Oporia (Lasofoxifene) - Investigational SERM for the Prevention and Treatment of Osteoporosis

The product of a joint development programme between Pfizer and Ligand Pharmaceuticals, Oporia (lasofoxifene) is a selective oestrogen receptor modulator (SERM). It is indicated for the prevention and treatment of osteoporosis in post-menopausal women.

In August 2004 Pfizer submitted an NDA to the FDA for the use of Oporia (lasofoxifene) as a preventative therapy for osteoporosis based on data from phase III clinical trials. An additional filing for treatment of vaginal atrophy followed in December 2004.

Oporia (lasofoxifene) is the first of three late-stage SERM products under development by Ligand Pharmaceuticals to have been submitted for regulatory approval in the US. In September 2005, however, Pfizer learnt that the FDA had rejected its NDA for Oporia (lasofoxifene) as a preventative therapy for osteoporosis. This is a disappointing outcome for a drug that analysts had predicted would reach the market in 2006. Phase III trials for its use as a treatment for reducing osteoporotic fractures in post-menopausal are still ongoing, with results expected in 2006.

SERMs FOR THE TREATMENT OF OSTEOPOROSIS

Osteoporosis is a disorder arising from the loss of bony tissue that results in bones becoming brittle and liable to fracture. It is especially common in post-menopausal women in whom oestrogen levels fall rapidly once menstruation ceases. Treatment is aimed at preventing osteoporosis from developing as well as preventing bone loss to reduce the risk of osteoporotic fracture. Antiresorptive drugs have a central role to play in treatment and prevention of osteoporosis and include:

• Hormone replacement therapy (HRT)
• Bisphosphonates
• Oestrogen analogues or SERMs

SERMs are the most recently approved class of antiresorptive drugs. In some tissues such as bone, they mimic the effects of oestrogen, while in others they act as anti-oestrogens and block unwanted oestrogenic effects on uterine and breast tissue. An ideal SERM should fulfil the following criteria:

• Protect against bone loss and so reduce fracture risk
• Protect against heart attack and stroke
• Not induce endometrial bleeding
• Not increase the risk of uterine cancer
• Reduce the risk of developing breast cancer
• Be safe in long-term use

CLINICAL TRIALS POINT TO POTENT EFFECTS OF OPORIA (LASOFOXIFENE) ON BONE DENSITY

Preclinical studies show Oporia (lasofoxifene) binds to oestrogen receptors with an affinity comparable to that of 17beta-estradiol and, in bone, duplicates many of the effects obtained following administration of oestrogen. These properties suggest efficacy in osteoporosis and this is indeed confirmed in phase II trials. Compared with raloxifene, the current leading SERM, Oporia (lasofoxifene) appeared more effective in improving spinal bone density in post-menopausal women. Long-term phase II data show that the improvements in bone density are sustained after two years of dosing. Compared with raloxifene, long-term administration of Oporia (lasofoxifene) significantly improved bone parameters, such as bone resorption and lumbar-spine bone mineral density. Reductions in LDL-C were also more pronounced in the Oporia (lasofoxifene) treatment arm compared with raloxifene.

Some 10,500 women have been enrolled in clinical trials in which the effect of Oporia (lasofoxifene) on bone loss prevention and fractures is being assessed. Outcome data from these large-scale trials is awaited with interest.

OPORIA (LASOFOXIFENE) MAY HAVE CLINICAL POTENTIAL IN THE PREVENTION OF BREAST CANCER AND HYPERCHOLESTEROLAEMIA

Among the most interesting potential applications of SERMs is for prevention of breast cancer. The widely used breast cancer agent tamoxifen is in fact a first-generation SERM. In addition to studies exploring the use of Oporia (lasofoxifene) for treatment and prevention of postmenopausal osteoporosis, it is also being investigated as an anti-cancer agent. Raloxifene, the first SERM to be approved for preventing bone loss in post-menopausal women, has been shown to markedly decrease the incidence of breast cancer in osteoporotic women.

SERMs can exert statin-like lipid-lowering effects, which suggests they may have potential as hypolipidaemic agents. Clinical data on Oporia (lasofoxifene) show it can produce significant reductions in levels of atherogenic low-density lipoprotein cholesterol. By reducing serum cholesterol levels it should be able to protect against the cardiovascular risks that increase once women reach the menopause. A trial in 2,000 post-menopausal women is already underway to evaluate the lipid-lowering effects of Oporia (lasofoxifene).

MARKETING COMMENTARY

Hormone replacement therapy (HRT) is the mainstay of prevention and treatment of osteoporosis. However, concerns about the safety of HRT in long-term use suggest that increasingly it will be restricted to short-term treatment of climacteric symptoms. This change in treatment practice will create opportunities in the market for new classes of drugs to treat osteoporosis, such as SERMs and bisphosphonates.

Osteoporosis is a serious health problem that affects millions of post-menopausal women. The progressive loss of bone density that follows the menopause predisposes women to greatly increased risk of bone fractures. As the population, especially that of industrialised nations, ages, so the problem will grow and place an increasingly heavy burden on healthcare budgets. Figures from the US illustrate the scale of the problem.

Over 10 million people in the US have osteoporosis with a further 18 million suffering from low bone mass, a risk factor for osteoporosis. Costs to the US healthcare system, which include hospital and nursing home care, are around $14 billion a year. This figure is expected to quadruple by 2030.

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