The product of a joint development programme between Pfizer and Ligand Pharmaceuticals, Fablyn, formerly 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 a new drug application (NDA) to the US Food and Drug Administration (FDA) for the use of Fablyn (lasofoxifene) as a preventative therapy for osteoporosis based on data from Phase III clinical trials.
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An additional filing for treatment of vaginal atrophy followed in December 2004.
Fablyn (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 Fablyn as a preventative therapy for osteoporosis.
This was a disappointing outcome for a drug that analysts had predicted would reach the market in 2006. In January 2006, the FDA also rejected Fablyn as a treatment for vaginal atrophy.
Phase III trials were conducted by Pfizer for use of Fablyn as a treatment for reducing osteoporotic fractures in post-menopausal women. Based on the results, Pfizer submitted an NDA with the FDA in 2007 and a marketing authorisation application with the European Commission in January 2008..
In January 2009, the FDA issued a complete response letter to Pfizer requesting additional information on the drug. In March 2009, Fablyn was approved by the European Commission for the treatment of osteoporosis fractures in post-menopausal women.
In 2010, Pfizer withdrew its NDA to focus on licensing options for Fablyn. In October 2011, Ligand entered into a licensing contract with Chiva Pharmaceuticals for the drug.
Under the agreement, Chiva Pharmaceuticals will provide $4m in licensing payments to Ligand. Ligand is also entitled to receive milestone payments and royalties from worldwide sales of Fablyn.
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 Fablyn on bone density
Preclinical studies showed that Fablyn (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 was indeed confirmed in Phase II trials. Compared with raloxifene, the leading SERM, Fablyn (lasofoxifene) appeared more effective in improving spinal bone density in post-menopausal women.
Long-term Phase II data showed that the improvements in bone density are sustained after two years of dosing. Compared with raloxifene, long-term administration of Fablyn (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 Fablyn (lasofoxifene) treatment arm compared with raloxifene.
About 10,500 women were enrolled in clinical trials in which the effect of Fablyn (lasofoxifene) on bone loss prevention and fractures was assessed.
Clinical potential in the 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 Fablyn (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 suggest they may have potential as hypolipidaemic agents.
Clinical data on Fablyn (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 Fablyn (lasofoxifene).
Marketing commentary
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 $14bn a year. This figure is expected to quadruple by 2030.
