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Dose-escalation of human anti-interferon-? receptor monoclonal antibody MEDI-546 in subjects with systemic sclerosis: a phase 1, multicenter, open label study.

ABSTRACT: Type I interferons (IFNs) are implicated in the pathogenesis of systemic sclerosis (SSc). MEDI-546 is an investigational human monoclonal antibody directed against the type I IFN receptor. This Phase 1 study evaluated the safety/tolerability, pharmacokinetics (PK), immunogenicity, and pharmacodynamics (PD) of single and multiple intravenous doses of MEDI-546 in adults with SSc.Subjects (?18 years) with SSc were enrolled in an open-label, dose-escalation study to receive single (0.1, 0.3, 1.0, 3.0, 10.0, or 20.0 mg/kg), or 4 weekly intravenous doses (0.3, 1.0, or 5.0 mg/kg/week) of MEDI-546. Subjects were followed for 12 weeks. Safety assessments included adverse events (AEs), laboratory results, and viral monitoring. Blood samples were collected from all subjects for determination of PK, presence of anti-drug antibodies (ADAs), and expression of type I IFN-inducible genes.Of 34 subjects (mean age 47.4 years), 32 completed treatment and 33 completed the study. Overall, 148 treatment-emergent AEs (TEAEs) were reported (68.9% mild, 27.7% moderate). TEAEs included one grade 1 infusion reaction (5.0 mg/kg/week multiple dose). Of 4 treatment-emergent serious AEs (skin ulcer, osteomyelitis, vertigo, and chronic myelogenous leukemia (CML)), only CML (1.0 mg/kg/week multiple dose) was considered possibly treatment-related. MEDI-546 exhibited non-linear PK at lower doses. ADAs were detected in 5 subjects; no apparent impact on PK was observed. Peak inhibition of the type I IFN signature in whole blood was achieved within 1 day and in skin after 7 days.The safety/tolerability, PK, and PD profiles observed in this study support further clinical development of MEDI-546.ClinicalTrials.gov NCT00930683.

SUBMITTER: Goldberg A

PROVIDER: S-EPMC3978926 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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Dose-escalation of human anti-interferon-α receptor monoclonal antibody MEDI-546 in subjects with systemic sclerosis: a phase 1, multicenter, open label study.

Goldberg Avram A Geppert Thomas T Schiopu Elena E Frech Tracy T Hsu Vivien V Simms Robert W RW Peng Stanford L SL Yao Yihong Y Elgeioushi Nairouz N Chang Linda L Wang Bing B Yoo Stephen S

Arthritis research & therapy 20140224 1

<h4>Introduction</h4>Type I interferons (IFNs) are implicated in the pathogenesis of systemic sclerosis (SSc). MEDI-546 is an investigational human monoclonal antibody directed against the type I IFN receptor. This Phase 1 study evaluated the safety/tolerability, pharmacokinetics (PK), immunogenicity, and pharmacodynamics (PD) of single and multiple intravenous doses of MEDI-546 in adults with SSc.<h4>Methods</h4>Subjects (≥18 years) with SSc were enrolled in an open-label, dose-escalation study ...[more]

PMID: 24559157

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Project description:ObjectiveThe objective of this study was to assess the effect of treatment with interferon (IFN) β-1a, 44 µg subcutaneously (sc) three times weekly (tiw), on clinical and magnetic resonance imaging (MRI) outcomes in patients with relapsing multiple sclerosis (MS) following mitoxantrone therapy.MethodsThis was an open-label, randomized, multicentre, rater-blinded, 96-week observational study conducted in Germany. Clinically stable patients with relapsing forms of MS, who had discontinued mitoxantrone treatment 1-6 months before study entry, were randomized to IFN β-1a sc 44 µg tiw, or no treatment. The primary endpoint was time to first relapse. Secondary endpoints included the number of relapse-free patients, disease activity assessed by MRI and time to 3-month confirmed Expanded Disability Status Scale (EDSS) progression, all at week 96.ResultsA total of 30 patients were randomized (intent-to-treat population: 14 IFN β-1a, 15 untreated; one patient from the safety population discontinued the study after 25 days owing to an adverse event and without providing any postbaseline efficacy data, and was thus excluded from the intent-to-treat population). Overall, 71.4% (10/14) of patients in the IFN β-1a group remained relapse free over 96 weeks, versus 46.7% (7/15) in the untreated group (p = 0.26). IFN β-1a delayed the time to first relapse versus no treatment (p = 0.14); time to first relapse (25th percentile) was 95.4 (IFN β-1a) versus 46.0 weeks (no treatment). Confirmed EDSS progression was observed in five patients in each treatment group. Mean change in EDSS score was 0.3 in both groups (p = 0.79). Changes in the number or volume of T1 and T2 lesions at week 96 were not significantly different between treatment groups (p > 0.05). There were no new or unexpected adverse events related to IFN β-1a treatment.ConclusionsSeveral endpoints appeared to show a benefit of IFN β-1a treatment, but no significant differences could be detected owing to the small sample. Therefore, these data only permit, at best, tentative conclusions about the disease course in patients with MS after de-escalation from mitoxantrone and continuation with or without IFN β-1a. Larger confirmatory studies are required.

Project description:BackgroundSystemic sclerosis (SSc) is a clinically heterogeneous, life-threatening disease characterized by fibrosis, microvasculopathy, and autoimmunity. Extensive nonclinical and clinical data implicate B cells in the pathogenesis of SSc. MEDI-551 is an investigational humanized monoclonal antibody that targets the B cell surface antigen CD19 and mediates antibody-dependent, cell-mediated cytotoxicity of B cells. This clinical study evaluated the safety and tolerability, pharmacokinetics, and pharmacodynamics of MEDI-551 in subjects with SSc.MethodsThis phase I multicenter, randomized, double-blind, placebo-controlled, single escalating dose study enrolled adult subjects with either limited or diffuse cutaneous SSc. A single intravenous dose of MEDI-551 was administered, and safety and tolerability were evaluated. MEDI-551 pharmacokinetics (PK), pharmacodynamics, and immunogenicity were also assessed. Safety assessments included the incidence of adverse events and changes in clinical and laboratory results. MEDI-551 serum concentrations, effects on circulating and tissue B cells and plasma cells (PCs), and antidrug antibodies were analyzed. Modified Rodnan skin score (MRSS) and pulmonary function tests were used to explore the clinical effect of MEDI-551.ResultsThe study enrolled 28 subjects with SSc (mean age, 47.3 years; 67.9 % female). Twenty-four received a single dose of MEDI-551 (0.1-10.0 mg/kg) and four received placebo. Treatment-emergent adverse events (TEAEs) occurred in 95.8 % of subjects in the MEDI-551 group and in 75.0 % of subjects in the placebo group; the majority of TEAEs were mild or moderate in severity. Two serious adverse events were considered possibly related to the study drug. One death, deemed not related to the study drug, occurred in a MEDI-551-treated subject. MEDI-551 exhibited linear PK in the dose range of 1.0 to 10.0 mg/kg, and more rapid clearance at lower doses. Dose-dependent depletion of circulating B cells and plasma cells was observed. MRSS assessments suggest a possible clinical effect of MEDI-551 on affected skin.ConclusionsA single escalating dose of MEDI-551 was tolerable and safe in this subject population. B cell depletion was achieved and was dose dependent. A signal of clinical effect was observed. Based on these results, further investigation of MEDI-551 as a disease-modifying treatment for SSc is warranted.Trial registrationwww.clinicaltrials.gov identifier, NCT00946699 ; registered 23 July 2009.

Project description:BACKGROUND:Infants presenting with lysosomal acid lipase deficiency have marked failure to thrive, diarrhea, massive hepatosplenomegaly, anemia, rapidly progressive liver disease, and death typically in the first 6 months of life; the only available potential treatment has been hematopoietic stem cell transplantation, which is associated with high morbidity and mortality in this population. The study objective was to evaluate safety and efficacy (including survival) of enzyme replacement with sebelipase alfa in infants with lysosomal acid lipase deficiency. This is an ongoing multicenter, open-label, phase 2/3 study conducted in nine countries. The study enrolled infants with growth failure prior to 6 months of age with rapidly progressive lysosomal acid lipase deficiency; they received once-weekly doses of sebelipase alfa initiated at 0.35 mg/kg with intrapatient dose escalation up to 5 mg/kg. The main outcome of interest is survival to 12 months and survival beyond 24 months of age. RESULTS:Nine patients were enrolled; median age at baseline was 3.0 months (range 1.1-5.8 months). Sixty-seven percent (exact 95% CI 30%-93%) of sebelipase alfa-treated infants survived to 12 months of age compared with 0% (exact 95% CI 0%-16%) for a historical control group (n?=?21). Patients who survived to age 12 months exhibited improvements in weight-for-age, reductions in markers of liver dysfunction and hepatosplenomegaly, and improvements in anemia and gastrointestinal symptoms. Three deaths occurred early (first few months of life), two patients died because of advanced disease, and a third patient died following complications of non-protocol-specified abdominal paracentesis. A fourth death occurred at 15 months of age and was related to other clinical conditions. The five surviving patients have survived to age ?24 months with continued sebelipase alfa treatment; all have displayed marked improvement in growth parameters and liver function. Serious adverse events considered related to sebelipase alfa were reported in one of the nine infants (infusion reaction: tachycardia, pallor, chills, and pyrexia). Most infusion-associated reactions were mild and non-serious. CONCLUSION:Sebelipase alfa markedly improved survival with substantial clinically meaningful improvements in growth and other key disease manifestations in infants with rapidly progressive lysosomal acid lipase deficiency TRIAL REGISTRATION: Clinicaltrials.gov NCT01371825 . Registered 9 June 2011.

Project description:BackgroundThe ability to self-inject in patients with multiple sclerosis (MS) has been associated with a reduced risk of missed injections and drug discontinuation, and a beneficial effect on patients' independence. However, injection anxiety, needle phobia and disease-related disability are major barriers to a patient's ability to self-administer treatment. Use of an autoinjector may improve patients' ability to self-inject. This study evaluated the safe and effective use of Avonex Pen™ (prefilled pen), a single use autoinjector, for intramuscular delivery of interferon beta-1a (IM IFNβ-1a, Avonex) in MS patients.MethodsThis was a Phase IIIb, open-label, single-country, multicenter trial in MS patients currently using IM IFNβ-1a prefilled syringes. Patients received weekly 30 mcg IM IFNβ-1a treatment over 4 weeks. On Day 1, patients self-administered IM IFNβ-1a using a prefilled syringe at the clinic. On Day 8, patients received training on the prefilled pen and self-administered IM IFNβ-1a using the device. On Day 15, patients self-administered IM IFNβ-1a at home using the prefilled pen. A final injection occurred at the clinic on Day 22 when patients self-administered IM IFNβ-1a using the prefilled pen while clinic staff observed and completed a detailed questionnaire documenting patients' ability to self-inject with the device. Serum neopterin levels were evaluated pre and post-injection on Days 1 and 8. Adverse events were monitored throughout.ResultsSeventy-one (96%) patients completed the study. The overall success rate in safely and effectively using the prefilled pen was 89%. No device malfunctions occurred. One unsuccessful administration occurred at Day 22 due to patient error; no patient injury resulted. Patients gave the prefilled pen high ratings (8.7-9.3) on a 10-point scale for ease of use (0 = extremely difficult, 10 = extremely easy). Ninety-four percent of patients preferred the prefilled pen over the prefilled syringe. Induction of serum neopterin levels, serving as a biomarker for type 1 interferon action, was similar to that of the prefilled syringe. The prefilled pen demonstrated a safety profile comparable to the prefilled syringe.ConclusionsThe prefilled pen is a safe and effective device for administration of IM IFNβ-1a and represents an alternative method for self-injection for MS patients using this therapy.Trial registrationThis study is registered at clinicaltrials.gov, identifier: NCT00828204.

Dataset Information

Dose-escalation of human anti-interferon-? receptor monoclonal antibody MEDI-546 in subjects with systemic sclerosis: a phase 1, multicenter, open label study.

Publications

Dose-escalation of human anti-interferon-α receptor monoclonal antibody MEDI-546 in subjects with systemic sclerosis: a phase 1, multicenter, open label study.

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