Neurocognitive and somatic stabilization in pediatric patients with severe Mucopolysaccharidosis Type I after 52 weeks of intravenous brain-penetrating insulin receptor antibody-iduronidase fusion protein (valanafusp alpha): an open label phase 1-2 trial

Abstract

Age (y) ID (mg/kg) Genotype Allele 1 Allele 2 202 H 0.7 8 101 19.6 9.0 1 p.W402X p.W402X 203 H-S 4.9 1.7 104 19.1 6.1 3 p.R621X het IVS9-12-4delCAGGCCCCG 204 H-S 5.0 9 144 37.1 14.8 1 p.R48del p.P533R 205 H 1.1 1.5 112 24.7 5.0 1 c.494-1G>A c.494-1G>A 206a H 1.8 1 81 11.6 3.1 1 p.W402X p.W402X 207 H 2.6 3 95 18.8 5.9 3 p.Q70X p.W402X 211 H 2.4 0 78 11.4 2∙5 3 p.G208D p.G208D 213 H-S 3.7 12 143 38.5 15.7 3 p.R383H p.W402X 214 H 1.8 0 85 13.0 2.0 3 p.W402Term p.W402Term 215 H 3.6 5.6 137 39.6 12.1 6 p.P533R p.G208D 216 H 0.7 5.6 118 26.4 7.8 6 p.G208D p.P533R apatient had failed bone marrow transplant 8 months prior to enrollment The study drug, valanafusp alpha, also called AGT-181 [9], had an IDUA enzyme specific activity of 1390-1668 units/ug protein, where 1 unit = 1 nmol/hr, and bound with high affinity to the recombinant HIR extracellular domain with an ED50 of 0.18-0.36 nM. Table 7 Change from baseline in total grey matter volume at week 52 patient age Total grey matter volume (mm3) BL 26 wk 52 wk 52wk-BL 202 9.0 797,018 792,018 788,648 -8,370 203 6.1 747,735 768,848 nd +21,113a 204 14.8 517,491 604,125 616,132 +98,641b 205 5.0 710,691 759,444 749,177 +38,486 206 3.1 621,494 673,817 703,973 +82,478 207 5.9 607,678 590,810 598,460 -9,218 211 2.5 589,439 npc npc 213 15.7 874,710 885,006 863,862 -10,848 214 2.0 744,555 764,571 780,779 +36,224 215 12.1 668,638 663,441 676,069 +7,431 216 7.8 739,492 708,228 717,836 -21,656 mean 692,631 +15,071 SEM 34,396 11,052 BL baseline, nd volumetrics analysis could not be performed a52-week volumetrics not available; difference computed from 26-week volume bPatient with braces; volumes not used to compute mean difference at 52 weeks cnp=not performed; volumetric analysis could not be completed Figure 2 Fig. 2 Concentration of heparan sulfate (HS, panel a) and dermatan sulfate (DS, panel b) in CSF of Stage 2 patients at baseline and at 26 weeks (wks) of treatment in comparison to HS and DS levels in CSF of 10 non-MPSI human pediatric subjects. [...]chronic weekly IV infusions of valanafusp alpha stabilize CNS function in severe forms of MPSI as judged by cognitive testing (Tables 4, 5 and 6), and total grey matter volume (Table 7). [...]valanafusp alpha also stabilizes signs of somatic function as shown by further reductions in liver and spleen volume (Table 8), further improvement in shoulder range of motion (Results), and stabilized urinary GAG levels (Fig. 3).