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Cotadutide Tames Metabolic Markers
in Overweight/Obese With Diabetes
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EASL 2020, Digital International Liver Congress, August 27-29, 2020
Mark Mascolini
Cotadutide, a subcutaneous dual-receptor agonist, improved metabolic and cardiovascular measures in overweight or obese people with type 2 diabetes through 54 weeks of a phase 2b trial [1]. About 17% of people randomized to cotadutide stopped treatment because of adverse events, compared with fewer than 5% in two control arms.
This novel drug now in trials for heart failure, kidney failure, type 2 diabetes, and nonalcoholic steatohepatitis (NASH) [2,3] acts as a dual receptor agonist with balanced glucagon-like peptide-1 (GLP-1) activity and glucagon activity [4]. Being developed by AstraZeneca, cotadutide may have a metabolic impact not only in adipose tissue, but also in muscle, brain, heart, stomach, kidney, intestines, and pancreas.
The phase 2b trial presented at the EASL meeting aimed to assess safety and efficacy of cotadutide in overweight or obese people with type 2 diabetes. Participants had to be at least 18 years old, have a body mass index (BMI) at or above 25 kg/m2, HbA1c between 7% and 10.5%, and aspartate or alanine aminotransferase levels below 3 times the upper limit of normal. Enrollees had to have diabetes treated by metformin monotherapy.
Researchers randomized participants to once-daily subcutaneous injections of cotadutide (100, 200, or 300 ug), the GLP-1 receptor agonist liraglutide (1.8 mg), or placebo. This large trial began with 100 people in the 100-ug cotadutide arm, 256 in the 200-ug arm, 256 in the 300-ug arm, 110 in the liraglutide arm, and 112 in the placebo arm. Across those 5 arms, age averaged 57.6, 57.3, 56.3, 55.5, and 57.3 years and BMI 35.0, 34.9, 35.2, 35.4, and 34.2 kg/m2. Respective proportions of women were 57%, 57%, 50%, 55%, and 49%, while respective durations of type 2 diabetes were 7.5, 7.7, 7.6, 7.6, and 7.6 years.
Proportions of participants who completed treatment and completed the study were 74% and 96% in the 100-ug cotadutide arm, 77% and 95% in the 200-ug arm, 73% and 96% in the 300-ug arm, 94% and 96% in the liraglutide arm, and 81% and 96% in the placebo arm. Respective proportions who discontinued because of adverse events were 13%, 15.2%, 21.5%, 1.8%, and 4.5% and proportions with serious adverse events 12%, 12.9%, 7.8%, 7.3%, and 10.7%.
Nausea, vomiting, and diarrhea were the most frequent adverse events. Nausea affected 23% in the 100-ug cotadutide arm, 33.2% in the 200-ug arm, 41% in the 300-ug arm, 15.5% in the liraglutide arm, and 10.7% in the placebo group. Adverse event rate per person per day declined sharply through the first 12 weeks of treatment in the 100-ug and 200-ug cotadutide arms, while falling more slowly in the 300-mg arm.
HbA1c, the blood sugar marker, reached a maximum decline after 14 weeks. These drops were greatest with 300 ug of cotadutide (about 1.4%), followed by 200 ug of cotadutide and liraglutide (about 1.2%) and then 100 ug of cotadutide (about 1%). From week 6 all HbA1c levels in drug-treated arms fell significantly more than in the placebo arm.
Through week 54 body weight fell by an average 3.7% with 100 ug of cotadutide (P < 0.001 vs placebo), 3.22% with 200 ug (P < 0.001 vs placebo), and 5.02% with 300 ug (P < 0.001 vs placebo, P = 0.009 vs liraglutide). The average week-54 drop with liraglutide was 3.33%.
ALT and AST dropped more through 54 weeks at each higher cotadutide dose. Average 54-week ALT declines were 7.52% with 100 ug (P = 0.165 vs placebo), 12.01% with 200 ug (P = 0.009 vs placebo, P = 0.063 vs liraglutide), and 14.15% with 300 ug (P = 0.003 vs placebo, P = 0.023 vs liraglutide). The average 54-week drop with liraglutide was 3.21%. The impact of cotadutide on ALT occurred independently of weight loss.
Nonalcoholic fatty liver disease fibrosis score through 54 weeks fell significantly more with 300 ug of cotadutide than with placebo (P = 0.010), but the declines were not significantly greater than placebo with the other cotadutide doses or with liraglutide. FIB-4 fell significantly more with 200 or 300 ug of cotadutide than with placebo (P = 0.032, P = 0.004), while the drop with liraglutide approached statistical significance versus placebo (P = 0.061). Through 54 weeks triglycerides fell significantly more with 200 ug of cotadutide (7.43%) than with placebo (P = 0.042) and with 300 ug of cotadutide (9.75%) than with placebo (P = 0.014).
AstraZeneca has begun a phase 2 proof-of-concept trial comparing a higher dose of cotadutide given with "an optimized titration schedule" in obese people with nonalcoholic fatty liver disease (NAFLD) or NASH [4].
References
1. Nahra R, Maaske J, Wang T, et al. Effects of cotadutide (MED10382) on biomarkers of nonalcoholic steatohepatitis in overweight or obese subjects with type 2 diabetes mellitus: a 54-week analysis of a randomized phase 2b study. EASL 2020, Digital International Liver Congress, August 27-29, 2020. Abstract AS076.
2. Al Idrus A. Astra Zeneca Cotadutide. FIERCE Biotech. December 10, 2019. https://www.fiercebiotech.com/special-report/astrazeneca-cotadutide
3. ClinicalTrials.gov. A study to evaluate safety and pharmacodynamic efficacy of 0382 in obese subjects with NAFLD/NASH. ClinicalTrials.gov identifier NCT04019561. https://clinicaltrials.gov/ct2/show/NCT04019561
4. Parker VER, Robertson D, Wang T, et al. Efficacy, safety, and mechanistic insights of cotadutide, a dual receptor glucagon-like peptide-1 and glucagon agonist. J Clin Endocrinol Metab. 2020;105(3):dgz047. doi: 10.1210/clinem/dgz047.
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