Exenatide
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| ExenatideClinical data | |
|---|---|
| INN | exenatide |
| Class | GLP-1 receptor agonist |
| Origin | Synthetic exendin-4 |
| First approval | 2005 |
| Properties | |
| Residues | 39 |
| Molar mass | 4,186.6 g·mol⁻¹ |
| Half-life, immediate release | ≈2.4 h |
| Half-life, extended release | ≈2 weeks apparent |
| Compound infobox · conventions | |
Exenatide is a synthetic version of exendin-4, a 39-residue peptide isolated from the venom of the Gila monster, Heloderma suspectum. It shares approximately 53% sequence identity with human Glucagon-like peptide-1 and is a full agonist at the GLP-1 receptor. Approved in 2005, it was the first GLP-1 receptor agonist to reach the market.[1]
Its therapeutic relevance rests on an accident of sequence: exendin-4 carries glycine rather than alanine at position 2, so DPP-4 does not cleave it. No engineering was required to obtain protease resistance — the peptide is naturally resistant, and this is why a venom peptide became a diabetes drug.[1]
Two formulations were marketed: a twice-daily immediate-release product, and a once-weekly extended-release product in which the peptide is encapsulated in poly(lactide-co-glycolide) microspheres. Both have been largely displaced by later agents with greater efficacy and simpler pharmacokinetics.[2]
Origin and sequence
[edit]Exendin-4 was identified in Gila monster venom in the early 1990s and shown to bind the mammalian GLP-1 receptor with high affinity despite substantial sequence divergence. The peptide is not a lizard GLP-1 orthologue; lizards have their own GLP-1, and exendin-4 is a separate gene product expressed in the salivary gland.[1]
The C-terminal nine residues, absent from human GLP-1, form a tryptophan-cage motif that stabilises the helix and contributes to receptor affinity. This "Trp-cage" extension is the reason exendin-4 binds more tightly than native GLP-1 and is a frequently cited example of a natural product outperforming the endogenous ligand at its own receptor.
Glycine at position 2 provides the DPP-4 resistance. The resulting half-life of about 2.4 hours is still short — renal clearance dominates once proteolysis is removed — which is why the immediate-release product required twice-daily injection.
As a 39-residue synthetic peptide, exenatide is characterised by the ordinary battery for a synthetic peptide drug substance — chromatographic purity, peptide content, water, counterion and related substances — rather than by the protein methods needed for a fusion construct.[3]
The extended-release formulation
[edit]The weekly product suspends exenatide in biodegradable poly(lactide-co-glycolide) microspheres, which release peptide as the polymer hydrolyses. This is a formulation solution to a pharmacokinetic problem rather than a molecular one, and it behaves differently from a long-half-life molecule.[2]
Concentrations rise slowly over six to seven weeks to a plateau, so the full effect of starting treatment is not seen for around two months, and concentrations decay over a comparable period after stopping. Neither the onset nor the offset can be accelerated. A distinctive injection-site nodule occurs in a substantial minority of recipients, attributable to the polymer matrix rather than to the peptide.
The suspension also requires reconstitution and vigorous mixing immediately before injection, a preparation burden that later single-solution products removed.
Clinical position
[edit]Exenatide reduces glycated haemoglobin by roughly 0.8–1.5 percentage points depending on formulation and background therapy, with modest weight reduction. The EXSCEL cardiovascular outcome trial of the extended-release product reported a hazard ratio of 0.91 (95% CI 0.83–1.00) for the primary composite, narrowly failing conventional significance for superiority while establishing non-inferiority.[4]
That result is worth noting whenever a cardiovascular benefit is described as a class effect: within the same class, LEADER and SELECT were positive, EXSCEL was neutral, and the outcome trial of lixisenatide was neutral. Whether the differences reflect molecule, dose, population or duration is unresolved.[4]
Exenatide retains some use where a short-acting agent is specifically wanted, since its effect on gastric emptying does not attenuate in the way that a continuously present long-acting agonist's does.
See also
References
- ^ a b c Nielsen LL, Young AA, Parkes DG. "Pharmacology of exenatide (synthetic exendin-4): a potential therapeutic for improved glycemic control of type 2 diabetes." Regulatory Peptides 117(2):77–88 (2004). PMID 14700743.
- ^ a b Drucker DJ. "Mechanisms of action and therapeutic application of glucagon-like peptide-1." Cell Metabolism 27(4):740–756 (2018). PMID 29617641.
- ^ United States Pharmacopeia, General Chapter <1503>, Quality Attributes of Synthetic Peptide Drug Substances.
- ^ a b Holman RR, Bethel MA, Mentz RJ, et al. "Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes." New England Journal of Medicine 377(13):1228–1239 (2017). DOI:10.1056/NEJMoa1612917. PMID 28910237.