Glucagon/GLP-1 receptor co-agonist NNC9204-1177 reduced body weight in adults with overweight or obesity but was associated with safety issues

Glucagon/glucagon-like peptide-1 (GLP-1) receptor co-agonists may provide greater weight loss than agonists targeting the GLP-1 receptor alone. We report results from three phase 1 trials investigating the glucagon/GLP-1 receptor co-agonist NNC9204-1177 (NN1177) for once-weekly subcutaneous use in adults with overweight or obesity. Our focus was a 12–week multiple ascending dose (MAD), placebo-controlled, double-blind trial in which adults (N=99) received NN1177 (dose-escalated to treatment doses of 200, 600, 1,300, 1,900, 2,800, 4,200, and 6,000 μg) or placebo. Two other trials also contribute to the findings in this report: a first human dose (FHD) / single ascending dose (SAD), placebo-controlled, double-blind trial in which adults (N=49) received NN1177 (treatment doses of 10, 40, 120, 350, 700 and 1,100 μg) or placebo, and a drug–drug interaction (DDI), open-label, single-sequence trial in which adults (N=45) received a 4,200 μg dose of NN1177. Pharmacokinetic, safety and tolerability, and pharmacodynamic endpoints were assessed. For the MAD and FHD/SAD trials, baseline characteristics were generally balanced across groups. The half-life of NN1177 was estimated at between 77.3 and 111 hours. NN1177 appeared tolerable across trials; however, a number of safety concerns were observed, including an increase in heart rate (range 5–22 beats per minute) and decrease in reticulocyte count, which were both dose dependent, and increased markers of inflammation (fibrinogen and C-reactive protein), hepatic disturbances (increased aspartate aminotransferase and alanine aminotransferase), impaired glucose tolerance (dose groups 2,800–6,000 ug) and reduced blood levels of some amino acids. Clinically relevant weight loss was achieved (up to 12.6% at week 12; 4,200 ug in the MAD trial), but this was not accompanied by cardiometabolic improvements. In conclusion, although treatment with NN1177 was associated with dose-dependent and clinically relevant weight loss, unacceptable safety concerns precluded further clinical development. ### Competing Interest Statement M. F., L.E., F.F.K, S.T., S.B.N. are employees of Novo Nordisk A/S. M.F., L.E., F.F.K. are shareholders in Novo Nordisk A/S. R.G. is an employee of Parexel International M.K. has received funding from Diffusion Pharmaceutical Inc., Grifols, Urovant Sciences, ViroDefense, Merck, PhaseBio Pharmaceuticals, Inc., Idorsia Pharmaceuticals Ltd, DynPort Vaccine company/FDA/NIH, and Aerovate Therapeutics ### Clinical Trial ClinicalTrials.gov ID [NCT03308721][1] ClinicalTrials.gov [NCT04059367][2] ClinicalTrials.gov ID [NCT02941042][3] ### Clinical Protocols ### Funding Statement This study was funded by Novo Nordisk A/S. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Not Applicable The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The studies obtained approval from local institutional review boards (Aspire IRB 11491 Woodside Ave Santee, CA 92071 and Midlands Independant Review Board 8417 Santa Fe Drive/Suite 100 Overland Park, KS 66212). Written consent was obtained from participants in all three trials. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Not Applicable I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Not Applicable I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Not Applicable All relevant data are within the manuscript and its Supporting Information files. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT03308721&atom=%2Fmedrxiv%2Fearly%2F2022%2F06%2F03%2F2022.06.02.22275920.atom [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT04059367&atom=%2Fmedrxiv%2Fearly%2F2022%2F06%2F03%2F2022.06.02.22275920.atom [3]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT02941042&atom=%2Fmedrxiv%2Fearly%2F2022%2F06%2F03%2F2022.06.02.22275920.atom