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Safety in Lactation: Other antidiabetic drugs

18 September 2020There is no published information on the use of these other antidiabetic drugs during breastfeeding. Therefore, alternative drugs should be used where this is clinically…

Cardiovascular outcomes with GLP-1 receptor agonists

28 May 2019This document reviews the evidence from the major cardiovascular clinical trials for GLP-1 receptor agonists.
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Refrigerated Storage

ByettaAstraZeneca

AstraZeneca
Byetta
Solution for injection, pre-filled pen

In the event of an inadvertent temperature excursion the following data may be used:
If the product is exposed to temperatures above 8°C but below 25°C, its shelf-life must be reduced to 30 days (regardless of whether the product is put back into the fridge or not).

There is no additional stability for the product when exposed to temperatures below 2°C and above 25°C and so in these cases, it is recommended that the product be discarded.

Please also refer to the manufacturer’s product literature for recommended storage information at https://www.medicines.org.uk

30 days
Yes
25 March 2021
London MI Service

BydureonAstraZeneca

AstraZeneca
Bydureon
2mg powder and solvent for prolonged-release suspension for injection in pre-filled pen

In the event of an inadvertent temperature excursion the following data may be used:
If the product is exposed to temperatures above 8°C but lower than 30°C, its shelf-life must be reduced to 30 days (regardless of whether the product is put back into the fridge or not).

There is no additional stability data for the product when exposed to temperatures below 2°C and above 30°C; and so in these cases, it is recommended that the product be discarded.

Please also refer to the manufacturer’s product literature for recommended storage information at https://www.medicines.org.uk

30 days
Yes
25 March 2021
London MI Service

Lactation Safety Information

Yes
Likely to be degraded in infant's GI tract
Low levels anticipated in milk due to the drug's properties
No published evidence of safety
16 September 2020

New Medicines

Bydureon BCiseType 2 diabetes mellitus - once-weekly suspension for injection formulation (pre-mixed)

Information

Bydureon BCise
New formulation
AstraZeneca
AstraZeneca

Development and Regulatory status

Launched
Launched
Launched
February 2020
Feb 20Available in the UK, Price for 4 x 1 single use pre-filled pen = £73.36 [14-16].
Aug 18Bydureon BCise has been available in US since Apr 18 [12].
Aug 18Approved in EU for use in combination with other glucose-lowering medicines, including basal insulin, to help improve glycaemic control in adults with type-2 diabetes whose blood sugar levels are inadequately controlled by other glucose-lowering medicines together with diet and exercise. Bydureon BCise (exenatide extended release) is an improved single-dose, pre-filled pen device that requires no titration [11].
Jan 18Filed in EU [10].
Oct 17Approved in US [9].
Mar 17Filed in US [8].
Feb 16Filing in EU & US now planned for 2017 [6].
Dec 15No change to filing plans [5].
Dec 14EU & US filings expected Q4 2015 [3].
Mar 14Filings planned in the US & EU for 2015 [1].

Category

Incretin mimetic in an autoinjector device.
Currently 3.8 million people in the UK are diagnosed with diabetes (90% type 2), and it is estimated that a further 1 million people with type 2 diabetes have not yet been diagnosed [13].
Type 2 diabetes mellitus - once-weekly suspension for injection formulation (pre-mixed)
Subcutaneous injection

Trial or other data

Dec 16PIII studies (DURATION-NEO- 1 and 2) have met their primary outcomes [7].
Sep 14 AstraZeneca initiates a randomised, double-blind, placebo-controlled PIII trial to assess the safety and efficacy of once weekly exenatide suspension added to titrated basal insulin glargine, with or without metformin, compared with placebo added to titrated basal insulin glargine, with or without metformin, in patients with T2DM (D5553C00002; NCT02229383). The trial will enrol 978 patients in the US [4].
Sep 14AstraZeneca initiate a PIII trial to investigate the efficacy and safety of simultaneous administration of exenatide and dapagliflozin [see RDI profile 800021756] compared with exenatide alone and dapagliflozin alone in patients with type 2 diabetes who have inadequate glycaemic control on metformin (EudraCT2014-003503-29; NCT02229396). This randomised, double-blind trial is a 28-week study followed by 24-week extension study. The trial intends to enrol 1100 patients in the US, Hungary, Poland, Romania, Slovakia and South Africa [4].
Sep 14Bristol-Myers Squibb completed a randomised, open-label PIII trial that assessed the long-term efficacy, safety and tolerability of exenatide once-weekly suspension, compared to exenatide twice-daily, in patients with T2DM (DURATION-NEO-1; NCT01652716). The 28-week trial enrolled 377 patients in the US 58. In September 2014, presented results at the 50th Annual Meeting of the European Association for the Study of Diabetes (EASD), demonstrating that the trial met its primary endpoint of non-inferiority [4]
Feb 13Amylin initiates a randomised, open-label PIII trial to assess the long-term efficacy, safety and tolerability of exenatide once-weekly suspension, compared to sitagliptin or placebo administered once-daily, in patients with T2DM (DURATION-NEO-2; NCT01652729). The 28-week trial enrolled 360 pts in the US [2].
Jan 13BMS initiates a randomised, open-label PIII trial to assess the long-term efficacy, safety and tolerability of exenatide once-weekly suspension, compared to exenatide twice-daily, in pts with T2DM (DURATION-NEO-1; NCT01652716). The 28-week trial will enrol 375 pts in the US [2].
Apr 09Amylin and Eli Lilly initiated a PI/II trial of a suspension formulation of exenatide once-weekly that eliminates the need to reconstitute the product prior to use (NCT00894322). The trial evaluated the pharmacokinetics, tolerability and safety of the newer formulation in both healthy volunteers and patients with T2DM. The study also evaluated efficacy in patients with T2DM [2].

Evidence based evaluations

Bydureon BCiseType 2 diabetes mellitus in adolescents aged 10 to 17 years - once-weekly suspension for injection formulation (pre-mixed)

Information

Bydureon BCise
Licence extension / variation
AstraZeneca
AstraZeneca

Development and Regulatory status

None
Phase III Clinical Trials
Approved (Licensed)
Jul 21The FDA has approved exenatide once-a-week glucose lowering drug for 10 to 17-year-olds with type 2 diabetes [3]

Category

Incretin mimetic in an autoinjector device
Currently 3.8 million people in the UK are diagnosed with diabetes (90% type 2), and it is estimated that a further 1 million people with type 2 diabetes have not yet been diagnosed [2].
Type 2 diabetes mellitus in adolescents aged 10 to 17 years - once-weekly suspension for injection formulation (pre-mixed)
Subcutaneous injection

Type 2 diabetes mellitus; subdermally placed osmotic mini-pump providing 3 or 6 months continuous delivery of exenatide - second or third-line

Information

New formulation
Servier
Intarcia Therapeutics

Development and Regulatory status

Phase III Clinical Trials
Phase III Clinical Trials
Not approved
Sep 20Sep 20: No longer listed in Servier pipeline, and Intarcia pipeline has not been updated nor news of the second US complete response announced; assume no plans for EU launch. Future of ITCA-650 appears uncertain [27,28].
Mar 20Rejected again by the FDA in the US. The company will meet with the FDA to decide the next steps [25].
Oct 19Intarcia report FDA acceptance of resubmitted NDA ITCA 650 [24].
Dec 18Intarcia intend to resubmit NDA to FDA Feb 2019 [22].
Sep 17FDA rejected implanted diabetic pump ITCA 650 due to concerns about manufacturing issues. Intarcia are working to address these manufacturing concerns [21].
Sep 17Intarcia Therapeutics announce it has received a complete response Letter from US FDA for exenatide implant for the treatment of type 2 diabetes. The company anticipates that no new pivotal trial will be required to satisfy the requirements of the FDA [20].
Feb 17The FDA has accepted the NDA for ITCA 650, according to Intarcia [17]. This suggests a decision by the FDA at the end of 2017 / beginning of 2018.
Nov 16Intarcia announces that the New Drug Application (NDA) for ITCA 650 has been filed with the FDA [16]: the FDA will now consider whether to accept the NDA as complete and if it passes this stage will give a Target Date for final review (normally ten months from acceptance date).
Sep 15Following positive data from the FREEDOM trials, Servier announce plans to initiate additional comparative PIIIb and IV trials assess real-world outcomes and adherence advantages vs. current standard of care medicines [11].
Aug 15Results from the FREEDOM trials are expected to support regulatory submissions in the US and the EU. Intarcia plans to file for regulatory approval in the first half of 2016 [9].
Jul 15Global regulatory filings are expected in H1 2016 [8].
Nov 14Intarcia to partner with Servier [7].
Nov 12Intarcia intends to initiate the global PIII programme for ITCA 650 in Q1 2013 [3].

Category

Glucagon-like peptide-1 (GLP-1) receptor agonist, delivered by a matchstick-sized osmotic pump which is inserted under the skin of the abdomen. Two doses - 20mcg/day delivered over 3 months & 60mcg/day over 6 months.
Currently 3.8 million people in the UK are diagnosed with diabetes (90% type 2), and it is estimated that a further 1 million people with type 2 diabetes have not yet been diagnosed [23].
Type 2 diabetes mellitus; subdermally placed osmotic mini-pump providing 3 or 6 months continuous delivery of exenatide - second or third-line
Subdermal

Trial or other data

Feb 18Intarcia have terminated two PIII studies involving ITCA-650 though neither were relevant to the NDA [21].
Jan 18Results of PIII study single arm PIII study of patients with T2DM and HbA1c >10% to ≤12% (n=60) published in Diabetes Care. Study included patients who were ineligible for participation in FREEDOM-1 because of severe hyperglycaemia (HbA1c >10% [86 mmol/mol]). Use of ITCA 650 in addition to previous therapy reduced HbA1c (mean reduction of -2.8%; P<0.001) at 39 weeks [19].
Dec 17Results of FREEDOM-1 published in Diabetes Care [18].
May 16Intarcia announces positive outcomes from the FREEDOM-CVO trial (NCT01455896), which met its primary (see Aug 13 below) and secondary outcomes; overall safety and tolerability was as expected and consistent with other GLP-1 agonists [15].
Nov 15Intarcia is developing ITCA 650 for once or twice yearly dosing, and state that, if approved, ITCA 650 would represent the first injection-free GLP-1 therapy capable of delivering up to a full year of treatment from a single subdermal placement of the osmotic mini-pump [13]; Servier is focusing on 3-monthly and 6-monthly formulations [12].
Oct 15PIIIb trial (NCT02638805) opens to study safety and tolerability of switching ITCA650 in patients with T2D receiving liraglutide and metformin. The study is expected to enrol ~ 120 patients with a primary completion date of April 17 [14].
Sep 15FREEDOM-1 HBL (High Baseline in high risk, refractory pts with type 2 Diabetes Mellitus) results presented at the 51st EASD meeting in Sweden. Sustained reductions in HbA1c levels were achieved by wk 6 (when pts were receiving only the initial 20 mcg/d ITCA 650 dose). Pts achieved a mean reduction in HbA1c of 3.4% at wk 39 and 22% achieved reductions of >4% and 25% achieved HbA1c levels of <7% at endpoint [11].
Sep 15FREEDOM-1 results presented at the 51st European Association for the Study of Diabetes (EASD) meeting in Sweden. ITCA 650 produced mean reductions in HbA1c of 1.4% after 39 wks. Mean HbA1c reductions in pts on background metformin (~40%), or diet and exercise (~11%), were 1.7% and for pts on SU background (47%), the mean HbA1c reduction was 1.2%. On average, pts lost ~4kg in the 60 mcg/d ITCA 650 dose grp vs. 2 kg in the placebo grp (statistically significant). ITCA 650 was well tolerated and GI events were similar between the 40mcg/d and the 60mcg/d gps with a few discontinuations for nausea [11].
Aug 15Positive results for ITCA 650 vs. sitagliptin from PIII Freedom-2 trial (NCT01455870). FREEDOM-2 is a global study of ITCA 650 as an add-on to metformin vs. sitagliptin in 535 pts in the US, Germany, Latvia, Croatia and Denmark. ITCA 650 reduced blood glucose by 1.5% vs. 0.8% for sitagliptin. ITCA 650 also resulted in an average weight loss of about 9lb compared to ~3lb for sitagliptin [9,10].
Jun 14Intarcia presents PIII data at conference. The data include the first 6-month, open-label experience with ITCA 650 mini-pumps from an ongoing multicenter study in subjects with T2DM who did not meet enrollment criteria for the double-blind placebo controlled trial because their HbA1C was greater than 10%, a population who is not appropriate for a placebo controlled trial. This open-label HBL study enrolled a total of 60 patients who met all of the qualifications for the double-blind study except for elevated blood sugar levels and an HbA1C between 10-12%. Entrance criteria for the open-label trial included: HbA1C >10% to =12%, age 18-80 years, BMI 25-45 kg/m2, a stable regimen (=3 months) of diet and exercise and/or mono, or combination therapy with any combination of metformin, sulfonylurea, and thiazolidinedione. 69% of subjects were on one or more diabetes medicines at baseline and still very poorly controlled. Treatment was initiated by placing a 3-month ITCA 650 mini-pump delivering 20 mcg/day, which was then replaced by a 6-month ITCA 650 mini-pump delivering 60 mcg/day for 26 weeks. Pre-study oral anti-diabetic agents (OADs) were maintained unchanged for the 39 weeks of treatment. Primary endpoint in the trial is: Change in HbA1C from baseline to week 39. At the time of the initial interim analysis, 50 patients completed 13 weeks, 39 patients completed 19 weeks, and 25 patients completed 26 weeks. Mean baseline characteristics for the entire cohort (n=60) were: HbA1C 10.7%, age 52.1 yrs, BMI 32.1 kg/m2, duration of diabetes 8.9 yrs, OADs use 69%. Mean reductions of HbA1C at Weeks 13 (n=50), 19 (n=39), and 26 (n=25) were -2.5%, -2.9%, and -3.2%, respectively. HbA1C reductions =2% were achieved by 78% of subjects who completed at least 13 weeks of treatment; 50% achieved >3% and 22% achieved =4% reductions. HbA1C targets of <7% were achieved in 26% of subjects who had completed at least 13 weeks of treatment. Adverse events were consistent with previous trials with ITCA 650. The interim analysis shows ITCA 650 has the potential to dramatically improve glycemic control in patients with severe hyperglycemia and longstanding diabetes [6].
Aug 13NCT01455896 (EudraCT Number: 2012-002219-25 [Study 107], FREEDOM CVO) is a randomized, multicentre study to evaluate cardiovascular outcomes with ITCA 650 in 3000 patients treated with standard of care for T2DM. The primary objective of is to obtain CV event data that will be pooled with CV event data from other PIII studies in a meta-analysis to demonstrate that the upper limit of the 95% CI of the hazard ratio of major adverse cardiac events (MACE) in adult patients on standard of care for T2D receiving either ITCA 650 or control, based on the time to first occurrence of any event in the MACE1 CV composite endpoint (CV death, non-fatal MI, non-fatal stroke, or hospitalization for unstable angina), does not exceed 1.8. The study started in Mar 13 and is due to complete Jul 18 [5].
Mar 13The first patient has been enrolled in FREEDOM-1, the first of four planned PIII clinical trials studying the safety and efficacy of ITCA 650 (continuous subcutaneous delivery of exenatide) for the treatment of T2DM. The FREEDOM programme aims to demonstrate that optimizing GLP-1 therapy with once- or twice-yearly dosing of ITCA 650 results in effective, well tolerated glycaemic control that virtually ensures longer-term compliance. The FREEDOM-1 study is a US based placebo-controlled, double-blind study of 450 T2D patients whose HbA1c is between 7.5% and 10%.and not controlled on up to 3 oral anti-diabetes drugs. Patients will be randomized into one of three groups: ITCA 650 40mcg/d, ITCA 650 60mcg/d and placebo. Subjects in the ITCA 650 arms will be treated with 3-month devices for the first 13 weeks that deliver an initial dose of 20 mcg/d, and then with 6-month ITCA 650 at doses of 40 or 60mcg/d. The primary endpoint will be change in HbA1c at 9 months; secondary endpoints include changes in weight, FPG, PPG and tolerability. An open-label study, FREEDOM-1 HBL (high baseline), will be run concurrently with FREEDOM-1 in patients who meet all eligibility criteria for FREEDOM-1, but whose baseline HbA1c is > 10%. All patients in this study will receive ITCA 650 20 mcg/d for the first 3 months and with ITCA 650 60mcg/d for the next 6 months. The FREEDOM-2 study will be a 500-patient, global, active-comparator controlled, double-blind study in patients on metformin only, comparing ITCA 650 20mcg/d for 13 weeks plus ITCA 650 60mcg/d for 39 weeks to vs sitagliptin; FREEDOM-CVO is a global, placebo-controlled cardiovascular outcomes study that will examine the safety of ITCA 650 at 60mcg/d vs. placebo in approximately 3,000 patients on a variety of approved anti-diabetes therapies [4].
Oct 11Six PIII studies of the efficacy and safety of ITCA 650 in patients with T2DM are planned to begin in Jan 12. Inclusion criteria for the first 5 studies described below include HbA1c between 7.5-11%, on metformin monotherapy and a BMI between 25 & 45 kg/m2. NCT01455857 is a placebo-controlled RCT in 450 patients using two doses, 40 and 60mcg/day of ITCA 650. The primary outcome is change in HbA1c at 39 weeks; the study also includes a 65-week extension period. Two studies NCT01455922 and NCT01455883, each in 500 subjects, will compare of ITCA 650 (60mcg/day) to glimepiride (up to 8mg/day) as add-on therapy to metformin. The primary outcome is change in HbA1c at 52 weeks. These studies will be followed by a 52 week extension period. NCT01455909 and NCT01455870, again each in 500 subjects, are comparing ITCA 650 to sitagliptin (100mg/day) as add-on therapy to metformin. The primary outcome is change in HbA1c at 39 weeks. These studies will be followed by a 65 week extension period. NCT01455896 will assess cardiovascular outcomes over 2 years in 2000 patients with a history of coronary, cerebrovascular or peripheral artery disease. The primary outcome is time to first occurrence of any event included in the MACE cardiovascular composite endpoint (CV death, non fatal MI, non fatal stroke, or hospitalization for unstable angina), Primary outcome data for the first five studies will be collected in 2013; with studies completing in 2014. The CV outcome study will complete in 2017 [2].
Sep 11The ITCA 650 Phase III programme will assess treatment regimens involving initial three-month ITCA 650 dosing at 20 mcg/day transitioning to 60 mcg/day and thereafter using ITCA 650 devices of both 6- and 12-month durations [1].
Sep 11Data from PII study (n=155) showed that pts receiving treatment with ITCA 650 experienced substantial and sustained reductions in HbA1c, fasting plasma glucose (FPG) and body weight during the 48 weeks of treatment at all doses. Doses during the first 12 weeks were ITCA 650 20 mcg/day or 40mcg/day, with the 20mcg/day providing improved glycaemic control with the most favourable tolerability profile as a starting dose, vs. twice daily injections. Treatment was continued with ITCA 650 doses of 40, 60 or 80 mcg/day. All doses led to statistically significant reductions in HbA1c, FPG and body weight after 24 and 48 weeks of treatment, with greatest reductions in HbA1c in the 60mcg and 80mcg arms (difference between the two not statistically significant). All pts continued with metformin monotherapy. Results from the Diabetes Medication Satisfaction Tool indicated that patients receiving ITCA 650 at doses of either 20 mcg/day or 40 mcg/day experienced a statistically significant improvement in their quality of life after eight weeks of ITCA 650 therapy vs. their level of satisfaction at study entry on oral metformin therapy. Patients on either dose of ITCA 650 also experienced a greater increase in their level of satisfaction with treatment compared with patients on twice-daily self-injections of exenatide [1].
Sep 11ITCA 650 therapy consists of DUROS continuous subcutaneous delivery of exenatide. The DUROS delivery technology comprises the DUROS device, a matchstick-size, miniature osmotic pump that is placed subcutaneously to provide continuous and consistent drug therapy. The technology maintains stability of therapeutic proteins and peptides at human body temperature for extended periods of time [1].