Skip to content
PeptideAI
Human RCTblood sugarcardiovascularfat loss

Efpeglenatide

Long-acting exendin-based GLP-1 agonist notable for the AMPLITUDE-O trial, which showed cardiovascular and kidney benefit in a high-risk diabetic population.

Also known as LAPS-Exd4, LAPSExd4, HM11260C

Human RCT — Randomised controlled trials in humans, but not an approved product for this use.

AMPLITUDE-O (4,076 patients) is a genuine positive phase 3 cardiovascular and renal outcomes trial, published in NEJM in 2021. Despite that, the programme was not taken to registration and the drug is not marketed anywhere.

How it works

Efpeglenatide uses Hanmi's LAPSCOVERY platform: an exendin-4 analogue is site-specifically linked through a PEG spacer to a non-glycosylated human IgG4 Fc fragment. FcRn recycling plus the increased hydrodynamic radius extends the half-life to roughly a week. Receptor pharmacology is standard exendin-based GLP-1 agonism. Its distinguishing feature is the AMPLITUDE-O cardiovascular outcomes trial, which enrolled a population with a high proportion of chronic kidney disease and showed a significant reduction in both cardiovascular events and composite kidney outcomes.

Targets: GLP-1 receptor

Dosing

ProtocolDoseFrequencyRoute
AMPLITUDE-O trial dosingSame day each week.4 mg – 6 mgonce weeklysubcutaneous
  • · The cardiovascular outcomes trial used 4 mg or 6 mg weekly after a stepped escalation. No approved regimen exists because the drug has never been marketed.

Titration

Trials escalated over 4-8 weeks to reach maintenance dose.

Cycling

Would be chronic therapy; not commercially available.

Work out your exact syringe units →

Pharmacology

Half-life
Roughly 6-7 days.
Onset
Glycaemic effect over 2-4 weeks.
Routes
subcutaneous
Molecule
Exendin-4 analogue conjugated to a human IgG4 Fc fragment via a polyethylene glycol linker

Handling

Diluent
Not applicable - trial material supplied as a solution
Lyophilised
Not applicable.
Reconstituted
Refrigerated at 2-8 C.
Light sensitive
Yes — keep it out of the light

Side effects

  • very commonNausea and vomiting— Dose-dependent; higher at 6 mg.
  • commonDiarrhoea
  • commonInjection-site reaction

Do not use if

  • History of pancreatitis.
  • Personal or family history of medullary thyroid carcinoma or MEN2 - class effect.
  • Pregnancy.

Combining it

  • redundantsemaglutide — Same receptor.
  • cautioninsulin-analogues — Hypoglycaemia risk in combination.

What to monitor

  • · HbA1c.
  • · eGFR and albuminuria - the kidney signal was its main selling point.
  • · Weight.

Legal status

Investigational; not approved or marketed in any jurisdiction.

References

  • Gerstein et al. 2021, AMPLITUDE-O, NEJM (trial)

Mechanism in depth

Efpeglenatide is exendin-4 pharmacology delivered with a large-protein half-life, and the combination produces something none of the small acylated analogues quite match: a GLP-1 agonist that works normally at low glomerular filtration rate. Unmodified exenatide is filtered by the kidney and is contraindicated below an eGFR of 30. Attaching an Fc fragment through a PEG spacer takes the molecular size well above the glomerular filtration threshold, so clearance becomes purely catabolic. AMPLITUDE-O was designed around this: roughly a third of participants had an eGFR below 60, and the trial showed a 27% reduction in major adverse cardiovascular events and a 32% reduction in a composite kidney outcome. The kidney result is the interesting one, because the mechanism is not obvious - GLP-1 receptors in the kidney are sparse and mostly vascular, and the leading explanations are reduced intraglomerular pressure through natriuresis, reduced inflammation, and effects secondary to blood pressure and glycaemia. There is also a dose-response signal: exploratory analyses found larger cardiovascular benefit at 6 mg than at 4 mg, which is unusual in an outcomes trial and suggests the benefit is exposure-related rather than a threshold effect. None of this ever became a product. Sanofi and Hanmi did not take the programme to registration, and efpeglenatide now exists as a positive phase 3 outcomes trial attached to no available drug.

What usually goes wrong

The relevant failure here is a commercial one rather than a clinical one, and it is worth understanding: a drug can produce a positive cardiovascular and renal outcomes trial in four thousand patients and still never reach a pharmacy, because registration and launch economics are separate questions from efficacy. For a reader, the practical implication is that anything sold as efpeglenatide is not efpeglenatide.

Titration ladder

  1. 2 mgWeeks 1-4 — AMPLITUDE-O escalation started here for both maintenance arms.
  2. 4 mgWeeks 5-8 — The lower maintenance dose in the trial.
  3. 6 mgWeek 9 onward — The higher maintenance dose, which showed the larger cardiovascular effect in exploratory dose-response analysis and also more nausea and vomiting.

Bloodwork worth running

MarkerWhenWhy it matters
eGFR and urine albumin-to-creatinine ratioBaseline, 3 months, then 6-monthly.This is the drug's distinguishing feature. AMPLITUDE-O's composite kidney outcome was driven mainly by reduced progression of albuminuria.Act if: Not applicable - the drug is not obtainable.
HbA1cBaseline and 3-monthly.Standard glycaemic monitoring.Act if: Not applicable.
Anti-drug antibodiesIf efficacy is lost.An exendin-based peptide conjugated to an Fc fragment carries immunogenicity risk from both components.Act if: Not applicable.

Pharmacokinetics

Time to steady state
35 days
Crosses blood-brain barrier
no
Accumulates
Yes — doses stack before steady state
Metabolism
Catabolic degradation of both the exendin-4 analogue and the Fc fragment. No renal filtration route because of the molecular size, which is the key difference from unmodified exendin-4.
Elimination
Catabolic. Renal function does not limit clearance - which matters, because the AMPLITUDE-O population was heavily enriched for chronic kidney disease.

Receptor targets

  • GLP-1 receptor (GLP1R) — Exendin-4-based full agonist; specific affinity for the conjugate was not resolved in this session

    Standard GLP-1 agonism - glucose-dependent insulin secretion, glucagon suppression, delayed gastric emptying, modest weight loss - delivered with a weekly-to-monthly duration and without renal clearance.

Trials

  • AMPLITUDE-O Phase 3 cardiovascular and renal outcomes · n=4076 · 78 weeks · 2021

    27% relative reduction in major adverse cardiovascular events, with a 32% reduction in a composite renal outcome, in a population enriched for chronic kidney disease.

What to expect, and when

Glycaemic effect over 2-4 weeks with steady state around five weeks, based on the trial escalation schedule. Not otherwise characterised in a public label.

Stacking and comparisons

Not applicable in practice - efpeglenatide has never been marketed and there is no legitimate supply. In the AMPLITUDE-O trial it was used on top of standard care including metformin, insulin and SGLT2 inhibitors, and the benefit was consistent regardless of baseline SGLT2 inhibitor use, which is a useful data point for anyone thinking about how GLP-1 and SGLT2 renal effects combine.

Against exenatide: the same active pharmacology with the renal clearance problem engineered out, which is a genuinely useful thing to have done. Against dulaglutide: both are Fc-based weekly GLP-1 agonists with modest weight effects; efpeglenatide has the stronger renal dataset, dulaglutide is the one you can actually get. Against semaglutide: efpeglenatide loses badly on weight. Its historical importance is that AMPLITUDE-O is the strongest kidney-outcome evidence in the GLP-1 class, and it sits behind a drug nobody can prescribe.

Rough cost

Never marketed in any jurisdiction. There is no price.

Genuinely uncertain

  • No verifiable human pharmacokinetic parameters exist in the public domain - volume of distribution, clearance, protein binding, bioavailability and tmax are all unresolved.
  • The mechanism of the renal benefit is not established.
  • The apparent 4 mg versus 6 mg dose-response for cardiovascular events comes from an exploratory analysis and should not be treated as definitive.
  • The precise structure of the PEG linker and conjugation site is proprietary and was not verified.

Papers