Taspoglutide

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Drug notes

Taspoglutide

Dipeptidyl-peptidase-4 Christopher JL Kueh 1 MBChB, MRCP, Specialty Trainee His Ala Glu Gly Thr Phe Thr Ser Asp Val Ser Miles Fisher 1 Ser MD, FRCP, Consultant Physician Ile Phe Glu Lys Ala Ala Gln Gly Glu Leu Tyr 1Glasgow Royal Infirmary, Glasgow, UK Ala Trp Leu Val Lys Gly Arg Gly Native GLP-1 Correspondence to: Professor Miles Fisher, Wards 3, 4 & 5, Glasgow Royal Plasmin and kallikrien Infirmary, 84 Castle Street, Glasgow G4 0SF, UK; email: [email protected] His Aib Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Ile Phe Glu Lys Ala Ala Gln Gly Glu Leu Tyr Ala Trp Leu Val Lys Aib Arg Taspoglutide

Figure 1. Two amino acid substitutions at enzymatic sites of action to achieve resistance to DPP-4 and plasma proteases. Taspoglutide has 97% homology with native GLP-1. In addition, zinc chloride is added to produce a sustained-release formulation Introduction pharmacodynamic profiles through Glucagon-like peptide-1 receptor attachment to larger protein mole - agonists (GLP-1 RAs) are now well cules – albiglutide through bonding established in the treatment of type 2 with human albumin and dulaglutide diabetes. Initially, GLP-1 RAs were through bonding with an inactivated injected either once or twice daily. A human IgG4-Fc immunoglobulin once-weekly formulation of exe - molecule. natide is available with the perceived Taspoglutide was a 30-amino acid benefit of the reduced frequency of derivative of native GLP-1 which administration with a once-weekly achieved a prolonged pharmacody - preparation. Two other once-weekly namic profile through amino acid GLP-1 RAs have recently been substitutions at position 8 (amino - approved by the EMEA (albiglutide, isobutyric acid substituted for ala - dulaglutide) and these should be nine), which resisted degradation by available shortly for clinical use. dipeptidyl-peptidase-4, and at posi - Taspoglutide was being developed as tion 35 (aminoisobutyric acid substi - a once-weekly GLP-1 RA for patients tuted for glycine) which resisted with type 2 diabetes, but develop - degradation by other plasma pro - ment was halted because of unac - teases such as plasmin and kallikrien 1 ceptable side effects. (Figure 1). This analogue was fully resistant Pharmacology to enzymatic cleavage, stable in The main actions of GLP-1 RAs are to plasma, and had similar binding stimulate insulin secretion from the affinity for the human GLP-1 recep - pancreas, suppress glucagon secre - tor and activated this receptor with tion, reduce gastric emptying and similar potency. It was then commer - increase satiety. The prolonged cially produced as a sustained-release action of once-weekly exenatide is once-weekly formulation by the addi - achieved by encapsulating exenatide tion of zinc chloride. 2 When injected in biodegradable polymer micros - subcutaneously the sustained-release pheres that slowly degrade and formulation peaked at 24 hours after release their contents. Albiglutide injection and plasma levels were and dulaglutide achieve prolonged sustained for over 14 days.

Trials of efficacy and clinically important. The most The T-emerge trial programme was a common side effects that occur with Key points large Phase 3 programme of taspog - GLP-1 RAs are gastrointestinal (GI) lutide to determine the efficacy and side effects. These were more com - l Taspoglutide was being developed as a safety of taspoglutide in patients with mon in taspoglutide-treated patients once-weekly GLP-1 receptor agonist type 2 diabetes. than with exenatide (nausea: taspog - l In a head-to-head study with exenatide T-emerge 1 was a randomised 24- lutide 10mg 53%, taspoglutide 20mg twice-daily, taspoglutide was more week, double-blind, placebo-con - 59%, and exenatide 35%; vomiting: effective in reducing HbA 1c , with similar trolled study that recruited 373 taspoglutide 10mg 33%, taspoglutide effects on weight patients with type 2 diabetes who had 20mg 37%, and exenatide 16%). 4 l An unexpectedly high number of not been on any previous diabetes Other side effects reported in the adverse events in Phase 3 trials, medications, and randomised them T-emerge 1 trial include abdominal including gastrointestinal symptoms to weekly taspoglutide vs placebo. As pain and distension, dyspepsia, and and local injection site reactions, expected, there was an HbA 1c reduc - diarrhoea. 3 caused Roche to withdraw taspoglutide tion in the treatment arm vs the An unexpected side effect that was prior to release placebo arm at 24 weeks. HbA 1c identified throughout the T-emerge improvements with taspoglutide series was local injection site reac - to emerge within the class in terms of 10mg, taspoglutide 20mg vs placebo tions. There were more injection site efficacy in reducing HbA 1c , efficacy were -1.01% (SE 0.07), -1.18% (0.06) reactions than compared to placebo in reducing weight, and side effects. and -0.09% (0.07), respectively. As in the T-emerge 1 trial (taspoglutide Due to the higher incidence of with other GLP-1 RAs there were also 10mg 36%, taspoglutide 20mg 34%, adverse reactions, including common weight reductions of -1.45kg (0.32) placebo 11%). These included: nod - class effects such as GI disturbance and with taspoglutide 10mg, -2.25kg ule formation (taspoglutide 10mg unexpected ones such as local hyper - (0.30) with taspoglutide 20mg, 12%, taspoglutide 20mg 9%, placebo sensitivity reactions, taspoglutide did and -1.23kg (0.31) with placebo. 3 1%); induration (taspoglutide 10mg not make it to market. In September T-emerge 2 was a direct head-to- 5%, taspoglutide 20mg 5%, placebo 2010, Roche voluntarily stopped fur - head trial to compare the efficacy of 1%); and pruritus (taspoglutide ther dosing in Phase 3 trials due to the taspoglutide with twice-daily exe - 10mg 4%, taspoglutide 20mg 5%, higher than expected discontinuation natide. 4 The investigators recruited placebo 0%). 3 rates, and to address the serious hyper - 1189 overweight type 2 diabetic adults As a consequence of injection site sensitivity reactions observed. Roche who were taking metformin with or reactions and GI side effects, there was continued to work on the root cause without a thiazolidedione and were a higher withdrawal rate from the stud - analysis and ultimately returned the failing treatment based on an HbA 1c of ies in the taspoglutide group than in product to the originator Ipsen. 7–10% (53 –86mmol/mol). They were the control groups (taspoglutide 34% Roche had identified an associa - randomised to either taspoglutide compared to exenatide 16% dropout tion between the noted hypersensitiv - 10mg weekly, taspoglutide 20mg rate). 3 In the T-emerge 2 trial, post- ity reactions and the development of weekly, or standard dose exenatide baseline anti-taspoglutide antibody anti-drug antibodies. These anti- 10 mg twice-daily. Following 24 weeks of levels were measured in the majority of taspoglutide antibodies were meas - treatment, both doses of taspoglutide patients. These were positive in 43% of ured in significant numbers of study achieved statistically superior HbA 1c the taspoglutide 10mg group and in patients, and antibody measurement reductions vs exenatide: taspoglutide 55% of the taspoglutide 20mg group. may have a role in predicting the inci - 10mg -1.24%; taspoglutide 20mg The proportion of patients with dence of hypersensitivity reactions -1.31%; exenatide -0.98%. There was strongly positive anti-taspoglutide anti - in other long-acting GLP-1 RAs. also a comparable weight loss achieved body tests also increased from 16% at Exenatide has similar rates of anti - with taspoglutide (taspoglutide 10mg: week 12 to 39% at week 24, with no fur - body formation and appeared to -1.6kg; taspoglutide 20mg: -2.3kg) ther increase at week 52. 4 demonstrate a higher incidence of compared with exenatide ( -2.3kg). injection site reactions in antibody There were several other trials in Discussion positive patients vs the anti body the T-emerge series investigating Taspoglutide was being developed as negative patients. It is noted that taspoglutide. Five further studies com - a newer, longer-acting GLP-1 RA with liraglutide has significantly lower pared taspoglutide with placebo as sec - the potential benefit of reduced fre - rates of development of anti- ond-line and as third-line therapy, and quency of dosing. With regard to effi - liraglutide antibodies compared to three head-to-head studies compared cacy, taspoglutide was more effective exenatide or taspoglutide. taspoglutide with sitagliptin, pioglita - than twice-daily exenatide in reduc - zone and insulin, and as additional ing HbA 1c and similar in reducing Declaration of interests therapy in patients already on existing weight. No trials were undertaken Prof Fisher has done advisory boards diabetes treatments. A large cardiovas - comparing once-weekly taspoglutide for AstraZeneca, Eli Lilly, GlaxoSmith cular safety study was also started. to the once-weekly preparation of Klein, Novo Nordisk, Roche, Sanofi. exenatide, or to other GLP-1 RAs. Side effects and adverse events Studies comparing the different References Throughout the T-emerge trial pro - GLP-1 RAs give useful clinical infor - References are available online at gramme, side effects were common mation, and differences are starting www.practicaldiabetes.com.

References 1. Kaptiza C, et al . Pharmacokinetic and pharmacody - namic properties of taspoglutide, a once-weekly, human GLP-1 analogue, after single dose adminis - tration in patients with type 2 diabetes. Diabet Med 2009;26:1156 –64. 2. Dong JZ, et al . Discovery and characterization of taspoglutide, a novel analogue of human glucagon- like peptide-1, engineered for sustained therapeutic activity in type 2 diabetes. Diabetes Obes Metab 2011;13:19 –25. 3. Raz I, et al . Efficacy and safety of taspoglutide monotherapy in drug-naïve type 2 diabetic patients after 24 weeks of treatment. Diabetes Care 2012;25: 485 –7. 4. Rosenstock J, et al . The fate of taspoglutide, a weekly GLP-1 receptor agonist, versus twice-daily exenatide for type 2 diabetes: the T-emerge 2 trial. Diabetes Care 2013;36:498 –504.