YUVIWEL Powder for solution for injection Ref.[116347] Active ingredients:

Natriuretic Peptide Receptor B (NPR-B) Activity Marker

There was a dose-dependent (0.006 mg/kg/week to 0.1 mg/kg/week) increase in plasma cGMP levels in pediatric patients with achondroplasia following 52 weeks of once-weekly administration of navepegritide.

Cardiac Electrophysiology

At the approved recommended dose, YUVIWEL does not prolong the QT interval to any clinically relevant extent.

The pharmacokinetics of navepegritide, a prodrug releasing CNP following subcutaneous administration, have been investigated at single doses of 0.003 to 0.15 mg/kg in healthy adults, and at weekly doses of 0.006 to 0.1 mg/kg in patients with achondroplasia. Plasma concentrations of navepegritide and CNP released from navepegritide increased proportionally with dose within the range of 0.01 to 0.15 mg/kg.

In patients with achondroplasia administered navepegritide 0.1 mg/kg once-weekly, the predicted steady state geometric mean (CV) maximum plasma concentration (C_max) of navepegritide was 1,360 ng/mL (8.3%) and the predicted geometric mean (CV) exposure over the weekly dosing interval AUC was 193,000 h*ng/mL (6.1%). For CNP released from navepegritide, the predicted geometric mean (CV) C_max was 36.0 pmol/L (23%) and the predicted geometric mean (CV) AUC over the weekly dosing interval was 4,410 h*pmol/L (23%).

In patients with achondroplasia, steady state levels of navepegritide and CNP released from navepegritide were achieved after approximately 3 once-weekly doses. Median accumulation ratios of navepegritide and CNP released from navepegritide following once-weekly dose administration were 1.9 and 1.7, respectively.

Absorption

In patients with achondroplasia administered navepegritide 0.1 mg/kg once-weekly, the geometric mean (CV) time to reach maximum concentration (T_max) of navepegritide was 43.4 hours (15%). For CNP released from navepegritide, the geometric mean (CV) T_max was 24.4 hours (13%).

The absolute bioavailability of navepegritide following subcutaneous dose administration has not been investigated.

Distribution

The model-derived geometric mean (CV) apparent volume of distribution of navepegritide and CNP released from navepegritide was 1.8 (33%) L and 5.1 (30%) L, respectively.

Elimination

The model-derived geometric mean (CV) steady state apparent clearance of navepegritide and CNP released from navepegritide was 0.052 (33%) and 1,950 (39%) L/day, respectively.

In patients with achondroplasia administered navepegritide 0.1 mg/kg once weekly, the predicted mean apparent elimination half-life of navepegritide was 6.7 days, and the mean apparent elimination half-life of CNP released from navepegritide was 5.3 days.

Metabolism

Following subcutaneous dose administration, navepegritide releases CNP via auto-cleavage of the TransCon Linker that follows first-order kinetics, resulting in continuous systemic exposure of CNP over the weekly dosing interval.

CNP metabolism follows natural degradation pathways for peptides, resulting in small peptide fragments and amino acids.

Specific Populations

Based on a population pharmacokinetic analysis, no clinically meaningful effects on the pharmacokinetics of navepegritide were observed for age (2 to 59.6 years), sex (66% male, 34% female), race (21% Asian, 1.8% Black or African American, 75% White, and 1.8% Other), ethnicity (11% Hispanic or Latino, 87% not Hispanic or Latino, 1% not reported or unknown) and mild (eGFR: 60 to <89 mL/min/1.73 m²) renal impairment. The effect of hepatic impairment on the pharmacokinetics of navepegritide was not studied.

Drug Interaction Studies

No in vitro assessments or clinical studies evaluating the drug-drug interaction potential of navepegritide have been conducted.

Carcinogenesis and Mutagenesis

Long-term animal studies to address the carcinogenic potential of navepegritide have not been conducted.

Navepegritide was not genotoxic in an in vitro bacterial reverse-mutation assay (Ames test), an in vitro human lymphocyte chromosomal aberration assay or an in vivo rat bone marrow micronucleus assay.

Impairment of Fertility

In fertility studies, navepegritide was administered by subcutaneous injection at 0.5, 1.0, and 2.0 mg/kg/week to male and female rats. Navepegritide had no effect on mating performance, fertility, litter characteristics or early embryo-fetal development up to the highest dose tested corresponding to 3-fold the MRHD in male rats (based on body surface area) and 4-fold exposure in female rats (based on AUC).

The effectiveness of YUVIWEL has been established in a clinical trial of navepegritide consisting of a randomized, double-blind, placebo-controlled 52-week period, followed by a single-arm 52-week OLE period (Trial 1; NCT05598320).

Trial 1 enrolled 84 treatment-naïve pediatric patients with genetically confirmed achondroplasia: 57 patients received navepegritide 0.1 mg/kg administered subcutaneously once weekly, and 27 received placebo.

The mean age at enrollment was 5.7 years (range: 2 to 12). Forty-five patients (54%) were male, and 39 patients (46%) were female. Overall, 74 patients (88%) were White, 8 patients (10%) were Asian, and 2 patients (2%) were mixed race. The patients had a mean baseline CDC-based height Z-score of -5.0 and mean baseline height of 89 cm (range: 64 to 120).

The primary efficacy endpoint was annualized growth velocity (AGV) at Week 52. Height Z-scores calculated using reference data from untreated children with achondroplasia (achondroplasia-specific height Z-score) and using reference data from the general population (CDC-based height Z-score) were also evaluated.

Treatment with once-weekly navepegritide for 52 weeks resulted in a least-squares mean treatment difference in AGV of 1.5 cm/year and a least-squares mean increase from baseline in achondroplasia-specific height Z-score of 0.3 (see Table 4).

Table 4. Growth Parameters in Pediatric Patients with Achondroplasia Treated with Navepegritide and Placebo at Week 52 in Trial 1:

Note: Data presented are least-square (LS) means unless otherwise noted.
Abbreviations: AGV, annualized growth velocity; CI, confidence interval; NA, not applicable.
^a Treatment differences between YUVIWEL and placebo were estimated from an analysis of covariance (ANCOVA) model that included treatment, strata (defined by sex and age), baseline age, and baseline achondroplasia-specific height Z-score as covariates.
^b Calculated using the reference data from untreated patients with achondroplasia (CLARITY Natural History Study).
^c Calculated using the Centers for Disease Control and Prevention (CDC) reference data from the general population.
^d The endpoint was analyzed outside of the pre-specified multiple testing strategy.

Improvements in AGV and height Z-scores were observed in navepegritide-treated patients across all predefined subgroups analyzed, including age group, sex, and region. In patients <5 years of age, the least- squares mean treatment difference for AGV at Week 52 was 1.0 cm/year. In patients ≥5 years of age, the least- squares mean treatment difference was 1.8 cm/year.

Long-term Treatment Effect

All 57 patients in a 52-week randomized, double-blind, placebo-controlled Phase 2 dose-finding trial (Trial 2; NCT04085523) entered the single-arm OLE and continued treatment with navepegritide. AGV was maintained among those who had received 2 years of treatment with navepegritide 0.1 mg/kg once weekly.