Horizon Scanning Centre September 2014

Abaloparatide for postmenopausal osteoporosis – first and second line

SUMMARY NIHR HSC ID: 6237

Abaloparatide is intended to be used as first and second line therapy for the treatment of postmenopausal osteoporosis. If licensed, it will offer an additional treatment option for this patient group. Abaloparatide is a first-in- class synthetic peptide analogue of parathyroid hormone-related protein This briefing is residues 37-70. In clinical trials, abaloparatide was administered via based on subcutaneous injection at 80µg, once daily. It does not currently have information Marketing Authorisation in the EU for any indication. available at the time of research and a Around 2 million women have osteoporosis in England and Wales, and an limited literature estimated 224,220 fragility fractures occur in postmenopausal women each year in the UK. A postmenopausal woman has a 50% chance of sustaining search. It is not an osteoporosis-related fracture in her lifetime. Fragility fractures are intended to be a associated with pain, poor functional outcomes and increased mortality. definitive statement

on the safety, Current pharmacological treatment options for primary and secondary efficacy or prevention of osteoporotic fragility fractures in postmenopausal women effectiveness of the include bisphosphonates, raloxifene, strontium ranelate, teriparatide and health technology denosumab. Abaloparatide is currently in phase III clinical trials comparing its covered and should effect on vertebral fractures against treatment with teriparatide and placebo. not be used for commercial purposes or commissioning without additional information.

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

• Osteoporosis: postmenopausal; women - o first line, in patients with FRAX-scores (10-year probability of a fracture) of 12% for hip fracture or ≥40% for any major osteoporotic fractures ≥ o second line, in patients with FRAX-scores of 8-12% for hip fracture or 24-40% for any major osteoporotic fractures.

TECHNOLOGY

DESCRIPTION

Abaloparatide (BA058; BIM44058) is a first-in-class synthetic peptide analogue of parathyroid hormone-related protein (hPTHrP) residues 37-70. PTHrP is thought to be a critical cytokine for promoting new bone formation, with a distinct role from parathyroid hormone (PTH). Abaloparatide binds the PTH receptor and produces only a transient cyclic AMP (cAMP) signal that is associated with more anabolism than PTH. Abaloparatide is designed to build bone rapidly without inducing hypercalcaemia or significant resorption, and has the potential to increase bone mineral density (BMD) and bone quality to a greater degree and at a faster rate than other approved treatments for osteoporosis. In clinical trials1, abaloparatide was administered via subcutaneous (SC) injection at 80µg, once daily.

Abaloparatide does not currently have Marketing Authorisation in the EU for any indication.

INNOVATION and/or ADVANTAGES

If licensed, abaloparatide will offer an additional treatment option for this patient group.

DEVELOPER

Radius Health, Inc.

AVAILABILITY, LAUNCH OR MARKETING

In phase III clinical trials.

PATIENT GROUP

BACKGROUND

Osteoporosis is a systemic skeletal disease characterised by low bone density and microarchitectural deterioration of bone tissue, leading to increased risk of fragility fractures2. It affects both sexes but is more common in women. BMD decreases with age in both sexes, but this is most marked at the menopause in women, when levels of the protective hormone oestrogen start to decline3. Osteoporosis is asymptomatic and often remains undiagnosed until a fracture occurs4. The most common sites for osteoporotic fracture are the spine, hip, distal forearm and proximal humerus; fractures may also occur to the pelvis, ribs, and distal femur and tibia5. Fragility fractures are associated with pain, poor functional outcomes and increased mortality2. Following a fracture of the hip, 50% of people are no longer able to live independently and 20% die within 6 months6.

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NHS or GOVERNMENT PRIORITY AREA

This topic is relevant to: • The National Service Framework for Older People (2001). • NHS England. 2013/14 NHS Standard Contract for Specialised Endocrinology Services (Adult). A03/S/a. • NHS England. 2013/2014. NHS Standard Contract for Specialised Rheumatology Services (Adult). A13/S/a.

CLINICAL NEED and BURDEN OF DISEASE

Around 2 million women have osteoporosis in England and Wales4, and an estimated 224,220 fragility fractures occur in postmenopausal women each year in the UK, of which around 23% are hip fractures and 14% vertebral fractures2. After the menopause, osteoporosis prevalence increases sharply with age, from around 2% of women at age 50, to more than 25% at age 803. The total number affected is set to rise significantly due to improvements in life expectancy2. A postmenopausal woman has a 50% chance of sustaining an osteoporosis-related fracture in her lifetime3, and following one fracture, the risk of subsequent fractures increases3. In 2011, fragility fractures were estimated to cost £2.3 billion in the UK, a burden expected to increase to more than £6 billion by 20367. The majority of these costs relate to hip fracture, which nearly always results in hospitalisation, and causes around 1,100 deaths each month in the UK3,7.

PATIENT PATHWAY

RELEVANT GUIDANCE

NICE Guidance

• NICE technology appraisal in development. Biphosphonates for preventing osteoporotic fragility fractures (including a partial update of NICE technology appraisal guidance 160 and 161) (ID782). Expected November 2015. • NICE technology appraisal. Percutaneous vertebroplasty and percutaneous balloon kyphoplasty for treating osteoporotic vertebral compression fractures (TA279). April 2013. • NICE technology appraisal. Denosumab for the prevention of osteoporotic fractures in postmenopausal women (TA204). October 2010. • NICE technology appraisal. Alendronate, etidronate, risedronate, raloxifene, strontium ranelate and teriparatide for the secondary prevention of ostoporotic fragility fractures in postmenopausal women (amended) (TA161). October 2008. • NICE technology appraisal. Alendronate, etidronate, risedronate, raloxifene and strontium ranelate for the primary prevention of osteoporotic fragility fractures in postmenopausal women (amended) (TA160). October 2008. • NICE clinical guideline. Osteoporosis: assessing the risk of fragility fracture (CG146). August 2012.

Other Guidance

• National Osteoporosis Guideline Group. Guideline for the diagnosis and management of osteoporosis. 20148.

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• European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis. European guidance for the diagnosis and management of osteoporosis in postmenopausal women. 20135. • Scottish Intercollegiate Guidelines Network. Management of osteoporosis (71). 20036.

CURRENT TREATMENT OPTIONS

General management for osteoporosis includes assessment of the risk of falls and their prevention, maintenance of mobility and correction of nutritional deficiencies, particularly calcium, vitamin D and protein5,8. Current pharmacological treatment options for postmenopausal osteoporosis include5,8,9,10: • Bisphosphonates – alendronate, risedronate, zoledronic acid and ibandronate • Raloxifene • Teriparatide (recombinant form of parathyroid hormone [PTH]) • Strontium ranelate • Denosumab • Hormone replacement therapy

NICE recommend bisphosphonates, raloxifene, strontium ranelate, teriparatide, and denosumab for primary and secondary prevention of osteoporotic fragility fractures in postmenopausal women4,11,12.

EFFICACY and SAFETY

Trial ACTIVE, NCT01343004, BA058-05-003; ACTIVExtend, NCT01657162, BA058-05- abaloparatide vs teriparatide vs placebo; 005; alendronate; phase III extension. phase III. Sponsor Radius Health, Inc. Radius Health, Inc Status Ongoing. Ongoing. 13 Source of Trial registry1. Trial registry . information Location EU (not UK), USA, Argentina, Brazil and EU (not UK), USA, Argentina, Brazil and China. China. Design Randomised, active- and placebo- Single arm. controlled. Participants n=2,400 (planned); aged 50-85 years; n=1,200 (planned); aged 50-85 years; female; osteoporosis; BMD T-scorea ≤ -2.5 female; osteoporosis; postmenopausal at the spine or hip and ≥2 fractures within (≥5 years); completed trial NCT01343004. past 5 years, or aged >65 who meet fracture criteria with T score ≤ -2.0, or aged >65 with T score ≤-3.0; T score > -5.0; postmenopausal (≥5 years). Schedule Randomised to abaloparatide, SC, 80µg All participants receive alendronate, SC, once daily; or teriparatide, SC, 20µg once 70mg once weekly. daily; or placebo, SC, once daily. Follow-up Active treatment for 18 months; 1 month Active treatment for 24 months; 1 month follow-up. follow-up. Primary New vertebral fractures. Safety. outcome/s

a A measure of reduced BMD, a T-score of -2.5 is defined as having a BMD that is 2.5 standard deviations or more below the average value for young healthy adults.

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Secondary BMD of lumbar spine, hip, and femoral Vertebral fracture incidence; non-vertebral outcome/s neck; non-vertebral fractures; fracture incidence. hypercalcaemic events. Expected Not reported. Not reported. reporting date

Trial NCT00542425, BA058-05-002; NCT01674621, BA058-05-007, 2012- abaloparatide vs teriparatide vs placebo; 001921-29; abaloparatide vs placebo; phase II. phase II. Sponsor Radius Health, Inc. Radius Health, Inc. Status Complete but unpublished. Complete but unpublished. Source of Trial registry14, manufacturer. Trial registry15. information Location USA. EU (not UK) and USA. Design Randomised, active- and placebo- Randomised, placebo-controlled. controlled. Participants n=222; aged 55-85 years; female; BMD T- n=250 (planned); aged <85 years; female; score ≤ -2.5 at spine or hip, or ≤ -2.0 with postmenopausal; BMD T-score ≤ -2.5 at previous fracture. spine or hip, or ≤ -2.0 with previous fracture. Schedule Randomised to abaloparatide, SC, 20µg, Randomised to abaloparatide, SC, 80µg 40µg, or 80µg once daily; or teriparatide, once daily; or abaloparatide, transdermal SC, 20µg once daily; or placebo, SC, once microneedle patch, 50µg, 100µg, or 150µg daily. appliced once daily; or placebo transdermal microneedle patch applied once daily. Follow-up Active treatment up to 48 weeks; 1 month Active treatment for 24 weeks; 1 month follow-up. follow-up. Primary Bone metabolism (P1NPb); BMD, total BMD, total spine. outcome/s spine at week 24. Secondary BMD (femoral neck and total hip) at week BMD, hip and forearm; serum markers of outcome/s 24; BMD (total spine) at week 48; safety bone formation and resorption; safety and and tolerability. tolerability. Key results For abaloparatide 20µg, 40µg, 80µg, - teriparatide, and placebo respectively: change in P1NP at 6 months (%, mean±SD): 20.0±61.05, 90.8±116.92, 97.2±123.88, 154.3±213.07, -13.1±26.47, p<0.001 (abaloparatide 40µg vs placebo); change in BMD, total spine at 6 months (%, mean±SD): 3.30±2.068, 5.21±4.427, 6.11±3.744, 5.47±4.218, 1.22±3.211, p<0.001 (abaloparatide 40µg vs placebo); change in BMD total spine at 12 months (%±SD): 5.14±3.16, 9.84±5.31, 12.94±3.25, 8.63±6.8, 0.74±3.54; change in BMD femoral neck at 6 months (%, mean±SD): 2.69±4.022, 2.20±4.406, 3.07±4.175, 1.07±4.564, 0.79±4.797; change in BMD total hip at 6 months (%, mean±SD): 1.43±2.639, 1.97±3.699, 2.60±3.488, 0.45±3.925, 0.39±3.053. Adverse AEs ≥5%, for abaloparatide 20µg, 40µg, - effects 80µg, teriparatide and placebo, (AEs) respectively (%): b N-terminal propeptide of type 1 procollagen, a marker of anabolic bone growth.

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influenza 4.7, 7.0, 11.1, 13.3, 15.6; nasopharyngitis, 11.6, 4.7, 6.7, 13.3, 4.4; bronchitis, 11.6, 4.7, 6.7, 4.4, 6.7; urinary tract infection, 9.3, 2.3, 4.4, 11.1, 2.2; headache, 4.7, 14.0, 13.3, 13.3, 6.7; dizziness, 0.0, 9.3, 11.1, 4.4, 4.4; injection site haematoma, 4.7, 11.6, 2.2, 13.3, 11.1, hypercalciuria, 7.0, 4.7, 8.9, 11.1, 8.9; back pain, 7.0, 14.0, 2.2, 2.2, 11.1; arthralgia, 4.7, 11.6, 2.2, 6.7, 8.9; diarrhoea, 2.3, 11.6, 8.9, 6.7, 0.0; hypercalcaemia, 2.3, 7.0, 4.4, 8.9, 2.2. Expected - Not reported. reporting date

ESTIMATED COST and IMPACT

COST

The cost of abaloparatide is not yet known. The costs of other selected treatments for postmenopausal osteoporosis are summarised below:

Drug Dose Annual cost16 Alendronate 70mg oral, once weekly £10.92 Teraparatide (Forsteo) 20µg SC, once daily £3,544.15 Denosumab (Prolia) 60mg SC, every 6 months £366.00

IMPACT - SPECULATIVE

Impact on Patients and Carers

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

 Other:  No impact identified

Impact on Health and Social Care Services

 Increased use of existing services:  Decreased use of existing services: potential for reduced number of fractures and subsequent need for services

 Re-organisation of existing services  Need for new services

 Other:  None identified

Impact on Costs and Other Resource Use

 Increased drug treatment costs  Reduced drug treatment costs

 Other increase in costs:  Other reduction in costs: potential for reduced number of fractures, limiting associated costs

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

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Other Issues

 Clinical uncertainty or other research question  None identified identified:

REFERENCES

1 ClinicalTrials.gov. Study to evaluate the safety and efficacy of BA058 (abaloparatide) for prevention of fracture in postmenopausal women (ACTIVE). http://clinicaltrials.gov/ct2/show/NCT01343004?term=NCT01343004&rank=1 Accessed 2 September 2014. 2 Gauthier A, Kanis JA, Jiang Y et al. Epidemiological burden of postmenopausal osteoporosis in the UK from 2010 to 2021: estimations from a disease model. Archives of Osteoporosis 2011;6:179-188. 3 International Longevity Centre – UK. Osteoporosis in the UK at breaking point. www.ilcuk.org.uk 4 National Institute for Health and Care Excellence. Alendronate, etidronate, risedronate, raloxifene, strontium ranelate and teriparatide for the secondary prevention of osteoporotic fragility fractures in postmenopausal women (amended). Technology appraisal TA161. London: NICE; October 2008, modified January 2011. 5 Kanis JA, McCloskey EV, Johansson H et al. European guidance for the diagnosis and management of osteoporosis in postmenopausal women. Osteoporosis International 2013;24:23- 57. 6 Scottish Intercollegiate Guidelines Network. Management of osteoporosis. National clinical guideline 71. Edinburgh: SIGN; June 2003. 7 National Institute for Health and Clinical Excellence. Ostoporosis: fragility fracture risk costing report. London: NICE; August 2012. 8 National Osteoporosis Guideline Group. Guideline for the diagnosis and management of osteoporosis. Sheffield: NOGG; March 2014. 9 National Ostoporosis Society. Drug treatment. http://www.nos.org.uk/page.aspx?pid=264&srcid=234 Accessed 4 September 2014. 10 National Institute for Health and Care Excellence. Bisphosphonates for preventing osteoporotic fragility fractures (including a partial update of NICE technology appraisal guidance 160 and 161. Draft scope. London: NICE; May 2014. 11 National Institute for Health and Clinical Excellence. Alendronate, etidronate, risedronate, raloxifene and strontium ranelate for the primary prevention of osteoporotic fragility fractures in postmenopausal women (amended). Technology appraisal 160. London: NICE; October 2008. 12 National Institute for Health and Clinical Excellence. Denosumab for the prevention of osteoporotic fractures in postmenopausal women. Technology appraisal 204. London: NICE; October 2010. 13 ClinicalTrials.gov. Twenty four month extension study of BA058-05-003 (ACTIVExtend). http://clinicaltrials.gov/show/NCT01657162 Accessed 3 September 2014. 14 ClinicalTrials.gov. Phase 2 dose-finding study to evaluate the effects of BA058 in the treatment of postmenopausal women with osteoporosis. http://clinicaltrials.gov/ct2/show/study/NCT00542425?term=NCT00542425&rank=1§=X70156 Accessed 3 September 2014. 15 ClinicalTrials.gov. Phase 2 study of BA058 (abaloparatide) transdermal delivery in postmenopausal women with osteoporosis. http://clinicaltrials.gov/ct2/show/NCT01674621?term=NCT01674621&rank=1 Accessed 3 September 2014. 16 British Medical Association and Royal Pharmaceutical Society of Great Britain. British National Formulary. BNF August 2014. www.bnf.org

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