What is MA-3RT and how does it work?

MA-3RT is a 39-amino acid unimolecular tri-agonist that simultaneously activates GLP-1, GIP, and glucagon receptors. GLP-1 agonism suppresses appetite and stimulates glucose-dependent insulin secretion; GIP agonism enhances metabolic flexibility and attenuates nausea; glucagon agonism drives hepatic fatty acid oxidation and thermogenesis in brown adipose tissue, increasing resting energy expenditure.

What are the molecular identifiers for MA-3RT?

MA-3RT is a 39-amino acid peptide (CAS 2381868-24-0) with a GIP-backbone, Aib at position 2, a C20 fatty diacid on Lys-20 for albumin binding, and a plasma half-life of approximately 6 days in humans.

What clinical findings support MA-3RT in weight management?

In a Phase 2 randomized controlled trial (48 weeks, n=338 adults with obesity), the 12 mg dose produced a mean 24.2% body weight reduction; 100% of participants on 8–12 mg achieved ≥5% loss and approximately two-thirds achieved ≥20% loss. A companion T2D trial showed 16.9% weight reduction and a 2.02 percentage-point HbA1c reduction at 36 weeks.

What dose ranges and administration routes have been studied?

Phase 2 studies used subcutaneous doses of 1 mg, 4 mg, 8 mg, and 12 mg once weekly, with a conservative titration schedule beginning at 2 mg and doubling every 4 weeks. Subcutaneous injection is the sole validated route.

How is MA-3RT stored and reconstituted?

Store lyophilized powder at −20 °C, protected from light. Reconstitute with bacteriostatic water; use within 28 days when stored at 2–8 °C. Use low-binding polypropylene labware to minimize adsorption, and avoid freeze-thaw cycling of the reconstituted solution.

MA-3RT

Description

Summary Abstract

MA-3RT (LY-3437943; tri-agonist peptide; 39 amino acids; C20 fatty diacid conjugate) is a unimolecular peptide engineered to simultaneously activate the receptors for Glucagon-Like Peptide-1 (GLP-1), Glucose-Dependent Insulinotropic Polypeptide (GIP), and Glucagon (GCG), representing the first clinically evaluated triple-receptor agonist of this class. Its structural backbone derives from the native GIP sequence, modified at position 2 with α-aminoisobutyric acid (Aib) to confer resistance to Dipeptidyl Peptidase-4 (DPP-4) cleavage, and conjugated at position 20 with a C20 fatty diacid moiety via a hydrophilic linker to enable reversible albumin binding and extend plasma half-life to approximately 6 days. Phase 2 clinical data demonstrate mean body weight reductions of 22.8–24.2% at 48 weeks in non-diabetic adults with obesity, with weight loss trajectories that had not plateaued at trial end. The compound also produced an 82.4% mean relative reduction in hepatic fat fraction by MRI-PDFF at 24 weeks, with resolution of steatosis in more than 85% of participants on higher-dose cohorts. Once-weekly subcutaneous dosing is supported by the pharmacokinetic profile, and the receptor potency is deliberately asymmetric — hyper-potent at GIP (~8.9×), moderately potent at GLP-1 (~2.5×), and sub-potent at Glucagon (~0.3×) — to maximize efficacy while managing gastrointestinal tolerability.

Clinical Indications

Investigated across the spectrum of metabolic and hepatic disease in Phase 2 and Phase 3 programs:

Obesity / Body-Weight Reduction: Phase 2 data show 24.2% mean weight loss at 48 weeks (12 mg dose) with 100% of participants on 8 mg and 12 mg doses achieving ≥5% reduction.
Type 2 Diabetes (T2D): HbA1c reductions of approximately 2.02 percentage points; up to 77% of T2D participants achieved HbA1c ≤6.5% in a dedicated Phase 2 trial.
Metabolic Dysfunction-Associated Steatohepatitis (MASH): 82.4% mean relative reduction in liver fat at 24 weeks; >85% complete steatosis resolution on 8–12 mg doses.
Chronic Kidney Disease (CKD): Renal hemodynamic and anti-inflammatory endpoints are being evaluated in the ongoing Phase 3 TRIUMPH-Outcomes cardiovascular outcomes trial (NCT06383390).

Contraindications

Personal or Family History of Medullary Thyroid Carcinoma (MTC) / MEN2: Long-acting GLP-1 agonists cause C-cell hyperplasia in rodent models; use is contraindicated in individuals with MTC history or Multiple Endocrine Neoplasia type 2.
Pregnancy: Unknown teratogenic risk and adverse fetal effects from rapid maternal weight loss; should be discontinued at least 2 months prior to planned conception.
Severe Gastroparesis: Delayed gastric emptying is a pharmacodynamic effect that may markedly worsen pre-existing gastric dysmotility.
Active Eating Disorders (Restrictive): The potent appetite suppression may exacerbate restrictive behaviors in patients with anorexia nervosa or related conditions.

Mechanism of Action (MOA)

MA-3RT operates through simultaneous agonism of three Class B G-protein-coupled receptors (GPCRs), each contributing a distinct layer of metabolic regulation:

GLP-1 Receptor Agonism — Satiety and Insulin Secretion

Activation of GLP-1 receptors in the Arcuate Nucleus and Paraventricular Nucleus (PVN) stimulates Pro-opiomelanocortin (POMC) neurons to release alpha-MSH, suppressing hunger via MC4R. Simultaneously, glucose-dependent insulinotropism in pancreatic beta-cells restores the biphasic insulin response, and slowed gastric emptying prolongs postprandial satiation.

GIP Receptor Agonism — Metabolic Flexibility and GI Tolerance

Hyper-potent (~8.9×) activation of the GIP receptor drives enhanced lipid buffering in white adipose tissue (WAT), reducing ectopic lipid deposition. GIP receptor engagement in the Area Postrema provides an anti-emetic “cushion” that attenuates the nausea response typically limiting GLP-1 dose escalation, allowing higher effective doses of the glucagon component to be tolerated.

Glucagon Receptor Agonism — Hepatic Lipolysis and Thermogenesis

Sub-potent (~0.3×) but meaningful activation of hepatic glucagon receptors (GCGRs) stimulates the cAMP-PKA pathway, upregulating CPT1A and PPARα to drive mitochondrial fatty acid beta-oxidation. Simultaneously, Fibroblast Growth Factor 21 (FGF21) is induced, and brown adipose tissue (BAT) thermogenesis is activated via UCP-1 uncoupling — increasing resting energy expenditure (REE) in a manner absent from GLP-1 mono-agonists.

CNS Dopaminergic and Vagal Integration

Descending vagal afferent signals from mechanical gastric distension reinforce central satiety. The dopaminergic “reward” circuitry in the Nucleus Accumbens is also modulated, which may underlie the reported reduction in food preoccupation (“food noise”) and, in distinction from pure GLP-1 agonists, a user-reported improvement in energy levels consistent with the glucagon-driven increase in mitochondrial function.

Key Features & Specifications

Defining pharmacological and structural attributes that distinguish this triple-agonist scaffold:

39-AA Unimolecular Tri-Agonist (GLP-1 / GIP / GCG)

~6-Day Half-Life via C20 Fatty Diacid Albumin Binding

DPP-4 Resistant (Aib Substitution at Position 2)

Asymmetric Potency: GIP ≫ GLP-1 > Glucagon

Thermogenic via BAT UCP-1 Activation

Once-Weekly Subcutaneous Administration

Chemical Analysis

Property	Specification Reference Data
Sequence	YA¹QGTFTSDYSIL²LDKK⁴AQA¹AFIEYLLEGGPSSGAPPPS³ (39 AA; GIP-backbone; Aib at pos. 2; alpha-methyl Leu at pos. 12; C20 fatty diacid on Lys-20; C-terminal amide)
CAS Number	2381868-24-0
Molecular Formula	Lipopeptide conjugate; peptide core C₂₀₉H₃₃₁N₄₇O₆₀ (approximate, excluding fatty diacid linker)
Molecular Weight	~4,760 g/mol (estimated intact conjugate)
Synonyms	LY-3437943; Triple G agonist; tri-agonist incretin mimetic
Half-Life	~6 days (human, via albumin binding)
Form / Variation	5 MG Lyophilized (P-032) / 10 MG Lyophilized (P10-031) / 12 MG Lyophilized (P-046) / 20 MG Lyophilized (P-049) / 30 MG Lyophilized (P-053) / 50 MG Lyophilized (P-069)

Storage, Safety, and Handling

Storage Protocol

Store lyophilized powder at −20 °C, protected from light and moisture. Once reconstituted with bacteriostatic water, store at 2–8 °C and use within 28 days; avoid freeze-thaw cycles of the reconstituted solution. The C20 fatty diacid moiety can promote peptide aggregation on plastic surfaces in the absence of pharmaceutical-grade surfactant excipients; use low-binding polypropylene syringes for handling.

Handling & Compliance

Handle with standard laboratory PPE (nitrile gloves, safety glasses) and employ aseptic technique throughout reconstitution. This compound is a potent endocrine agonist with dose-dependent cardiovascular effects (heart rate elevation 5–10 bpm at therapeutic doses) and gastrointestinal activity; dose escalation protocols from clinical literature should be observed. MA-3RT is listed as a prohibited substance under the World Anti-Doping Agency (WADA) S4 Hormone and Metabolic Modulators classification.

Additional information

Size	5 MG, 10 MG, 12 MG, 20 MG, 30 MG, 50 MG