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Pharmacology: Mechanism of action (MOA): UPERIO exhibits the novel mechanism of action of an angiotensin receptor neprilysin inhibitor (ARNI) by simultaneously inhibiting neprilysin (neutral endopeptidase; NEP) via sacubitrilat, the active metabolite of the prodrug sacubitril, and by blocking the angiotensin II type-1 (AT1) receptor via valsartan. The complementary cardiovascular benefits and renal effects of UPERIO in heart failure patients are attributed to the enhancement of peptides that are degraded by neprilysin, such as natriuretic peptides (NP), by sacubitrilat and the simultaneous inhibition of the deleterious effects of angiotensin II by valsartan. NPs exert their effects by activating membrane-bound guanylyl cyclase-coupled receptors, resulting in increased concentrations of the second messenger cyclic guanosine monophosphate (cGMP), thereby promoting vasodilation, natriuresis and diuresis, increased glomerular filtration rate and renal blood flow, inhibition of renin and aldosterone release, reduction of sympathetic activity, and anti-hypertrophic and anti-fibrotic effects. Sustained activation of the renin-angiotensin-aldosterone system results in vasoconstriction, renal sodium and fluid retention, activation of cellular growth and proliferation, and subsequent maladaptive cardiovascular remodeling. Valsartan inhibits detrimental cardiovascular and renal effects of angiotensin II by selectively blocking the AT1 receptor, and also inhibits angiotensin II-dependent aldosterone release.
Pharmacodynamics (PD): The pharmacodynamic effects of UPERIO were evaluated after single and multiple dose administrations in healthy subjects and in patients with heart failure, and are consistent with simultaneous neprilysin inhibition and RAAS blockade. In a 7-day valsartan-controlled study in patients with reduced ejection fraction (HFrEF), administration of UPERIO resulted in an initial increase in natriuresis, increased urine cGMP, and decreased plasma MR-proANP and NT-proBNP compared to valsartan. In a 21-day study in HFrEF patients, UPERIO significantly increased urine ANP and cGMP and plasma cGMP, and decreased plasma NT-proBNP, aldosterone and endothelin-1 compared to baseline. UPERIO also blocked the AT1-receptor as evidenced by increased plasma renin activity and plasma renin concentrations. In PARADIGM-HF, UPERIO decreased plasma NT-proBNP and increased plasma BNP and urine cGMP compared with enalapril. While BNP is a neprilysin substrate, NT-proBNP is not. Therefore, NT-proBNP (but not BNP) is a suitable biomarker for monitoring of heart failure patients treated with UPERIO.
In a thorough QTc clinical study in healthy male subjects, single doses of 400 mg and 1200 mg UPERIO had no effect on cardiac repolarization.
Neprilysin is one of multiple enzymes involved in the clearance of amyloid-beta (A-beta) from the brain and cerebrospinal fluid (CSF). Administration of UPERIO 400 mg once daily for 2 weeks to healthy subjects was associated with an increase in CSF A-beta 1-38 compared to placebo; there were no changes in concentrations of CSF A-beta 1-40 and 1-42. The clinical relevance of this finding is unknown (see Nonclinical studies as follows).
Clinical studies: Dosing in clinical trials was based on the total amount of both components of Uperio, i.e., 24/26 mg, 49/51 mg and 97/103 mg were referred to as 50 mg, 100 mg, and 200 mg, respectively.
PARADIGM-HF: PARADIGM-HF was a multinational, randomized, double-blind study of 8,442 patients comparing UPERIO to enalapril, both given to adult patients with chronic heart failure, NYHA class II-IV, and systolic dysfunction (left ventricular ejection fraction ≤ 40%), in addition to other heart failure therapy. The primary endpoint was the composite of cardiovascular (CV) death or hospitalization for heart failure (HF).
Prior to study participation, patients were well treated with standard of care therapy which included ACE inhibitors/ARBs (>99%), beta-blockers (94%), mineralocorticoid antagonists (58%), and diuretics (83%). The median follow- up duration was 27 months and patients were treated for up to 4.3 years.
Patients were required to discontinue their existing ACE inhibitor or ARB therapy and entered a sequential single-blind run-in period during which patients received treatment with enalapril 10 mg twice daily, followed by treatment with UPERIO 100 mg twice daily, increasing to 200 mg twice daily. Patients were then randomized to the double-blind period of the study to receive either UPERIO 200 mg or enalapril 10 mg twice daily [UPERIO (n= 4209); enalapril (n= 4233)].
The mean age of the population studied was 64 years of age and 19% were 75 years or older. At randomization, 70% of patients were NYHA Class II and 25% were Class III/IV.
In the UPERIO group, 76% of patients remained on the target dose of 200 mg twice daily at the end of the study (mean daily dose of 375 mg). In the enalapril group, 75% of patients remained on the target dose of 10 mg twice daily at the end of the study (mean daily dose of 18.9 mg).
UPERIO demonstrated clinically relevant and statistically significant superiority to enalapril, reducing the risk of cardiovascular death or heart failure hospitalizations by 20% (hazard ratio (HR): 0.80, 95% CI [0.73; 0.87], 1-sided p =0.0000002) versus enalapril. This effect was observed early and was sustained throughout the duration of the trial. The absolute risk reduction was 4.69%. A statistically significant reduction for CV death and first HF hospitalization was observed (CV death, RRR 20%, HR 0.80; 95% CI [0.71, 0.89], 1-sided p= 0.00004; and hospitalization for heart failure RRR 21%; HR 0.79; 95% CI 0.71, 0.89], 1-sided p= 0.00004); see Table1 and Figure 1. Sudden death accounted for 45% of cardiovascular deaths and was reduced by 20% in UPERIO treated patients compared to enalapril treated patients (HR 0.80, p= 0.0082).
Pump failure accounted for 26% of cardiovascular deaths and was reduced by 21% in UPERIO treated patients compared to enalapril treated patients (HR 0.79, p = 0.0338).
This risk reduction was consistently observed across subgroups including: age, gender, race, geography, NYHA class, ejection fraction, renal function, history of diabetes or hypertension, prior heart failure therapy, and atrial fibrillation.
UPERIO also significantly reduced all-cause mortality by 16% compared with enalapril (RRR 16%, HR 0.84; 95% CI [0.76 to 0.93], 1-sided p=0.0005) (Table 1). The absolute risk reduction was 2.84%. (See Table 1.)
Click on icon to see table/diagram/imageThe Kaplan-Meier presented in the figure as follows (left) shows time to first occurrence of the primary composite endpoint of CV death or heart failure hospitalization. UPERIO treatment effect was evident early and sustained for the duration of the study. The Kaplan-Meier figure presented as follows (right) shows the time to CV death endpoint. (See Figure).
Click on icon to see table/diagram/imageOverall, there were fewer all cause hospital admissions in patients treated with UPERIO compared to enalapril, including a 12% relative risk reduction for the first hospitalization (HR 0.88 [95% CI: 0.82, 0.94], P<0.001), and a 16% relative rate reduction for total number of hospitalizations (RR 0.84 [95% CI: 0.78, 0.91], P<0.001).
UPERIO demonstrated a significantly better clinical summary score for the domains related to HF symptoms and physical limitations as assessed by the Kansas City Cardiomyopathy Questionnaire (KCCQ), a self- administered questionnaire. More patients had improved NYHA functional class from baseline to Month 8 on UPERIO (16%) compared to enalapril (14%), and fewer patients had worsened NYHA functional class (10% vs 13%, respectively).
TITRATION: TITRATION was a 12 week safety and tolerability study in 538 patients with chronic heart failure (NYHA class II-IV) and systolic dysfunction (left ventricular ejection fraction ≤ 35%) naïve to ACE inhibitor or ARB therapy or on varying doses of ACE inhibitors or ARBs prior to study entry. Patients initiated UPERIO 50 mg twice daily, were uptitrated to 100 mg twice daily and then to the target dose of 200 mg twice daily with either a 3-week or 6-week regimen.
Overall, 76% of patients achieved and maintained the target dose of UPERIO 200 mg twice daily without any dose interruption or down-titration over 12-weeks. More patients who were naïve to previous ACE inhibitor or ARB therapy or on low dose therapy (equivalent to < 10 mg of enalapril/day) were able to achieve and maintain UPERIO 200 mg when uptitrated over 6 weeks versus 3 weeks.
Pharmacokinetics (PK): Absorption: Following oral administration, UPERIO dissociates into sacubitril, which is further metabolized to sacubitrilat, and valsartan, which reach peak plasma concentrations in 0.5 hours, 2 hours, and 1.5 hours, respectively. The oral absolute bioavailability of sacubitril and valsartan is estimated to be ≥ 60% and 23%, respectively. The valsartan in Uperio is more bioavailable than the valsartan in other marketed tablet formulations.
Following twice daily dosing of UPERIO, steady state levels of sacubitril, sacubitrilat, and valsartan are reached in 3 days. At steady state, sacubitril and valsartan do not accumulate significantly, while sacubitrilat accumulates by 1.6-fold. UPERIO administration with food has no clinically significant impact on the systemic exposures of sacubitril, sacubitrilat and valsartan. Although there is a decrease in exposure to valsartan when UPERIO is administered with food, this decrease is not accompanied by a clinically significant reduction in the therapeutic effect. UPERIO can therefore be administered with or without food.
Distribution: UPERIO is highly bound to plasma proteins (94%-97%). Based on the comparison of plasma and CSF exposures, sacubitrilat does cross the blood brain barrier to a limited extent (0.28%). UPERIO has an apparent volume of distribution ranging from 75 L to 103 L.
Biotransformation/metabolism: Sacubitril is readily converted to sacubitrilat by esterases; sacubitrilat is not further metabolized to a significant extent. Valsartan is minimally metabolized, as only about 20% of the dose is recovered as metabolites. A hydroxyl metabolite has been identified in plasma at low concentrations (<10%). Since CYP450 enzyme mediated metabolism of sacubitril and valsartan is minimal, co-administration with drugs that impact CYP450 enzymes is not expected to impact the pharmacokinetics.
Elimination: Following oral administration, 52-68% of sacubitril (primarily as sacubitrilat) and ~13% of valsartan and its metabolites are excreted in urine; 37-48% of sacubitril (primarily as sacubitrilat), and 86% of valsartan and its metabolites are excreted in feces.
Sacubitril, sacubitrilat, and valsartan are eliminated from plasma with a mean elimination half-life (T1/2) of approximately 1.43 hours, 11.48 hours, and 9.90 hours, respectively.
Linearity/non-linearity: The pharmacokinetics of sacubitril, sacubitrilat, and valsartan are linear in the dose range tested (50-400 mg of UPERIO).
Special populations: Elderly patients (aged over 65 years): The exposures of sacubitrilat and valsartan are increased in elderly subjects by 42% and 30%, respectively, compared to younger subjects. However, this is not associated with clinically relevant effects and therefore no dosage adjustment is necessary.
Pediatric patients (aged below 18 years): UPERIO has not been studied in pediatric patients.
Impaired renal function: A correlation was observed between renal function and systemic exposure to sacubitrilat in patients with mild (60 ml/min/1.73 m2 ≤ eGFR <90 ml/min/1.73 m2) to severe renal impairment. The exposure of sacubitrilat in patients with moderate (30 ml/min/1.73 m2 ≤ eGFR <60 ml/min/1.73 m2) and severe renal impairment (15 ml/min/1.73 m2 ≤ eGFR <30 ml/min/1.73 m2) was 1.4-fold and 2.2-fold higher compared to patients with mild renal impairment (60 ml/min/1.73 m2 ≤ eGFR <90 ml/min/1.73 m2), the largest group of patients enrolled in PARADIGM-HF). The exposure of valsartan was similar in patients with moderate and severe renal impairment compared to patients with mild renal impairment.
No studies have been performed in patients undergoing dialysis. However, sacubitrilat and valsartan are highly bound to plasma protein and therefore unlikely to be effectively removed by dialysis.
Impaired hepatic function: In patients with mild to moderate hepatic impairment, the exposures of sacubitril increased by 1.5- and 3.4- fold, sacubitrilat increased by 1.5- and 1.9-fold, and valsartan increased by 1.2-fold and 2.1-fold, respectively, compared to matching healthy subjects. However, in patients with mild to moderate hepatic impairment, the exposures of free concentrations of sacubitrilat increased by 1.47- and 3.08-fold, respectively, and the exposures of free concentrations of valsartan increased by 1.09-fold and 2.20-fold, respectively, compared to matching healthy subjects. UPERIO should be used with caution in patients with moderate hepatic impairment (Child-Pugh B classification) or with AST/ALT values more than twice the upper limit of the normal range and the recommended starting dose is 50 mg twice daily. UPERIO has not been studied in patients with severe hepatic impairment, biliary cirrhosis or cholestasis (see Contraindications and Precautions).
Ethnic groups: The pharmacokinetics of UPERIO (sacubitril, sacubitrilat and valsartan) are comparable across different race and ethnic groups (Caucasians, Blacks, Asians, Japanese and others).
Effect of gender: The pharmacokinetics of UPERIO (sacubitril, sacubitrilat and valsartan) are similar between male and female subjects.
Toxicology: Non-clinical safety data: Non-clinical safety studies conducted with UPERIO included assessment of safety pharmacology, repeated dose toxicity genotoxicity carcinogenicity and reproductive and development toxicity UPERIO had no adverse effects on vital organ systems. Most findings seen in repeated toxicity studies were reversible and attributable to the pharmacology of AT1 receptor blockade. Carcinogenicity, mutagenesis and genetic toxicity: Carcinogenicity studies conducted in mice and rats with sacubitril and valsartan did not identify any carcinogenic potential for UPERIO. The doses of sacubitril studied (high dose of 1200 and 400 mg/kg/day in mice and rats, respectively) were about 29 and 19 times, respectively, the maximum recommended human dose (MRHD) on a mg/m2 basis. The doses of valsartan studied (high dose of 160 and 200 mg/kg/day in mice and rats, respectively) were about 4 and 10 times, respectively, the maximum recommended human dose on a mg/m2 basis.
Mutagenicity and clastogenicity studies conducted with UPERIO, sacubitril, and valsartan did not reveal any effects at either the gene or chromosome level.
Fertility, reproduction and development: UPERIO did not show any effects on fertility or early embryonic development in rats up to a dose of 150 mg/kg/day (≤1.0 fold and ≤0.18 fold the MRHD on the basis of valsartan and sacubitrilat AUC, respectively).
UPERIO treatment during organogenesis resulted in increased embryo-fetal lethality in rats at doses ≥100 mg/kg/day [≤0.72 fold the MRHD on the basis of AUC] and rabbits at doses ≥10 mg/kg/day [2 fold and 0.03 fold the MRHD on the basis of valsartan and sacubitrilat AUC, respectively]. UPERIO is teratogenic based on a low incidence of fetal hydrocephaly, associated with maternally toxic doses, which was observed in rabbits at a UPERIO dose of ≥10 mg/kg/day. The adverse embryo-fetal effects of UPERIO are attributed to the angiotensin receptor antagonist activity (see Use in Pregnancy & Lactation).
Pre- and postnatal development studies in rats conducted with sacubitril at doses up to 750 mg/kg/day [2.2 fold the MRHD on the basis of AUC] and valsartan at doses up to 600 mg/kg/day [0.86 fold the MRHD on the basis of AUC] indicate that treatment with UPERIO during organogenesis, gestation and lactation may affect pup development and survival.
Other preclinical findings: UPERIO: The effects of UPERIO on amyloid-beta concentrations in CSF and brain tissue were assessed in young (2 to 4 years old) cynomolgus monkeys treated with UPERIO (50 mg/kg/day) for two weeks. In this study CSF A-beta clearance in cynomolgus monkeys was reduced, increasing CSF A-beta 1-40, 1-42, and 1-38 levels; there was no corresponding increase in A-beta levels in the brain. Increases in CSF A-beta 1-40 and 1-42 were not observed in a two-week healthy volunteer study in humans. Additionally, in a toxicology study in cynomolgus monkeys treated with UPERIO at 300 mg/kg/day for 39-weeks, there was no evidence for the presence of amyloid plaques in the brain. Amyloid content was not, however, measured quantitatively in this study.
Sacubitril: In juvenile rats treated with sacubitril (postnatal days 7 to 70), there was a reduction in age-related bone mass development and bone elongation. A study in adult rats showed only a minimal transient inhibitory effect on bone mineral density but not on any other parameters relevant for bone growth, suggesting no relevant effect of sacubitril on bone in adult patient populations under normal conditions. However, a mild transient interference of sacubitril with the early phase of fracture healing in adults cannot be excluded.
Valsartan: In juvenile rats treated with valsartan (postnatal days 7 to 70), doses as low as 1 mg/kg/day produced persistent irreversible kidney changes consisting of tubular nephropathy (sometimes accompanied by tubular epithelial necrosis) and pelvic dilatation. These kidney changes represent an expected exaggerated pharmacological effect of angiotensin converting enzyme inhibitors and angiotensin II type 1 blockers; such effects are observed if rats are treated during the first 13 days of life. This period coincides with 36 weeks of gestation in humans, which could occasionally extend up to 44 weeks after conception in humans.
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