Development of a novel therapeutic for osteoporosis

Osteoporosis, which affects a large proportion of the elderly population, frequently results in bone fractures due to uncontrolled bone loss; 1 in 2 women and 1 in 5 men over the age of 50 will experience an osteoporosis-related fracture during their lifetime. This severely impacts on quality of life and 20-30% of hip fractures lead to death within 12 months. There is currently no ideal treatment for osteoporosis due to side effects and problems associated with their long-term use, e.g. atypical fractures of the hip and immune suppression resulting in infections. Poor compliance (due to these side effects and under diagnosis) is a significant problem and consequently treatment rates are less than 20% throughout the world. Most importantly osteoporosis is a long-term condition that requires long-term therapy, i.e. up to several decades. Therefore, there is a growing clinical need for the development of new therapies to provide additional treatment options to allow better management of this common, debilitating and potentially fatal condition.

We have identified a molecule that is a potent inhibitor of bone loss, which we propose to develop as a novel treatment for osteoporosis. This drug candidate is derived from a human protein that has a role in the normal regulation of bone turnover. We anticipate that this protein will have limited undesirable side effects (unlike existing therapies), thus enabling its long-term use (and improving compliance).

This project will build on our preliminary data and is aimed at establishing an optimal treatment protocol in an approved experimental model of post-menopausal osteoporosis; initial safety testing will also be carried out. This preclinical evaluation will inform and facilitate future studies, including trials in humans, and help us obtain a commercial partner with whom to co-develop our technology.

Osteoporosis, which affects a large proportion of the elderly population, frequently results in fragility fractures due to uncontrolled bone loss; 1 in 2 women and 1 in 5 men over the age of 50 will experience an osteoporosis-related fracture during their lifetime. This severely impacts on quality of life and 20-30% of hip fractures lead to death within 12 months. There is currently no ideal treatment for osteoporosis (i.e. due to side effects and problems associated with long-term use, e.g. atypical fractures of the femur and immune suppression) and poor compliance is a significant problem; consequently, treatment rates are less than 20% throughout the world. Most importantly osteoporosis is a long-term condition that requires long-term therapy, i.e. in order to effectively manage the multi-decade "osteoporotic career" of sufferers. Therefore, there is a growing clinical need for the development of new therapies to provide additional treatment options to allow better management of this common, debilitating and potentially fatal disease.

We have identified a biologic that is a potent inhibitor of bone loss in vivo, which we propose to develop as a novel treatment for osteoporosis. This drug candidate is derived from a human protein that has a role in the endogenous regulation of bone turnover/remodelling. We anticipate that this recombinant protein domain will have limited undesirable off-target effects (unlike existing therapies), thus enabling its long-term use.

This development plan will build on our preliminary efficacy data in order to establish an optimal treatment regime in an FDA-approved model of post-menopausal osteoporosis; initial pharmacokinetic and toxicological testing will also be carried out. This preclinical evaluation will inform and facilitate future studies, including trials in humans, and help us obtain a commercial partner with whom to co-develop our technology.

The aim of this DPFS proposal is to continue the pre-clinical development of our drug candidate with the ultimate goal of generating a novel treatment for osteoporosis. Thus, if successful, this work will benefit osteoporosis patients, healthcare providers and the pharmaceutical industry (e.g. in the UK, Europe, Japan and USA). We anticipate our drug will have a similar efficacy to existing treatments but without the side effects that lead to poor compliance and that limit their long-term use; this should result in good uptake and its use as a prolonged treatment. This would help to increase the treatment rates of osteoporosis, leading to improved quality of life and a reduction in mortalities.

Thus, this work has the potential to provide significant socioeconomic impact (e.g. reducing the burden on the healthcare system and carers (as a result of osteoporotic fractures) and have a beneficial environmental impact (a lower number of hospital visits, both in terms of less patient travel and reduced hospital activity); currently women over 45 years spend more days in hospital due to osteoporosis than diabetes, heart attack or breast cancer, and hip fractures alone account for >20% of orthopaedic bed occupancy in the UK.

In the shorter term, the outcomes of this work will improve our understanding of the regulation of the bone remodelling process, which will be of benefit to other investigators working in this field. This might ultimately lead to the development of other treatments for bone disease. We know that our drug candidate acts by inhibiting bone-resorbing osteoclasts and this activity could form the basis of therapies for conditions or diseases associated with bone loss, e.g. bone metastases, osteoarthritis and Paget's disease.