Is glepaglutide FDA-approved, and what does the research show?

What is glepaglutide?

Glepaglutide is an investigational peptide drug, a long-acting analog of GLP-2, glucagon-like peptide-2 ¹, ⁶. A peptide is a short chain of amino acids, and an analog is a modified version of a natural molecule. One trial report says GLP-2 "enhances intestinal adaptation and absorption," meaning it helps the bowel adjust and take up more ⁶. Zealand Pharma sponsors the trials, and the registry gives glepaglutide as the official generic name for the company's code name, ZP1848 ⁷.

GLP-2 is not GLP-1, glucagon-like peptide-1. In FDA's drug records, tirzepatide, sold as Zepbound, carries the class "GLP-1 Receptor Agonist," while teduglutide, sold as Gattex, carries the class "GLP-2 Analog" ³, ². Glepaglutide's phase 3 trial and its absorption study both enrolled people with short bowel syndrome ¹, ⁶. Neither tested it as a wellness, weight-loss or performance peptide ¹, ⁶.

Short bowel syndrome, or SBS, is defined in the phase 3 trial's registry record as less than 200 centimeters of small intestine left in continuity, meaning still connected ⁷. EASE SBS 5, the trial now recruiting, requires that the last resection, the surgical removal of bowel, took place at least six months before screening ⁸. The phase 3 trial enrolled people with SBS and intestinal failure, who needed parenteral support at least three days a week ¹. Parenteral support is nutrition and fluid given into a vein instead of through the gut, and the trials measure it by weekly volume and energy content ⁶, ⁷.

Is glepaglutide FDA-approved?

Glepaglutide is not FDA-approved: Drugs@FDA lists no approved glepaglutide product as of November 9, 2026 ⁴. It is an investigational drug in a phase 3 trial, EASE SBS 5, which the registry lists as recruiting ⁸. Phase 3 is the late stage of testing, when a drug is compared in larger groups before a company seeks approval.

Zealand Pharma US, Inc. filed a new drug application, NDA 218828, the file a company sends FDA to ask for approval ⁵. It was for "glepaglutide injection proposed for the treatment of short bowel syndrome (SBS)" ⁵. FDA answered on December 19, 2024 with a complete response letter, writing that it could not approve the application "in its present form" ⁵. A complete response letter tells an applicant that the agency cannot approve an application as it stands.

FDA wrote in the letter that it was "unable to conclude that there is substantial evidence of effectiveness (SEE), nor that the benefits outweigh the known and anticipated risks" ⁵. It wrote that the results of the phase 3 trial, which the letter calls EASE-1, were "not sufficiently persuasive and robust" ⁵. To resolve this, FDA wrote, "we recommend you conduct a second adequate and well-controlled trial before resubmitting your application" ⁵.

EASE SBS 5 is placebo-controlled, and its registered title says it is meant "to Confirm the Efficacy and Safety" of twice-weekly glepaglutide ⁸. It started on February 11, 2026, and its primary completion is estimated for October 2028 ⁸. Zealand Pharma says it submitted the application in 2023 ⁹. No source cited here says whether it has been resubmitted.

FDA wrote in the letter: "The product may not be legally marketed until you have been notified in writing that this application is approved" ⁵. Compounding is a pharmacy's preparation of a medicine to a prescription, and FDA keeps lists of substances nominated for it. The list under section 503A of the drug law, updated May 14, 2026, does not name glepaglutide ¹⁰. Neither does the 503B list, for outsourcing facilities, updated March 21, 2025 ¹¹. With no approved product and no entry on either list, no source cited here shows a route to glepaglutide outside a clinical trial ⁴, ¹⁰, ¹¹.

Outside the United States, the only regulators' records cited here are those of the European Medicines Agency (EMA) and the European Commission ¹², ¹³. In the European Union, EMA's committee recommended authorizing glepaglutide, as Zeydovio, on September 17, 2026; the Commission's register, updated November 10, 2026, lists none ¹², ¹³.

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How does glepaglutide work?

The phase 3 paper describes glepaglutide as "developed to improve intestinal absorption in patients with short bowel syndrome (SBS)" ¹. EMA calls glepaglutide a long-acting analog of GLP-2, a peptide that acts on the growth of the intestine ¹². The registry record for that trial refers to "the long half-life of glepaglutide" ⁷. Half-life is the time the body takes to clear half of a drug, and the phase 3 trial injected glepaglutide once or twice a week ¹.

Studied in people: EASE SBS 4, a single-center, open-label study of 10 patients with SBS, measured absorption directly ⁶, ¹⁴. Open-label means every patient knew they were receiving the drug, and there was no placebo group. Patients stayed at the site for 48-hour balance studies, which weigh what is eaten and drunk against what leaves the body ¹⁴. After 24 weeks, the energy they absorbed had risen by a mean of 1,038 kilojoules a day (P = 0.0215) ⁶. P is the probability of a difference at least this large if the drug had no true effect, and by convention a value under 0.05 is called statistically significant.

Fluid absorption was that study's primary measure. It rose by a mean of 398 grams a day, which did not reach statistical significance (P = 0.0585) ⁶.

FDA wrote in its letter that one study "did not meet its primary endpoint" ⁵. It wrote that EASE-4 and an earlier phase 2 study, ZP1848-15073, "did not provide adequate mechanistic or confirmatory evidence to support EASE-1 results" ⁵, ¹⁵. FDA wrote that exposure-response analyses "suggested a lack of relationship between observed glepaglutide exposure and the primary efficacy endpoint" in the phase 3 trial ⁵. Exposure here means how much drug reached a patient's blood.

What does the research show?

Studied in people: EASE SBS 1, a randomized, double-blind, placebo-controlled phase 3 trial, 106 patients with SBS and intestinal failure, change in weekly parenteral support volume at 24 weeks ¹. Randomized means chance decided each patient's group. A placebo is an inactive injection used for comparison, and in a double-blind trial neither the patients nor the trial staff know who receives it.

Patients needed parenteral support at least three days a week, and they were assigned in equal proportions to three groups ¹. The paper names the groups glepaglutide twice weekly, glepaglutide once weekly, and placebo ¹. The registry counts 35, 35 and 36 patients in them, at sites in nine countries ⁷.

Weekly support volume fell by a mean of 5.13 liters with glepaglutide twice weekly, against 2.85 liters with placebo (P = .0039) ¹. That was the primary end point, the one result a trial is designed to test. With glepaglutide once weekly the fall was 3.76 liters, and the difference from placebo was not statistically significant ⁷, ¹.

Two key secondary results also favored the twice-weekly group ¹. A cut of at least 20% in weekly support volume, held at both weeks 20 and 24, was reached by 65.7% against 38.9% on placebo (P = .0243) ¹. At least one more day a week off support was gained by 51.4% against 19.4% (P = .0043) ¹. In the once-weekly group the registry counts 16 and 12 of 35 patients for the same two results, neither significantly different from placebo ⁷, ¹.

Five patients on glepaglutide twice weekly (14%) came off parenteral support entirely, which the paper calls enteral autonomy, against none on placebo ¹. The registry counts four of 35 in the once-weekly group ⁷. The trial finished in July 2022 by the registry's dates, and the paper appeared online on December 19, 2024 ⁷, ¹.

FDA wrote in its December 19, 2024 letter that the twice-weekly group showed "a statistically significant difference from placebo on the primary efficacy endpoint" ⁵. The letter also lists "numerous uncertainties" ⁵. Among them, FDA wrote, were changes to support volume that departed from the trial's protocol, and missing records of urine output ⁵. By the letter's account, the protocol used urine output to decide when support could be reduced ⁵.

The patients in this trial had short bowel syndrome and depended on parenteral support ¹. In its letter FDA treats weight loss as a reason to doubt the benefit of the reduced support ⁵. It states: "Up to 23% of subjects in the TW dosage group lost significant (>10%) body weight during EASE-1 and EASE-2" ⁵. TW is the twice-weekly group, and EASE-2 is the extension trial that followed, which had no placebo group ¹⁵. The letter gives no matching figure for the placebo group.

FDA wrote that when sensitivity analyses left out those patients, the two key secondary results were "no longer statistically significant" ⁵. In FDA's words, "significant weight loss raises concerns regarding whether the reduction in PS was appropriate and consistent with clinically meaningful benefit" ⁵. PS is parenteral support.

The registry's adverse-event table lists "Weight decreased" for two of 35, one of 35 and two of 36 patients in the twice-weekly, once-weekly and placebo groups ⁷. That table counts events investigators reported, a different measure from FDA's count.

EASE SBS 4, the absorption study, also tracked parenteral support, with every patient on glepaglutide once weekly ⁶. Eight had intestinal failure and two had intestinal insufficiency, a lesser loss of gut function that does not require parenteral support; the support results cover only the eight ⁶, ¹⁴. At week 52, mean support volume was down by 800 milliliters a day (P = 0.0106), and its energy content by 866 kilojoules a day (P = 0.0103) ⁶. The authors report that body composition and weight "remained stable" in this one-group study, which had no placebo ⁶. The registry's adverse-event table for the same 10 patients lists "Weight decreased" for three and "Weight increased" for two ¹⁴.

Patients could continue from the phase 3 trial into an extension, EASE SBS 2, in which every patient received glepaglutide ¹⁵. The registry lists it as completed on April 30, 2026, with no results posted ¹⁵. FDA's letter says the extension trials "provide additional safety data but were not designed to provide an independent source of evidence of effectiveness" ⁵.

EASE SBS 5, a double-blind, placebo-controlled phase 3 trial of glepaglutide twice weekly, is listed by the registry as recruiting ⁸. The registry gives an estimated enrollment of 90 adults with SBS who need parenteral support at least three days a week ⁸. Its primary measure is again the change in weekly support volume at 24 weeks, with further measures at 52 weeks ⁸. FDA wrote in its letter that controlled data beyond 24 weeks were necessary to show that the early reduction "can be maintained over time, with concurrent maintenance of body weight/nutritional status" ⁵.

The two papers, four registry records and FDA letter cited here report no trial in children and no head-to-head trial against another GLP-2 drug. None of them reports a trial of glepaglutide for weight loss.

What are the side effects?

Glepaglutide has no approved product in Drugs@FDA, so the side effects described here come from the trials and from FDA's letter, not from an FDA label ⁴. A label is the document that sets out an approved drug's uses and warnings. The phase 3 paper's summary says only that the drug "was assessed to be safe and well tolerated" ¹. The registry's posted results give the counts by group ⁷. An adverse event is any health problem recorded during a trial, whether or not the drug caused it.

In EASE SBS 1, most patients in every group had an adverse event of some kind ⁷. The counts were 33 of 35 on glepaglutide twice weekly, 33 of 35 on once weekly and 27 of 36 on placebo ⁷. Serious adverse events were recorded for nine, 10 and seven patients in the same order, and no patient died ⁷. Events graded severe were recorded for 10, five and two ⁷. The safety table lists two patients with adverse events leading to withdrawal from the trial, both in the twice-weekly group ⁷.

Reactions where the drug was injected were the most frequent: nine, 15 and one patient in the three groups ⁷. Nausea was recorded for seven, three and one; abdominal pain for five, six and two; vomiting for three, six and none ⁷. Fatigue, dehydration and swelling of the limbs, listed as peripheral edema, were each recorded more often on glepaglutide twice weekly than on placebo ⁷. Fatigue was recorded for four, four and none; dehydration for four, one and none; swelling of the limbs, peripheral edema, for four, none and two ⁷. Among serious events, sepsis related to a medical device was recorded for two, two and one ⁷.

Most treated patients formed antibodies against the drug, immune proteins that can bind a medicine ⁷. The registry counts 30 of 35 and 31 of 35 in the two glepaglutide groups, and none on placebo ⁷. The sources cited here do not say whether those antibodies changed how the drug worked.

In the 10-patient EASE SBS 4 study, the registry records serious adverse events in six patients and one death ¹⁴. The registry's mortality count carries no cause of death and no judgment of whether the drug was involved ¹⁴. One serious event is listed as "Metastatic neoplasm," a cancer that has spread ¹⁴. One patient stopped the study because of an adverse event, and the paper's summary calls the safety profile "manageable" ¹⁴, ⁶.

FDA wrote in its December 19, 2024 letter: "Multiple safety concerns, including potential drug-induced liver injury, cancers (gastric neuroendocrine carcinoma, basal cell carcinoma of skin and basosquamous carcinoma of skin), and gastric polyps were identified within this limited safety database" ⁵. FDA also wrote that the safety database was too small for a new drug meant for long-term use. It recommended "at least ~100 subjects" treated for a year or more ⁵.

FDA wrote that an inspection of one trial site identified "numerous unreported adverse events in 6 out of 9 enrolled subjects," two of them serious ⁵. It wrote that the findings "raise significant concerns regarding the reliability of the data to inform the benefit-risk assessment of glepaglutide" ⁵.

No source cited here gives contraindications for glepaglutide. The phase 3 trial excluded people with any history of colon cancer, a bowel obstruction or decompensated heart failure, meaning heart failure no longer under control, among other conditions ⁷. Those are the trial's entry rules, recorded in the registry, and not guidance for patients.

In sport

Glepaglutide is not named on the 2026 Prohibited List of WADA, the World Anti-Doping Agency ¹⁶. The list does not mention its code name, ZP1848, or GLP-2 ¹⁶.

Section S0 of the list reads: "Any pharmacological substance which is not addressed by any of the subsequent sections of the List and with no current approval by any governmental regulatory health authority for human therapeutic use (e.g. drugs under pre-clinical or clinical development or discontinued, designer drugs, substances approved only for veterinary use) is prohibited at all times" ¹⁶. FDA's record shows no approved glepaglutide product ⁴. In the European Union, EMA's committee recommended authorizing glepaglutide, as Zeydovio, on September 17, 2026; the Commission's register, updated November 10, 2026, lists none ¹², ¹³.

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JumpstartMD does not prescribe glepaglutide. Our peptide library covers it so you have the facts on its FDA status and the evidence, current as of November 10, 2026.

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