Source: FDA, National Drug Code (US) Revision Year: 2026
Hunter syndrome is an inherited X-linked recessive lysosomal storage disease caused by a deficiency of iduronate-2-sulfatase (IDS), a lysosomal enzyme, that degrades heparan sulfate (HS) and dermatan sulfate (DS), the two primary glycosominoglycans (GAGs) in the lysosome. Insufficiency or absence of IDS leads to accumulation of GAGs, including HS and DS, and subsequent lysosome dysfunction in multiple organs and tissues, including the central nervous system (CNS).
Tividenofusp alfa-eknm provides an exogenous source of IDS. The fragment, crystallizable (Fc) component of tividenofusp alfa-eknm binds to the apical domain of the transferrin receptor (TfR) and delivers IDS to peripheral tissues and to the CNS through receptor-mediated transcytosis across the blood-brain barrier. Tividenofusp alfa-eknm is internalized via binding to the mannose-6-phosphate receptor on the cell surface and transported into lysosomes where it is thought to exert enzymatic activity and reduce accumulated GAGs. In addition, since TfR is ubiquitously expressed, it is expected that the interaction of tividenofusp alfa-eknm and TfR will contribute to its uptake into cells in the brain and peripheral tissues.
In clinical studies with AVLAYAH, the relative concentrations of HS or DS in human cerebrospinal fluid (CSF) and urine were estimated based on an assessment of selected disaccharides following enzymatic digestion of HS or DS. It is not possible to directly quantify intact HS or DS concentrations in human CSF or urine using currently available bioanalytical methods. Differences in bioanalytical methods preclude meaningful comparison of the pharmacodynamic results based on HS or DS concentrations in clinical studies with AVLAYAH with the results in other clinical studies.
In Trial 1, reductions in CSF HS from baseline were observed in AVLAYAH-treated pediatric patients with Hunter syndrome [see Clinical Studies (14)]. Reductions in urine HS (86%), urine DS (91%), and total urine GAGs (57%) from baseline were observed at Week 24 in AVLAYAH-treated pediatric patients with Hunter syndrome. At baseline, 2 of 47 (4%) patients had total urine GAG levels below the upper limit of normal (ULN). At Week 24, 26 of 38 (68%) patients had total urine GAG levels below the ULN. The relationship between changes in CSF HS, urine HS, urine DS, and total urine GAG levels to clinical response in patients with Hunter syndrome has not been established.
In Trial 1, higher serum tividenofusp alfa-eknm concentrations appeared to be associated with greater reductions of CSF HS and urine HS concentrations from baseline, with maximum effect achieved at 15 mg/kg of AVLAYAH once weekly (the recommended maintenance dosage).
The time to maximum effect on pharmacodynamic response and the exposure-response relationship for the safety and effectiveness of tividenofusp alfa-eknm have not been fully characterized.
The pharmacokinetics of tividenofusp alfa-eknm were evaluated in pediatric patients with Hunter syndrome aged 3 months to 13 years (age at baseline).
The maximum serum concentration (Cmax) increased proportionally with dose, while the area under the serum concentration-time curve (AUCtau) increased in a greater-than-dose-proportional manner across the dose range of 3 mg/kg to 30 mg/kg (0.2 to 2 times the approved recommended maintenance dosage). Table 5 shows the Cmax and AUCtau of tividenofusp alfa-eknm following the recommended starting dosage and recommended maintenance dosage [see Dosage and Administration (2.2)].
Table 5. Cmax and AUCtau of Tividenofusp Alfa-eknm in Pediatric Patients With Hunter Syndrome:
| Pharmacokinetic Parameter | Week 1 (3 mg/kg weekly) | Week 24 (15 mg/kg weekly) |
| Geometric Mean (Range) | Geometric Mean (Range) | |
| Cmax (mcg/mL) | 33.1 (19.9 – 50.3) | 204 (19.5 – 615) |
| AUCtau (h∙mcg/mL) | 277 (82.4 – 446) | 3,000 (839 – 12,100) |
Abbreviations: AUCtau = area under the serum concentration-time curve from 0 to 168 hours after the start of infusion; Cmax = maximum serum concentration.
The geometric mean (range) volume of distribution of tividenofusp alfa-eknm was 2.7 (1.4 to 9.6) L.
Tividenofusp alfa-eknm is cleared via linear and nonlinear mechanisms and the total clearance was increased in the presence of anti-tividenofusp alfa-eknm antibodies [see Clinical Pharmacology (12.6)]. The geometric mean (range) total clearance of tividenofusp alfa-eknm was 0.14 (0.05 to 0.45) L/h following 15 mg/kg weekly dosing of AVLAYAH at Week 24.
Patients are predicted to have a 97% reduction from Cmax in tividenofusp alfa-eknm concentrations at a median time of 40 hours (5th to 95th percentile: 18.6 to 74.1 hours) after the end of the first 3 mg/kg AVLAYAH infusion at Week 1 and 41 hours (5th to 95th percentile: 23.3 to 100 hours) after the end of the first 15 mg/kg AVLAYAH infusion at Week 9.
Tividenofusp alfa-eknm is expected to be metabolized into small peptides via catabolic pathways.
Following the approved recommended weight-based dosage, no clinically significant differences in tividenofusp alfa-eknm serum Cmax or AUCtau were observed based on age (3 months to 16 years) or body weight (7 kg to 80 kg).
Animal studies to evaluate the carcinogenic potential of tividenofusp alfa-eknm have not been conducted.
Studies to evaluate the mutagenic potential of tividenofusp alfa-eknm have not been conducted.
In a fertility and embryonic development study in transgenic mice, twice weekly intravenous tividenofusp alfa-eknm doses were administered to females for two weeks prior to mating and through day 4 of gestation, and to males two weeks prior to mating. No adverse effects on fertility parameters were observed in either female or male transgenic mice at exposures approximately 12-fold greater than those observed in patients at the maintenance dosage level of 15 mg/kg (based on AUC).
Trial 1 (NCT04251026) was a Phase ½ multi-center, international, multi-cohort, single-arm, open-label trial of AVLAYAH in 47 pediatric patients with Hunter syndrome including 44 patients with neuronopathic Hunter syndrome and 3 patients with non-neuronopathic Hunter syndrome. Of the 47 patients enrolled, 46 patients completed part 1 of the study (up to Week 24) and 1 patient discontinued the study due to an adverse reaction prior to Week 24. In part 1 of Trial 1, patients received a starting dosage of AVLAYAH ranging from 3 mg/kg to 15 mg/kg weekly and a maximum dosage ranging from 3 mg/kg to 30 mg/kg weekly (0.2 to 2 times the approved recommended maintenance dosage) [see Dosage and Administration (2.2)]. Patients who received 30 mg/kg weekly dosage (2 times the approved recommended maintenance dosage) did not show additional reductions from baseline in cerebrospinal fluid (CSF) or urine heparan sulfate (HS) concentration compared to patients who received 15 mg/kg weekly [see Clinical Pharmacology (12.2)]. The most common AVLAYAH dosage (57% of the patients) in Trial 1 was 15 mg/kg administered once weekly.
All 47 patients in Trial 1 were male, with a baseline median age of 5 years (range: 3 months to 13 years of age). The patient population consisted of 27 White (57%), 4 Black or African American (9%), 4 Asian (9%), 3 who were more than one race (6%), 1 of another race (2%), and 8 of an unknown race (17%). Ethnicity consisted of 7 patients who were Hispanic or Latino (15%), 38 who were Not Hispanic or Latino (81%), and 2 of an unknown ethnicity (4%). Of the 47 patients, 15 patients were enzyme replacement therapy (ERT)-naïve, and 32 patients were ERT-experienced, 2 of whom had a history of prior treatment for Hunter syndrome with hematopoietic stem cell transplantation (HSCT), and 2 of whom had a history of prior treatment for Hunter syndrome with gene therapy. The median duration of previous ERT treatment was 26 months (range: 1 to 134 months).
In Trial 1, treatment with AVLAYAH resulted in a significant reduction of CSF HS. For the 44 patients who had measurements at Week 24, the CSF HS mean percent reduction from baseline was 91% (95% CI: 89%, 92%); the minimum and maximum percent change in CSF HS from baseline were 72% and 98%, respectively. At baseline, 0% (0 of 47) of patients had CSF HS levels below the upper limit of normal (ULN). At Week 24, 93% (41 of 44) of AVLAYAH-treated patients had CSF HS levels below the ULN.
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