Interim results of the first stage of a multicenter open multi-cohort study of the safety, pharmacokinetics, pharmacodynamics and efficacy of veranafusp alfa in adult patients with mucopolysaccharidosis type II

This article presents the interim results of the first stage (administration of the drug to patients aged ≥18 years with mucopolysaccharidosis type II) of a multicenter open multi-cohort phase II-III study (IDB-MPS-II-III), the aim of which was to assess the safety, pharmacokinetics (PK), pharmacodynamics (PD) and efficacy of veranafusp alfa in patients with MPS II. Material and methods. The interim analysis included data from 3 patients aged 18 years and older who had previously received idursulfase (2/3) and idursulfase beta (1/3). An individual dose increase (1–2–3 mg/kg) was performed after 2 weeks, followed by administration at a dose of 3 mg/kg for up to 52 weeks (a total of 52 weekly infusions). Standard PK parameters were evaluated. The PD criterion was the level of glycosaminoglycans (GAGs) in urine, blood and cerebrospinal fluid (CSF). Efficacy parameters included assessment of the dynamics of GAGs concentration in urine, blood and CSF, range of motion in joints, liver and spleen volume, change in the 6-minute walk test (6MWT, 6-minute test), left ventricular myocardial mass, forced vital capacity of the lungs (FVC). Safety parameters included assessment of the frequency of adverse events (AEs) and adverse reactions (ARs), including allergic and infusion reactions, as well as assessment of the frequency of formation of anti-drug antibodies (ADAs) and their neutralizing activity. Results. The studied drug demonstrated non-linear PK in the blood and a dose-dependent increase in concentration in the CSF. Patients showed a decrease or stability in the level of GAG in the urine, a decrease in the level of heparan sulfate (HS) in the CSF in 2 (66.6%) of 3 patients, as well as a decrease in the level of dermatan sulfate (DS) in the CSF in the range of 17.19–80.96%. There was an average decrease in liver volume by 42.500 ± 218.496 cm 3 , spleen volume by 24.350 ± 9.405 cm 3 and left ventricular myocardial mass by 15.333 ± 43.016 g relative to the baseline level. The average increase in walking distance according to the results of the 6MWT, after 1 year of therapy, was 76.067 ± 83.561 m. The average values of FVC and FEV1 did not change statistically significantly. 9 AEs were registered in 3 patients (100.0%) of mild severity, mainly from the liver and biliary tract, and 3 ARs, which were infusion reactions and were registered mainly in the first 4 months of therapy. During the analyzed period, the frequency of formation of ADAs at screening was in 2 patients, and at week 52 — in 3 patients, which indicates the development of de novo ADAs during treatment with veranafusp alfa in 1 patient. Conclusion. Weekly intravenous administration of the drug under study to adult patients at a dose of 3 mg/kg for 1 year provided control of the level of GAG in the urine and stabilization and/or improvement of somatic symptoms according to spirometry, echocardiography, 6MWT, range of motion in large joints, liver and spleen size, comparable to the results of the effectiveness of treatment with idursulfase in patients previously receiving enzyme replacement therapy. There was a tendency to decrease the level of HS in the cerebrospinal fluid, which may indicate the ability of veranafusp alfa to penetrate the BBB and deliver idursulfase to brain tissue, preventing the accumulation of pathological substrate in the CNS to prevent neurodegenerative changes.