glepaglutide (ZP1848) / Zealand Pharma - LARVOL DELTA

LONG-ACTING GLP-2 ANALOG GLEPAGLUTIDE INCREASES INTESTINAL ABSORPTION AND REDUCES THE NEED FOR PARENTERAL SUPPORT IN PATIENTS WITH SHORT BOWEL SYNDROME (DDW 2025) - "Once-weekly glepaglutide treatment resulted in clinically relevant increases in intestinal absorptions of fluids, electrolytes, macronutrients and energy along with sustained reductions in PS needs, without compromising body weight. Treatment was assessed to be safe and well-tolerated supporting a favorable benefit-risk profile of glepaglutide for managing patients with SBS."

Clinical • Gastrointestinal Disorder • Short Bowel Syndrome

Upcoming events next 12 months (GlobeNewswire) - "In the second half of 2025, Zealand Pharma expects to submit a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) and initiate a Phase 3 clinical trial of glepaglutide (EASE-5) that is anticipated to provide further confirmatory evidence for a regulatory submission in the U.S. and to support regulatory submissions outside the U.S. and the EU. In parallel, the company is engaging in partnership discussions for future commercialization...Zealand Pharma is ready to resubmit the New Drug Application for dasiglucagon for up to three weeks of dosing and to submit the requested analyses from existing continuous glucose monitoring datasets to support use beyond three weeks...In parallel, the company is engaging in partnership discussions for future commercialization....Zealand Pharma expects to complete the first-in-human clinical trial with ZP9830 in the fourth quarter of 2025 and report topline data in the first half of 2026."

EMA filing • FDA filing • New P3 trial • P1 data • Immunology • Rare Diseases • Short Bowel Syndrome

Highlights of the year and key events anticipated in 2025 (GlobeNewswire) - "Zealand Pharma is prepared to resubmit the New Drug Application (NDA) for three weeks of dosing to the U.S. FDA contingent on the third-party manufacturing facility receiving an inspection classification upgrade. Subsequently, Zealand Pharma also expects to submit the required and detailed analyses from existing continuous glucose monitoring datasets to support the use of dasiglucagon beyond three weeks....In 2025, the company expects to initiate a single placebo-controlled Phase 3 trial (EASE-5) to provide further confirmatory evidence for a regulatory submission in the U.S. and to support regulatory submissions for glepaglutide in geographies outside the U.S. and the EU. In parallel, Zealand Pharma anticipates proceeding with current plans to submit a Marketing Authorization Application to support EU approval."

EMA filing • FDA filing • New P3 trial • Rare Diseases • Short Bowel Syndrome

Glepaglutide-Loaded Foam for the Induction of Mucosal Healing in the Treatment of Inflammatory Bowel Disease. (PubMed, Adv Healthc Mater) - "The foam formulation improved macromolecule absorption in the colon, with fast recovery of enhanced permeation that dissipated after 4 h. This study highlights GLF as a promising formulation for GL administration, balancing systemic and local anti-inflammatory effects."

Journal • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • Short Bowel Syndrome

Creating Glepaglutide, the First Long-Acting GLP-2 Analogue to Enable a Ready-to-Use Injection. (PubMed, J Med Chem) - "One hGLP-2 analogue described herein is glepaglutide ([Gly2Glu3Thr5Ser8Leu10Ala11,16,24,28] hGLP-2[1-33]-NH-[Lys]6-NH2), the first long-acting analogue with excellent physicochemical stability, making it suitable for liquid formulation. Glepaglutide is currently in phase 3 clinical trials as a potential new therapy for SBS and is the only hGLP-2 analogue in clinical testing that is dosed subcutaneously from a ready-to-use formulation in an autoinjector."

Journal • Gastrointestinal Disorder • Short Bowel Syndrome

Glepaglutide, a Long-acting Glucagon-like Peptide-2 Analog, Reduces Parenteral Support in Patients with Short Bowel Syndrome: a Phase 3, Randomized, Controlled Trial. (PubMed, Gastroenterology) - "Glepaglutide treatment in SBS-IF patients resulted in clinically relevant reductions in PS requirements and was well tolerated."

Journal • P3 data • Gastrointestinal Disorder • Short Bowel Syndrome

U.S. Food and Drug Administration issues Complete Response Letter for the glepaglutide New Drug Application for the treatment of short bowel syndrome (GlobeNewswire) - "Zealand Pharma A/S...announced that the...FDA has issued a Complete Response Letter (CRL) for the company’s New Drug Application (NDA) for glepaglutide...under development for the treatment of adult patients with short bowel syndrome (SBS) with intestinal failure (IF) who are dependent on parenteral support. The submitted NDA included a single randomized, placebo-controlled Phase 3 registration trial...In the CRL, the FDA recommended an additional clinical trial to provide further evidence to confirm the efficacy and safety of glepaglutide at the to-be-marketed dose...Zealand Pharma expects to initiate a single Phase 3 trial in 2025 that is anticipated to support marketing authorizations for glepaglutide in geographies outside the U.S. and the EU and provide further confirmatory evidence for a regulatory resubmission in the U.S...Zealand Pharma expects to proceed with its current plans for a European Marketing Authorization Application submission in 2025."

CRL • EMA filing • New P3 trial • Short Bowel Syndrome

Use of glucagon-like polypeptide 2 analogs for intestinal failure. (PubMed, Expert Opin Pharmacother) - "More recently, ultralong acting GLP-2 analogs with half-lives of 70-80 hours can improve gastrointestinal function in surgically foreshortened bowel with only one injection every three to seven days. Future research is likely to focus upon the potential complementary role of GLP-1 and GLP-2 in treating short bowel syndrome."

Journal • Gastrointestinal Disorder • Pediatrics • Short Bowel Syndrome

EASE SBS 4: The Long-term Effect on Intestinal Absorption and Safety of Treatment With Glepaglutide in Patients With Short Bowel Syndrome (clinicaltrials.gov) - P3 | N=12 | Completed | Sponsor: Zealand Pharma | Phase classification: P3b ➔ P3

Phase classification • Gastrointestinal Disorder • Short Bowel Syndrome

Real-world experience with glucagon-like peptide 2 analogues in patients with short bowel syndrome and chronic intestinal failure: results from an international survey in expert intestinal failure centers. (PubMed, Clin Nutr ESPEN) - "The results of this survey completed by expert IF centers show the real-life use of GLP-2 analogues in clinical practice. Key learning points identified include the accounting for a period of intestinal adaptation before starting GLP-2 analogues and not stopping the treatment too early in case of non-response. The best strategy in case of adverse effects should be studied further."

Journal • Real-world • Real-world evidence • Gastrointestinal Disorder • Short Bowel Syndrome

GLEPAGLUTIDE REDUCES NEED OF PARENTERAL SUPPORT OF FLUIDS, ELECTROLYTES, ENERGY AND MACRONUTRIENTS IN SHORT BOWEL SYNDROME PATIENTS: RESULTS FROM THE 52-WEEK OPEN-LABEL EASE SBS-4 STUDY (UEGW 2024) - "Glepaglutide induced clinically meaningful, sustained reduction in the PS need, including fluids, electrolytes, energy and macronutrients at 52 weeks in SBS patients with and without CIC. These data are in alignment with glepaglutide-induced increases in intestinal absorptive capacity as demonstrated in state-of-art metabolic balance studies."

Clinical • Gastrointestinal Disorder • Short Bowel Syndrome

EASE SBS 2: Evaluation of Long Term Safety and Efficacy of Glepaglutide in Treatment of SBS (clinicaltrials.gov) - P3 | N=145 | Active, not recruiting | Sponsor: Zealand Pharma | Recruiting ➔ Active, not recruiting | Trial completion date: Dec 2024 ➔ Oct 2026 | Trial primary completion date: Dec 2024 ➔ Oct 2026

Enrollment closed • Trial completion date • Trial primary completion date • Gastrointestinal Disorder • Short Bowel Syndrome

Intestinal adaptation and rehabilitation in adults with short bowel syndrome. (PubMed, Curr Opin Clin Nutr Metab Care) - "Real-world data confirmed the teduglutide efficacy not only in weaning off IVS in accurately selected patients but also increased the alert on the risk of development of gastrointestinal polyps related to the drug; the impact of the therapy on patients' QoL deserves further studies and the cost-utility of the treatment is still uncertain. Some case reports highlighted the potential benefit of treatment with teduglutide in non-SBS gastrointestinal diseases, such as graft-versus-host disease, primary amyloidosis and refractory microscopic colitis. Phase 2 RCTs on safety and efficacy of two new long-acting GLP-2 analogues, glepaglutide and apraglutide, were published, and phase 3 RCTs have been completed."

Journal • Amyloidosis • Gastroenterology • Gastrointestinal Disorder • Graft versus Host Disease • Immunology • Short Bowel Syndrome

Emerging drugs for the treatment of short bowel syndrome. (PubMed, Expert Opin Emerg Drugs) - "Clinical trials and real-world experience demonstrated that Teduglutide   reduces dependence on parenteral support andhas a place in the management of patients with SBS-CIF.  The use of Teduglutide should be discussed inpatients stabilized after resection and its introduction requires the advice ofan expert center capable of assessing the benefit-risk ratio. The complex, individualized management of SBS-C IF requires theexpertise of a specialized IF center which a multidisciplinary approach. Thearrival of new treatments will call for new therapeutic strategies, and thequestion of how to introduce and monitor them will represent a new therapeuticchallenge."

Journal • Review • Gastrointestinal Disorder • Short Bowel Syndrome

EFFECT OF GLEPAGLUTIDE, A LONG-ACTING GLP-2 ANALOG, ON HEPATIC, RENAL AND BONE MARKERS IN PATIENTS WITH SHORT BOWEL SYNDROME: RESULTS OF EASE SBS-1 PHASE 3 TRIAL (DDW 2024) - "In addition to clinically relevant reductions in PS requirements, short-term treatment (24 weeks) of SBS-IF patients with the long-acting GLP-2 analog glepaglutide also led to improvement in liver function tests, with no short-term change in renal function or bone markers. It is possible that longer-term monitoring is required to show additional changes, and these outcomes are pending."

Clinical • P3 data • Gastrointestinal Disorder • Hepatology • Nephrology • Osteoporosis • Renal Disease • Rheumatology • Short Bowel Syndrome

Zealand Pharma Announces Financial Results for the First Quarter of 2024 (GlobeNewswire) - "Glepaglutide, GLP-2 analog: US FDA has granted a Prescription Drug User Fee Act (PDUFA) date of December 22, 2024. Zealand’s new drug application (NDA) is for glepaglutide administered twice weekly for the treatment of short bowel syndrome (SBS) with intestinal failure."

PDUFA • Gastroenterology • Short Bowel Syndrome

Efficacy and safety of glucagon-like peptide-2 (GLP-2) in patients with short bowel syndrome; A Systematic Review and Network Meta-analysis. (PubMed, J Gastrointest Surg) - "Despite the small number of patients in the included studies and variable follow-up duration, GLP-2 seems safe and effective in patients with SBS. GLP-2 showed a positive effect on increasing plasma citrulline level and decreasing alkaline phosphatase level."

Journal • Retrospective data • Review • Gastrointestinal Disorder • Infectious Disease • Short Bowel Syndrome

EASE SBS 3: Evaluation of Long Term Safety and Efficacy of Glepaglutide in Treatment of SBS - Extension Trial (clinicaltrials.gov) - P3 | N=129 | Enrolling by invitation | Sponsor: Zealand Pharma

Trial completion date • Trial primary completion date • Gastrointestinal Disorder • Short Bowel Syndrome

Zealand Pharma submits New Drug Application to the US FDA for glepaglutide in short bowel syndrome (GlobeNewswire) - "Zealand Pharma A/S...announced the submission of a New Drug Application (NDA) to the US Food and Drug Administration (FDA) for glepaglutide, a long-acting GLP-2 analog, for the treatment of adult patients with short bowel syndrome (SBS) dependent on parenteral support....The submission is based on the results from a pivotal Phase 3 trial (EASE-1), supported by interim results from two ongoing long-term extension trials (EASE-2 and EASE-3), and a mechanistic trial (EASE-4)."

NDA • Gastroenterology • Short Bowel Syndrome

Zealand Pharma Announces Financial Results for the First Nine Months of 2023 (GlobeNewswire) - "Zealand Pharma A/S...today announced the interim report for the nine months ended September 30, 2023, and provided a corporate update...In the fourth quarter of 2023, Zealand expects to submit an NDA to the FDA for glepaglutide administered via autoinjector for the treatment of short bowel syndrome with intestinal failure and subsequently engage in more detailed partnership discussions....In the first half of 2024, Zealand anticipates topline results from the ongoing investigator-led DREAM trial that aims to evaluate the potential for weight loss following 12 weeks of treatment and gain key mechanistic insights into the effects of dapiglutide on inflammatory markers. In the second half of 2024, Zealand expects topline results from the 13-week dose titration trial."

NDA • P2 data • Gastroenterology • Gastrointestinal Disorder • Metabolic Disorders • Obesity • Short Bowel Syndrome

Correction: Zealand Pharma Announces Full Year Results for 2022 (GlobeNewswire) - "Glepaglutide, a long-acting GLP-2 analog in short bowel syndrome (SBS). Results from the EASE-1 Phase 3 trial in SBS patients with intestinal failure have been accepted for presentation at scientific conferences in the first half of 2023. The EASE-2 and EASE-3 long-term safety and efficacy extension trials are ongoing, with the first interim data expected in the first half of the year as the company decided to include analysis from at least 24 weeks of treatment from EASE-2....Based on data from the full EASE clinical trial program, Zealand anticipates submitting an NDA to the FDA in the second half of 2023 for glepaglutide administered via autoinjector for the treatment of SBS."

NDA • P3 data • Short Bowel Syndrome

EASE SBS 4: The Long-term Effect on Intestinal Absorption and Safety of Treatment With Glepaglutide in Patients With Short Bowel Syndrome (clinicaltrials.gov) - P3b | N=12 | Completed | Sponsor: Zealand Pharma | Active, not recruiting ➔ Completed

Trial completion • Gastrointestinal Disorder • Short Bowel Syndrome

EARLY RESPONSE TO GLEPAGLUTIDE, A NOVEL LONG-ACTING GLP-2 ANALOG, IN SHORT BOWEL SYNDROME PATIENTS WITH INTESTINAL FAILURE: RESULTS OF 24-WEEK PHASE 3 TRIAL (UEGW 2023) - "Treating SBS patients with chronic IF with glepaglutide was assessed to be safe, well tolerated and resulted in early (by 12 weeks of treatment) sustained reductions in PS needs including the achievement of enteral autonomy in a meaningful number of patients within 24 weeks. Data supports glepaglutide as a novel medical treatment option for the management of SBS patients that results in early and significant reductions in PS support."

Clinical • P3 data • Gastrointestinal Disorder • Renal Disease • Short Bowel Syndrome

Beneficial Effect on Intestinal Growth of a Long-Acting GLP-2 Analog, HM15912, after Treatment Switching from Conventional GLP-2 Drug or Other Long-Acting GLP-2 Analogs under Clinical Development in Animal Model (ENDO 2023) - "The widespread use of teduglutide, which is only approved GLP-2 analog drug for short bowel syndrome (SBS), may be still limited due to insufficient efficacy and leading to a significant burden for patients by daily administration...Next, we synthesized GLP-2 analogs to have same sequences with glepaglutide and apraglutide...Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.*"

Preclinical • Gastrointestinal Disorder • Short Bowel Syndrome

Differential Responses of the GLP-1 and GLP-2 Receptors to N-Terminal Modification of a Dual Agonist. (PubMed, J Am Chem Soc) - "Using variants of the hormone GLP-2 and the designed clinical agonist glepaglutide (GLE), we find that the GLP-2R is quite tolerant of variations in α-helical propensity near the agonist N-terminus, which contrasts with signaling at the GLP-1R...This comparison supports the conclusion that the GLP-1R and GLP-2R differ in their response to variations in helical propensity near the agonist N-terminus. The data offer a basis for development of new hormone analogues with distinctive and potentially useful activity profiles; for example, one of the GLE analogues is a potent agonist of the GLP-2R but also a potent antagonist of the GLP-1R, a novel form of polypharmacology."

Journal