Phase 1 Renal Impairment Trial Results Supports Targeted Individualized Dosing of ELX-02 in Patients With Nephropathic Cystinosis.

The aim of this study was to assess the pharmacokinetics (PK) and safety of ELX-02 in a renally impaired population and apply these findings to the individualized dosing of patients with nephropathic cystinosis. This phase 1 renal impairment (RI; mild, moderate, or severe), single-dose, PK, and safety evaluation included 6 participants assigned to each RI group. Six healthy controls with normal renal function were matched to participants with renal impairment. All received a single subcutaneous dose of 1-mg/kg ELX-02 on day 1 and were monitored for 72 hours after dosing with serial blood and urine samples. An estimated glomerular filtration rate (eGFR)-PK model of ELX-02 was developed from the RI study data and used to implement individualized dosing in a phase 2a study in patients with nephropathic cystinosis to achieve a weekly targeted exposure (area under the plasma concentration-time curve [AUC]). In participants with RI, ELX-02 clearance decreased, and exposure increased with severity of RI. ELX-02 plasma exposure was similar to healthy controls in participants with mild RI, but increasing severity of RI resulted in significantly decreased clearance, increased maximum plasma concentration, AUC from time zero to infinity, and half-life compared to controls. ELX-02 urinary clearance showed a similar pattern. Relationships between eGFR and exposure were defined supporting individualized dose determination for prediction of dose and AUC in patients with nephropathic cystinosis, achieving overall mean 110.7% of AUC targets. ELX-02 was well tolerated by RI and nephropathic cystinosis populations. ELX-02 exhibits a consistent PK profile across increasing degrees of RI with reduced clearance, increased exposure, and prolonged renal elimination proportional to reductions in eGFR. The defined relationship between eGFR and plasma exposure enabled individualized dose adjustment in patients with nephropathic cystinosis.

Rebound eosinophilia after treatment of hypereosinophilic syndrome and eosinophilic gastroenteritis with monoclonal anti-IL-5 antibody SCH55700.

BACKGROUND: Hypereosinophilic syndrome and eosinophilic gastroenteritis with peripheral eosinophilia are characterized by sustained eosinophilia and eosinophil-mediated tissue damage. Although treatment with the humanized monoclonal anti-IL-5 antibody SCH55700 resulted in improvement of eosinophilia and clinical symptoms in 6 of 8 of patients with hypereosinophilic syndrome or eosinophilic gastroenteritis with peripheral eosinophilia for as long as 12 weeks, eosinophil counts subsequently rose above baseline levels, accompanied by an exacerbation of symptoms. OBJECTIVE: To identify the mechanism underlying this rebound eosinophilia. METHODS: Purified eosinophils from patients or normal donors were cultured with IL-5, patient serum, and/or anticytokine antibodies, and eosinophil survival was assessed by flow cytometry. Serum and intracellular cytokine levels were measured by multiplex sandwich ELISA and flow cytometry, respectively. RESULTS: Before treatment with SCH55700, in vitro eosinophil survival in media and in response to recombinant IL-5 was similar in patients and normal donors. At 1 month posttreatment, the eosinophil survival curves were unchanged in 4 of 5 patients in media and in all 5 patients in response to recombinant IL-5. Normal eosinophil survival was prolonged in cultures containing posttreatment but not pretreatment sera (pretreatment vs posttreatment, 10.74% vs 73.02% live cells; P = .01). This posttreatment serum effect on eosinophil survival was reversed by the addition of the monoclonal anti-IL-5 antibody TRFK5. Although increased levels of serum IL-5 were observed at 1 month compared with 2 to 3 days posttreatment in 5 of 6 patients ( P = .04), intracellular cytokine analysis did not reveal increased production of IL-5 by peripheral blood mononuclear cells. CONCLUSIONS: The rebound eosinophilia after SCH55700 treatment is a result of a serum factor that enhances eosinophil survival. Reversal of this effect by the addition of antibody to IL-5 suggests that this factor may be IL-5 itself.

Safety and efficacy of the monoclonal anti-interleukin-5 antibody SCH55700 in the treatment of patients with hypereosinophilic syndrome.

Four patients with hypereosinophilic syndrome (HES) refractory to or intolerant of treatment with conventional therapy were treated with a single 1 mg/kg dose of SCH55700. SCH55700 was extremely well tolerated. Two of the 4 patients responded with a fall in eosinophil counts to within the normal range within 48 hours of receiving the drug, accompanied by marked improvement in clinical signs and symptoms. Response was not predicted by serum interleukin-5 (IL-5) levels or presence of the FIP1L1/PDGFRA mutation. Eosinophil counts remained suppressed for up to 12 weeks after treatment; however, exacerbation of symptoms and eosinophilia above baseline levels occurred as drug levels waned. Reinstitution of treatment with monthly SCH55700 led to decreased eosinophilia and symptomatic improvement, albeit to a lesser degree than that seen after the initial dose. These data suggest that anti-IL-5 therapy may be useful in the treatment of HES irrespective of the underlying etiology, although the observed rebound eosinophilia and attenuation of response require further study.