Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics Of Amg 986, a Novel Small Molecule Apelin Receptor Agonist, in Healthy Subjects and Heart Failure Patients

Hellawell, Jennifer; Abbasi, Siddique; Trivedi, Ashit; Tsirtsonis, Kate; Kaufman, Allegra

doi:10.1016/j.cardfail.2020.09.200

Cited by 8 publications

(31 citation statements)

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“…AMG 986 is a first-in-class, novel apelin receptor small molecule initially developed as a treatment for HF [4,5].…”

Section: Discussionmentioning

confidence: 99%

“…AMG 986 is a first-in-class, novel apelin receptor small molecule initially developed as a treatment for HF [ 4 , 5 ]. In patients with HF, RI is a common comorbidity that can influence the efficacy and safety of drug therapies [ 6 – 10 ].…”

Section: Discussionmentioning

confidence: 99%

“…There are limitations to the current study. In the first-in-human study, AMG 986 was evaluated with single and multiple daily ascending doses up to 650 mg [ 4 ]; however, the current study used a lower, single dose of 200 mg because the limited data available when this study was planned indicated that this dose had acceptable safety and tolerability. Additionally, the plasma protein binding of AMG 986 was not evaluated in this study; thus, further studies are required to evaluate whether protein binding is altered in participants with RI.…”

Section: Discussionmentioning

confidence: 99%

“…The prognosis for patients with HF remains poor and there is an unmet need for novel therapies [ 2 ]. The apelin receptor is a G-protein coupled receptor that counteracts the pressor effect of angiotensin II, attenuates ischemic injury, and contributes to neovascularization in HF [ 3 , 4 ]. AMG 986 is a first-in-class, novel apelin receptor small molecule agonist that binds and activates the apelin receptor to improve cardiac function by increasing cardiac contractility without affecting heart rate [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

“…Recently, a phase 1b, first-in-human study in healthy and HF participants (NCT03276728) reported that AMG 986 exposure increased non-linearly with increasing oral doses of 5 mg to 650 mg, with a trend of decreasing dose-normalized exposures observed across multiple ascending dose groups [ 4 ]. The oral bioavailability of AMG 986 ranged from 40 to 80%, and the terminal half-life ( t ½ ) of AMG 986 650 mg was 21 h; repeated once-daily dosing resulted in minimal accumulation across dose groups [ 4 ]. Additional studies indicate AMG 986 was highly protein bound (99.6% bound in human plasma) and did not preferentially distribute into blood cells, and the in vitro unbound fraction in human plasma was 0.004.…”

Section: Introductionmentioning

confidence: 99%

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Effect of Severe Renal Impairment on the Safety, Tolerability, and Pharmacokinetics of AMG 986

et al. 2022

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Introduction AMG 986 is a first-in-class, novel apelin receptor small molecule agonist initially developed for the treatment of heart failure (HF). The safety and pharmacokinetics (PK) of AMG 986 in participants with renal impairment (RI) remains unknown. Methods This phase 1 study compared the safety and PK of AMG 986 200 mg in six participants with severe RI (estimated glomerular filtration rate [eGFR] 15-29 mL/min/1.73 m 2 ) versus six participants with normal renal function (eGFR ≥ 90 mL/min/1.73 m 2 ).Results Following a single oral dose of AMG 986 200 mg on day 1, the maximum observed concentration increased 1.41fold (90% confidence interval [CI] 0.88-2.27) and the area under the curve from time zero to infinity increased 1.23-fold (90% CI 0.73-2.06) in participants with severe RI versus normal renal function. AMG 986 had an acceptable safety profile; all adverse events were mild in severity. ConclusionsThe results of this study support the enrollment of HF patients with RI to clinical trials of AMG 986 without the need for dose adjustments. Trial Registration Number NCT03318809 (registered: October 24, 2017).

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“…AMG 986 is a first-in-class, novel apelin receptor small molecule initially developed as a treatment for HF [4,5].…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Effect of Severe Renal Impairment on the Safety, Tolerability, and Pharmacokinetics of AMG 986

et al. 2022

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A Phase 1, Open‐Label Study to Evaluate the Effect of Food and Concomitant Itraconazole Administration on the Pharmacokinetics of AMG 986 in Healthy Subjects

Trivedi

Mather

Vega

et al. 2022

Clinical Pharm in Drug Dev

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This phase 1, open‐label study evaluated the effect of food and administration of the cytochrome P450 3A4 and P‐glycoprotein inhibitor itraconazole (ITZ) on the pharmacokinetics of AMG 986. In cohort 1, 12 healthy subjects received a single oral dose of AMG 986 200 mg ± food on days 1 and 10. In cohort 2, 15 healthy subjects received oral ITZ 200 mg once daily on days 8 to 15 and a single oral dose of AMG 986 10 mg on days 1 and 11. The geometric least squares mean ratios of fed/fasted for AMG 986 maximum observed concentration (Cmax) and area under the plasma concentration–time curve from time 0 to infinity (AUCinf) were 0.76 (90%CI, 0.61‐0.95) and 1.07 (90%CI, 0.94‐1.22), respectively. The geometric least squares mean ratios of AMG 986 10 mg plus ITZ 200 mg/AMG 986 10 mg alone for AMG 986 Cmax and AUCinf were 1.36 (90%CI, 1.25‐1.48) and 5.13 (90%CI, 4.71‐5.59), respectively. Overall, 3 subjects experienced mild treatment‐related adverse events; there were no serious or fatal adverse events. In conclusion, food had no apparent effect on the exposure of AMG 986 200 mg; therefore, food restrictions are not required. Potent cytochrome P450 3A4 and/or P‐glycoprotein inhibitors may warrant AMG 986 dose reduction and should be coadministered with caution in patients with heart failure treated with AMG 986.

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A Phase I, Open-label, Single-Dose Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of AMG 986 in Healthy Japanese Subjects

et al. 2022

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Background and Objective AMG 986 is a first-in-class, novel apelin receptor small molecule agonist initially developed as a treatment for patients with heart failure (HF). Previously, a first-in-human study of AMG 986 was conducted in healthy and HF subjects; however, AMG 986 was not evaluated in Japanese subjects. Methods This was a phase I, open-label, single-dose, single-center study conducted to evaluate the safety and pharmacokinetics (PK) of AMG 986 200 mg and 400 mg in 12 healthy Japanese subjects. Six subjects received AMG 986 200 mg and six subjects received AMG 986 400 mg. Results Following oral administration, median time to maximum observed plasma concentration (t max ) was 1.0 h for both the AMG 986 200 mg and 400 mg groups, and mean terminal half-life (t ½ ) was 15.1 h and 17.6 h, respectively. When comparing the AMG 986 200 mg and 400 mg groups, 1.33-fold and 1.18-fold higher maximum observed plasma concentration (C max ) and AUC ∞ , respectively, were observed for the 2-fold increase in dose. AMG 986 exhibited an acceptable safety and tolerability profile; all adverse events were mild in severity. Conclusion AMG 986 exposure increased with increasing dose, and the increase was less than dose proportional in healthy Japanese subjects. The results of this study could facilitate the subsequent clinical development of AMG 986 for the treatment of Japanese patients with HF.

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Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics Of Amg 986, a Novel Small Molecule Apelin Receptor Agonist, in Healthy Subjects and Heart Failure Patients

Cited by 8 publications

References 0 publications

Effect of Severe Renal Impairment on the Safety, Tolerability, and Pharmacokinetics of AMG 986

Effect of Severe Renal Impairment on the Safety, Tolerability, and Pharmacokinetics of AMG 986

A Phase 1, Open‐Label Study to Evaluate the Effect of Food and Concomitant Itraconazole Administration on the Pharmacokinetics of AMG 986 in Healthy Subjects

A Phase I, Open-label, Single-Dose Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of AMG 986 in Healthy Japanese Subjects

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