Taspoglutide for mellitus – add-on therapy

August 2010

This technology summary is based on information available at the time of research and a limited literature search. It is not intended to be a definitive statement on the safety, efficacy or effectiveness of the health technology covered and should not be used for commercial purposes.

The National Horizon Scanning Centre Research Programme is part of the National Institute for Health Research

August 2010

Taspoglutide for type 2 diabetes mellitus – add-on therapy

Target group • Type 2 diabetes mellitus - in combination with , or metformin and a sulphonylurea or a .

Technology description Taspoglutide is a long-acting like (GLP-1) analogue which binds specifically with glucagon-like-peptide 1 receptors (GLP-1R) found on pancreatic β cells. In addition to the short term effects of enhancing glucose-induced secretion, continuous GLP-1R activation also increases insulin synthesis, β cell proliferation and gluconeogenesis.

Taspoglutide will be self-administered by subcutaneous (SC) injection and is currently being trialled at a dose of 10-20mg once weekly.

Innovation and/or advantages If licensed taspoglutide may provide a longer-acting treatment option for patients with hyperglycaemia uncontrolled by current . Taspoglutide may also be useful in treating early phase diabetes for patients who still have pancreatic β cell function.

Developer Roche Products.

Availability, launch or marketing dates, and licensing plans In phase III trials.

NHS or Government priority area This topic is relevant to the National Service Framework for Diabetes (2007).

Relevant guidance • NICE technology appraisal in development. for the treatment of type 2 diabetes. Expected October 20101. • NICE short clinical guideline. Type 2 diabetes: newer agents for blood glucose control in type 2 diabetes. 20092. 3 • NICE clinical guideline. Type 2 diabetes: the management of type 2 diabetes. 2008 . • Clinical Knowledge Summaries. NHS Clinical Knowledge Summary. Diabetes – type 2. Version 2.5. 2010 4. 5 • International Diabetes Federation. Global guideline for type 2 diabetes. 2005 .

Clinical need and burden of disease The prevalence of diabetes in the UK is increasing, but is not accurately known, and varies with factors including the mix of ethnic groups and degree of social deprivation. In England and Wales the prevalence is estimated to be between 3.5% and 5%, with around 1.6 million people diagnosed, and more than 85% of adults with diabetes having type 2 diabetes3. It is accepted that a number of people with type 2 diabetes remain undiagnosed.

An estimated 4.2% of deaths in men and 7.7% of deaths in women in the UK can be attributed to diabetes. However, these are likely to be underestimates as death registrations for vascular events, such as stroke and myocardial infarction, frequently

2 August 2010

under record the underlying causative disease3. Life expectancy is reduced by up to 10 years in people with diabetes6. Cardiovascular disease is the most common complication in Europeans with type 2 diabetes and is a significant cause of morbidity and premature death in this patient group, accounting for around 60% of all deaths7. Other long-term complications associated with the condition include: nephropathy, retinopathy and neuropathy, leading respectively to renal failure, reduced vision or blindness, and foot ulceration and amputation.

Existing comparators and treatments Current treatment options include: • Oral anti-diabetes drugs (alone or in combination) • Metformin. • : , , , , . • Alpha-glucosidase inhibitors: . • (glitazones): , . • DPP-4 inhibitors: , , . • Injectable drugs • (twice daily SC). • Liraglutide (once daily SC). • Insulin (human or analogue).

Efficacy and safety Trial NCT00423501; metformin with taspoglutide or placebo; phase II. Sponsor Hoffman-La Roche. Status Published. Source of Publication8. information Location EU, USA and other countries. Design Randomised, placebo-controlled. Participants and n=306; adults; type 2 diabetes inadequately controlled with metformin. schedule Randomised to taspoglutide 5, 10 or 20mg once weekly, 10 or 20mg once every two weeks, or placebo. Subjects enrolled were on stable doses of metformin ≥ 1500mg/day, which they received throughout study. Follow-up 8 week active treatment period and 4 week follow up. Primary Change in baseline HbA1c at week 8. outcome Secondary Fasting plasma glucose (FPG), body weight, glucagon, fasting insulin, C-peptide outcomes and lipid profile. Key results At 8 weeks, reduction in HbA1c for all taspoglutide groups (baseline mean 7.9) statistically significantly greater than placebo (-1.0, -1.2, -1.2, -0.9 and -1.0 vs - 0.2, all p<0.0001). At 8 weeks, reduction in body weight statistically significantly greater than placebo for 10mg and 20mg once weekly, and 20mg once every two weekly taspoglutide groups (-2.1, -2.8 and -1.9 vs -0.8kg, all p<0.01).

Adverse effects Most common AE: dose-dependent, mild to moderate nausea (22% of patients in (AEs) 20mg taspoglutide arm). Other AEs included mild to moderate gastrointestinal disturbance and injection site reactions. Hypoglycaemia incidence low across all arms.

Trial NCT01051011; NCT00909597; NCT00717457; metformin with taspoglutide vs taspoglutide vs exenatide; taspoglutide or insulin pioglitazone; phase III. phase III.

3 August 2010

glargine; phase III. Sponsor Hoffman-La Roche. Hoffman-La Roche. Hoffman-La Roche. Status Ongoing. Ongoing. Ongoing.

Source of Trial registry9. Trial registry10. Trial registry11. information Location Hong Kong. EU (inc UK), USA, EU (inc UK), USA, Canada and other Canada and other countries. countries. Design Randomised, open-label, Randomised, active- Randomised, active- active-controlled. controlled. controlled. Participants and n= 570 (planned); adults; n= 648 (planned); adults; n=990 (planned); adults schedule type 2 diabetes type 2 diabetes type 2 diabetes inadequately controlled inadequately controlled inadequately controlled with metformin and with alone or with metformin, sulfonylurea combination in combination thiazolidinedione or a therapy (metformin (metformin combination (metformin ≥1500mg/day). ≥1500mg/day). ≥1500mg/day). Randomised to Randomised to Randomised to taspoglutide 10mg once taspoglutide 10mg once taspoglutide 10mg once weekly, taspoglutide weekly, taspoglutide weekly, taspoglutide 20mg once weekly or 10mg once weekly (for 4 10mg once weekly (for 4 titrated to weeks) followed by 20mg weeks) followed by 20mg FPG. once weekly, or once weekly, or exenatide All arms receive currently pioglitazone 30mg once 5mg twice daily (for 4 prescribed metformin daily (4 weeks) followed weeks) followed by 10mg throughout study. by 45mg once daily. twice daily.

Follow-up 24 weeks with option to 24 week treatment period. 24 week treatment period. continue assigned treatment for additional 28 weeks. Primary HbA1c at week 24. HbA1c at week 24. HbA1c at week 24. outcome Secondary FPG, incidence of Target HbA1c at week 24, Body weight, target outcomes hypoglycaemia, body 52 and 104; body weight. HbA1c, β cell function weight, lipid profile, and relative change in glucagon, C-peptide and glucose, insulin, C- insulin. peptide and glucagon values. Expected Expected completion June Expected completion July Expected completion Apr reporting date 2012. 2012. 2012.

4 August 2010

Trial NCT00744367; NCT00754988; NCT00755287; metformin and taspoglutide with metformin with pioglitazone with metformin and placebo vs taspoglutide or insulin taspoglutide or placebo; sitagliptin with metformin glargine; phase III. phase III. and placebo; phase III. Sponsor Hoffman-La Roche. Hoffman-La Roche. Hoffman-La Roche. Status Ongoing. Ongoing. Ongoing.

Source of Trial registry12. Trial registry13. Trial registry14. information Location EU, USA, Canada and EU, USA, Canada and EU, USA, Canada and other countries. other countries. other countries. Design Randomised, placebo- Randomised, active and Randomised, active controlled. placebo-controlled. controlled. Participants and n= 330 (planned); adults; n= 630 (planned); adults; n= 990 (planned); adults; schedule type 2 diabetes type 2 diabetes type 2 diabetes inadequately controlled inadequately controlled inadequately controlled with metformin plus with metformin. with metformin plus a pioglitazone. Randomised to sulphonylurea Randomised to taspoglutide 10mg once (metformin taspoglutide 10mg weekly with metformin ≥1500mg/day). weekly, taspoglutide and oral placebo, Randomised to 10mg once weekly (4 taspoglutide 10mg once taspoglutide 10mg once weeks) then 20mg once weekly (4 weeks) weekly, taspoglutide weekly, or placebo. followed by 20mg once 10mg once weekly (4 All arms to receive weekly with metformin weeks) then taspoglutide pioglitazone (>30mg/day) and oral placebo, 20mg once weekly, or and metformin sitagliptin 100mg once insulin glargine (starting (>1500mg/day) daily, SC placebo once dose of 10 IU daily). throughout study. weekly and metformin, or All arms receive SC placebo once weekly prescribed metformin with metformin and oral dose throughout study. placebo. Follow-up Treatment period 52 Study treatment period of Study treatment period of weeks. 24 weeks with extension 24 weeks with extension to 52 weeks. Follow up 2 to 52 weeks. Follow up 2 weeks after last study visit weeks after last study with additional long term visit with additional long- extension at week 52 term extension at week under separate protocol. 52 under separate protocol. Primary HbA1c at week 24. HbA1c at week 24. HbA1c at week 24. outcome Secondary FPG, body weight, β cell FPG, beta cell function, FPG, body weight, outcomes function at week 24. lipid profile, body weight. incidence of hypoglycaemia, lipid profile, glucose, insulin, C-peptide and glucagon at week 24. Expected Expected completion Sept Expected completion Jan Expected completion reporting date 2010. 2013. June 2012.

Trial NCT00744926; NCT00823992; NCT01018173; taspoglutide vs placebo; metformin with taspoglutide vs placebo; 5 August 2010

phase III. taspoglutide or placebo; phase III. phase III. Sponsor Hoffman-La Roche. Hoffman-La Roche. Hoffman-La Roche. Status Trial complete and Trial complete and Ongoing. published in abstract. published in abstract.

Source of Abstract15. Abstract16. Trial Registry17. information Location USA and other countries. EU (inc UK), USA, EU (inc UK), USA, Canada and other Canada and other countries. countries. Design Randomised, placebo- Randomised, placebo- Randomised, placebo- controlled. controlled. controlled. Participants and n=373; adults; type 2 n= 305; adults; obese n= 2000 (planned); adults; schedule diabetes inadequately with type 2 diabetes type 2 diabetes controlled with diet and inadequately controlled inadequately controlled exercise. with metformin and cardiovascular Randomised to monotherapy. disease. taspoglutide 10 mg once Randomised to Randomised to weekly, taspoglutide taspoglutide 10mg once taspoglutide 10mg once 10mg once weekly (4 weekly (4 weeks), weekly (4 weeks), weeks) followed by 20mg followed by 20mg once followed by 20mg once once weekly, or placebo. weekly, or placebo. weekly or placebo. All arms received metformin as prescribed throughout study. At week 24 those in placebo group receive taspoglutide 20mg once weekly. Follow-up 24 week treatment period. 24 week treatment period. Treatment period continues until 88 cardiovascular events contributing to primary endpoint have occurred and all subjects have completed a minimum of 6 months treatment. Follow up 4 weeks post study. Primary HbA1c at week 24. HbA1c at week 24. Composite vascular outcome endpoint at weeks 1, 4, 12 and every 3-4 months thereafter. Secondary FPG, body weight, Body weight, FPG, lipid Secondary composite outcomes relative change in profile, C-peptide and vascular endpoint, total glucose, insulin, C- glucagon at week 24. mortality at weeks 1, 4, peptide and glucagon at 12 and every 3-4 months week 24. thereafter and metabolic and renal function at weeks 4, 13 and every 3-6 months thereafter.

6 August 2010

Key results For taspoglutide 10mg, For taspoglutide 20mg vs - 20mg and placebo groups placebo: HbA1c ≤7%: respectively: target 72.5% and 36.4%; HbA1c ≤7% was reduction in body weight: achieved by 80%, 83% -3.2kg and -1.9kg at week and 42%; reduction in 24. body weight of -1.5kg, - 2.2kg and -1.2kg. Expected - - Expected completion June reporting date 2013. Adverse effects Greater incidence of Greater incidence of - (AEs) nausea and vomiting in gastrointestinal AEs in taspoglutide groups. taspoglutide group. Led Withdrawals due to to withdrawal in 3.9% and gastrointestinal AEs 1.3% of taspoglutide occurred in 5.2%, 7.8% 20mg and placebo groups and 0.8% of taspoglutide respectively. 10mg, 20mg and placebo groups respectively.

Estimated cost and cost impact The cost of taspoglutide is not yet known.

Claimed or potential impact – speculative

Patients Reduced mortality or increased  Reduction in associated Quicker, earlier or more accurate length of survival morbidity or Improved quality of diagnosis or identification of life for patients and/or carers disease Other: None identified

Services Increased use Service organisation Staff requirements

Decreased use Other:  None identified

Costs Increased unit cost compared to Increased costs: more patients Increased costs: capital alternative coming for treatment investment needed  New costs: additional treatment Savings: Other: option.

References

1 National Institute for Health and Clinical Excellence. Liraglutide for the treatment of type 2 diabetes. Technology appraisal in development. Expected October 2010. 2 National Institute for Health and Clinical Excellence. Type 2 diabetes: newer agents for blood glucose control in type 2 diabetes. Clinical guideline CG87. London: NICE; May 2009 (review May 2012). 3 National Institute for Health and Clinical Excellence. Type 2 diabetes: the management of type 2 diabetes (update). Clinical guideline CG66. May 2008 (review May 2010). 4 Clinical Knowledge Summaries. Diabetes type 2- management http://www.cks.nhs.uk/diabetes_type_2 Accessed 3 August 2010. 5 International Diabetes Federation. Global guideline for type 2 diabetes. Brussels: IDF; 2005. 6 Marshall S and Flyvbjerg A. Prevention and early detection of vascular complications of diabetes. British Medical Journal 2006;333:475-480. 7 British Medical Association. Diabetes mellitus an update for healthcare professionals. London:2004. 8 Nauk MA, Ratner RE, Kapitza C et al. Treatment with the human once-weekly glucagon-like peptide-1 analog taspoglutide in combination with metformin improves glycemic control and lowers body weight in patients with type 2 diabetes inadequately controlled with metformin alone. Diabetes Care 2009; 32:1237-1243. 7 August 2010

9 ClinicalTrials.gov. A study to compare taspoglutide and insulin glargine in insulin naive patients with type 2 diabetes mellitus inadequately controlled on metformin and sulfonylurea combination therapy. http://clinicaltrials.gov/ct2/results?term=NCT01051011 Accessed 5 May 2010. 10 ClinicalTrials.gov. A study of taspoglutide versus pioglitazone in patients with type 2 diabetes. http://clinicaltrials.gov/ct2/results?term=NCT00909597 Accessed 7 May 2010. 11 ClinicalTrials.gov. A study of taspoglutide versus exenatide for the treatment of patients with type 2 diabetes mellitus inadequately controlled with metformin, thiazolidinedone or a combination of both. http://clinicaltrials.gov/ct2/results?term=NCT00717457 Accessed 7 May 2010. 12 ClinicalTrials.gov. A study of taspoglutide versus placebo for the treatment of patients with type 2 diabetes mellitus inadequately controlled with metformin plus pioglitazone. http://clinicaltrials.gov/ct2/results?term=NCT00744367 Accessed 7 May 2010. 13 ClinicalTrials.gov. A study of taspoglutide versus sitagliptin for the treatment of patients with type 2 diabetes mellitus inadequately controlled with metformin. http://clinicaltrials.gov/ct2/results?term=NCT00754988 Accessed 7 May 2010. 14 ClinicalTrials.gov. A study of the safety, tolerability and effect on glycemic control of taspoglutide versus insulin glargine in insulin naive type 2 diabetic patients inadequately controlled with metformin plus suphonylurea. http://clinicaltrials.gov/ct2/results?term=NCT00755287 Accessed 7 May 2010. 15 Raz I, Fonseca V, Kipnes M et al. Taspoglutide, a once weekly human GLP-1 analog, as monotherapy significantly lowers A1c and body weight in patients with type 2 diabetes (T2D): results from the T-Emerge 1 phase 3 trial. American Diabetes Association 70th Scientific Sessions. 2010. 399-PP. 16 Hollander P, Bengus M, Barnett A et al. Once-weekly taspoglutide, a human GLP-1 analog, is superior to placebo in improving gylcemic control and body weight loss in obese patients with type 2 diabetes (T2D) inadequately controlled with metformin monotherapy: results from the T-emerge 7 trial. American Diabetes Association 70th Scientific Sessions. 2010. 585-P. 17 ClinicalTrials.gov. A study of taspoglutide in patients with inadequately controlled diabetes mellitus type 2 and cardiovascular disease. http://clinicaltrials.gov/ct2/results?term=nct01018173 Accessed 5 May 2010.

The National Institute for Health Research National Horizon Scanning Centre Research Programme is funded by the Department of Health. The views expressed in this publication are not necessarily those of the NHS, the NIHR or the Department of Health

The National Horizon Scanning Centre, Department of Public Health and Epidemiology University of Birmingham, 90 Vincent Drive, Edgbaston, Birmingham, B15 2SP, England Tel: +44 (0)121 414 7831 Fax +44 (0)121 414 2269 www.haps.bham.ac.uk/publichealth/horizon

8