Efpeglenatide: A Once Monthly GLP-1 RA in the Pipeline

Special Article - Complications of Diabetes

Austin J Endocrinol Diabetes. 2016; 3(4): 1053.

Efpeglenatide: A Once Monthly GLP-1 RA in the Pipeline

Davies ML¹*, Thiman ML² and Kugler AJ¹

1Department of Pharmacy Practice and Administration, Western University of Health Sciences College of Pharmacy, USA

2Department of Clinical & Administrative Pharmacy, University of Georgia College of Pharmacy, USA

*Corresponding author: Davies ML, Department of Pharmacy Practice and Administration, Western University of Health Sciences College of Pharmacy, 309 E. Second Street, Pomona, USA

Received: October 06, 2016; Accepted: November 08, 2016; Published: November 15, 2016


Efpeglenatide is a potential once-monthly, subcutaneous Glucagon-Like- Peptide-1 Receptor Agonist (GLP-1 RA) and is currently being studied as a treatment option for patients with Type 2 Diabetes (T2DM). Its novel mechanism utilizes a long acting protein technology, where the modified Exendin-4, GLP-1 RA, molecule is attached to a flexible linker to the Fc fragment of IgG, allowing for a longer half-life and monthly administration. In phase II trials, efpeglenatide weekly demonstrated a reduction in A1C of 1.24-1.61% and monthly administration reduced A1C 0.7-1.2%, with most doses producing significant A1C lowering when compared to placebo. Additionally, efpeglenatide resulted in weight loss of ~2-3.5 kg in trials including patients with T2DM and greater weight reduction in one trial of obese patients without diabetes. Efpeglenatide has also been shown to target fasting plasma glucose, an effect seen previously with other long-acting GLP-1 RAs. Although gastrointestinal events were as high as 67%, nausea, the main side effect of GLP-1 RAs, was similar when efpeglenatide weekly was compared to liraglutide in one of the trials (33% in each group). The potential for increased adherence with monthly administration and the positive effects of glycemic control and weight loss may make this upand- coming GLP-1RA a promising option.

Keywords: Efpeglenatide; Glucagon-like peptide-1 receptor agonist; GLP- 1; GLP-1 RA


GLP-1 Ras: Glucagon-Like Peptide-1 Receptor Agonists; T2DM: Type 2 Diabetes Mellitus; GI: Gastrointestinal; IR: Immediate- Release; ER: Extended-Release; GLP-1R: Glucagon-Like Peptide-1 Receptor; DPP-IV: Dipeptidyl Peptidase-IV; LAPSCOVERY: Long Acting Protein / Peptide Discovery Platform Technology; t1/2: Half- Life; QW: Weekly; Q2W: Every Other Week; FPG: Fasting Plasma Glucose; PPG: Post-Prandial Glucose


Glucagon-Like Peptide-1 Receptor Agonists (GLP-1 RAs) have proven to be an effective drug class at improving glycemic control in patients with Type 2 Diabetes Mellitus (T2DM) [1]. This class has been shown to reduce A1C in ranges of 1-1.5% in addition to standard of care [2]. Furthermore, GLP-1 RAs delay gastric emptying time, which slows carbohydrate absorption and increases satiety, often reducing overall food intake and resulting in weight reduction [1,3]. Unfortunately, the delay in gastric emptying also leads to the main adverse events seen in this class, Gastrointestinal (GI) events, especially nausea which can be seen in up to 30% of patients [1,4].

It has been over a decade since the first GLP-1 RA, exenatide, was approved by the FDA [4]. There are now 6 GLP-1 RAs available in the US, including exenatide Immediate-Release (IR) (Byetta), liraglutide (Victoza), lixisenatide (Adlyxin), dulaglutide (Trulicity), albiglutide (Tanzeum), and exenatide Extended-Release (ER) (Bydureon). Exenatide IR is administered twice daily by subcutaneous injection, liraglutide and lixisenatide offer a once daily injection, and dulaglutide, albiglutide, and exenatide ER are once weekly medications, lessening injection burden, and potentially improving patient adherence. The move to weekly GLP-1 RA administration not only has the potential to improve adherence, but also mechanistically, with an extended-release function, decreases the incidence of nausea and vomiting commonly seen with the class [5,6]. Efpeglenatide is a potential monthly GLP-1 RA in the pipeline, which may offer additional administration and side-effect profile benefits. The purpose of this review is to evaluate the pharmacologic design, efficacy, and tolerability of efpeglenatide, a potential once-monthly GLP-1 RA currently under investigation.

Pharmacology of Efpeglenatide

Mechanistically, the GLP-1 RAs have the ability to suppress glucagon release and enhance insulin secretion in a glucosedependent manner, by binding to the GLP-1 Receptor (GLP-1R) on the beta cells of the pancreas [7,8]. Unfortunately, endogenous GLP- 1 is degraded within 1-2 minutes by Dipeptidyl Peptidase-IV (DPPIV) [7]. Compounds have been discovered and synthesized that mitigate this degradation. Exenatide IR (also known as Exendin-4) is a GLP-1 discovered from saliva of the Gila monster, a venomous lizard. This compound does not have the DPP-IV cleavage site, which increases the GLP-1 RA half-life [7]. Weekly GLP-1 RAs, albiglutide and dulaglutide also have been synthetically modified with DPPIV resistance. In addition, albiglutide is attached to human serum albumin protein to decrease elimination and extend the half-life (t1/2) to 6-7 days [9]. Dulaglutide is fused with the Fc region of IgG4 to prolong t1/2 and decrease immunogenicity via antibody formation [9]. Immunogenicity is a concern, as low titer anti-exenatide antibodies have been shown in up to 45% of patients treated with exenatide [10]. In an analysis of 17 trials, low titers of anti-exenatide antibodies did not result in reduced efficacy; however, higher titers, seen in 12% of patients on exenatide ER, did result in reduced efficacy [10].

Efpeglenatide (HM-11260C or LAPSCA-Exendin 4) is a GLP-1 RA that has been synthetically modified for a potential once-monthly injection. CA-Exendin 4 has a single amino acid modification, decreasing its degradation by DPP-IV [11]. Additionally, the Long Acting Protein / Peptide Discovery Platform Technology (LAPSCOVERY) developed by Hanmi Pharmaceuticals allows for an extended t1/2. The LAPSCOVERY system conjugates the IgG4 Fc fragment with a flexible linker to the middle of the CAExendin 4 peptide to potentially decrease loss of activity from antidrug antibodies [9,12,13]. The increased size resulting from the conjugation decreases renal clearance, and preclinical studies have shown efpeglenatide results in decreased GLP-1R internalization and degradation, another mechanism of clearance and shortened half-life of the GLP-1 Ras [11].

Clinical Trials Reviewed

In a 12-week dose ranging study, subjects with T2DM were randomized to one of 7 arms –a placebo control, an active control of liraglutide dosed daily (titrated to 1.8 mg), or efpeglenatide0.3 mg, 1 mg, 2 mg, 3 mg, or 4 mg dosed weekly [14]. The study was double-blinded with the exception of those in the active control arm. Variations in metformin use were accounted for in the randomization process. On average, subjects (n=254) had T2DM for 73.08 months, were 55.3 years old, had a baseline weight of 86-95 kg, BMI of 31.76 kg/m2, and a baseline A1C ranging from 7.7-8.0%.Fifty-three percent of subjects were male. All active arms showed a statistically significant (p<0.05) reduction in A1C from baseline at week 13, with the largest decrease in the efpeglenatide4 mg group (-1.61%). Approximately 83.3% and 80.6% of subjects reached an A1C of ≤7% at 12 weeks with efpeglenatide 3 mg and 4 mg respectively compared to only 27% of subjects receiving placebo (p<0.0001 for both) and 61.1% of subjects receiving liraglutide1.8 mg daily. Reduction in Fasting Plasma Glucose (FPG) from baseline to week 13was 2.19mmol/L (39.4 mg/dL), 2.44 mmol/L (43.9 mg/dL), and 1.46mmol/L (26.3 mg/dL) in the efpeglenatide 3 mg, efpeglenatide 4mg, and liraglutide groups respectively, which were all statistically significant compared to placebo (p<0.05). Statistically significant weight loss of 2.73 kg (p<0.05), 3.31 kg (p<0.05), and 3.21 kg was reported in the 3 mg efpeglenatide, 4 mg efpeglenatide, and liraglutide arms respectively, as compared to 1.29 kg of weight loss in the placebo group. GI disorders occurred in 51-73% of efpeglenatide groups, the highest occurrence being in the 3 mg arm, compared to 81% in the liraglutide group and 62% in placebo. Of note, daily liraglutide doses were titrated, whereas weekly efpeglenatide doses were not. Injection site reactions were more common in the liraglutide arm, occurring in 36% of subjects, as opposed to 3-24% in the efpeglenatide arms (Table 1).

Citation: Davies ML, Thiman ML and Kugler AJ. Efpeglenatide: A Once Monthly GLP-1 RA in the Pipeline. Austin J Endocrinol Diabetes. 2016; 3(4): 1053. ISSN:2381-9200