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

Abstract

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.

BI 456906: Discovery and preclinical pharmacology of a novel GCGR/GLP-1R dual agonist with robust anti-obesity efficacy

“…The potency of BI 456906 for the human GCGR and GLP-1R was differently affected by the presence of mouse or human plasma and was compared with liraglutide, semaglutide, cotadutide, or tirzepatide ( Table S4 ), peptide agonists containing different fatty acid types to extend their in vivo half-life [ 60 ]. BI 456906 demonstrated a receptor ratio of approximately 1:8 in human plasma, comparable to the once-daily dual agonist cotadutide and different to the 1:3 ratio reported for the recently clinically discontinued dual GCGR/GLP-1R dual agonist NN-1177 in human plasma [ 34 , 35 ]. For the clinical-stage GCGR/GLP-1R agonist cotadutide, the relative receptor ratio in vitro in the absence of human plasma was described as 1:5, considered to be optimal for achieving weight loss and glycemic control [ 58 ].…”

“…As conceptualized by the pharmacology of oxyntomodulin, the simultaneous activation of the GCGR and GLP-1R shows the therapeutic potential of targeting energy intake and expenditure for weight loss, while maintaining glycemic control [ 26 , 32 ]. The need to appropriately balance the dual mechanism of GCGR/GLP-1R action requires a thorough pharmacological characterization and biomarker strategy for optimal development of unimolecular peptide agonists [ [33] , [34] , [35] ].…”

LY3437943, a novel triple glucagon, GIP, and GLP-1 receptor agonist for glycemic control and weight loss: From discovery to clinical proof of concept

“…The NN-1177 (a dual GLP-1R/GCGR agonist) program was terminated after the completion of phase 1 studies and cotadutide (a dual GLP-1R/GCGR agonist) is currently in phase 3 development (NCT05364931). NN-1177 was associated with an increase in pulse rate up to 22 bpm after a single dose (Friedrichsen et al, 2022). After 12-week dosing, the pulse rate increased up to 15 bpm.…”

Hypoaminoacidemia underpins glucagon-mediated energy expenditure and weight loss

“…Together, these findings demonstrate that the long-acting glucagon analog G108 potently stimulates hypoaminoacidemia via hepatic GCGR signaling and that this is associated with a reduction in muscle function in lean mice. As hypoaminoacidemia has been recently associated with GCGR-targeted agonists in clinical studies, 26 , 27 our findings suggest that strategies to prevent hypoaminoacidemia and preserve lean mass may be important for their long-term use in a therapeutic setting.…”

“…However, their relevance is highlighted by recent clinical studies reporting hypoaminoacidemia associated with GCGR-targeted multi-agonists. 26 , 27 , It is therefore essential to determine the chronic effect of GCGR agonism on plasma amino acids and how this influences lean mass, EE, and body weight. It is also important to determine the effect of strategies to mitigate hypoaminoacidemia, for example increased dietary protein intake.…”