Cagrilinitide Dose-Response: What the Clinical and Preclinical Evidence Shows

Overview

Cagrilinitide (INN; development code NNC0174-0833) is a long-acting acylated amylin analogue designed for once-weekly subcutaneous injection. Its dose-response relationship has been characterized across first-in-human Phase 1 studies, a five-arm Phase 2 dose-finding trial, and a series of Phase 3 randomized controlled trials. The body of evidence is unusual in its transparency: five dose levels were formally randomized in a single Lancet-published trial, giving direct within-study comparisons across the dose range.

This page summarizes what those studies found and how preclinical receptor pharmacology explains the shape of the dose-response curve.

Preclinical Dose-Response: Receptor and Animal Models

Receptor Binding Pharmacology

Cagrilinitide activates the amylin receptor family. Cryo-EM structures published in Nature Communications in 2025 (PMID 40204768) resolved cagrilintide bound to AMY1R, AMY2R, AMY3R, and the calcitonin receptor (CTR) in active Gs-coupled states. Cagrilintide’s N-terminal lipid modification and an ionic lock interaction (E14-R17) produce conformational dynamics at the extracellular domain that are distinct from those of native rat amylin or salmon calcitonin. These structural features underlie its prolonged half-life and sustained receptor engagement across the weekly dosing interval.

Comparative preclinical work published in Molecular Metabolism in 2025 (PMID 41109426) on the related compound eloralintide found that cagrilintide dose-dependently reduced food intake across a 1-100 nmol/kg range in rodents. Eloralintide matched cagrilintide’s food intake reductions at equivalent doses, but cagrilintide’s activation of the calcitonin receptor (in addition to AMY1R and AMY3R) was associated with greater conditioned taste avoidance responses at higher doses.

Central Mechanism and Dose-Dependent Weight Loss in Mice

A 2025 EBioMedicine study (PMID 40609154) systematically mapped the receptor dependence of cagrilintide’s dose-response effects. In high-fat-diet-fed C57BL/6 mice, cagrilintide was administered at 0.3, 3, and 30 nmol/kg over 21 days:

• At 3 nmol/kg, wild-type animals lost approximately 3.4 g (mean; p < 0.005 vs. vehicle).
• On day 1, treated mice consumed approximately 1.2 g of food versus 2.7 g in vehicle controls (p < 0.0001), showing acute appetite suppression.
• In RAMP1/RAMP3 double-knockout mice, which lack functional AMY1R and AMY3R, this dose-dependent weight loss was substantially attenuated.

Brain regional mapping via cFos immunostaining showed that higher doses activated more neurons in the area postrema, dorsal vagal complex, and lateral parabrachial nucleus. RAMP1/RAMP3 deletion produced a 57% decrease in area postrema cFos signal at the same dose, directly linking receptor occupancy to downstream satiety circuitry engagement.

Phase 1: First-in-Human Single and Multiple Dose Studies

First-in-Human Single-Dose Study (NCT02300844)

This Phase 1 trial enrolled normal-weight, overweight, and obese healthy male subjects to investigate the safety, tolerability, and pharmacokinetics of single subcutaneous doses of NNC0174-0833. Concentrations were characterized across a dose range consistent with subsequent multi-milligram clinical testing. The study confirmed subcutaneous bioavailability and a half-life that supported once-weekly dosing.

Phase 1 Multiple-Dose Study (NCT02958085)

A Phase 1 multiple-dose trial in US subjects with overweight or obesity characterized the pharmacokinetic and pharmacodynamic profile of repeated weekly dosing. Steady-state exposures accumulated predictably with weekly administration. Pharmacodynamic endpoints included body weight and food intake measures, providing the first signal of dose-dependent weight reduction in a clinical setting.

Phase 1 Combination PK Study (NCT04940078)

This trial examined pharmacokinetics when cagrilintide was co-administered with semaglutide versus separate injections. No clinically meaningful pharmacokinetic interaction was observed between the two compounds at their respective doses, supporting the feasibility of fixed-ratio co-formulation.

Phase 2: The Dose-Finding Lancet Trial (NCT03856047, PMID 34798060)

Design

This multicentre, randomized, double-blind, placebo-controlled trial enrolled adults with overweight or obesity (BMI 27 kg/m² or higher) at 57 sites across 10 countries. Participants were randomized to one of five cagrilintide doses, an active comparator arm (liraglutide 3.0 mg once daily), or placebo. Treatment duration was 26 weeks.

Dose arms:

• Cagrilintide 0.3 mg once weekly
• Cagrilintide 0.6 mg once weekly
• Cagrilintide 1.2 mg once weekly
• Cagrilintide 2.4 mg once weekly
• Cagrilintide 4.5 mg once weekly
• Liraglutide 3.0 mg once daily (active comparator)
• Placebo

Weight Loss Results

The primary endpoint was change in body weight (%) from baseline to week 26. Published results showed a graded, dose-dependent response:

The 4.5 mg dose produced numerically greater weight loss than liraglutide 3.0 mg, with a treatment difference of 1.8 percentage points (p = 0.03). The dose-response relationship was progressive across the tested range, with no plateau evident at 4.5 mg.

Responder analyses showed dose-dependent increases in the proportion of participants achieving thresholds of 5% and 10% body weight loss. These secondary endpoints followed the same rank ordering as the primary endpoint, reinforcing that the graded response was not an artifact of averaging.

Gastrointestinal Adverse Events by Dose

Gastrointestinal adverse events were the main tolerability signal and also dose-dependent:

• Placebo: ~32% GI events
• Cagrilintide doses: 41-63% GI events, increasing with dose
• Nausea: 20-47% across doses, versus 18% with placebo

Discontinuation rates due to adverse events were higher at the 4.5 mg dose. This dose-related tolerability curve influenced the selection of 2.4 mg as the target dose for Phase 3 programs, balancing efficacy against GI burden.

Phase 2 Combination: CagriSema in Type 2 Diabetes (NCT03600480 / PMID 37364590)

A 32-week Phase 2 multicentre trial published in The Lancet (2023) evaluated once-weekly cagrilintide 2.4 mg co-administered with once-weekly semaglutide 2.4 mg in adults with type 2 diabetes. Comparator arms received semaglutide monotherapy, cagrilintide monotherapy, or placebo.

At the single combination dose tested:

• CagriSema: -15.6% mean body weight reduction
• Semaglutide alone: -5.1%
• Cagrilintide alone: -8.1%

HbA1c reduction: CagriSema achieved -2.2 percentage points versus -1.8 for semaglutide and -0.9 for cagrilintide.

Continuous glucose monitoring data showed time-in-range (3.9-10.0 mmol/L) improving from a baseline of approximately 45.9% to 88.9% at week 32 with CagriSema.

The additive weight loss (15.6% vs. 8.1% for cagrilintide alone or 5.1% for semaglutide alone) suggested pharmacodynamic complementarity between the amylin receptor pathway and GLP-1 receptor signaling. This Phase 2 result provided the rationale for selecting 2.4 mg/2.4 mg as the Phase 3 dose.

Phase 3: REDEFINE Program at 2.4 mg Fixed Dose

REDEFINE-1: Obesity Without Diabetes (NCT05394519, PMID 40544433)

The pivotal REDEFINE-1 trial enrolled 3,417 participants with overweight or obesity but without type 2 diabetes. Treatment lasted 68 weeks. All active doses were 2.4 mg weekly for both agents.

Primary endpoint results at week 68:

• CagriSema 2.4 mg/2.4 mg: mean -20.4% body weight
• Cagrilintide monotherapy 2.4 mg: lower reduction (monotherapy arm)
• Semaglutide monotherapy 2.4 mg: lower reduction (monotherapy arm)
• Placebo: -3.0%

Treatment difference for CagriSema versus placebo: -17.3 percentage points (95% CI: -18.1 to -16.6; p < 0.001).

Proportions achieving categorical thresholds all favored CagriSema versus placebo at p < 0.001 for the 5%, 20%, 25%, and 30% body weight loss thresholds.

A secondary cardiovascular analysis published in Hypertension (2026, PMID 41328546) using REDEFINE-1 data reported systolic blood pressure reductions of -10.9 mm Hg with CagriSema versus -2.8 mm Hg with placebo. These reductions were observed at the fixed 2.4 mg/2.4 mg dose over 68 weeks.

REDEFINE-2: Type 2 Diabetes (NCT05394519 data subset, PMID 40544432)

In 1,206 adults with type 2 diabetes, CagriSema 2.4 mg/2.4 mg once weekly over 68 weeks produced:

• Mean body weight reduction: -13.7% versus -3.4% for placebo
• HbA1c target achievement: 73.5% of participants reached HbA1c 6.5% or lower versus 15.9% on placebo

The weight loss response at the 2.4 mg/2.4 mg dose in type 2 diabetes was lower than in the obesity-only trial, consistent with patterns observed with other GLP-1-based therapies, where type 2 diabetes attenuates incretin-driven weight loss.

Dose-Escalation Schedule

Both Phase 3 REDEFINE trials used a 16-week dose-escalation period before reaching the 2.4 mg maintenance dose. This step-wise titration approach, common to long-acting amylin and incretin therapies, is used to minimize early GI adverse events. The escalation schedule moved participants through sub-therapeutic intermediate doses before the pharmacologically relevant maintenance exposure was achieved. No published data compare titration schedules head-to-head, but the GI adverse event profile in Phase 2 informed the design of the Phase 3 titration.

Receptor Pharmacology and Dose-Response Shape

The dose-response curve for cagrilinitide has several mechanistic features worth noting from the preclinical literature.

flowchart TD
    A["Cagrilinitide (s.c. injection)"] --> B["Systemic absorption\nWeekly half-life kinetics"]
    B --> C["AMY1R / AMY3R\n(brain: area postrema,\ndorsal vagal complex)"]
    B --> D["CTR\n(lower affinity at\ntherapeutic doses)"]
    C --> E["Reduced food intake\nAcute satiety signal"]
    C --> F["Reduced body weight\n(dose-dependent)"]
    D --> G["Calcitonin-pathway effects\n(GI tolerability signal\nat higher doses)"]
    E --> H["Synergy with GLP-1R\n(semaglutide co-admin)"]
    F --> H
    H --> I["Additive weight loss\nCagriSema combination"]

Cagrilintide is more potent at AMY1R and AMY3R than at the calcitonin receptor (CTR). At low doses, the amylin receptor pathways dominate: satiety signaling through the area postrema and brainstem circuitry reduces food intake. At higher doses, increasing CTR engagement may account for the steeper GI adverse event rate seen in Phase 2 (41-63% GI events at doses above 1.2 mg). This receptor selectivity pattern was directly compared with eloralintide, an AMY1R-selective compound, in Molecular Metabolism (2025, PMID 41109426): equivalent food intake suppression was achieved at similar doses, but cagrilintide’s CTR activity produced greater conditioned taste avoidance in rat models.

The structural explanation comes from the 2025 Nature Communications cryo-EM paper (PMID 40204768). Cagrilintide’s lipidated N-terminus and peptide backbone make contacts with the extracellular domain of all four amylin-family receptors (AMY1R, AMY2R, AMY3R, CTR), but the extracellular domain motions induced by cagrilintide differ from native amylin. This receptor-specific conformational selectivity likely determines both the magnitude and shape of dose-response curves at different receptor subtypes.

Summary of Dose-Response Parameters Across the Development Program

The data collectively support a dose-response relationship that is steep in the 0.3-2.4 mg range, with diminishing incremental efficacy per unit dose above 2.4 mg and increasing GI adverse event burden. The 2.4 mg once-weekly dose was selected for Phase 3 as the point offering the most favorable risk-benefit balance. Combination with semaglutide at the same 2.4 mg dose substantially extends the efficacy ceiling without requiring dose escalation of either agent beyond what monotherapy programs had established.

This page is a research-educational summary. All data are sourced from published peer-reviewed literature and registered clinical trial records. Nothing here constitutes medical advice or a dosing recommendation.

See also

More on Cagrilinitide:

• Cagrilinitide research overview
• Cagrilinitide: Mechanism of action
• Cagrilinitide: Clinical & preclinical evidence
• Cagrilinitide: Safety profile
• Cagrilinitide: Pharmacokinetics

Head-to-head comparisons:

• Semaglutide vs Cagrilinitide