Dapiglutide

Dapiglutide was tied to a mean reduction of up to 8.3% in body weight. On the heels of disappointing low-dose data results, Zealand Pharma is back with separate findings for its GLP-1/GLP-2 receptor dual agonist that have emboldened the biotech to push the candidate into phase 2b development.  The Danish biotech’s investigational weight loss candidate, dubbed dapiglutide, was tied to a mean placebo-adjusted reduction of up to 8.3% in body weight in a phase 1b multiple ascending dose trial, according to a Sept. 9 release.The trial, known as MAD, assessed dapiglutide among 54 people overweight or obese against placebo. Patients were split up across three dose cohorts receiving 13 once-weekly doses of up to 13 mg of dapiglutide or placebo, with rapid up-titration every second week. Lifestyle modifications, such as diet or exercise, were not included in the study.The trial’s primary endpoint, as listed on ClinicalTrials.gov, is the incidence of treatment-emergent adverse events (TEAEs). The new findings show dapiglutide to be safe and well tolerated, according to Zealand Pharma, with gastrointestinal (GI) symptoms reported as the most common TEAEs. Two participants discontinued treatment due to GI system adverse events. Overall, the number of GI events observed was consistent with studies with a similar escalation design for other incretin-based therapies, according to Zealand Pharma. Higher dosing regimens up to 26 mg over 28 weeks are currently being tested in part 2 of the trial, with topline results slated for the first half of next year. “Preliminary data further support that dapiglutide possesses a differentiated profile based on its unique dual agonist effects which we expect to translate to a positive effect on inflammation,” Zealand’s Chief Medical Officer David Kendall, M.D., said in the release. “Importantly, today’s exciting data give us the confidence needed to rapidly progress dapiglutide into a comprehensive phase 2b trial in people living with overweight and obesity planned for initiation in the first half of 2025.”The biotech also intends to examine dapiglutide’s potential in certain obesity-related comorbidities, according to the company.Back in May, dapiglutide failed to impress in a phase 2 trial, mustering up to an average 4.3% reduction in weight loss when given in low doses. The 54-person study involved administering either 4 mg weekly subcutaneous doses of dapiglutide, a 6 mg dose or placebo over 12 weeks. Participants who received 4 mg saw an average weight loss of 2.9%, barely above the 2.2% seen in the placebo arm. The 6 mg group saw a slightly larger weight loss of 4.3%.  The results suggest that the 4 mg and 6 mg doses are at the “lower end of the therapeutic range,” according to Zealand.At the time, the biotech pointed to the MAD study, noting the higher doses being investigated.The biotech’s main focus centers around petrelintide, a long-acting amylin analog. After reporting phase 1b data that suggest petrelintide may provide GLP-1-like efficacy without the side effects, Zealand Pharma said it believes the candidate could be “the backbone of therapy for weight management.”

Company announcement – No. 44 / 2024 Zealand Pharma announces positive topline results from 13-week Phase 1b multiple ascending dose clinical trial with GLP-1/GLP-2 receptor dual agonist dapiglutide Placebo-adjusted reductions in body weight of up to a mean of 8.3% with dapiglutide after 13 weekly dosesDapiglutide treatment with doses up to 13 mg was assessed to be safe and well-tolerated with gastrointestinal adverse events consistent with the profile reported with other incretin-based therapies Higher doses up to 26 mg over a 28-week treatment period are being evaluated in the ongoing Part 2 of the trial with topline results expected in the first half of 2025 Copenhagen, Denmark, 9 September 2024 – Zealand Pharma A/S ("Zealand") (Nasdaq: ZEAL), (CVR-no. 20 04 50 78), a biotechnology company focused on the discovery and development of innovative peptide-based medicines, today announces positive topline clinical results from a Phase 1b multiple ascending dose (MAD) trial, investigating safety, tolerability, and clinical effects of 13 weeks of dosing with dapiglutide, a long-acting GLP-1/GLP-2 receptor dual agonist in development for weight management1. “We are both excited and very encouraged by these data from this short-term trial showing substantial and clinically relevant reductions in body weight. Preliminary data further support that dapiglutide possesses a differentiated profile based on its unique dual agonist effects which we expect to translate to a positive effect on inflammation,” said David Kendall, MD, Chief Medical Officer of Zealand Pharma. “We are now evaluating the potential use of higher doses of dapiglutide up to 26 mg over a longer treatment duration of 28 weeks in Part 2 of this ongoing trial and anticipate topline results in the first half of 2025. Importantly, today’s exciting data give us the confidence needed to rapidly progress dapiglutide into a comprehensive Phase 2b trial in people living with overweight and obesity planned for initiation in the first half of 2025.” In Part 1 of the Phase 1b trial, a total of 54 participants (~85% male) with a median age of 46 years and a median baseline BMI of 30.0 kg/m2 were randomized to receive 13 weekly doses of either dapiglutide or placebo (14:4) within three dose cohorts. At week 13, the estimated mean body weight had decreased by up to 8.3% on a placebo-corrected basis among participants on dapiglutide treatment (up to 6.2% mean weight loss on dapiglutide; 2.1% mean weight gain on placebo)2. No lifestyle modifications, such as diet or exercise, were included in the trial. Dapiglutide was assessed to be safe and well-tolerated in Part 1 of the trial, with no severe treatment-emergent adverse events (TEAEs) and one serious AE, which was deemed not related to the drug. The most common TEAEs were gastrointestinal (GI), including nausea and vomiting. Only two participants discontinued treatment due to AEs, which were related to the GI system (moderate vomiting). Overall, the number of GI events observed were consistent with clinical trials of other incretin-based therapies with a similar, rapid dose escalation scheme. A low number of participants reported injection site reactions, all of which were mild. Anti-drug antibodies were observed in 14.3% of participants. Part 2 of this Phase 1b trial is evaluating higher doses of dapiglutide up to 26 mg over a 28-week treatment period with up-titration every fourth week. Zealand expects to report topline results from Part 2 in the first half of 2025 and present further details from Part 1 and Part 2 of this Phase 1b trial at a future scientific congress. The company plans to progress the clinical development of dapiglutide into a Phase 2b trial in people living with overweight and obesity, with initiation expected in the first half of 2025. Also, the company expects to evaluate the potential of dapiglutide in select obesity-related comorbidities. About the Phase 1b trialThe Phase 1b trial is a single-center, randomized, double-blind, placebo-controlled clinical trial in participants with overweight or obesity (eligible BMI 27.0 to 39.9 kg/m2), investigating safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple doses of dapiglutide as subcutaneous injections using a dose escalation scheme (NCT06000891). The trial consists of Part 1 and Part 2. Part 1 includes 54 participants in three cohorts receiving 13 once-weekly doses of dapiglutide or placebo, with rapid up-titration every second week. Participants randomized to the highest dose cohort (13 mg) received the target dose for a period of 5 weeks. Part 2 of the trial includes 30 participants receiving 28 once-weekly doses of dapiglutide or placebo within one dose cohort, with up-titration every fourth week. Participants will receive the target dose of 26 mg for a period of 4 weeks. No lifestyle modifications, such as diet or exercise, are included in the trial. About dapiglutideDapiglutide is a long-acting, dual GLP-1/GLP-2 receptor agonist for the potential treatment of overweight and obesity. This is a first-in-class peptide designed to leverage the weight loss effects of a potent GLP-1 agonist and address co-morbidities associated with low-grade inflammation through improved intestinal barrier function by GLP-2. Previous Phase 1 results of dapiglutide in healthy volunteers demonstrated dose-dependent weight loss of up to 4.3% from baseline body weight after four weeks of treatment (NCT04612517). Dapiglutide also delayed gastric emptying and reduced plasma glucose and insulin concentrations in a dose-dependent manner. Pharmacokinetics showed a mean half-life of 123-129 hours across the four dose cohorts, which supports once-weekly dose administration. Multiple weekly doses of dapiglutide were well-tolerated and the safety profile was as expected for GLP-1 and GLP-2 receptor agonists. These results were presented at the ADA 82nd Scientific Sessions in June 2022. About obesity and low-grade inflammationObesity is a chronic disease that results in substantial global morbidity and mortality. Excess fat storage associated with obesity can trigger low-grade systemic inflammation through reduced intestinal barrier integrity, or “leaky gut”. Obesity-related low-grade inflammation may result in several comorbidities, including cardiovascular disease, liver disease, inflammatory bowel disease, and neuro-inflammation. About Zealand Pharma Zealand Pharma A/S (Nasdaq: ZEAL) ("Zealand") is a biotechnology company focused on the discovery and development of peptide-based medicines. More than 10 drug candidates invented by Zealand have advanced into clinical development, of which two have reached the market and three candidates are in late-stage development. The company has development partnerships with a number of pharma companies as well as commercial partnerships for its marketed products. Zealand was founded in 1998 and is headquartered in Copenhagen, Denmark, with a presence in the U.S. For more information about Zealand, please visit www.zealandpharma.com. Forward-looking statements This company announcement contains forward-looking statements that provide Zealand Pharma’s expectations or forecasts of future events regarding the research, development and commercialization of pharmaceutical products. These forward-looking statements may be identified by words such as “aim,” “anticipate,” “believe,” “could,” “estimate,” “expect,” “forecast,” “goal,” “intend,” “may,” “plan,” “possible,” “potential,” “will,” “would” and other words and terms of similar meaning. You should not place undue reliance on these statements, or the scientific data presented. The reader is cautioned not to rely on these forward-looking statements. Such forward-looking statements are subject to risks, uncertainties and inaccurate assumptions, which may cause actual results to differ materially from expectations set forth herein and may cause any or all of such forward-looking statements to be incorrect, and which include, but are not limited to, the occurrence of adverse safety events; risks of unexpected costs or delays; unexpected concerns that may arise from additional data, analysis or results obtained during clinical trials; failure to protect and enforce our data, intellectual property and other proprietary rights and uncertainties relating to intellectual property claims and challenges; regulatory authorities may require additional information or further studies, or may fail to approve or may delay approval of our drug candidates or expansion of product labelling; failure to obtain regulatory approvals in other jurisdictions; and product liability claims. If any or all of such forward-looking statements prove to be incorrect, our actual results could differ materially and adversely from those anticipated or implied by such statements. The foregoing sets forth many, but not all, of the factors that could cause actual results to differ from our expectations in any forward-looking statement. All such forward-looking statements speak only as of the date of this company announcement and are based on information available to Zealand Pharma as of the date of this announcement. We do not undertake to update any of these forward-looking statements to reflect events or circumstances that occur after the date hereof. Information concerning pharmaceuticals (including compounds under development) contained within this material is not intended as advertising or medical advice. Contacts:Adam Lange (Investors)Investor Relations OfficerZealand Pharmaalange@zealandpharma.com Anna Krassowska (Investors and Media)Vice President, Investor Relations & Corporate CommunicationsZealand Pharmaakrassowska@zealandpharma.com Sources1ClinicalTrials.gov. A Trial Assessing Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of ZP7570. Available at https://clinicaltrials.gov/study/NCT06000891. Last accessed September 2024.2Hypothetical estimand = treatment effect if all participants adhered to treatment (also known as the efficacy estimand).