By Jennifer Van Brunt

Our skeletons undergo a fair amount of remodeling throughout life: Cells known as osteoblasts build new bone, while cells called osteoclasts break it down. This is a coupled cycle, influenced by various hormones and other factors – including the all-important sex hormones. As we age, the relative abundance of the sex hormones changes: In older women, a decrease in estrogen levels can lead to bone loss and osteoporosis. In older men, elevated estrogen levels (caused by decreased androgen levels) can result in prostate cancer. To combat osteoporosis and certain cancers, drug developers have come up with a number of therapies aimed at restoring hormonal balances, decreasing the rate at which bone is broken down or stimulating bone formation. These include the bisphosphonates, calcitonin and parathyroid hormone – as well as the newer SERMs and SARMs (selective estrogen/androgen receptor modulators) and even a monoclonal antibody that targets a key molecular mediator of bone loss.

Early on, biotechnology companies searching for lucrative therapeutic franchises identified osteoporosis as one that was ripe for exploitation: Not only does this disease affect millions of individuals – men as well as women – but also the first class of drugs to hit the market were far from ideal. These drugs, which were actually so-called "sex" hormones, turned out to be double-edged swords: Estrogens, for instance, are able to prevent bone loss and the lowering of cholesterol, but they also increase the risks of uterine and breast cancer in women patients. In older men, elevated estrogen levels can lead to prostate cancer. The main androgen in men is testosterone, which is important for muscle size and strength and bone strength, among other typical male characteristics. In older men, the levels of testosterone decrease, resulting in various changes, including osteoporosis and bone fractures.

Over time, the catalog of risks associated with the estrogen-based drugs has expanded. Famously, Wyeth's conjugated estrogen drug Premarin, prescribed as an estrogen replacement therapy in post-menopausal women, was found to put patients at risk for stroke, deep vein thrombosis, coronary heart disease and even dementia. This is on top of the known risks of developing uterine cancer and possibly breast cancer. As a result, doctors now prescribe the lowest effective dose for the shortest amount of time possible for patients taking Premarin.

Apparently, the jury is still out on the safety of hormone replacement therapy: Most recently, Wyeth reported in the Archives of Internal Medicine that conjugated estrogen therapy did not increase the risk lf coronary heart disease in women aged 50 to 79 after about seven years of therapy.

Risky business

Despite the risks, though, hormone therapies have not been abandoned. Yet, drug developers are always on the hunt for newer, safer treatments. These include the non-hormonal therapies Fosamax, developed by Merck & Co. Inc. and Roche's Boniva, for instance. These drugs are classed as bisphosphonates, which are thought to decrease the rate at which bone is broken down. They also include Novartis' Miacalcin, a different sort of hormone, and Eli Lilly and Co.'s Evista (raloxifene), the first in a new class of drugs called selective estrogen receptor modulators (of which we will hear more later).

Merck's Fosamax, which the FDA first approved in September 1995 for treating osteoporosis in post-menopausal women, was then approved in April 1997 for preventing osteoporosis as well. And Lilly's Evista is also approved for preventing and treating osteoporosis in post-menopausal women. As well, it shows benefits for preventing breast cancer, but increases the risks of stroke and blood clots.

Of these newer drugs, Fosamax and Boniva are the most popular in the U.S., where 24 million prescriptions for bone health drugs were written in 2005. But the side effects can be severe, and have caused many patients to drop the drugs. Ill effects include heartburn, ulcers, esophageal bleeding and osteonecrosis of the jaw ("dead jaw"). Even though dead jaw is a rare side effect, lawyers have smelled the blood in the water, and are already soliciting clients in preparation for potential litigation.

Miacalcin's active ingredient is salmon calcitonin, a small hormone produced by the thyroid gland that is necessary for the proper functioning of bone, stomach, intestines and kidneys. Calcitonin has a dual mode of action: It inhibits osteoclast activity and promotes osteoblast activity, resulting in an increase in bone mass. The drug is delivered via nasal spray to treat post-menopausal osteoporosis. It's positioned as the drug of choice for women who won't or can't take estrogens and has been available in the U.S. since 1995.

Simply irresistible

Osteoporosis therapies, as we've mentioned, address a huge market. In terms of dollars, it's eminently appealing. In 2005, for instance, pharma giant Lilly reaped $1.04 billion from sales of Evista, which has been on the market since 1997. And the pharma sold $389 million of its newer osteoporosis drug Forteo, a recombinant parathyroid hormone fragment that was approved in November 2002.

In 2005, Merck's Fosamax franchise (which includes Fosamax Plus D) represented the most-prescribed medicines worldwide for the treatment of postmenopausal, male and glucocorticoid-induced osteoporosis, with global sales of $3.2 billion.

Wyeth's Premarin racked up $909 million in sales last year, and Novartis' Miacalcin (FDA-approved in 1995) harvested $365 million in 2005 sales. Boniva, marketed by Roche and GlaxoSmithKline plc (GSK), was launched in the U.S. in April 2005 and in Europe in September 2005. Sales for the year totaled about $65 million. This new drug comes in pill form and only needs to be taken once a month – and the convenience almost guarantees that sales will be very strong.

Plus, the patient population continues to expand. According to the National Osteoporosis Foundation, 44 million Americans, or 55 percent of individuals aged 50 and older, are at risk for contracting osteoporosis. Of those about 10 million people already have the disease, and 20 percent of those are men. By 2010, the number of individuals at risk could jump to 52 million.

Because osteoporosis is characterized by low bone mass and structural deterioration of bone tissue, the bones become fragile and susceptible to fractures, especially of the wrist, hip and spine. These last two place an enormous burden on the healthcare system: In 2002, the estimated expenditures by U.S. hospitals and nursing homes on hip fractures alone were $18 billion.

Bone loss is not restricted to osteoporosis, though: It's also a side effect of various types of cancer therapies. As well, several cancers can involve or metastasize to the bone, including lung cancer, breast cancer, prostate cancer, multiple myeloma, and others – indications that biotechs are pursuing, as we'll see.

Slow start

No wonder, then, that biotech companies are attracted to this market. Unfortunately, of the many firms that started out 10-15 years ago to develop new therapies for bone loss and osteoporosis, only a few have actually been able to get a product on the market. And even so, the competition from big pharma drugs is so intense that they've had trouble making a dent in overall sales.

Back in 1997, for instance, several biotech companies were developing their own versions of calcitonin, but most have fallen by the wayside. The product developed by tiny Unigene Laboratories Inc., however, managed to finally make it to the market. The company was testing its salmon calcitonin, called Fortical, as an injection and as an oral dose in the clinic. Finally, in August 2005, the FDA approved Fortical nasal spray for treating postmenopausal osteoporosis. Partner Upsher-Smith Laboratories Inc. has the U.S. rights to Fortical. Sales figures are not available, unfortunately, but Unigene says that pharmaceutical sales tracking services indicate the product is gaining market share. The company anticipates that it will be an important revenue-driver in the future.

At the same time, Unigene was investigating a parathyroid hormone (PTH) analog for osteoporosis in a 2002 partnership with giant GSK, which now has an exclusive license to the PTH technology and is conducting early-stage trials on the compound, which induces bone formation by increasing the number of osteoblasts. This ability to stimulate bone formation differentiates PTH from the other compounds mentioned above, which by and large act by preventing further bone loss by inhibiting bone breakdown or resorption.

GlaxoSmithKline wasn't the only big pharma exploring PTH's potential in osteoporosis: As you may recall, Lilly was actually the first to market, having garnered FDA approval for its recombinant PTH Forteo in November 2002.

A different tack

Unigene wasn't the only biotech firm working on PTH, however. Canadian firm Allelix Biopharmaceuticals Inc. was developing recombinant human PTH in a partnership with Swedish giant Astra AB, which was signed in June 1996. At the time, Allelix's compound (ALX1-11) was in Phase II clinical trials in post-menopausal women, where the drug showed an average increase in bone mineral density of seven percent in the spine over 12 months, Astra originally intended to take the product forward, but by September 1998 it had decided to cancel the deal altogether for undisclosed reasons.

That event turned out to be fortunate for NPS Pharmaceuticals Inc., which acquired Allelix in December 1999 – thereby bringing this advanced clinical-stage drug candidate in-house. NPS changed the product's name to Preos, and completed the clinical work and regulatory filings.

Preos also fit nicely with NPS' osteoporosis program on calcilytic compounds, which it is developing in partnership with GSK. Calcilytic compounds are small molecule antagonists of the calcium receptor that briefly increase the body's own secretion of parathyroid hormone which could result in new bone formation. GSK is running the clinical program. The lead product candidate SB-751689 was found to be safe and well tolerated in a Phase I trial. It also elicited a rapid and transient increase in circulating levels of endogenous PTH and the levels of key bone formation biomarkers suggest net bone formation. GSK plans to start later-stage trials early next year.

Preos was approved for sale in the European Union in April 2006 (where it is being marketed by Nycomed Danmark ApS under the name Preotact), but its fate in the U.S. remains questionable. NPS filed an NDA on Preos in May 2005 and the agency accepted the NDA for filing two months later. In March 2006, the FDA issued an approvable letter for Preos' use in treating post-menopausal osteoporosis – but asked for more data regarding hypercalcemia associated with drug dosing as well as the injection device used for the drug.

NPS has now decided that it will not be able to address the agency's concerns by analyzing existing clinical data. In June 2006, the biotech firm announced a cost-cutting and restructuring plan that included discontinuing all activities related to the U.S. commercialization of Preos. The company is still evaluating its course of action, but for now Preos sits on a shelf until a pharma partner agrees to fund additional clinical trials.

Yin and yang

Like bones, certain cancers are affected by the presence or absence of androgens and estrogens. As mentioned previously, these hormones are essential to life: Not only do they regulate the reproductive system, but also they affect the skeletal, cardiovascular, muscular and central nervous systems. It's the balance of the two that keeps the body functioning as it should.

In order for these hormones to do their job, they must interact with their receptors, thus setting off a cascade of events within the cell. If those events are unwelcome, then it should be possible to block them by preventing the hormone/receptor interaction.

Indeed, drugs that target these hormone receptors have been available for a half century. Steroids – either natural or synthetic -- stimulate androgen receptors. But they do so indiscriminately in all tissues bearing the receptors: While a testosterone-based drug can reverse age-related muscle wasting and a number of other conditions, for instance, it may also stimulate prostate cancer growth in men and masculinization in women.

To address these sorts of problems, a number of companies have focused on developing nonsteroidal small molecule drugs that act as selective androgen receptor modulators (SARMS) and selective estrogen receptor modulators (SERMS) to fight both bone loss and cancer.

In fact, some of the newer drugs to come out of big pharma are SERMs. We've already mentioned Lily's Evista, a SERM that's been approved for preventing and treating osteoporosis. And AstraZeneca plc's breast cancer drug Nolvadex, which is now available in the U.S. as generic tamoxifen, is also a SERM. Moreover, GTx Inc. is selling the SERM Fareston (toremifene) for treating advanced breast cancer. There are no SARMs on the market yet.

Fighting cancer

These experimental small molecule drugs are being tested for their abilities to fight cancer directly and also to stave off the serious side effects of some cancer therapies.

In prostate cancer, for instance, physicians generally treat patients with advanced, recurrent or metastatic forms of the disease with androgen deprivation therapy (ADT). ADT, however, can cause some serious side effects, including osteoporosis and bone fractures, lipid changes, and even hot flashes and breast swelling. To combat these side effects, GTX has turned to the SERM acapodene (toremifene citrate).

"Men develop prostate cancer when testosterone levels decline and the ratio of androgen to estrogen flips," explained Mitchell Steiner, GTX' co-founder and CEO. "If we block estrogen [receptors in the prostate], can we block prostate cancer?"

Importantly, toremifene is also the active ingredient in GTX' marketed drug Fareston, which is prescribed for treating metastatic breast cancer in post-menopausal women. The drug has been available in the U.S. for more than eight years and in Europe for nearly twice as long, meaning that there's an extensive record of the drug's safety in women, Steiner said.

GTx initially licensed the rights to develop acapodene for certain indications in men's health from Orion Corp. in March 2000; in January 2005 GTx expanded its control by licensing the U.S. distribution rights to Fareston in all indications (including breast cancer) and the worldwide rights to toremifene for all indications except breast cancer.

In June, the Memphis, TN company presented interim results of a Phase III clinical trial testing acapodene in prostate cancer patients at the 42nd annual meeting of the American Society of Clinical Oncology (ASCO). In these patients, who were on ADT, the drug produced highly statistically significant increases in bone mineral density (BMD). This, in turn, should result in fewer fractures, a main goal of the study (the primary endpoint is a reduction in vertebral fractures).

GTx is also conducting a pivotal Phase III trial testing acapodene's ability to prevent prostate cancer in men with precancerous prostate lesions (PIN, or prostatic intraepithelial neoplasia). These men are at high risk for contracting the disease: About half of those diagnosed with high grade PIN via biopsy develop prostate cancer within three years. Steiner said that this is a three-year trial, and the first peek at efficacy will occur in the second half of 2007 or the first quarter of 2008. "We are asking for a 30 percent reduction in prostate cancer," he explained. "There are no other companies in this space," Steiner said, although some firms are testing chemopreventive drugs in low-risk patients or those with elevated PSA (prostate specific antigen) levels. The men in GTx' trials, though "are the highest-risk patients," he added.

GTx has more compounds in the clinic, too: Ostarine, a SARM, is being tested in various disease settings, including muscle wasting and bone loss in elderly men and women, the subject of a Phase II trial. It's developing another SARM, called andarine, in partnership with Ortho Biotech Products L.P. for treating cancer-associated cachexia, or muscle wasting. And GTX' third SARM, prostarine, is in preclinical development for benign prostatic hyperplasia.

The long way home

GTx is not the only small company to tackle SERMs and SARMs, though, nor is it the first. That honor no doubt goes to Ligand Pharmaceuticals Inc., which has probably invested more time and energy into developing SARMs and SERMs than any other company.

In June 2001, Ligand forged a joint R&D alliance with TAP Pharmaceutical Products Inc. to discover and develop SARMs. By the spring of 2005, TAP had filed an IND on a compound discovered under this collaboration – LGD2941, an androgen agonist which it is testing as a therapy for osteoporosis and frailty.

Although Ligand claims that its SARM program has been one of its largest over the last several years, the biotech company's earlier collaborations focused on SERMs. In May 1991, for instance, Ligand and pharma giant Pfizer Inc. signed an alliance to develop better therapies for osteoporosis. One compound that emerged from this deal is lasofoxifene, a second-generation estrogen partial agonist. Pfizer conducted clinical trials on this drug for the prevention and treatment of osteoporosis, vaginal atrophy and the prevention of breast cancer.

The pharma submitted an NDA on lasofoxifene – trade name Oporia -- for preventing osteoporosis in postmenopausal women in August 2004 and an sNDA for the drug's use in treating vaginal atrophy in December 2004. Unfortunately, the FDA sent Pfizer non-approvable letters for both indications in September 2005 and February 2006, respectively. Apparently, Pfizer is still in discussions with the FDA about those letters and has not dropped product development yet.

Building a franchise

Ligand also signed a major women's health collaboration with Wyeth in September 1994 – a deal that initially involved screening both parties' compound libraries for progesterone and estrogen receptor modulators for use in hormone replacement therapy, cancer, and other diseases.

Of the many potential compounds stemming from this long-term collaboration, Wyeth currently is focused on two SERMs -- bazedoxifene (TSE-424) and bazedoxifene CE – both for postmenopausal osteoporosis. In fact, the big pharma submitted an NDA on bazedoxifene for preventing osteoporosis in late June 2006.

At the same time, the company submitted an NDA for desvenlafaxine succinate, a non-hormonal agent for treating vasomotor symptoms associated with menopause, such as hot flashes and night sweats. This product was developed from Wyeth's in-house programs, explained Joseph Camardo, the company's SVP, Global Medical Affairs.

In fact, Wyeth researchers are also developing desvenlafaxine as a therapy for major depressive disorder. The company filed an NDA on this drug candidate, a serotonin-norepinephrine reuptake inhibitor, in late December 2005. Its potential use to alleviate menopausal symptoms is "a new indication for our product," Camardo said.

Wyeth also intends to continue development of bazedoxifene CE (Premarin combo) as a progesterone-free treatment for menopausal symptoms – especially in the light of the caution with which doctors and the FDA now view hormone replacement therapies (HRT) in postmenopausal women (including Wyeth's Premarin; see above for details).

In fact, this conservative outlook could be behind the agency's decisions to issue non-approvable letters for Ligand/Pfizer's Oporia, which though not a hormone per se, still acts like one. If so, then the FDA could express reservations about bazedoxifene, too.

Wyeth has developed an important franchise in women's health, so branching out into SERMs and other non-hormonal drugs was a natural. And all the more important because of the issues raised in HRT. "We continue to support our women's health business. It's where we want the company to be," Camardo said.

A different path

Of all the biotech companies seeking to expand into new markets, Amgen Inc.'s R&D program in osteoporosis and cancer-associated bone problems has drawn the most attention from analysts and industry observers. That's because Amgen has so far confined itself to so-called niche markets – yes, even anemia associated with end-stage renal disease is a niche in this regard, with about 400,000 people on long-term dialysis – rather than the very broad markets encompassed by common diseases such as osteoporosis (as you may recall, 44 million Americans, or more than half the population over the age of 50, are at risk for developing osteoporosis).

If the biotech heavyweight breaks into the massive market for osteoporosis therapies – pegged at about $6 billion in worldwide sales today – it will do battle face-to-face with products such as Merck's Fosamax, which by itself reaped $3.2 billion in worldwide sales last year, and Roche/GSK's Boniva, which is still new to the market.

The product in question is denosumab (formerly AMG162), a fully human monoclonal antibody (created via Abgenix Inc.'s XenoMouse technology) that targets the receptor activator of nuclear factor kappa B ligand (RANKL), a key mediator of the formation, function and survival of osteoclasts, the cells responsible for resorbing or breaking down bone.

In fact, RANKL is the primary mediator of bone loss. Its expression is first induced in osteoblasts (which build bone) by growth factors, hormones and cytokines, after which RANKL binds to the RANK receptor on osteoclasts (which remove bone), activating them.

But RANKL can also be inhibited by a molecule called osteoprotegerin (OPG), which acts as a decoy receptor for RANKL. This results in the inhibition of osteoclast formation and survival, and, thus, the inhibition of bone loss. "OPG is an important mediator in this process," explained Willard Dere, Amgen's chief medical officer and SVP of global development. "It acts as a soluble substitute for RANKL."

Amgen's antibody denosumab works by specifically binding to RANKL, thus preventing it from binding to its receptor. This event inhibits the differentiation, activation and survival of osteoclasts – and, therefore, inhibits bone loss. According to Amgen, the antibody is more potent and has a longer half life that OPG.

RANK Ligand is also a key mediator in the vicious cycle of bone destruction in metastases. Simply put, tumor cells interact with the bone marrow to drive bone destruction and tumor growth. Tumor cells secrete various factors that stimulate the production of RANKL, which results in bone resorption. In turn, the bone releases growth factors which increase the production of factors that promote tumor growth. Tumor cell proliferation stimulates the production of RANKL – and so forth.

Breaking the cycle

According to Dere, "The RANK pathway was deeply explored by Amgen scientists 10 years ago." This important discovery in bone biology and understanding of the various factors and checks and balances that are involved in the pathway have resulted in the specific design of the company's therapeutic antibody candidate.

Amgen is testing denosumab in various disease indications, including osteoporosis, bone metastases in breast cancer; bone loss induced by hormone ablation therapy in breast and prostate cancer; rheumatoid arthritis; and multiple myeloma.

The product's already in late-stage trials, and Amgen intends to make significant investments in the drug's development going forward – especially an increase in the number, size, duration and complexity of the trials. This means lots of trials that encompass 200 or more sites each as well as trials in new geographic locations.

The most advanced clinical programs center on osteoporosis and cancer, with two Phase III trials in postmenopausal osteoporosis (prevention and treatment) and several Phase III trials in breast cancer and prostate cancer.

Amgen reported interim results of a Phase II trial of denosumab in postmenopausal women with low bone mass at the American College of Rheumatology annual meeting in November 2005. The antibody, dosed twice yearly, was able to increase bone mineral density in the spine, hip, radius and total body at 24 months, as compared to placebo.

Phase II trials of denosumab for treating bone metastases to prevent skeletal related events (fractures and other complications) were fully enrolled last year, and Amgen reported the interim results at this year's ASCO meeting. In two trials, denosumab treatment rapidly suppressed bone turnover in advanced cancer patients with bone metastases, which are not only painful but also can lead to complications, including fractures and bone surgery.

The fact that Amgen's denosumab targets RANK Ligand makes it stand out among the other treatments for bone loss – and may eventually give it an edge in the market. Even so, it will be up against some strong and well established competitors, backed by major pharmaceutical houses that will fight to keep the lead.

This article originates from Signals Magazine

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