What is abaloparatide?
Abaloparatide (formerly known as BA058) is an investigational analog of human PTHrP (1-34) being developed for the treatment of osteoporosis. The amino-acid sequence of abaloparatide is identical to that of PTHrP in the first 20 amino-acids, while over half of the remaining amino-acids are different. It was selected to retain potent anabolic activity with decreased bone resorption, less calcium-mobilizing potential, and improved room temperature stability. Studies performed in animals have demonstrated marked bone anabolic activity of abaloparatide with complete reversal of bone loss in ovariectomy-induced osteopenic rats and monkeys.
Why do we need abaloparatide?
Osteoporosis is a common multifactorial systemic skeletal disease, characterized by low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and in susceptibility to fracture. Fractures related to osteoporosis are currently considered a public health problem since they significantly increase the morbidity and mortality of affected patients, especially in the case of hip fracture. It is expected that 42% - 56 % of all women and 27% - 29% of all men will develop osteoporotic fractures after the age of 50 years and, due to aging populations, it is predicted that the number of fractures will increase by 4% per annum. The most commonly used medications for treatment of osteoporosis are antiresorptive agents. Although antiresorptive drugs are able to partially correct disruption in bone architecture, the principal bone quality defect in osteoporosis, they cannot restore mechanical bone integrity because of the absence of anabolic effect. Thus, new agents are required which can increase bone mineral density and reduce fracture beyond the levels achievable using antiresorptives. Abaloparatide might be one of these new agents.
How to help osteoporotic fractures treatment?
Abaloparatide is currently being assessed as a new treatment for osteoporosis. The growing interest for abaloparatide is based on results of some studies in animals and in humans which reported that abaloparatide presented a potent and rapid anabolic activity with reduced effects on bone resorption as compared to that observed with teriparatide and improved room temperature stability. Recent studies have reported that PTH or PTHrP analogs can distinguish between two high affinity PTHR1 conformations, R0 and RG, and that an efficient binding to R0 results in prolonged signaling responses in cells and prolonged calcemic responses in animals, whereas the binding to RG results in more transient responses. Moreover, abaloparatide binds more selectively to the RG versus to the R0 PTHR1 conformation than teriparatide does, and thus induces more transient signaling responses in cells. The high RG selectivity (or lower R0 affinity) hypothesized for abaloparatide is supported by the observation that the cAMP signaling responses induced by abaloparatide are more transient in duration, as compared to those induced by similar concentrations of teriparatide. Therefore, the selective binding of abaloparatide to the RG conformation of PTHR1 may mediate more transient cAMP responses in PTHR1 expressing cells and account for the favorable anabolic effect of abaloparatide on bone.
Clinical Effect
In a clinical trial called ACTIVExtend (Fig. 1), patients with postmenopausal osteoporosis treated with abaloparatide therapy for 18 months switched to enter alendronate treatment with open label. Alendronate is a type of aminophosphonate, which is used to inhibit osteoclast activity and thus slow bone absorption. The purpose of this "relay" treatment strategy is to use abaloparatide to strengthen bone strength, and then to use alendronate sodium to slow down the rate of bone absorption, thereby extending the effect of abaloparatide. The results showed that patients treated with abaloparatide were 84 percent less likely to have a new spine fracture than those who received a placebo in the 43rd month of the trial. Abaloparatide compared with placebo, meanwhile, will have a 39% lower risk of spinal fractures, a 34% lower risk of clinical fractures, and a 50% lower risk of major osteoporosis fracture.
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Fig. 1 Study Design of the ACTIVE and ACTIVExtend Phase 3 Trial (Gonnelli, 2016)
Reference:
Gonnelli, S. (2016). 'Abaloparatide’, Clinical Cases in Mineral and Bone Metabolism, 13(2), 106-109.
