Prilocaine (Citanest) is an amide local anesthetic with the lowest systemic toxicity in the class, reflecting rapid hepatic clearance and high tissue redistribution. It is the partner of lidocaine in EMLA cream, where the eutectic mixture of the two oils provides effective topical anesthesia of intact skin for venipuncture and minor procedures. The defining downside: dose-dependent methemoglobinemia. Liver enzymes hydrolyze prilocaine to o-toluidine, which is hydroxylated to a metabolite that oxidizes hemoglobin iron and prevents oxygen binding. Cumulative doses above 600 mg in adults (or 8 mg/kg in children) can produce clinically significant methemoglobinemia requiring methylene blue therapy. Risk amplifies in G6PD deficiency, NADH-methemoglobin reductase deficiency, or with concurrent oxidant drugs. Widely used in European and Asian dental cartridges. Not stocked by Kodiac. This monograph is provided for research and educational reference.
Intrigue 0–100 blends mechanism novelty, evidence strength, and translational potential. Kodiac editorial, not peer-reviewed.
Amide local anesthetic (intermediate-acting, low-toxicity)
An amide local anesthetic with the lowest systemic toxicity in the class but the dose-dependent risk of methemoglobinemia from o-toluidine metabolite generation.
Abstract
Prilocaine (N-(2-methylphenyl)-2-(propylamino)propanamide; CAS 721-50-6; molecular formula C13H20N2O; molecular weight 220.31) is an amide local anesthetic developed at AB Astra in the late 1950s and introduced clinically in the 1960s (Citanest). The compound has the lowest systemic toxicity in the amide class (CNS and cardiac toxic doses higher than lidocaine, mepivacaine, or bupivacaine on a milligram-per-kilogram basis), reflecting rapid hepatic clearance and high tissue redistribution. Prilocaine is the principal component of the EMLA cream alongside lidocaine, where the eutectic mixture of the two oils provides effective topical anesthesia of intact skin for venipuncture and minor superficial procedures. The principal clinical limitation is dose-dependent methemoglobinemia: prilocaine is hydrolyzed in the liver to o-toluidine, which is hydroxylated to a methemoglobin-generating metabolite. Cumulative doses above approximately 600 mg in adults or 8 mg/kg in children produce clinically significant methemoglobinemia that may require methylene blue therapy. The risk is amplified in patients with G6PD deficiency, NADH-methemoglobin reductase deficiency, or concurrent administration of other oxidant drugs (dapsone, sulfamethoxazole, benzocaine). Mechanism is the standard amide voltage-gated sodium channel block. Onset and duration are intermediate (similar to lidocaine and mepivacaine). Prilocaine is widely used in dental anesthesia in Europe and Asia and is the principal component of dental cartridges in several markets. Maximum recommended dose is 8 mg/kg without epinephrine.
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A 15-residue synthetic peptide modeled on the second fibronectin-like domain of neural cell adhesion molecule, an FGFR1 partial agonist with neuroprotective and pro-cognitive activity in rodent models.
Abstract
FGL (FG Loop peptide; Glu-Val-Tyr-Val-Val-Ala-Glu-Asn-Gln-Gln-Gly-Lys-Ser-Lys-Ala; sometimes called the FGL peptide or NCAM-derived FGFR agonist; molecular weight approximately 1622 Da) is a synthetic 15-residue peptide modeled on the second fibronectin type III repeat (FnIII) domain of neural cell adhesion molecule (NCAM), specifically the Phe-Gly loop responsible for fibroblast growth factor receptor 1 (FGFR1) interaction. NCAM is a transmembrane glycoprotein expressed at high levels in developing and adult nervous system tissue that mediates cell-cell adhesion through homophilic NCAM-NCAM binding and signals across the membrane through cis-binding to FGFR1. The FGL peptide was designed at the University of Copenhagen by Elisabeth Bock and Vladimir Berezin as a small-molecule mimetic of the NCAM-FGFR interaction, capable of activating FGFR1 signaling without the broad effects of full NCAM ectodomain or full-length FGF ligands. Reported activities include neurite outgrowth promotion in primary cortical and hippocampal neurons, protection against glutamate excitotoxicity, anxiolysis and pro-cognitive effects in rodent fear conditioning and Morris water maze paradigms, and recovery promotion in models of traumatic brain injury and stroke. Routes studied include subcutaneous, intraperitoneal, and intranasal administration. Plasma half-life is short (approximately 30 minutes); the central nervous system exposure after intranasal administration is substantially higher than after parenteral routes, owing to direct olfactory and trigeminal pathway transport. The compound advanced through ENKAM Pharmaceuticals (a University of Copenhagen spin-out) into early clinical development for Alzheimer’s disease and cognitive impairment in the late 2000s; clinical development has not produced a marketed agent. The principal limitation on the strength of the evidence is the dominance of the originating laboratory’s publications and the absence of independent replication of key behavioral findings.
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A 24-amino-acid peptide encoded within the 16S rRNA of the mitochondrial genome, identified as a neuroprotective and metabolic factor with broad anti-apoptotic activity.
Abstract
Humanin (Met-Ala-Pro-Arg-Gly-Phe-Ser-Cys-Leu-Leu-Leu-Leu-Thr-Ser-Glu-Ile-Asp-Leu-Pro-Val-Lys-Arg-Arg-Ala; molecular weight 2687.27 free peptide; CAS 330936-69-1) is a 24-residue peptide encoded within the 16S ribosomal RNA gene of the mitochondrial genome, identified by Yuichi Hashimoto and colleagues at Keio University in 2001 in a screen for anti-apoptotic factors that protected against amyloid-beta-induced neuronal death. Humanin is the founding member of the mitochondrial-derived peptide (MDP) family, a class of peptides encoded within mitochondrial DNA and translated from short open reading frames in mitochondrial RNAs; other family members include MOTS-c (KDC-MN-008), the SHLP family (small humanin-like peptides 1 through 6), and gau (gene antisense ubiquitous). The pharmacological signature of humanin includes anti-apoptotic activity through binding the BAX and BIM Bcl-2 family pro-apoptotic proteins, suppression of caspase activation, neuroprotection against amyloid-beta, prion peptide, and ALS-associated SOD1 toxicity in rodent and cell culture models, modulation of metabolic phenotypes (improved insulin sensitivity in rodent obesity models), and cytoprotection in models of myocardial ischemia and chemotherapy-induced toxicity. Receptors include the heterotrimeric ciliary neurotrophic factor (CNTF) receptor complex (CNTFR-WSX-1-gp130), the formyl peptide receptor 2 (FPR2), and direct cytoplasmic protein-protein interactions with BAX/BIM. The S14G analog of humanin (HNG; gly substituted for ser at position 14) is approximately 1000-fold more potent in neuroprotection assays and is the principal research-grade analog used in pharmacology studies. The compound is research-grade with no regulatory approval; clinical development has been limited despite the strong preclinical signal, attributed in part to the narrow therapeutic window for neurodegenerative disease drugs and the sparse human pharmacokinetic characterization.
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A first-in-class bispecific antibody-peptide conjugate developed at Amgen that pairs a fully human monoclonal glucose-dependent insulinotropic polypeptide receptor antagonist antibody with two covalently linked glucagon-like peptide 1 analogue agonist peptides, yielding a long-acting once-monthly injectable for chronic weight management distinguished from existing incretin therapeutics by simultaneous GIP receptor blockade and an approximately 21-day elimination half-life.
Abstract
Maridebart cafraglutide (MariTide; development code AMG 133) is a first-in-class bispecific peptide-antibody conjugate engineered at Amgen by covalent attachment of two glucagon-like peptide 1 (GLP-1) receptor agonist peptide analogues to a fully human immunoglobulin G2 (IgG2) monoclonal antibody that functions as a potent antagonist of the glucose-dependent insulinotropic polypeptide receptor (GIPR). The molecule was designed to exploit the additive weight-loss pharmacology of simultaneous GLP-1 receptor (GLP-1R) activation and GIP receptor blockade, a mechanistic combination that in preclinical diet-induced obese mouse and cynomolgus monkey models produced greater body-weight reduction than either moiety alone. In cell-based functional assays the compound demonstrates GLP-1R agonist activity with EC50 values of 24.4 picomolar (human), 5.7 picomolar (cynomolgus monkey), 2.4 picomolar (rat), and 123 picomolar (mouse), and GIPR antagonist activity with IC50 values of 46.4 nanomolar (human), 26.5 nanomolar (cynomolgus monkey), and 822.3 nanomolar (rat) [1, 2]. The antibody scaffold confers a terminal elimination half-life of approximately 21 days in humans after subcutaneous administration, approximately three-fold longer than the longest-acting approved once-weekly GLP-1 receptor agonists, and supports once-monthly or less frequent dosing [1]. In a Phase 1 randomized, double-blind, placebo-controlled single- and multiple-ascending-dose study (NCT04478708) in 163 adults with obesity, maridebart cafraglutide produced dose-dependent weight loss of up to 14.5 percent at 12 weeks with weight loss maintained for up to 150 days after the final dose, accompanied by an acceptable safety and tolerability profile in which gastrointestinal adverse events (nausea, vomiting) were predominantly mild and transient [1]. A Phase 2 dose-ranging study (NCT05669599) in 592 adults with obesity with or without type 2 diabetes randomized to subcutaneous maridebart cafraglutide at 140, 280, or 420 mg every four weeks or 420 mg every eight weeks versus placebo for 52 weeks demonstrated mean weight loss of 12.3 to 20 percent in participants without type 2 diabetes and 8.4 to 17 percent in participants with type 2 diabetes, with HbA1c reductions of up to 2.2 percentage points, without evidence of a weight-loss plateau at 52 weeks [3, 4]. The Phase 2 study further reported no clinically significant changes in bone mineral density and body-composition data indicating that the majority of weight lost was fat mass rather than lean tissue. Gastrointestinal adverse events were the most common treatment-emergent events and were mitigated by dose escalation from a lower starting dose; discontinuation rates due to gastrointestinal events were approximately 8 percent with dose escalation compared with 12 to 27 percent without [3, 4]. Amgen initiated the Phase 3 MARITIME program in 2025, comprising chronic weight management trials (MARITIME-1 in obesity without type 2 diabetes, MARITIME-2 in obesity with type 2 diabetes) with planned 72-week treatment duration and primary readouts expected in early 2027, as well as planned Phase 3 cardiovascular outcomes, heart failure, and obstructive sleep apnea studies [5, 6]. The compound is not approved by any regulatory authority as of the monograph date. This monograph documents the molecular design and structural biology of the peptide-antibody conjugate; the dual-receptor pharmacology at GLP-1R and GIPR in molecular and cellular detail; the preclinical pharmacology in rodent and primate models; the comprehensive human pharmacokinetic record; the clinical evidence base across Phase 1 and Phase 2 obesity and type 2 diabetes endpoints; sourcing and handling considerations; stack-interaction implications; adverse-event profile; and a comparative assessment of five incretin-class obesity therapeutics against maridebart cafraglutide on five competency standards.
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Selective vasopressin V1a receptor peptide full agonist
A synthetic nonapeptide vasopressin analog developed at Ferring Pharmaceuticals as a potent, highly selective, short-acting full agonist of the vasopressin type 1a receptor, designed to replicate the vasoconstrictive hemodynamic support of arginine vasopressin in septic shock while eliminating V2-receptor-mediated antidiuretic, procoagulant, and fluid-retaining liabilities.
Abstract
Selepressin (FE 202158; [Phe(2),Ile(3),Hgn(4),Orn(iPr)(8)]vasopressin; CAS 876296-47-8; molecular formula C46H73N13O11S2; molecular weight 1048.29) is a synthetic nonapeptide analog of arginine vasopressin (AVP) and a potent, selective, short-acting full agonist of the human vasopressin type 1a receptor (V1aR), developed by Ferring Pharmaceuticals for the treatment of vasodilatory hypotension in septic shock. The compound was identified through a systematic structure-activity relationship campaign at the Ferring Research Institute in San Diego, in which modifications at positions 2, 4, and 8 of the vasopressin backbone were explored to dissociate V1a-mediated vasoconstriction from the V2-receptor-mediated antidiuresis, V1b-mediated corticotropin release, and oxytocin-receptor-mediated uterotonic effects that complicate clinical AVP administration [1, 2]. Selepressin activates the human V1a receptor with an EC50 of 2.4 nanomolar in functional assays, producing a selectivity ratio of 1:142:1107:440 relative to V1b, V2, and oxytocin receptors, respectively [2]. This selectivity profile confers three pharmacological advantages over AVP in the septic shock setting: absence of V2-receptor-mediated free water retention and consequent fluid overload; absence of V2-receptor-mediated release of von Willebrand factor and consequent procoagulant risk [3]; and absence of V2-receptor-mediated exacerbation of capillary leak through endothelial aquaporin-2 trafficking. Preclinical pharmacology in ovine fecal peritonitis, ovine Pseudomonas aeruginosa pneumonia, canine hemodynamic, and rabbit endotoxemia models demonstrated that selepressin maintains mean arterial pressure comparably to AVP, reduces cumulative fluid requirements, attenuates pulmonary edema, preserves mesenteric perfusion more favorably than AVP, and improves survival relative to both AVP and norepinephrine when administered early in the septic course [4, 5, 6, 7]. In vitro, selepressin protects human lung microvascular endothelial barrier integrity against thrombin, vascular endothelial growth factor, angiopoietin-2, and lipopolysaccharide challenge through V1a-receptor-dependent activation of p53, suppression of RhoA/myosin light chain 2 signaling, and activation of the Rac1 GTPase barrier-protective pathway [8]. A Phase IIa randomized, double-blind, placebo-controlled trial in 53 patients with early septic shock (Russell et al. 2017) demonstrated that selepressin at 2.5 nanograms per kilogram per minute effectively substituted for norepinephrine, reduced 7-day cumulative norepinephrine dose from 761 to 249 micrograms per kilogram, lowered cumulative net fluid balance from day 5 onward, and increased ventilator-free days [9]. The pivotal SEPSIS-ACT adaptive Phase 2b/3 randomized clinical trial (Laterre et al. 2019, JAMA) enrolled 868 adults with septic shock across 63 hospitals in Belgium, Denmark, France, the Netherlands, and the United States. Three selepressin dosing regimens (starting infusion rates of 1.7, 2.5, and 3.5 nanograms per kilogram per minute) were compared to placebo. The trial was stopped for futility at the completion of Part 1: the primary endpoint of ventilator- and vasopressor-free days within 30 days was 15.0 days with selepressin versus 14.5 days with placebo (difference 0.6 days; 95 percent confidence interval, negative 1.3 to 2.4; P equals 0.30), and 90-day mortality was 40.6 percent versus 39.4 percent [10]. Selepressin did produce statistically significant reductions in cardiovascular Sequential Organ Failure Assessment score at 24 hours (difference negative 0.42; P less than 0.001) and in hourly fluid balance at 24 hours (81 versus 107 milliliters per hour; P less than 0.001), confirming the hemodynamic and fluid-sparing pharmacodynamic effects observed in Phase IIa. The compound is not approved by any regulatory authority. It is available from chemical suppliers as a research-grade peptide. This monograph reviews the chemistry and structure-activity relationships, the receptor pharmacology and selectivity, the comprehensive preclinical evidence base across multiple sepsis models, the human pharmacokinetic profile, the Phase IIa and Phase 2b/3 clinical evidence, sourcing and reconstitution considerations, stack-interaction implications, adverse-event signal, and a comparative assessment of five vasopressor alternatives on five competency standards.
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Procaine is the original synthetic local anesthetic, synthesized in 1905 by Alfred Einhorn and marketed by Hoechst as Novocain. It was developed as a non-addictive cocaine substitute and dominated the field from 1905 through the 1950s before lidocaine and the amide class displaced it owing to faster onset, longer duration, and far fewer allergic reactions. The ester-class downside: hydrolysis by plasma cholinesterase produces para-aminobenzoic acid (PABA), the dominant allergen in the class. Plasma half-life of procaine itself is under one minute; clinical infiltration block lasts only 30 to 60 minutes. Modern use is essentially restricted to short-procedure infiltration in patients with documented amide allergy and to a few dental applications. Procaine penicillin (the depot antibiotic formulation) is the oldest application of procaine in pharmaceutical formulation and is the principal reason most clinicians have heard of it. Not stocked by Kodiac. This monograph is provided for research and educational reference.
Intrigue 0–100 blends mechanism novelty, evidence strength, and translational potential. Kodiac editorial, not peer-reviewed.
Ester local anesthetic (short-acting)
The original synthetic local anesthetic introduced in 1905 as Novocaine, displaced by amide agents but retaining historical and reference status.
Abstract
Procaine (2-(diethylamino)ethyl 4-aminobenzoate; CAS 59-46-1; molecular formula C13H20N2O2; molecular weight 236.31) is the original synthetic local anesthetic, synthesized by Alfred Einhorn at the University of Munich in 1905 and marketed by Hoechst as Novocain. The compound was developed as a cocaine substitute that lacked the abuse liability and addictive potential of the natural alkaloid; the ester linkage between the aromatic ring and the amino alcohol substantially reduces lipophilicity relative to cocaine while preserving sodium channel block. Procaine was the dominant local anesthetic from 1905 through approximately the 1950s, when lidocaine and the amide class displaced it owing to faster onset, longer duration, and substantially lower allergic reaction incidence. The principal limitation of procaine and the ester class is hydrolysis by plasma cholinesterase to para-aminobenzoic acid (PABA), the dominant allergen in the class and a substrate for hapten-mediated immune reactions in sensitized individuals. The plasma half-life is short (less than 1 minute through cholinesterase clearance); duration of clinical infiltration block is 30 to 60 minutes, much shorter than amide agents. Mechanism is voltage-gated sodium channel block with state-dependent kinetics; the lower lipid solubility relative to amide agents corresponds to slower onset and weaker block per milligram. Maximum recommended dose is 7 mg/kg, with adjustment for patients with cholinesterase deficiency (prolonged duration, increased systemic exposure). Modern clinical use is limited to short-procedure infiltration in patients with documented amide allergy and to several dental applications in markets where the ester formulations remain available. Procaine penicillin (combined with penicillin G as a depot) extends antibiotic plasma levels and is the oldest application of procaine in formulation.
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A growth differentiation factor in the TGF-beta superfamily originally implicated in parabiosis-mediated rejuvenation and subsequently a focus of contested replication studies in cardiac and skeletal muscle aging.
Abstract
GDF-11 (growth differentiation factor 11; bone morphogenetic protein 11, BMP-11; CAS 268544-12-9; mature peptide molecular weight approximately 12.5 kDa as a homodimer) is a member of the transforming growth factor beta (TGF-beta) superfamily, closely related to myostatin (GDF-8) with which it shares approximately 90 percent amino acid identity in the mature C-terminal domain. The compound came to prominence in 2013 when a heterochronic parabiosis study by Amy Wagers and Richard Lee at the Harvard Stem Cell Institute identified GDF-11 as a putative young-blood-borne rejuvenation factor that reversed age-related cardiac hypertrophy when administered to old mice. Subsequent studies extended the proposed rejuvenation activity to skeletal muscle and the central nervous system. The original GDF-11 papers triggered substantial follow-up research and substantial contested replication: independent groups (notably the Glass laboratory at Eli Lilly and the Wagers laboratory’s own subsequent work) reported that the original immunoassays did not adequately distinguish GDF-11 from myostatin, that circulating GDF-11 levels do not in fact decline with age, and that recombinant GDF-11 administered to old mice produces muscle wasting at high doses (consistent with the myostatin-like activity expected from the structural homology) rather than rejuvenation. The contested literature has not produced consensus; some groups continue to report modest pro-cardiac and pro-cognitive effects of GDF-11 at carefully titrated doses, while others find no effect or harmful effects. Mechanism is canonical TGF-beta superfamily signaling through ActRIIA/B receptors and downstream SMAD2/3 transcription factor activation; GDF-11 and myostatin share the same receptor and signaling pathway, distinguishing them principally through tissue-specific expression patterns and post-translational propeptide regulation. The compound is research-grade with no regulatory approval and no active clinical development. Investigators studying GDF-11 should be aware of the contested replication literature and the importance of distinguishing GDF-11 from myostatin in immunoassays.
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A rationally designed, DPP-IV-resistant, long-acting synthetic analog of human glucagon-like peptide-2 bearing four amino acid substitutions that confer very low systemic clearance and high plasma protein binding, enabling once-weekly subcutaneous dosing for the treatment of short bowel syndrome with intestinal failure and under investigation for steroid-refractory gastrointestinal acute graft-versus-host disease.
Abstract
Apraglutide (FE 203799) is a synthetic 33-amino-acid peptide analog of human glucagon-like peptide-2 (GLP-2) and a potent, selective, full agonist of the GLP-2 receptor (GLP-2R), developed as a next-generation intestinotrophic agent for the treatment of short bowel syndrome with intestinal failure (SBS-IF) and under investigation for steroid-refractory gastrointestinal acute graft-versus-host disease (GI aGVHD). The compound differs from native human GLP-2(1-33) by four amino acid substitutions ([Gly2, Nle10, D-Phe11, Leu16]hGLP-2(1-33)-NH2) that confer resistance to dipeptidyl peptidase-IV (DPP-IV) degradation, very low systemic clearance, slow absorption from the subcutaneous depot, and high plasma protein binding, resulting in an elimination half-life of approximately 72 hours in healthy volunteers and enabling once-weekly subcutaneous administration [1, 2]. In head-to-head rat intravenous pharmacokinetic comparisons, apraglutide demonstrated a clearance of 0.27 mL/kg per minute versus 9.9 mL/kg per minute for teduglutide and 2.8 mL/kg per minute for glepaglutide, and an elimination half-life of 159 minutes versus 19 minutes for teduglutide and 16 minutes for glepaglutide [1]. The compound retains potency and selectivity at the human GLP-2 receptor comparable to native GLP-2 and teduglutide, with approximately two-fold greater potency than both in cell-based receptor activation assays [1]. Apraglutide was originally discovered at Ferring Pharmaceuticals (development code FE 203799) and subsequently licensed to GLyPharma Therapeutic in 2012, acquired by Therachon (a Novo Holdings-backed rare disease company), transitioned to VectivBio AG, and acquired by Ironwood Pharmaceuticals in 2023 [3, 4]. The compound received orphan drug designation from the United States Food and Drug Administration, the European Medicines Agency, and the Japanese regulatory authority for SBS-IF. The pivotal Phase 3 STARS trial (NCT04627025), a global, randomized, double-blind, placebo-controlled study in 164 adults with SBS-IF across 73 centers in 18 countries, met its primary endpoint: apraglutide-treated patients achieved a 25.5 percent relative reduction in weekly parenteral support volume at week 24 versus 12.5 percent for placebo (P = 0.001), with treatment effect evident from week 8 [5, 6]. Secondary endpoints demonstrated that 43 percent of apraglutide-treated patients gained at least one additional day off parenteral support per week (versus 27.5 percent for placebo, P = 0.04), and 6.4 percent of apraglutide-treated patients achieved complete enteral autonomy at week 24 compared to 0 percent on placebo [5]. Long-term extension data through 48 weeks showed 12.5 percent of apraglutide-treated patients achieving enteral autonomy versus 7.4 percent on placebo, with 27 patients overall achieving enteral autonomy across the development program [7]. In metabolic balance studies, once-weekly apraglutide at 5 mg subcutaneous increased wet weight absorption by 741 g/day, increased energy absorption by 1095 kJ/day, and increased sodium absorption by 38 mmol/day, making apraglutide the first GLP-2 analog to significantly improve energy absorption across the full SBS patient spectrum as measured by bomb calorimetry [8, 9]. The Phase 2 STARGAZE trial in steroid-refractory GI aGVHD demonstrated a 58.1 percent overall response rate at day 28 (versus 38.8 percent in a matched MAGIC control cohort) and a lower cumulative non-relapse mortality at day 180 (33.3 percent versus 41.9 percent) [10]. Adverse events across the clinical program have been predominantly mild to moderate gastrointestinal effects (decreased stoma output, stoma complications, nausea, flatulence, abdominal pain) consistent with the pharmacological intestinotrophic mechanism, with injection site reactions, polyuria, and edema also reported at low incidence [8, 11]. Ironwood Pharmaceuticals initiated a rolling NDA submission in January 2025; following FDA feedback requiring a confirmatory Phase 3 trial, the STARS-2 study is planned with site initiations in the second quarter of 2026 and an NDA submission target before end of 2029 [7, 12]. This monograph reviews the chemistry and peptide engineering of apraglutide; the GLP-2 receptor pharmacology and downstream intestinotrophic signaling; the comprehensive pharmacokinetic profile in healthy volunteers, SBS patients, and special populations; the preclinical intestinal growth pharmacology; the clinical evidence base across SBS-IF, metabolic balance, and GI aGVHD indications; sourcing and quality verification; reconstitution and handling; stack interactions; adverse events and safety signal; and a comparative assessment of five GLP-2 receptor agonist candidates against apraglutide on five competency standards. The compound is not approved by any regulatory authority as of the monograph revision date.
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Long-acting glucagon-like peptide-2 (GLP-2) receptor agonist peptide analog
A 39-amino-acid synthetic peptide analog of human glucagon-like peptide-2 engineered by Zealand Pharma with nine amino acid substitutions and a C-terminal hexalysine tail to enable depot formation, extended half-life, and ready-to-use liquid formulation for subcutaneous administration in short bowel syndrome.
Abstract
Glepaglutide (ZP1848) is a long-acting, synthetic peptide analog of human glucagon-like peptide-2 (GLP-2) developed by Zealand Pharma A/S (Soeborg, Denmark) for the treatment of short bowel syndrome (SBS) with intestinal failure in patients dependent on parenteral support. The compound comprises 39 amino acids and differs from native human GLP-2(1-33) by the incorporation of nine amino acid substitutions at positions 2, 3, 5, 8, 10, 11, 16, 24, and 28, together with a C-terminal amidated hexalysine tail ([Lys]6-NH2) derived from Zealand Pharma’s proprietary Structure Inducing Probe (SIP) technology. The substitutions confer resistance to dipeptidyl peptidase-4 (DPP-4) degradation, improved physicochemical stability enabling a ready-to-use aqueous liquid formulation, and formation of a subcutaneous depot from which the parent compound and its active C-terminally truncated metabolites (M1, 35 amino acids; M2, 34 amino acids) are slowly released into systemic circulation. The resulting effective half-life of approximately 50 to 124 hours in humans permits twice-weekly or once-weekly subcutaneous dosing, a substantial advance over the daily injection requirement of teduglutide (Gattex), the first-in-class approved GLP-2 analog. Glepaglutide binds and activates the GLP-2 receptor (GLP-2R), a class B G-protein-coupled receptor expressed on intestinal subepithelial myofibroblasts, enteroendocrine cells, and enteric neurons. Receptor activation triggers downstream release of intestinal growth mediators including insulin-like growth factor-1 (IGF-1), epidermal growth factor (EGF), and keratinocyte growth factor, resulting in crypt cell proliferation, villus elongation, inhibition of enterocyte apoptosis, enhanced intestinal barrier function, increased mesenteric blood flow, and suppression of gastric acid hypersecretion and accelerated gastrointestinal motility. The net physiological effect is increased intestinal absorptive capacity for fluid, electrolytes, and macronutrients in patients with anatomically shortened bowel. Clinical development has progressed through Phase 1 healthy volunteer pharmacokinetic studies, a Phase 2 randomized crossover trial in 18 SBS patients published in The Lancet Gastroenterology and Hepatology (Naimi et al., 2019) demonstrating dose-dependent improvements in intestinal wet weight absorption and plasma citrulline, and the pivotal Phase 3 EASE-SBS 1 trial (NCT03690206), a multinational, double-blind, placebo-controlled study in 106 patients that met its primary endpoint of significant reduction in weekly parenteral support volume at 24 weeks (mean change minus 5.13 versus minus 2.85 liters per week for glepaglutide twice weekly versus placebo; P equals 0.0039). The compound received orphan drug designation from both the United States Food and Drug Administration and the European Medicines Agency. Zealand Pharma submitted a New Drug Application to the FDA in late 2023; in December 2024, the FDA issued a Complete Response Letter citing insufficient evidence to confirm efficacy and safety at the proposed marketed dose and recommending an additional confirmatory trial. A Marketing Authorization Application was submitted to the European Medicines Agency in June 2025, and Zealand Pharma plans an additional Phase 3 trial to support regulatory resubmission in the United States. The safety profile is consistent with the known GLP-2 class effects. The most frequent adverse events in clinical trials are injection site reactions, stoma complications (primarily swelling or enlargement of the stoma nipple), gastrointestinal events (nausea, vomiting, abdominal pain), peripheral edema, fatigue, and headache. Anti-drug antibodies develop in a proportion of treated patients with a trend toward higher injection site reaction incidence in antibody-positive individuals, though no firm causal relationship has been established. The compound does not require reconstitution and is administered as a fixed-dose, ready-to-use subcutaneous injection via autoinjector, representing a practical advantage over lyophilized GLP-2 analogs requiring daily preparation. This monograph documents the chemistry, design rationale, and synthesis of glepaglutide; the GLP-2 receptor pharmacology and downstream intestinotrophic signaling; the comprehensive human pharmacokinetic profile including depot formation and metabolite characterization; the preclinical pharmacology in intestinal growth and inflammatory bowel disease models; the clinical evidence base from Phase 1 through Phase 3; sourcing and quality verification; reconstitution and handling; stack interaction considerations; adverse events and safety signals; and a comparative assessment of five GLP-2 receptor agonist candidates (teduglutide, apraglutide, dapiglutide, elsiglutide, and native GLP-2) against glepaglutide on five competency standards.
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Recombinant human insulin-like growth factor-1 and insulin-like growth factor binding protein-3 equimolar binary complex (rhIGF-1/rhIGFBP-3)
A recombinant equimolar binary protein complex of human IGF-1 and its principal binding protein IGFBP-3, developed by Insmed as iPLEX for subcutaneous replacement therapy in severe primary IGF-1 deficiency and subsequently investigated in amyotrophic lateral sclerosis and complications of extreme prematurity.
Abstract
Mecasermin rinfabate (International Nonproprietary Name; brand name iPLEX) is a pharmaceutical-grade equimolar binary complex of recombinant human insulin-like growth factor-1 (rhIGF-1, 70 amino acids, 7,649 Da) and recombinant human insulin-like growth factor binding protein-3 (rhIGFBP-3, 264 amino acids, approximately 28,700 Da unglycosylated), produced in Escherichia coli expression systems and formulated for subcutaneous injection at a combined molecular weight of approximately 36,381 daltons. The complex was designed to replicate the physiological binary association of IGF-1 with its most abundant circulating binding protein, thereby extending the plasma half-life of administered IGF-1 from approximately 10 to 20 minutes (free rhIGF-1) to approximately 13 to 21 hours (complexed form), reducing hypoglycemic risk relative to unbound IGF-1, and enabling once-daily subcutaneous dosing in contrast to the twice-daily regimen required for mecasermin (rhIGF-1 alone, marketed as Increlex). Upon subcutaneous administration, the binary complex associates with endogenous acid-labile subunit (ALS) to form the approximately 150 kDa ternary complex that represents the principal physiological reservoir of circulating IGF-1, thereby normalizing the IGF-1 axis in patients with deficient endogenous production.
The compound received United States Food and Drug Administration approval on December 12, 2005 (NDA 021884) for the treatment of growth failure in children with severe primary insulin-like growth factor-1 deficiency (Primary IGFD) or with growth hormone gene deletion who have developed neutralizing antibodies to growth hormone. The approved dose range was 0.5 to 2.0 mg/kg administered once daily by subcutaneous injection, titrated to achieve physiological IGF-1 levels measured 8 to 18 hours post-dose. Clinical development was conducted in two cohort studies enrolling 36 children and adolescents with primary IGFD, predominantly growth hormone receptor deficiency (Laron syndrome), demonstrating statistically significant dose-dependent increases in height velocity from a pre-treatment baseline of approximately 3 to 4 cm/year to 6 to 9 cm/year during the first year of treatment.
The commercial trajectory of mecasermin rinfabate was truncated by patent litigation. In March 2007, Insmed Incorporated settled a patent infringement action brought by Tercica (the manufacturer of mecasermin/Increlex) by agreeing to withdraw iPLEX from the United States market for all short stature indications and to abandon its European regulatory application for these uses. The settlement extinguished the primary commercial indication. Insmed subsequently investigated mecasermin rinfabate in amyotrophic lateral sclerosis (ALS) under both clinical trial and compassionate-use frameworks; a Phase II randomized controlled trial in 330 ALS patients failed to demonstrate benefit on muscle strength, need for tracheostomy, or survival at the end of a two-year treatment period. More recently, the rhIGF-1/rhIGFBP-3 complex (under the development name of the successor product) has been investigated by Shire (now Takeda) and collaborators in extremely preterm infants for prevention of retinopathy of prematurity and other complications of prematurity, with a Phase 2 randomized controlled trial (NCT01096784) demonstrating a 53 percent decrease in severe bronchopulmonary dysplasia but no reduction in retinopathy of prematurity severity.
The pharmacology of mecasermin rinfabate is that of its constituent IGF-1 moiety acting through the type 1 IGF receptor (IGF-1R), a transmembrane receptor tyrosine kinase that activates the phosphatidylinositol 3-kinase/Akt and mitogen-activated protein kinase (MAPK/ERK) signaling cascades to promote linear growth, cellular proliferation, differentiation, and survival. The IGFBP-3 moiety serves as a pharmacokinetic modulator, extending half-life and buffering against acute hypoglycemia, while also exerting IGF-independent effects including proapoptotic activity through nuclear receptor interactions and antiproliferative signaling in certain cellular contexts. The principal adverse events at approved doses are hypoglycemia (31 percent), headache (22 percent), arthralgia, injection site reactions, and lymphadenopathy. Safety data beyond 21 months of continuous treatment have not been established. This monograph reviews the molecular composition, development history, mechanism of action, pharmacokinetics, clinical evidence base across all studied indications, handling considerations, adverse-event profile, and a comparative assessment of five IGF-1 axis therapeutics against mecasermin rinfabate on five competency standards.
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