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 provides an exogenous source of IDS. The fragment, crystallizable (Fc) component of tividenofusp alfa 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 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 and TfR will contribute to its uptake into cells in the brain and peripheral tissues.
In clinical studies with tividenofusp alfa, 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 tividenofusp alfa with the results in other clinical studies.
In Trial 1, reductions in CSF HS from baseline were observed in tividenofusp alfa-treated pediatric patients with Hunter syndrome. Reductions in urine HS (86%), urine DS (91%), and total urine GAGs (57%) from baseline were observed at Week 24 in tividenofusp alfa-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 tividenofusp alfa 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 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). The following table shows the Cmax and AUCtau of tividenofusp alfa following the recommended starting dosage and recommended maintenance dosage.
Cmax and AUCtau of Tividenofusp Alfa 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 was 2.7 (1.4 to 9.6) L.
Tividenofusp alfa is cleared via linear and nonlinear mechanisms and the total clearance was increased in the presence of anti-tividenofusp alfa antibodies [see Clinical Pharmacology (12.6)]. The geometric mean (range) total clearance of tividenofusp alfa was 0.14 (0.05 to 0.45) L/h following 15 mg/kg weekly dosing of tividenofusp alfa at Week 24.
Patients are predicted to have a 97% reduction from Cmax in tividenofusp alfa 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 tividenofusp alfa 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 tividenofusp alfa infusion at Week 9.
Tividenofusp alfa 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 serum Cmax or AUCtau were observed based on age (3 months to 16 years) or body weight (7 kg to 80 kg).
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