Proof of mechanism for the DGAT1 inhibitor AZD7687: results from a first‐time‐in‐human single‐dose study

Aims Inhibition of diacylglycerol acyltransferase 1 ( DGAT1 ), which catalyses the final step in triacylglycerol ( TAG ) assembly, is suggested as a treatment for type 2 diabetes and obesity based on animal data indicating insulin sensitization and weight reduction. This first‐time‐in‐human single ascending dose study explored the safety, tolerability, pharmacokinetics and pharmacodynamics of the selective DGAT1 inhibitor AZD7687 . Methods Eighty healthy male subjects were enrolled. In each of 10 cohorts, six subjects received the same dose of AZD7687 orally (range across cohorts 1–60 mg) and two placebo. Plasma AZD7687 exposure was measured repeatedly. Postprandial serum TAG excursion was measured during 8 h after a standardized mixed meal with fat energy content of 60% ( SMM 60%; five cohorts, 1–20 mg), before (baseline) and after dosing, to assess effects on gut DGAT1 activity. Results AZD7687 markedly reduced postprandial TAG excursion with a steep concentration–effect relationship. Incremental TAG AUC (area under the serum concentration vs. time curve) following SMM 60% was decreased >75% from baseline at doses ≥5 mg (p < 0.0001 vs. placebo). Serum levels of diacylglycerol, specifically measured with mass spectrometry, did not increase after AZD7687 administration. Nausea, vomiting and diarrhoea were reported with increasing doses and they limited dose escalation. Lowering of SMM fat content to 45 or 30% in five cohorts gradually reduced the frequency of gastrointestinal symptoms at a given dose of AZD7687 . Conclusions The attenuating effect of AZD7687 on postprandial TAG excursion provides proof of mechanism with respect to gut DGAT1 inhibition. However, dose and diet‐related gastrointestinal side effects may impact further development of DGAT1 inhibitors.