World Congress on Osteoporosis 2010. It is anticipated that the FRAX iPhone app, selling for $5.99, will "vastly increase the accessibility of the FRAX tool to thousands more physicians and health care practitioners worldwide."

According to Colin G. Miller, PhD, Senior Vice President of Medical Affairs at BioClinica (Newtown, PA), the FRAX tool builds in multifaceted information to make for more robust and accurate identification of fracture risk. Miller said that more European agencies are adopting the FRAX criteria for fracture risk as an end-point in clinical trials, and believes that ultimately it will be adopted more widely in the United States.