Safety, immunogenicity, and clinical outcomes in patients with Morquio A syndrome participating in 2 sequential open-label studies of elosulfase alfa enzyme replacement therapy (MOR-002/MOR-100), representing 5 years of treatment

Elosulfase alfa is an enzyme replacement therapy for Morquio A syndrome (mucopolysaccharidosis IVA), a multisystemic progressive lysosomal storage disorder. This report includes the primary treatment outcomes and immunogenicity profile of elosulfase alfa in patients with Morquio A syndrome from 2 sequential studies, MOR-002 (ClinicalTrials.govNCT00884949) and MOR-100 (NCT01242111), representing >5 years of clinical study data. MOR-002 was an open-label, single-arm phase 1/2 study that evaluated the pharmacokinetics, safety, immunogenicity, and preliminary efficacy of 3 sequential doses of elosulfase alfa (0.1, 1.0, and 2.0 mg/kg/week) in patients with Morquio A syndrome (n = 20) over 36 weeks, followed by an optional 36- to 48-week treatment period using elosulfase alfa 1.0 mg/kg once weekly (qw). During the 0.1 mg/kg dosing phase, 1 patient discontinued due to a type I hypersensitivity adverse event (AE), and that patient's sibling voluntarily discontinued in the absence of AEs. An additional patient discontinued due to recurrent infusion reactions during the 1.0 mg/kg continuation phase. The remaining 17 patients completed MOR-002 and enrolled in MOR-100, an open-label, long-term extension study that further evaluated safety and clinical outcomes with elosulfase alfa administered at 2.0 mg/kg qw. During the course of MOR-100, patients were given the option of receiving elosulfase alfa infusions at home with nursing assistance. Over the course of both studies, all patients experienced ≥1 AE and most patients experienced a drug-related AE, generally of mild or moderate severity. Hypersensitivity reactions reported as related to study drug occurred in 25% of patients. Thirteen patients who chose to receive infusions at home had the same tolerability and safety profile, as well as comparable compliance rates, as patients who chose to receive on-site infusions. All patients developed antibodies to elosulfase alfa. Positivity for neutralizing antibodies was associated with increased drug half-life and decreased drug clearance. Despite formation of antidrug-binding (total antidrug antibodies, TAb) and in vitro neutralizing antibodies (NAb) in all patients, these types of immunogenicity to elosulfase alfa were not correlated with safety or clinical outcomes. In contrast with the reported natural history of Morquio A, no trends toward decreasing endurance, respiratory function, or ability to perform activities of daily living were observed in this cohort over the 5-year period.Supplementary Fig. 1. Mean 6-min walk test distance versus age in Morquio A Clinical Assessment Program subjects aged ≤20 years. Reproduced with permission from P.R. Harmatz, K.E. Mengel, R. Giugliani, V. Valayannopoulos, S.P. Lin, R. Parini, N. Guffon, B.K. Burton, C.J. Hendriksz, J.J. Mitchell, A.M. Martins, S.A. Jones, N. Guelbert, A. Vellodi, F.A. Wijburg, K. Yang, P. Slasor, C. Decker. Longitudinal analysis of endurance and respiratory function from a natural history study of Morquio A syndrome, Mol. Genet. Metab. 114 (2015) 186–194. http://dx.doi.org/10.1016/j.ymgme.2014.10.015. MorCAP, Morquio A Clinical Assessment Program.Supplementary Fig. 2. Log10 mean TAb titer by study week in MOR-002 and MOR-100.Supplementary Fig. 3. (A) uKS versus TAb titer; (B) uKS versus NAb positivity; (C) 6MWT versus TAb titer; (D) 6MWT versus NAb positivity (E) 3MSCT versus TAb titer; (F) 3MSCT versus Nab positivity.Supplementary Table 1. Study drug-related adverse events and serious adverse events in MOR-002 and MOR-100.Supplementary Table 2. Hypersensitivity AEs in MOR-002 and MOR-100 using MedDRA SMQs.Supplementary Table 3. Patients who developed elosulfase alfa TAb, NAb, and IgE during MOR-002 and MOR-100.Supplementary Table 4. Mean TAb titer and NAb responses by hypersensitivity AE severity in IgE-negative patients (safety population).Supplementary Table 5. Incidence of hypersensitivity AEs in IgE-negative patients (safety population) by TAb response group using MedDRA SMQs by preferred term.BioMarin Pharmaceutical Inc.http://www.elsevier.com/locate/ymgmePaediatrics and Child Healt

Anti-CS1 humanized monoclonal antibody HuLuc63 inhibits myeloma cell adhesion and induces antibody-dependent cellular cytotoxicity in the bone marrow milieu

Currently, no approved monoclonal antibody (mAb) therapies exist for human multiple myeloma (MM). Here we characterized cell surface CS1 as a novel MM antigen and further investigated the potential therapeutic utility of HuLuc63, a humanized anti-CS1 mAb, for treating human MM. CS1 mRNA and protein was highly expressed in CD138-purified primary tumor cells from the majority of MM patients (more than 97%) with low levels of circulating CS1 detectable in MM patient sera, but not in healthy donors. CS1 was expressed at adhesion-promoting uropod membranes of polarized MM cells, and short interfering RNA (siRNA) targeted to CS1 inhibited MM cell adhesion to bone marrow stromal cells (BMSCs). HuLuc63 inhibited MM cell binding to BMSCs and induced antibody-dependent cellular cytotoxicity (ADCC) against MM cells in dose-dependent and CS1-specific manners. HuLuc63 triggered autologous ADCC against primary MM cells resistant to conventional or novel therapies, including bortezomib and HSP90 inhibitor; and pretreatment with conventional or novel anti-MM drugs markedly enhanced HuLuc63-induced MM cell lysis. Administration of HuLuc63 significantly induces tumor regression in multiple xenograft models of human MM. These results thus define the functional significance of CS1 in MM and provide the preclinical rationale for testing HuLuc63 in clinical trials, either alone or in combination