Interferon Gamma-1b

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Abstract
Chronic granulomatous disease is a group of rare x-linked or autosomal genetic disorders of the phagocytic NADPH oxidase system involved in host defence against various microorganisms. It is manifested by a common phenotype consisting of recurrent serious, life-threatening infection and granuloma formation. Following the finding that interferon gamma-1b (IFNγ-1b) can potentiate phagocyte activity in some other disease states as well as restoring defective phagocyte NADPH oxidase system activity in at least some patients with chronic granulomatous disease, a large-scale placebo-controlled trial was undertaken with IFNγ-1b in patients with chronic granulomatous disease. Long term treatment with a therapeutic dosage of IFNγ-1b produced a significant reduction in the incidence of serious clinical events necessitating hospitalisation. The relative risk of serious infection and the number of days in hospital were each reduced by about two-thirds, and the mean duration of hospital stay by about one-third in those who did experience infection. The greatest therapeutic benefit was found in patients aged < 10 years, but all patients were improved regardless of age, sex, use of prophylactic antibiotics or genetic pattern of inheritance. The drug was well tolerated with the commonest adverse effects (e.g. fever, headache, chills, injection site erythema) usually being mild, transient, and relieved by symptomatic treatment. IFNγ-1b therefore provides an effective and well tolerated therapy for patients with chronic granulomatous disease, offering an important clinical advance in the treatment of this rare genetic disorder by improving the prognosis of its serious and life-threatening infectious sequelae. IFNγ-1b is an Escherichia coli-derived recombinant DNA product which has biological activity identical to natural human IFNγ. IFNγ possesses pleiotropic effects as a biological response modifier, but of specific relevance to chronic granulomatous disease, it has been shown in vitro and in vivo to increase the response of normal phagocytes with enhanced production of toxic oxygen metabolites via the NADPH oxidase pathway and by more efficient killing of various microorganisms. Indeed, chronic granulomatous disease is a heterogeneous group of x-linked and autosomal recessive disorders of the phagocytic NADPH oxidase system, which renders the host prone to recurrent severe infection that can be life-threatening. These patients also exhibit abnormal inflammatory responses that can induce granuloma formation. However, preclinical in vitro and in vivo studies have not always revealed an enhancement of defective phagocyte function by IFNγ in cells derived from patients with chronic granulomatous disease: it was very frequent in those with x-linked disease but less common in those with autosomal recessive disease. Furthermore, despite the equal therapeutic benefit related to IFNγ-1b for both forms of the disease in the large-scale clinical trial of the drug, complementary ex vivo study of phagocytes revealed no change in superoxide production, bacterial killing or cytochrome b levels compared with placebo in either genetic form of the disease. The precise mechanism of action of interferon gamma in chronic granulomatous disease therefore requires further elucidation. Pharmacokinetic studies have been performed in healthy subjects but not in patients with chronic granulomatous disease. IFNγ-1b was rapidly cleared after intravenous injection of a single 100 μg/m2 dose (1.4 L/min), and was slowly absorbed after intramuscular or subcutaneous injection of the same dose (> 89% of the dose absorbed). Mean elimination half-lives were 0.6, 2.9 and 5.9 hours after intravenous, intramuscular and subcutaneous injection, respectively, while mean peak plasma concentration occurred at 4 hours (1.5 μg/L) and 7 hours (0.6 μg/L) after intramuscular and subcutaneous injection, respectively. No accumulation was evident after repeated once daily administration of IFNγ-1b 100 μg/m2 subcutaneously for 12 days. The drug is not detected in urine after parenteral administration to humans, and animal studies indicated clearance by the liver and kidneys. The clinical efficacy (and tolerability) of IFNγ-1b is essentially based on the results of a multicentre double-blind placebo-controlled parallel-group trial in 128 evaluable patients with x-linked or autosomal recessive chronic granulomatous disease. After randomisation and stratification patients received IFNγ-1b or placebo by subcutaneous injection 3 times weekly for up to 12 months. The dose was administered on the basis of body surface area if ⩾ 0.5m2 (50 μg/m2) and on the basis of bodyweight if < 0.5m2 (1.5 μg/kg). The mean duration of treatment was 8.9 months (equivalent to 95 patient-years). Based on Kaplan-Meier plots, more patients receiving IFNγ-1b were free of serious infection at 12 months than were placebo recipients (77 vs 30%, p=0.0006). 14 of 63 patients receiving IFNγ-1b (22%) and 30 of 65 receiving placebo (46%) experienced at least 1 serious infection (p = 0.0006). The total number of infections was also significantly lower in the patients receiving IFNγ-1b (20 vs 56, p < 0.0001). Placebo recipients required about 3 times as many days of hospitalisation (1493 vs 497 days) and their mean hospital stay when infection did occur was longer (48 vs 32 days) compared with patients receiving IFNγ-1b. IFNγ-1b conferred clinical benefit when subanalysis was performed for the main demographic and clinical factors used for stratification (age, pattern of inheritance, prophylactic antibiotic use and sex). While all patients benefited from therapy, patients aged < 10 years received the greatest benefit. During the placebo-controlled trial of IFNγ-1b in patients with chronic granulomatous disease, adverse effects occurring at a significantly higher rate during active treatment (compared with placebo) included fever, headache, chills and erythema at the injection site. Most symptoms were mild and relieved by paracetamol (acetaminophen). There were fewer reactions with administration of IFNγ-1b at bedtime. Adverse effects occurred more frequently in those aged > 10 years compared with < 10 years. Withdrawals because of toxicity were infrequent, and resulted most commonly from rash, flu-like symptoms and worsened granulomatous colitis. No laboratory test abnormalities (including rheumatoid factor or antinuclear antibodies, ESR, thyroid function or sex hormone levels) or neutralising antibodies to IFNγ-1b were detected. Certain other adverse effects have been reported with the higher dosages of IFNγ-1b used in disease states other than chronic granulomatous disease. The recommended dosage of IFNγ-1b is 50 μg/m2 (1.5 × 106 U/m2) if body surface area is > 0.5m2, and 1.5 μg/kg if body surface is ⩽ 0.5m2, administered subcutaneously 3 times weekly. The dose should be halved or the drug withdrawn in the event of serious adverse reactions, and caution is required when treating patients with pre-existing cardiac or CNS disorders.