Exenatide LAR, subsequently designated Exenatide once weekly Ex(OW), has been studied in a head to head comparison (DURATION-1) against twice daily exenatide, in a non-inferiority open label study over 30-wks, in 295 patients with type 2 diabetes (A1C 8.3±1.0%, FPG 168±42 mg/dL, weight 103±20 kg, BMI 35±5.0 kg/m2, diabetes duration 6.7±5.0 years; mean±SD). Patients were drug naïve or treated with 1 or more oral glucose-lowering therapies. Over 30 weeks, treatment with Ex(OW) resulted in significantly greater improvements in A1C compared to exenatide BID [A1C change from baseline: -1.9%±0.08 (LS mean±SE) vs 1.5%±.0.08 (P=0.002)]. A significantly greater percentage of evaluable patients treated with Ex(OW) achieved A1C levels of ≤7.0% (77% versus 61% respectively). Remarkably, 33% of Ex(OW) patients with a starting HbA1c of 9% or greater achieved an end of study A1c of <6.5%. Ex(OW) was also associated with significantly lower fasting glucose concentrations (-41.5mg/dL±3.0, OW Ex; -24.6mg/dL±2.9 BID, P=0.001). Both treatments showed significant glycemic improvements irrespective of baseline A1C, and were associated with ~4 kg reductions in body weight. Nausea was predominantly mild and transient and occurred less frequently with Ex(OW) (26% vs 35%). OW Ex was well-tolerated with no increased risk of hypoglycemia and ~90% of patients completed the 30 wks of treatment. These findings, together with data on antibody responses, and mechanistic data describing effects of Ex(OW) on gastric emptying and plasma glucagon, were published in Exenatide once weekly versus twice daily for the treatment of type 2 diabetes: a randomised, open-label, non-inferiority study Lancet. 2008 2008 Oct 4; 372 (9645):1240-50.
Exenatide once weekly Ex(OW) was approved for marketing in Europe in 2011-See the EMA Prescribing information for Exenatide once weekly Ex(OW) (Bydureon). Exenatide once weekly was approved in the United States January 27 2012
Subsequently, patients were followed out to 52 weeks, and all patients who initially received Exenatide b.i.d over the initial 30 weeks were then switched to Ex(OW). The glucoregulatory and weight loss effects of Ex(OW) were sustained over 52 weeks of therapy and patients who were switched from Exenatide twice daily to once weekly ended up with the same improvements in glycemic control compared to the group treated with Ex(OW) for the entire 52 weeks DURATION-1: Exenatide Once Weekly Produces Sustained Glycemic Control and Weight Loss Over 52 Weeks Diabetes Care published ahead of print March 9, 2010, doi:10.2337/dc09-1914
Ongoing observation of the initial cohort of patients revealed that 73% (n=216) completed 2 years of treatment on Ex(OW) (completer population). Reductions in BP and weight loss were sustained over the 2 year treament period. The percentages of patients who achieved an A1C of <7.0% and 6.5% at 2 years were 60% and 39%, respectively. Nauseas remained the principal AE in the study population Exenatide Once Weekly Treatment Maintained Improvements in Glycemic Control and Weight Loss Over 2 Years BMC Endocr Disord. 2011 Apr 29;11(1):9. [Epub ahead of print
In DURATION 6, patients were randomized either to therapy with once daily liraglutide, with a forced titration to 1.8 mg per day, vs. once weekly therapy with Ex(OW), for a total of 26 weeks. The 26-week, head-to-head, open-label, superiority study enrolled approximately 900 patients in 19 countries outside the U.S. with type 2 diabetes who were not achieving adequate A1C control with diet and exercise in conjunction with metformin, a sulfonylurea, metformin plus a sulfonylurea or metformin plus Actos(R) (pioglitazone HCI). Patients had an average type 2 diabetes diagnosis of more than eight years. Patients receiving Ex(OW) experienced a reduction in A1C of 1.28 percentage points from baseline, compared to a reduction of 1.48 percentage points for liraglutide. Ex(OW), did not meet the pre-specified primary endpoint of non-inferiority to Victoza. Ex(OW), appeared to be slightly better tolerated (less nausea, vomiting and diarrhea), however injection site nodules were more common with Ex(OW). Exenatide once weekly versus liraglutide once daily in patients with type 2 diabetes (DURATION-6): a randomised, open-label study Lancet. 2012 Nov 6. doi:pii: S0140-6736(12)61267-7
A head to head study of Ex(OW) was carried out to assess the relative efficacy of Ex(OW) vs. metformin (2 grams/day), pioglitazone (45 mg), or sitagliptin (100 mg), in drug naiive subjects with T2DM, mean starting A1c of 8.5%. Pioglitazone produce the most effective reduction in A1c over 26 weeks. Ex(OW) was non-inferior to metformin, and superior to sitagliptin. Both Ex(OW) and metformin therapy was associated with ~ 2kg of weight loss, whereas subjects on sitagliptin lost 0.8 kg. Nausea (11.3%) and diarrhea (10.9%) were the most commonly reported AEs with Ex(OW). Beta cell function estimated by HOMA was improved to a greater extent in subjects treated with Ex(OW), whereas insulin sensitivity was preferentially improved in subjects on metformin or pioglitazone. Systolic BP was reduced to a greater extent in the sitagliptin vs. Ex(OW) groups, with a mean HR of 1.5 bpm in Ex(OW) patients. 43.1 and 11.3% of patients developed low and high titer antibodies on Ex(OW) and injection site reactions were reported to a greater extent in antibody+ subjects. Efficacy and Safety of Exenatide Once Weekly Versus Metformin, Pioglitazone, and Sitagliptin Used as Monotherapy in Drug-Naive Patients With Type 2 Diabetes (DURATION-4): A 26-week double-blind study Diabetes Care. 2011 Dec 30.
A head to head study of Ex(OW), (DURATION-5) against twice daily exenatide, was carried out to determine whether Ex(OW) produced at commercial scale in a new plant would still perform in a similar manner relative to Ex(OW) drug produced earlier using a different process. A 24 week randomized non-blinded open label study of 252 patients with T2DM was carried out, mean baseline HbA1c of 8.4%, 19% drug naive, 47% treated with one and 35% treated with multiple oral medications. The mean change in A1c achieved at week 24 was 1.6% vs. -0.9% for Ex(OW)vs. twice daily exenatide with non-significant differences in weight loss (2.3 vs. 1.4 kg), respectively. Injection site reactions and antibody formation were observed more frequently and nausea was less common in subjects treated with Ex(OW). Reductions in systolic blood pressure and fasting cholesterol and LDL and increases in heart rate were also more notable with Ex(OW). Pancreatic amylase and lipase were elevated in 5 and 14% of the patients prior to treatment. No significant changes in mean plasma calcitonin levels were reported DURATION-5: Exenatide Once Weekly Resulted in Greater Improvements in Glycemic Control Compared with Exenatide Twice Daily in Patients with Type 2 Diabetes J Clin Endocrinol Metab. 2011 Feb 9.
The results of the DURATION-2 study were reported in a March 31 2009 Press Release and published in June 2010. Exenatide once weekly Ex(OW) produced superior HbA1c reduction (1.5%) and weight loss (6.2 lbs) compared to results obtained with sitagliptin (0.9% A1c reduction, 1.9 lbs weight loss) or pioglitazone (1.2% A1c reduction, 7.4 lbs weight gain) in a head to head study of patients with T2DM not achieving adequate glycemic control (starting HbA1c of 8.5%) on metformin therapy. Efficacy and safety of exenatide once weekly versus sitagliptin or pioglitazone as an adjunct to metformin for treatment of type 2 diabetes (DURATION-2): a randomised trial. Lancet. 2010 Jun 25. [Epub ahead of print]. After the first 26 weeks patients on oral medications (pioglitazone or sitagliptin) were then switched to Ex(OW). Patients who were maintained on Ex(OW) for the entire 52 weeks finished with a mean HbA1c reduction of 1.6 percent and 1.8 kg weight loss. Patients switching from sitagliptin experienced a further 0.3% reduction in A1c, whereas those switching from pioglitazone had significant weight reduction (3 kg, reversing the original weight gain) but no further reduction in A1c. Systolic BP, BNP, and urinary albumin-creatinine ratios were reduced with Ex(OW) DURATION-2: efficacy and safety of switching from maximum daily sitagliptin or pioglitazone to once-weekly exenatide Diabet Med. 2011 Mar 22. doi: 10.1111/j.1464-5491.2011.03301.x
The preliminary results for the Duration-3 study were reported in a July 20 2009 Duration 3 Press Release. Exenatide once weekly achieved a significantly greater reduction in A1c with weight loss, compared to insulin glargine. For top line summaries of Duration 2&3, see slides from the July 21 200 Amylin Quarterly earnings call
The Duration-4 study compared Ex(OW) head to head with metformin, pioglitazone, or sitagliptin. As announced on June 15 2010: "This 26-week clinical study compared BYDUREON monotherapy to Januvia(R) (sitagliptin), Actos(R) (pioglitazone HCI) or metformin, three oral type 2 diabetes medications commonly prescribed early in the treatment of type 2 diabetes. Study participants were not achieving adequate A1C control using diet and exercise, and were not on any diabetes therapy when they entered the study. After 26 weeks of treatment, patients randomized to BYDUREON experienced a reduction in A1C of 1.5 percentage points from baseline, which was significantly greater than the reduction of 1.2 percentage points for Januvia. Patients randomized to metformin experienced a reduction in A1C of 1.5 percentage points, and patients receiving Actos experienced a reduction of 1.6 percentage points. Patients receiving BYDUREON, Actos and metformin treatment achieved an average A1C of less than 7 percent by study end.
Treatment with BYDUREON produced an average weight loss of 4.5 pounds, which was statistically significantly greater than the average 1.7 pounds patients lost with Januvia and the average 3.3 pounds patients gained with Actos. Patients receiving metformin experienced an average weight loss of 4.4 pounds.
More than 80 percent of patients in all treatment arms completed the study. There were no major hypoglycemia events in any treatment group. The most frequently reported adverse events among BYDUREON users were nausea (withdrawal rate less than 1 percent) and diarrhea; metformin, diarrhea and headache; Actos, upper respiratory tract infection, headache, hypertension and peripheral edema; and Januvia, upper respiratory tract infection and headache.
The 26-week, double-blind, randomized, four-arm parallel study enrolled 820 patients who were not achieving adequate A1C control on diet and exercise. Patients had an average type 2 diabetes diagnosis of two to three years. The patients were randomized as follows: BYDUREON (2 mg, once per week) (n=248); metformin (dose escalated up to 2,500 mg/day) (n=246); Actos (dose escalated up to 45 mg/day) (n=163); and Januvia (100 mg/day) (n=163). The primary endpoint was reduction in A1C, while secondary endpoints included change in body weight along with other parameters of glucose control, cardiovascular health and patient-reported outcomes.
Exenatide once weekly Ex(OW),has also been studied in Japanese subjects with T2DM using the 0.8 and 2 mg doses. The drug was well tolerated and efficacious in this small pharmacokientic pilot study Safety, tolerability, pharmacokinetics, and pharmacodynamics of exenatide once weekly in Japanese patients with type 2 diabetes Endocr J. 2009;56(8):951-62. Epub 2009
For top line highlights of Exenatide LAR early clinically development also referred to as once weekly Exenatide, Phase 3 studies, as originally described in Oct 31 2007 LAR Press Release
Oct 31 2007
exenatide, an investigational drug, showed a statistically significant
improvement in A1C of approximately 1.9 percentage points from baseline,
compared to an improvement of approximately 1.5 percentage points for BYETTA.
Approximately three out of four subjects treated with once-weekly exenatide
achieved an A1C of 7 percent or less. A1C of less than 7 percent is the target
for good glucose control as recommended by the American Diabetes Association.
weeks of treatment, both once-weekly exenatide and BYETTA treatment resulted in
an average weight loss of approximately eight pounds. Nearly 90 percent of
subjects in both groups completed the study, which enrolled patients not
achieving adequate glucose control with either diet and exercise or with use of
oral glucose-lowering agents.
There was no
major or severe hypoglycemia regardless of background therapy. As expected based
on prior BYETTA studies, minor hypoglycemia with once-weekly exenatide use was
limited to subjects using background sulfonylurea therapy. Once-weekly exenatide
was associated with approximately 30 percent less nausea than BYETTA.
Approximately one out of five subjects receiving once-weekly exenatide reported
treatment-related nausea during the 30-week study. In both groups nausea was
predominantly mild and transient. The antibody profile of subjects treated in
this study was consistent with the previously reported profiles of BYETTA and
Exenatide LAR was examined in Phase 2 studies at two doses, 0.8 and 2.0 mg, once weekly in subjects with type 2 diabetes, either controlled on diet alone, or on metformin, for 15 weeks. All patients received a lead in phase of Exenatide 5 ug twice daily for 3 days prior to the first administration of LAR.
Both subgroups of patients exhibited significant reductions in levels of HbA1c, with an end of study HbA1c less than 7% achieved by 36 and 86% of patients in the low and high dose respectively. Weight reduction (~3.8 kg) was observed in the high dose LAR treatment group, and no patients withdrew from the study in either subgroup.
Pharmacokinetic studies demonstrated that plasma levels of Exenatide peaked around week 6. Steady state concentrations of Exenatide after a 2 mg LAR injection were 232 pg/ml, similar to levels that would be achieved after a single 10 ug Exenatide injection (211 pg/ml).
Nausea was the most frequent adverse
event reported (27% for the 2 mg dose vs 15% for placebo). Analysis of antibody
status demonstrated that 67% of patients were antibody positive at week 15,
however there did not appear to be a correlation between antibody status and the
clinical response observed in individual patients in this small study. See Effects
of Once-Weekly Dosing of a Long-Acting Release Formulation of Exenatide on
Glucose Control and Body Weight in Subjects With Type 2 Diabetes. Diabetes
Care. 2007 Mar 12; [Epub ahead of print]