Horizon Scanning Centre May 2013

Odanacatib for male osteoporosis – first and second line

SUMMARY NIHR HSC ID: 6411

Odanacatib is intended to be used as therapy for the treatment of men with osteoporosis following bisphosphonate therapy in patients who cannot tolerate, do not wish to persist with or do not respond to oral bisphosphonates, or first-line in patients who are contraindicated for oral bisphosphonate therapy. Odanacatib is a cathepsin K inhibitor and if This briefing is licensed, will offer an additional oral treatment option for males with osteoporosis. based on

information Osteoporosis is a common condition that affects 1 in 3 women and 1 in 5 available at the time men over the age of 50, with a lifetime risk of fracture in this age group being of research and a estimated at 50% in women and 20-30% in men. Around 50% of men with limited literature osteoporosis have at least one secondary cause, which most commonly search. It is not include treatment with glucocorticoids, hypogonadism, alcohol abuse, intended to be a smoking, gastrointestinal disease, hypercalciuria and immobilisation. definitive statement Approximately 20% of symptomatic vertebral fractures, 25% of forearm on the safety, fractures and 30% of hip fractures occur in men, and men have a higher efficacy or incidence of hip and vertebral fractures following distal forearm fractures in effectiveness of the comparison to women. These fractures have a profound impact on the health technology individual in terms of morbidity and mortality, with 20% overall mortality in the covered and should first 12 months following hip fracture, with higher mortality rates in men than not be used for women. In England during 2011-2012, there were 4,341 hospital admissions commercial for osteoporosis in men, 1,699 of which were with a pathological fracture. purposes or commissioning First line therapy for osteoporosis usually involves treatment with without additional bisphosphonates. Odanacatib is currently in one phase III clinical trial information. comparing its effect on bone mineral density against treatment with placebo. This trial is expected to complete in 2013.

This briefing presents independent research funded by the National Institute for Health Research (NIHR). The views expressed are those of the author and not necessarily those of the NHS, the NIHR or the Department of Health.

NIHR Horizon Scanning Centre, University of Birmingham Email: [email protected] Web: http://www.hsc.nihr.ac.uk NIHR Horizon Scanning Centre

TARGET GROUP

• Male osteoporosis: in patients who cannot tolerate, do not wish to persist with, do not respond to, or are contraindicated for oral bisphosphonate therapy – first and second line.

TECHNOLOGY

DESCRIPTION

Odanacatib (MK-0822) is an inhibitor of cathepsin K, a protease that is involved in the catabolism of elastin, collagen and gelatine. Abnormal cathepsin activity may result in bone disorders such as osteoporosis. Odanacatib treatment decreases bone resorption by selectively inhibiting the proteolysis of matrix protein by cathepsin K without affecting other osteoclast activities or osteoclast viability. Odanacatib is intended for the treatment of men with osteoporosis, either first line (in patients who have contraindications to oral bisphosphonates) or second line (in patients who cannot tolerate, do not wish to persist with, or who do not respond to oral bisphosphonate therapy). Odanacatib is administered orally at 50mg once weekly.

Odanacatib is in phase III clinical trials for post-menopausal osteoporosis and also in phase II clinical trials for bone metastases in patients with breast cancer.

INNOVATION and/or ADVANTAGES

If licensed, odanacatib will offer an additional oral treatment option for men with osteoporosis.

DEVELOPER

Merck Sharp & Dohme Ltd.

AVAILABILITY, LAUNCH OR MARKETING

In phase III clinical trials.

PATIENT GROUP

BACKGROUND

Osteoporosis is a progressive, systemic skeletal disorder characterised by low bone mass and micro-architectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture1. Osteoporotic fractures are defined as fractures associated with low bone mineral density (BMD) and typically affect the spine, forearm, hip and shoulder2.

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NHS or GOVERNMENT PRIORITY AREA

This topic is relevant to: • The Musculoskeletal Services Framework (2006). • National Service Framework for Older People (2001).

CLINICAL NEED and BURDEN OF DISEASE

Osteoporosis is a common condition that affects 1 in 3 women and 1 in 5 men over the age of 503, with a lifetime risk of fracture in this age group being estimated at 50% in women and 20-30% in men4,5. Nearly 75% of hip, spine and distal forearm fractures occur in patients ≥65 years5. Around 50% of men with osteoporosis have at least one secondary causea, which most commonly include treatment with glucocorticoids, hypogonadism, alcohol abuse, smoking, gastrointestinal disease, hypercalciuria and immobilisation6. In England during 2011-2012, there were 4,341 hospital admissions for osteoporosis in men, 1,699 of which were with a pathological fracture7.

Approximately 20% of symptomatic vertebral fractures, 25% of forearm fractures and 30% of hip fractures occur in men5. Men have a higher incidence of hip and vertebral fractures following distal forearm fractures in comparison to womenb. These fractures have a profound impact on the individual in terms of morbidity and mortality, with 20% overall mortality in the first 12 months following hip fracture, and higher mortality rates in men than women5. The mortality rate in men after hip fracture increases with age and over the first 6 months is approximately double that compared to similarly aged women5. Hip fracture permanently disables 50% of those affected and only 30% of patients fully recover2.

PATIENT PATHWAY

RELEVANT GUIDANCE

NICE Guidance

• NICE clinical guideline. Osteoporosis: assessing the risk of fragility fracture (CG146). August 20122.

Other Guidance

• The Endocrine Society. Osteoporosis in men: an Endocrine Society clinical practice guideline. June 20128. • National Institutes of Arthritic and Musculoskeletal and Skin Diseases. Osteoporosis in men. January 20116. • National Osteoporosis Guideline Group. Guideline for the diagnosis and management of osteoporosis in postmenopausal women and men from the age of 50 years in the UK. 20109. • National Osteoporosis Foundation. Clinician’s guide to prevention and treatment of osteoporosis. 201010. • Clinical Knowledge Summaries. Osteoporosis – steroid-induced. June 200911. • British Orthopaedic Association. The care of patients with fragility fractures: the “blue book”. 200712.

a Expert personal communication.

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• Clinical Knowledge Summaries. Osteoporosis – treatment (and prevention of fragility fractures). 200513. • Scottish Intercollegiate Guidelines Network. Management of osteoporosis: a national clinical guideline. 200314.

EXISTING COMPARATORS and TREATMENTS

Men who are found to have a high risk of fracture or who have already suffered a fragility fracture should normally be referred to specialist centres for assessment. The diagnosis of osteoporosis is typically more complex in men and some treatments are only licensed for use in post-menopausal women or men on corticosteroid therapy15. In addition to pharmacological treatments, patients may be given concurrent calcium and vitamin D supplements and advised to make lifestyle changes16.

Current licensed pharmacological treatment options for men include15,16,17: Bisphosphonates • Alendronate, 10mg daily. • Risedronate, 35mg once weekly. • Zoledronic acid (Aclasta), yearly intravenous (IV) administration.

Other medications • Teriparatide, a recombinant fragment of human parathyroid hormone, SC administration. • Strontium ranelate (Protelos). • Hormone replacement therapy (testosterone) – for hypogonadal men; however this is associated with increased cardiovascular events and risk of prostate cancer in older menb. • Denosumab – licenced for use in men with bone loss caused by treatments for prostate cancer. • Calcitriol. • Calcitonin – this is no longer used in the UK.

Although not licensed for use in men, alendronate (Fosamax 70mg once weekly) and ibandronate (Bonviva) are often prescribed, as is Preotact, another recombinant parathyroid hormone treatment15.

EFFICACY and SAFETY

Trial NCT01120600, EUCTR2010-019454-41-LV, MK0822-053; odanacatib vs placebo; phase III. Sponsor Merck Sharp & Dohme. Status Ongoing. Source of Trial registry18. information Location Not reported. Design Randomised, placebo-controlled. Participants n=266 (planned); aged 40-95 years; males; osteoporosis; ambulatory; suitable for dual energy x-ray absorptiometry scan; no fragility fractures in 12 months prior to study; no current treatment with oral bisphosphonates or other agents. Schedule Randomised to odanacatib 50mg oral once weekly, or placebo oral once weekly, both with vitamin D3 5,600 IU once weekly and calcium carbonate.

b Expert personal communication.

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Follow-up Active treatment period 24 months. Primary Lumbar spine bone mineral density (BMD). outcome Secondary Total hip, femoral neck and trochanter BMD; serum C-telopeptide and urine N- outcomes telopeptide fraction of type 1 collagen. Expected Study completion date reported as Jul 2013. reporting date

ESTIMATED COST and IMPACT

COST

The cost of odanacatib is not yet known. The cost of other selected treatments for male osteoporosis are19:

Drug Dose Cost for 1 year Alendronate 10mg once daily £18.72 70mg weekly oral tablet (unlicensed)20 £14.30 Risedronate 35mg weekly oral tablet £248 Zoledronic acid 5mg IV infusion over 15 mins once a year £253 (Aclasta) Teriparatide 20µg daily SC £3,262

IMPACT - SPECULATIVE

Impact on Patients and Carers

 Reduced mortality/increased length of survival  Reduced symptoms or disability

 Other:  No impact identified

Impact on Services

 Increased use of existing services  Decreased use of existing services

 Re-organisation of existing services:  Need for new services Appropriate monitoring will be required, initially in the secondary sector in specialised units (endocrine or rheumatological)c.

 Other: There is currently a difficulty in  None identified identifying at risk males and getting them onto treatmentd.

Impact on Costs

 Increased drug treatment costs  Reduced drug treatment costs

 Other increase in costs:  Other reduction in costs:

 Other: uncertain unit cost compared to  None identified existing treatments.

c Expert personal communication.

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Other Issues

 Clinical uncertainty or other research question  None identified identified: Expert opinion suggests that as the pathogenesis of male osteoporosis is different to that of women, further research is required to obtain anti-fracture data in addition to bone density, as a lack of fracture risk evidence is one of the main challenges clinicians face when choosing treatments for men. Expert opinion also suggests that comparator studies are required to inform the best choice of agents. Further research into optimum duration of therapy, appropriate treatments in renal failure and the efficacy of odanacatib in prostate cancer are also suggested. In addition, as poor long-term compliance is a problem with osteoporosis treatment, data on odanacatib compliance would also be useful. Expert opinion expresses uncertainty surrounding the proposed place of treatment for odanacatib; as 50% of males have secondary causes of osteoporosis, other treatments e.g. testosterone, may be more appropriate. As there is a lack of knowledge on how far testosterone replacement therapy benefits fracture risk in hypogonadal men, expert opinion suggests that these patients should be excluded from odanacatib trials and further research for hormone replacement therapy should be conductedd.

REFERENCES

1 National Institute for Health and Clinical Excellence. Osteoporosis: primary prevention. Alendronate, etidronate, risedronate, raloxifene and strontium ranelate for the primary prevention of osteoporotic fragility fractures in postmenopausal women. Technology appraisal TA160. London: NICE; January 2011. 2 National Institute for Health and Clinical Excellence. Osteoporosis: assessing the risk of fragility fracture. Clinical Guideline 146. NICE: London; August 2012. 3 International Osteoporosis Foundation. Osteoporosis and Muscoskeletal disorders. http://www.iofbonehealth.org/osteoporosis-musculoskeletal-disorders Accessed 17 April 2013. 4 Van Staa TP, Dennison EM, Leufkens HG et al. Epidemiology of fractures in England and Wales. Bone. 2001;29:517–22. 5 International Osteoporosis Foundation. Facts and statistics. http://www.iofbonehealth.org/facts- statistics#category-15 Accessed 16 April 2013. 6 National Institutes of Arthritic and Musculoskeletal and Skin Diseases. Osteoporosis in men. http://www.niams.nih.gov/Health_Info/Bone/Osteoporosis/men.asp Accessed 17 April 2013. 7 NHS. Hospital Episode Statistics. NHS England 2011-2012. HES data 2012. http://www.hscic.gov.uk/hes 8 The Endocrine Society. Osteoporosis in men: an endocrine society clinical practice guideline. June 2012. http://www.endo-society.org/guidelines/upload/FINAL-Osteoporosis-in-Men- Guideline.pdf 9 National Osteoporosis Guideline Group (NOGG). Guideline for the diagnosis and management of osteoporosis in postmenopausal women and men from the age of 50 years in the UK. Sheffield: NOGG; 2010. 10 National Osteoporosis Foundation (NOF). Clinician’s guide to prevention and treatment of osteoporosis. Washington, DC, US: NOF; 2010.

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11 Clinical Knowledge Summaries. Osteoporosis – steroid-induced. June 2009. 12 British Orthopaedic Association. The care of patients with fragility fractures: the “blue book”. September 2007. 13 Clinical Knowledge Summaries. Osteoporosis – treatment (and prevention of fragility fractures). July 2005. 14 Scottish Intercollegiate Guidelines Network. Management of osteoporosis: a national clinical guideline. Guideline 71. June 2003. 15 National Osteoporosis Society. Osteoporosis in men leaflet. http://www.nos.org.uk/~/document.doc?id=1303 Accessed 17 April 2013. 16 International Osteoporosis Foundation. Treating Osteoporosis. http://www.iofbonehealth.org/treating-osteoporosis Accessed 17 April 2013. 17 National Osteoporosis Society. Drug treatments for osteoporosis leaflet. http://www.nos.org.uk/document.doc?id=385 Accessed 17 April 2013. 18 ClinicalTrials.gov. A study to assess safety and efficacy of odanacatib (MK-0822) in men with osteoporosis (MK-0822-053 AM1). http://clinicaltrials.gov/ct2/show/NCT01120600?term=odanacatib+AND+male+osteoporosis&rank =1&submit_fld_opt= Accessed 16 April 2013. 19 British Medical Association and Royal Pharmaceutical Society of Great Britain. British National Formulary. BMJ Group and RPS Publishing. London; March 2011. 20 NIHR Horizon Scanning Centre. Denosumab (Prolia) for osteoporosis in men. Birmingham: NIHR HSC; August 2011.

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