Anakinra in children and adults with Still's disease.

Systemic juvenile idiopathic arthritis and adult-onset Still's disease are rare autoinflammatory disorders with common features, supporting the recognition of these being one disease-Still's disease-with different ages of onset. Anakinra was recently approved by the European Medicines Agency for Still's disease. In this review we discuss the reasoning for considering Still's disease as one disease and present anakinra efficacy and safety based on the available literature. The analysis of 27 studies showed that response to anakinra in Still's disease was remarkable, with clinically inactive disease or the equivalent reported for 23-100% of patients. Glucocorticoid reduction and/or stoppage was reported universally across the studies. In studies on paediatric patients where anakinra was used early or as first-line treatment, clinically inactive disease and successful anakinra tapering/stopping occurred in >50% of patients. Overall, current data support targeted therapy with anakinra in Still's disease since it improves clinical outcome, especially if initiated early in the disease course.

Development and effect of antibodies to anakinra during treatment of severe CAPS: sub-analysis of a long-term safety and efficacy study.

Anakinra is an effective, well-tolerated, long-term anti-inflammatory treatment for cryopyrin-associated periodic syndromes (CAPS), yet evidence shows that it can induce the development of anti-drug antibodies (ADA). This analysis aims to determine ADA occurrence in CAPS patients and elucidate their effects on anakinra dosing and drug efficacy. A post hoc analysis was performed on data from a long-term safety and efficacy study in patients with severe CAPS. Patients were initiated on an anakinra dose of 1.0-2.4 mg/kg once daily subcutaneously, which was increased (in 0.5-1.0 mg/kg increments) to 2.0-5.0 mg/kg/day according to clinical need (median 3.1 mg/kg/day). ADA, serum amyloid A (SAA), and C-reactive protein (CRP) levels were measured at various time points, and pharmacokinetic (PK) parameters at 1 and 3 months. Efficacy was evaluated using a diary symptom sum score (DSSS), and SAA and CRP levels were evaluated as proxies of efficacy. Safety was evaluated by an analysis of adverse events (AEs). Anakinra dose levels were unrelated to ADA status. A high proportion of patients with at least one post-baseline assessment developed ADA (83%), the majority (79%) within 3 months. However, anakinra treatment markedly improved symptoms and was effective regardless of the presence of ADA; the annual rates of AEs were comparable between ADA-negative and ADA-positive patients. While ADA are likely to occur in CAPS patients treated with anakinra, our evidence shows that chronic daily subcutaneous treatment with anakinra is safe and effective regardless of the development and presence of ADA.

Long-term safety profile of anakinra in patients with severe cryopyrin-associated periodic syndromes.

OBJECTIVE: Anakinra is approved for the treatment of RA and cryopyrin-associated periodic syndromes (CAPS). While the anakinra safety profile is well established in RA, the long-term safety profile in severe CAPS is less well documented and will therefore be discussed in this report. METHODS: A prospective, open-label, single centre, clinical cohort study was conducted at the National Institutes of Health in the USA, from 2003 to 2010, investigating the efficacy and safety of anakinra treatment for up to 5 years in 43 patients with CAPS. Safety was evaluated using adverse event (AE) reports, laboratory assessments, vital signs and diary reports. RESULTS: In total, 1233 AEs were reported during the study, with a yearly rate of 7.7 AEs per patient. The event rate decreased over time, and dose escalation during the study did not affect AE frequency. Anakinra had similar safety profiles in adults and children. The most frequently reported AEs were typical CAPS disease symptoms such as headache and arthralgia. Injection site reactions occurred mainly during the first month of anakinra treatment. In total, 14 patients experienced 24 serious AEs (SAEs), all of which resolved during the study period. The most common types of SAEs were infections such as pneumonia and gastroenteritis. There were no permanent discontinuations of treatment due to AEs. CONCLUSION: In this study anakinra treatment of patients with severe CAPS for up to 5 years was safe and well tolerated both in paediatric and adult patients, with most AEs emerging during the first months after treatment initiation. TRIAL REGISTRATION: ClincialTrials.gov, clinicaltrials.gov, NCT00069329.

Suitability Of Nitisinone In Alkaptonuria 1 (SONIA 1): an international, multicentre, randomised, open-label, no-treatment controlled, parallel-group, dose-response study to investigate the effect of once daily nitisinone on 24-h urinary homogentisic acid excretion in patients with alkaptonuria after 4 weeks of treatment.

BACKGROUND: Alkaptonuria (AKU) is a serious genetic disease characterised by premature spondyloarthropathy. Homogentisate-lowering therapy is being investigated for AKU. Nitisinone decreases homogentisic acid (HGA) in AKU but the dose-response relationship has not been previously studied. METHODS: Suitability Of Nitisinone In Alkaptonuria 1 (SONIA 1) was an international, multicentre, randomised, open-label, no-treatment controlled, parallel-group, dose-response study. The primary objective was to investigate the effect of different doses of nitisinone once daily on 24-h urinary HGA excretion (u-HGA24) in patients with AKU after 4 weeks of treatment. Forty patients were randomised into five groups of eight patients each, with groups receiving no treatment or 1 mg, 2 mg, 4 mg and 8 mg of nitisinone. FINDINGS: A clear dose-response relationship was observed between nitisinone and the urinary excretion of HGA. At 4 weeks, the adjusted geometric mean u-HGA24 was 31.53 mmol, 3.26 mmol, 1.44 mmol, 0.57 mmol and 0.15 mmol for the no treatment or 1 mg, 2 mg, 4 mg and 8 mg doses, respectively. For the most efficacious dose, 8 mg daily, this corresponds to a mean reduction of u-HGA24 of 98.8% compared with baseline. An increase in tyrosine levels was seen at all doses but the dose-response relationship was less clear than the effect on HGA. Despite tyrosinaemia, there were no safety concerns and no serious adverse events were reported over the 4 weeks of nitisinone therapy. CONCLUSIONS: In this study in patients with AKU, nitisinone therapy decreased urinary HGA excretion to low levels in a dose-dependent manner and was well tolerated within the studied dose range. TRIAL REGISTRATION NUMBER: EudraCT number: 2012-005340-24. Registered at ClinicalTrials.gov: NCTO1828463.

Long-Term Safety Outcomes in Patients with Hematological Malignancies Undergoing Autologous Hematopoietic Stem Cell Transplantation Treated with Palifermin to Prevent Oral Mucositis.

The purpose of our study was to compare long-term safety outcomes (overall survival, disease progression, and incidence of secondary malignancies) between palifermin and placebo in the prevention of oral mucositis in patients with hematological malignancies undergoing autologous hematopoietic stem cell transplantation (HSCT). Patients were enrolled between 1997 and 2005 into 4 phase I to III studies (3 double-blind placebo-controlled and 1 open-label) conducted at 31 sites in Australia, Europe, and the United States. Survival outcomes (overall survival, progression-free survival) were compared using hazard ratios (HRs) estimated with a Cox model that included treatment group, baseline age, disease type, Eastern Cooperative Oncology Group performance status, country, and presence of prior radiotherapy as covariates. The incidence of secondary malignancies was compared with a chi-square test. A total of 672 patients were randomized into the studies (428 palifermin and 244 placebo). The median follow-up time for subjects alive at last visit was 7.9 years (range, .1 to 14.9) for palifermin and 8.8 years (range, .1 to 14.8) for placebo. Palifermin-treated patients had overall survival (HR, 1.01; 95% confidence interval [CI], .78 to 1.31; P = .921) and progression-free survival times (HR, 1.04; 95% CI, .83 to 1.31; P = .733) that were comparable with placebo-treated patients. Secondary malignancies were reported by 13% of palifermin-treated patients versus 11% of placebo patients (P = .477). Breakdown into secondary hematological malignancies (7% versus 6%) or solid tumors (6% versus 6%) did not suggest any differences between the treatment groups. After a follow-up of up to 15 years, comparable long-term safety outcomes (overall survival, progression-free survival, and incidence of secondary malignancies) were observed for palifermin- and placebo-treated patients undergoing autologous HSCT.

Pharmacokinetic and pharmacodynamic interactions between palifermin and heparin.

Oral mucositis, a severe complication during chemo- and/or radiotherapy, is prevented with palifermin treatment, a recombinant human keratinocyte growth factor (KGF/FGF-7). The FGF family belongs to the larger family of heparin-binding growth factors. Because it has been shown that heparin modulates binding of KGF to the KGF receptor and subsequently affects cellular proliferation induced by the KGF mitogenic signal, it is critical to understand the drug-drug interactions between palifermin and heparin, particularly because of heparin's narrow therapeutic margin. Two studies were performed in healthy subjects to characterize the effect of palifermin on the pharmacodynamics of heparin (activated partial thromboplastin time) and evaluate the impact of heparin on the pharmacokinetics and pharmacodynamics (Ki67 staining of buccal mucosal tissue) of palifermin. Results demonstrated a pronounced pharmacokinetic interaction; heparin coadministration increased the palifermin AUC 4- to 5-fold and decreased its half-life by 40%-45%, suggesting an approximate 70%-80% decrease in palifermin clearance and volume of distribution. These changes in the pharmacokinetics of palifermin during coadministration of heparin, however, did not affect the pharmacodynamic effect of palifermin, or the anticoagulant activity of heparin, and did not lead to increased safety findings. Therefore, these results suggest that dose adjustments for heparin and palifermin are not warranted when administered concurrently.