DRUG EVALUATION

Drugs 43 (I): 111-122. 1992 0012-6667/92 /000 1-0111/$06.00/0 © Adis Interna tiona l Limited. All rights reserved. ORE1 78

Interferon Gamma-lb

A Review of its Pharmacology and Therapeutic Potential in

Chronic Granulomatous Disease

Peter A. Todd and Karen L. Goa Adis International Limited, Auckland , New Zealand

Various sections of the manuscript reviewed by: G. Berton, Istituto diPatologia Generale , Universita degli Studi di Verona, Verona, Italy; L.A. Boxer, Department of Pediatrics, C.S. Mott Children's Hosp ital, Uni versity of Michigan Hosp itals, Ann Arbor, Michigan, USA; R. Dijkmans, SCK/CEN (VITO), Laboratory of Genetics and Biotechn ology, Boeretang, Belgium; J. French, Department of Medicine, Th e Rayne Institute, Un iversity College an d Middlesex School of Medicine, London, England ; A. Kemp, Department of Microbiology and Infectious Diseases, Royal Children' s Hospit al, Melbourne, Victoria , Australia; A. Mantovani, Istituto .Di Ricerche Farmacologiche, Mario Negri Inst itut e, Milan, Italy; H. W. Murray, Division ofInfectious Diseases, The New York Hosp ital - Corne ll Medica l Center , New York, New York, USA; M. Takagi, Department of Pediatrics, Shinshu University School of Medic ine, Matsumoto, Japan; R.S. Weening, Department of Pediatrics, Academic Medical Centre, University of Amsterdam, Amsterda m, The Netherlands.

Contents III I 13 114 116 II7 118 1/9 120 120

Summary I. Path oph ysiology of Chronic Granulomatous Disease 2. Pha rma codynami c Prop ert ies of Interferon Gamma 3. Pharmacokinetic Propert ies 4. Th erapeutic Use 5. Clinical Tolerability 6. Drug Interactions 7. Dosage and Adm inist ration 8. Place ofInterferon Gamma-I b in Therapy

Summary Synopsis 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 ofrecurrent serious, life-threateninginjection and granuloma formation. Following the finding that interferon gamma-Ib (IFNy-Ib) can potentiate phagocyte activity in some other disease states as well as restoring def ective phagocyte NADPH oxidase system activity in at least some patients with chronicgranulomatous disease. a large-scale placebo-controlled trial was undertaken with IFNy-Ib in patients with chronic granulomatous disease. Long term treatment with a therapeutic dosage of IF'N."..lb produced a significant reduction in the incidence ofserious clinical events necessitating hospitalisation. The relative risk ofserious

Drugs 43 (1) 1992

112

infection and the numberofdays in hospital were each reduced by abouttwo-thirds, and the mean duration of hospital stay by about one-third in those who did experience infection. The greatest therapeutic benefit wasfound in patientsaged < 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) usuallybeing mild, transient, and relieved by symptomatic treatment. 1FNr-1b therefore provides an effective and well tolerated therapy for patients with chronic granulomatous disease, offering an importantclinical advance in the treatment ofthis rare genetic disorder by improving the prognosis of its serious and life-threatening infectious sequelae.

Pharmacodynamic Properties IFN-y-Ib is an Escherichia coli-derived recombinant DNA product which has biological activity identical to natural human IFN-y. IFN-ypossesses pleiotropic efTectsas 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 IFN-y 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 IFN-yIb 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 Properties Pharmacokinetic studies have been performed in healthy subjects but not in patients with chronic granulomatous disease. IFN-y-Ib was rapidly cleared after intravenous injection of a single 100 p.g/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 (1.5p.g/L) and 7 hours (0.6 p.g/L) after intramuscular and subcutaneous injection, respectively. No accumulation was evident after repeated once daily administration of If'Nv-Ib 100 /Lg/m 2 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.

Therapeutic Use The clinical efficacy (and tolerability) of IFN-y-Ib 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 IFN-y-Ib .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~ 0.5m 2 (50 /Lg/m2) and on the basis ofbodyweight if < 0.5m 2 (1.5 /Lg/kg). The mean duration of treatment was 8.9 months (equivalent to 95 patient-years). Based on Kaplan-Meier .plots, more patients receiving IFN-y-Ib were free of serious infection at 12 months than were placebo recipients (77 vs 30%, p = 0.0006). 14 of 63 patients receiving

Interferon Gamma-I b: A Review

113

IFN'Y-I b (22%) and 30 of 65 receiving placebo (46%) experienced at least I serious infection (p = 0.0006). The total number of infections was also significantly lower in the patients receiving IFN'Y-Ib (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 IFN'Y-Ib. IFN'Y-I b 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.

Clinical Tolerability During the placebo-controlled trial of If'Nv-Ib 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 IFN'Y-Ib 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 IFN'Y-Ib were detected. Certain other adverse effects have been reported with the higher dosages of IFN'Y-Ib used in disease states other than chron ic granulomatous disease.

Dosage and Administration The recommended dosage of IFN'Y-Ib is 50 /lg/m 2 (1.5 x 106 U/m 2) if body surface area is > 0.5m 2, and 1.5 /lg/kg if body surface is ~ 0.5m 2, 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 .

1. Pathophysiology of Chronic Granulomatous Disease The pathophysiology of chronic granulomatous disease has been the subject of several detailed reviews (Curnette 1988; Dinauer & Orkin 1988; Gallin & Malech 1990; Orkin 1989; Segal 1989).·The following brief overview is based primarily on these sources. Chronic granulomatous disease is a rare genetic syndrome characterised by recurrent and severe infection. It has an incidence ranging from about I in 250 000 to I in I million. There is a varied pattern of inheritance: about 60% of patients have xlinked, about 40% have autosomalreces~ive, and less than I % have autosomal dominant disease. All patients, however, have a common phenotype of recurrent infection most commonly caused by catalase-positive microorganisms, such as Staphylo-

coccus aureus and Aspergillus species. Other infecting organisms may include Serratia marcescens, Pseudomonas cepacia, Klebsiella species, Chromobacterium violaceum, Escherichiacoli and Nocardia species. Cutaneous infection is common but rarely life-threatening. The most severe infections include pulmonary and hepatic abscesses, and osteomyelitis. It is possible that patients with x-linked disease may show more severe diseasethan those with an autosomal recessive pattern of inheritance (Weening et al. 1985). In addition to recurrent infection, patients with chronic granulomatous dis" ease also exhibit abnormal inflammatory responses that induce granuloma formation. This can lead to obstruction of vital structures, e.g. urinary or gastrointestinal tract. The formation of chronic granuloma may be caused by inadequate antigenic debris breakdown or inadequate feedback inhibition

114

of inflammation by toxic oxygen products (Gallin 1988). Chronic granulomatous disease has recently been recognised as a heterogeneous group of genetic disorders in phagocytic oxidative metabolism, resulting from defective function of the microbicidal enzyme complex NADPH oxidase. In healthy subjects, phagocytes are activated by exogenous particulate and soluble stimuli to reduce NADP to NADPH in the hexose monophosphate shunt. NADPH acts as a substrate for NADPH oxidase (fig. 1). NADPH oxidase activation occurs by interaction between at least 2 cytosolic proteins (Abo et al. 1991; Nunoi et al. 1988; Volpp et al. 1988) and a membrane-associated electron transport cascade that contains flavoprotein and cytochrome b-558 as the terminal electron acceptor (Segal et al. 1983). Cytochrome b-558, a membrane-bound haem protein made up of 2 subunits (91 and 22kD, respectively) , has an electron potential of -245mV and can transfer electrons to oxygen. The resultant superoxide anion can be converted to hydrogen peroxide either spontaneously or by dismutation by superoxide dismutase, which in turn can be converted to hypochlorous acid and eventually N-chloramines in the presence of phagocytic myeloperoxidase, These potent oxidative products playa key role in host defence . Chronic granulomatous disease can result from defects in either the cytosolic or membrane components of the NADPH oxidase system (fig. 1). About 60% of patients have a membrane defect which is generally inherited in a x-linked manner and involves the 91kD component of cytochrome b-558 (Segal et al. 1983). The remainder have a cytosolic defect which is generally autosomal recessive . The cytosolic defect may be one of several. The second most common form of chronic granulomatous disease (about 30% of patients) is caused by a deficiency in the 47kD cytosolic protein (Nunoi et al. 1988; Volpp et al. 1988). A small number of patients « 5%) exhibit a deficiency in the 22kD component of cytochrome b-558 (Lomax et al. 1988; Ohno et al. 1986). Lastly, < 5% of patients with chronic granulomatous disease exhibit an autosomal recessive disorder of the 65kD cytosolic

Drugs 43 (1) 1992

protein (Nunoi et al. 1988; Volpp et al. 1988). Rarely , deficiency in the 47kD protein may be inherited in an autosomal dominant manner « 1% of patients). Clinical diagnosis is based on abnormal tests of phagocyte oxidative metabolism, e.g. nitroblue tetrazolium dye reduction, oxygen consumption, hydrogen peroxide or superoxide production, and chemiluminescence by phagocytes.

2. Pharmacodynamic Properties pf Interferon Gamma The interferon family is a group of species-specific proteins produced by eukaryotic cells in response to viruses and a variety of natural and synthetic stimuli. With the recent advances in the field of molecular biology, there has been a rapid increase in the understanding of the function of these biological response modifiers and research into their application for the treatment of various disease states. While the different interferons (alpha, beta, and gamma) have certain common properties, interferon gamma (IFNy) alone possesses potent phagocyte-activating effects, including the generation of toxic oxygen products to kill microorganisms (see below). Studies in patients treated with IFNI' have revealed a wide variety of biological responses, additional to the enhancement of macrophage oxidative metabolism which appears to be the key role behind the rationale for using the drug in patients with chronic granulomatous disease . The reader is directed to a number of recent reviews on IFNI' for more detail concerning its pleiotropic biological responses, which include enhancement of antibody-dependent cellular cytotoxicity and natural killer cell activity as well as monocyte and granulocyte Fe receptor expression and major histocompatibility antigen expression (Billiau & Dijkmans 1990;B()nnem & Oldham 1987; Dijkmans & Billiau 1988;i ;:I~ermans & Marquet 1989; Murray 1988, 1990;Perussia et al. 1987). IFN'Y-lb is a product obtained by fermentation of genetically .engineered E. coli containing DNA encoding for the human protein. Purified IFN'Y-Ib

115

Interferon Gamma-Ib: A Review

(Oxygen) (Superoxid_e..:.. ) _ _-l~~(Hydrogen peroxide) 02 ---:-+.~ 0 2H202

e-I

Cell membrane

Cytosol ~factors

~ I 47kD I

I

I I

~

,

\ ,Cytochrome b-558 \ \ \ \ \ \ \ \ \

~

m

,, ,

@

Fig. 1. Schematic representation of NADPH oxidase and abnormalities in chronic granulomatous disease (COD). FAD = flavin adenine dinucleotide; X = x-linked COD; AR = autosomal COD (3 forms) [after Gallin & Malech 1990].

is obtained by conventional column chromatography. IFN')'-Ib is a noncovalent dimer of 2 identical 16.465kD monomers, each a single chain polypeptide containing 140 amino acids with biological activity identical to naturally occurring human IFN-y. In vitro and in vivo, IFN')' has been shown to increase the response of normal phagocytes, as exhibited by the enhanced production of toxic oxygen metabolites from the NADPH oxidase pathway and by more efficient killing of various bacterial, fungal and protozoal pathogens (e.g. Chlamydia psittaci, Plasmodium falciparum, Leishmania donovani, Toxoplasma gondii, Staphylococcus aureus, Listeria monocytogenes) [Murray 1988, 1990; Murray et a!. 1983, 1985; Newburger et a!. 1988; Ockenhouse et al. 1984; Rothermel et a!. 1986]. In addition, clinical trials in humans have shown that IFN')' can stimulate phagocyte activity in patients with lepromatous leprosy, cancer and acquired immunodeficiency syndrome (Murray et a!. 1987; Nathan eta!. 1985, 1986), as well as being a useful adjunct in the treatment of patients with systemic leishmaniasis (Badaro et al. 1990). The precise mechanism whereby IFN-y improves host defence mechanisms in

patients with chronic granulomatous disease remains unclear. In vitro and in vivo studies of phagocytes from patients with rare variants of chronic granulomatous disease indicate that IFN-y could increase superoxide levels and improve killing of microorganisms such as S. aureus and Aspergi//usfumigatus (Ezekowitz & Newburger 1988; Ezekowitz et al. 1987, 1988, 1990; Murray et al. 1985; Newburger & Ezekowitz 1988; Rex et al. 1991; Sechler et al. 1988;Weening et a!. 1988). Enhanced phagocyte activity was not, however, a consistent finding in all patients in these studies: it was very frequent in patients with x-linked disease but was inconsistent in those with autosomal recessive forms of the disease. Based on these experimental findings of improved phagocyte activity, a clinical trial of IFN-yIb was undertaken in a large number of patients with both x-linked and autosomal recessive chronic granulomatous disease (section 4). Despite the finding of an equal significant therapeutic benefit conferred by IFN-y-Ib in both the x-linked and autosomal recessive forms of the disease for the prevention of severe infectious episodes, complementary ex vivo study of phagocytes revealed no significant differences between the IFN-y-I b- and

116

placebo-treated groups for superoxide production, bacterial killing or cytochrome b levels (or any correlation of these factors to clinical response). This lack of a significant difference may be accounted for by the marked variability of biological assays used by various investigators. Another possibility is that the preclinical studies recruited rare patients in whom the genetic disorder still allows superoxide enhancement by the NADPH oxidase pathway in response to IFNI'. Indeed, this respiratory burst, oxygen-dependent pathway may contribute to the clinical response in these patients. The majority of patients may, however, derive benefit from oxygen-independent antimicrobial pathways of phagocytes, which have yet to be determined. This is supported by early work showing that IFNI' could enhance monocyte and macrophage antimicrobial activity in the absence of any detectable enhancement in respiratory burst activity (Murray et al. 1983, 1985). Alternatively, IFNI' may stimulate intracellular superoxide production, which could not be detected by extracellular superoxide assay. Clearly , the mechanism of action of IFNI' in patients with chronic granulomatous disease requires further elucidation. IFNI' may possibly affect other components of the immune system. In a study of patients treated with IFN'Y-1 b or placebo (Rosenblatt et al. 1991), lymphocyte subpopulation analysis revealed significantly lower CD2+ and CDllb+ levels in actively treated patients, while other subpopulations (CD3+, CD4+,CD8+, CD 19+ and Leu8+ CD20+) were unaltered. It is possible that the change in CD2+ and CDllb+ levels occurred in response to the lower infection rate rather than to a direct effect of IFNI'. Another recent investigation (Zavala et al. 1990a) has shown that IFNI' can restore neutrophil peripheral type benzodiazepine receptor expression, which ' is deficient in x-linked but not autosomal recessive chronic granulomatous disease. This receptor is an l8kD protein suggested to be a component of the NADPH oxidase complex (Zavala et al. 1990b).

3. Pharmacokinetic Properties The pharmacokinetics of IFN'Y-lb have been investigated in healthy subjects (Chen et al. 1990; Reed et al. 1990) and have been recently reviewed

Drugs 43 (1) 1992

by Mordenti and colleagues (1992). Unreferenced statements are derived from the prescribing information data sheet for the drug (data on file, Genentech). No pharmacokinetic studies have been performed in patients with chronic granulomatous disease. Pharmacokinetic parameters were investigated in 24 healthy male subjects after the intravenous, intramuscular and subcutaneous injection of a single dose of IFN'Y-lb 100 j.tg/m2 (Chen et al. 1990). IFN'Y-lb was rapidly cleared after intravenous administration (1.4 Lzmin) and slowly absorbed after intramuscular or subcutaneous injection. The apparent fraction of dose absorbed after intramuscular or subcutaneous injection was greater than 89%. Mean elimination half-lives were 0.6, 2.9 and 5.9 hours after intravenous, intramuscular and subcutaneous injection, respectively. The mean peak plasma concentration (C max) after intravenous injection was 5.3 j.tg/L; C max values were achieved about 4 hours (1.5 j.tgfL) after intramuscular and 7 hours (0.6 j.tgfL) after subcutaneous injection. No accumulation occurred after the repeated subcutaneous injection of IfNv-Ib 100 j.tg/ m 2 once daily for 12 days in 38 healthy male subjects (Mordenti et al. 1992). The pharmacokinetics of.IfNv-Ib may represent those of both the parent compound and metabolites (Reed et al. 1990), as the immunoassay used to quantitate plasma concentrations of IFN'Y-lb did not discriminate between intact protein and processed forms containing minor changes in the primary and secondary structure (Chen et al. 1991). The drug is not detected in the urine of healthy subjects after the administration of a 100 j.tg/m2 dose intravenously, intramuscularly or subcutaneously. Only trace amounts were measurable in the urine of squirrel monkeys after a single intravenous dose of IFN'Y-lb 500 j.tg/kg. In vitro animal organ perfusion studies indicated that IFNI' is cleared by the liver and kidneys. Studies in nephrectomised an imals demonstrate that the clearance of IFNI' is reduced, but elimination was not prevented, by prior nephrectomy (Mordenti et al. 1992). .

Interferon

Gamma-Ib: A Review

117

4. Therapeutic Use

'" E

1.0-.-,-_ _

\

.!!1

Until recently, the only treatment for infection associated with chronic granulomatous disease has been a direct aggressive approach, including prompt surgical drainage of abcesses, prolonged use of intracellularly active systemic antimicrobial agents and white blood cell transfus ions. However, ant imicrobial prophylaxis is being used more routinely. The regular prophylactic use of cotrimoxazole appears to increase the interval between lifethreatening infections from about once every 9 months to once every 4 years (Gallin et al. 1983). While cotrimoxazole exerts direct antimicrobial activity , it may also stimulate phagocyte bactericidal activity. Despite this advance, life-threatening infections remain a major problem in patients with chronic granulomatous disease. It is within this context that IFN'Y-l b has been evaluated. There have been several isolated case reports of individual patients with chronic granulomatous disease who appeared to derive significant benefit against pyogenic infection during treatment with IFN'Y-l b (Bernhisel-Broadbent et al. 1991 ; Gallin & Malech 1990; Johnston et al. 1989). On the strength of these encouraging reports a placeboTable I. Demographic and clinical characteristics of patients in the ICGDCSG (1991) trial Variable

No. enrolled No. complet ing Sex Male Female Mean age (years) Pattern of inheritance x-Linked Autosomal recessive Prophylactic antibiotic use Yes No Corticosteroid use Yes No

Treatment IFNy-1b

placebo

63 57

65 54

51 (81%) 12 (19%) 14.3

53(82 %) 12(18%) 15.0

45(71%) 18(29%)

41 (63%) 24(37%)

56(89%) 7 (11%)

55(85%) 10 (15%)

1 (2%) 62 (98%)

2(3%) 63(97%)

tii

o.c

'0:8 5~ 0";;; a."

0.8

Ql

.............

-"\.-'\.

L._"\.

:;:;c:

e0.:0.Q

~-'\.

"'1'1.••

06 .

L ••

L,

I

"'--I,

'"

~ E 0.4

"

~g E

oe "

Ql

, I

L. ••

Ql

P

= 0.0006

0 .2.......,~---.----.----.----.

o

90 180 270 Time after randomisation (days)

360

Fig. 2. ·Cumulati ve proportion of patients (Kaplan-Meier plot) treated with IFNoy-lb (green) or placebo (black) who were free of serious infections during the 12-month period followi ng randomisation to treatment (after ICGDCSG 1991).

controlled clinical trial in patients with chronic granulomatous disease has been performed [International Chronic Granulomatous Disease Cooperative Study Group (ICGDCSG) 1991]. In view of the rarity of such patients and the relatively large number of subjects required for this clinical trial, it was necessary to adopt an international multicentre protocol recruiting patients at 13 centres in 4 countries. 128 eligible patients with x-linked or autosomal recessive chronic granulomatous disease were involved in this double-blind parallel-group trial. They were randomised to treatment with IFN'Y-Ib or placebo after stratification on the basis of the pattern of disease inheritance, study-centre institution, and use or nonuse of prophylactic antibiotics and corticosteroids. The 2 groups were comparable at entry for demographic and clinical data (table I). The median age of the patients was 15 years, and 37 patients were less than 9 years of age. Patients received IFN'Y-lb 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 this was at least 0.5m2~ a 50 ~g/m2 dose was administered. When body surface area was less than 0.5m 2, the dose was administered on the basis of bodyweight, as 1.5 ~g/ kg. The primary end-point was the time to appearance of serious infection.

Drugs 43 (1) 1992

118

The study was terminated prematurely because of the statistically and clinically significant benefit gained with active therapy: the mean duration of treatment was 8.9 months, which was equivalent to 95 patient-years . Figure 2 shows the Kaplan-Meier plot for patients who were free from serious infection 12 months after randomisation to IFNy-l b or placebo (77 vs 30%, p = 0.0006). Corresponding values at 6 months were 89% vs 72%, indicating a progressive beneficial effect during the first year of treatment. 14 of 63 patients receiving IFN'Y-lb (22%) and 30 of 65 patients receiving placebo (46%) had at least I serious infection (p = 0.0006) during the study period . In total, there were more infections in patients receiving placebo than in those receiving IFN'Y-l b (fig. 3) [56 vs 20; p < 0.0001]. The nature of the infections is shown in table II. IFN'Y-l b appeared most effective in reducing the incidence of adenitis, abscesses, cellulitis and pulmonary infections. Placebo recipients required about 3 times as many days of hospitalisation for the treatment of clinical events than did those who received IFN'Y-1b (1493 vs 497 days, respectively) [fig. 3]. In addition, mean hospital stay was longer in the placebo recipients (48 vs.32 days; p = 0.02). Table III shows the percentage of patients in

60

III IFN) - 1b Placebo

o

p < 0.0001 r-::::J

50 40 Q;

~

::J

p = 0.02 ~

P

= 0.0006

,----,

30

Z

20 10

No. of patients with ~ 1 serious infection

Tota l no. of infections

Mean days of hospitalisation

Fig. 3. Effects of IFN')'-lb or placebo on parameters of infection in 128 patients with chronic granulomatous disease (after ICGDCSG 1991).

each treatment group who were free from infection when analysed for some of the main demographic and clinical factors used in stratification (age, pattern of inheritance, prophylactic antibiotic use and sex). In all cases, IFN'Y-l b conferred benefit when compared with placebo (this was also confirmed by Kaplan-Meier plots). The greatest benefit of 1FN'Y1b was observed in patients aged less than 10 years.

5. Clinical Tolerability Table II: Clinical events requiring hospitalisation and use of intravenous antibiotics (ICGDCSG 1991) Event

No. of events (no. of patients) IFNy-1b (n = 14)

placebo (n

= 30)

Pulmonary infections Adenitis

7 (5) 2(2)

Genitourinary tract infection or obstruction Hepatic infection Sinusitis Osteomyelitis or joint infection

1

5 (3)

4 (3)

3 (3) 2 (2) 2 (2)

Bacteraemia Gastrointestinal obstruction or colitis Abscess or cellulitis Other infections

o 1

o 2 (2)

2 (2)

1

12 (11) 11 (10)

2 (2)

1 16 (14)

1

The most common adverse clinical reactions which occurred during the ICGDCSG (1991) trial (see section 4 for protocol details) are summarised in table IV. The most frequent adverse reactions occurring at a statistically significant higher rate during 1FN'Y-1b treatment compared with placebo were fever, headache, chills and erythema at the injection site. The majority of these reactions were mild in intensity and were relieved by the administration of paracetamol (acetaminophen). There were fewer reactions when IFN'Y-1b was administered at bedtime than when given at other times of the day. Adverse effects were more frequent with increasing age, with flu-like symptoms occurring twice as frequently in patients aged more than 10

Interferon Gamma-l b: A Review

119

years compared with those aged less than 10 years. Four patients receiving IFN'Y-I b had to be withdrawn from treatment because of toxicity: rash (1); flu-like symptoms (2) and worsened granulomatous colitis (I). No differences were observed in haematological and biochemical test values, rheumatoid factor or antinuclear antibodies, ESR, thyroid function and sex hormone levels in the IFN'YIb and placebo groups. Neutralising ant ibodies to IFN'Y-I b were not detected in any of the 54 patients receiving treatment for whom testing was performed. IFN'Y-Ib has been administered by intramuscular injection or intravenous infusion in other diseases at generally higher dosages (> 100Jlg/m2/day) than are used in chronic granulomatous disease (usually 50 Jlgfm 2 3 times weekly). All the adverse reactions previously described in patients with chronic granulomatous disease were seen at the higher dosages (data on file, Genentech). However, other rare adverse reactions occurred with higher dosages: cardiovascular (hypotension, syncope, tachyarrhythm ia, heart block, heart failure and Table III. Percentage of patients free from serious infection 12 months after randomisation adjusted for stratification factors (ICGDCSG 1991)

Variable

No. of patients (n = 128)

Percentage of patients without serious infection (%)

IFNr1b

placebo

81 73

20 34

79 71

33 39

78 69

33 28

76 83

28 56

77

30

Age

< 10 years

52 76 '" 10 years Pattern of inheritance x-Linked 86 Autosomal recessive 42 Prophylactic antibiotic use Yes 111 No 17 Sex Male 104 Female 24 Overall percentage

Table IV. The most common clinical adverse events occurring during the ICGDCSG (1991) trial comparing IFNr1b and placebo in patients with chronic granulomatous disease Adverse reaction

Patients with reaction (%)

Fever Headache Rash Chills Injection site erythema or tenderness Fatigue Diarrhoea Vomiting Nausea Weight loss Myalgia Inflammatory process requiring steroid therapy Anorexia Arthralgia Injection site pain Symbol: • significantly (p

IFNr1b (n = 63)

placebo (n = 65)

52' 33' 17 14' 14'

28 9 6 0 2

14 14 13 10 6 6 6

11 12 5 2 6 0 6

3 2 0

5 0 2

< 0.05) higher than placebo.

myocardial infarction); central nervous system (confusion, disorientat ion, gait disturbanc e, Parkinsonian symptoms, seizure, hallucinations and transient ischaemic attacks);haematological (deep vein thrombosis and pulmonary embolism); pulmonary (tachypnoea, bronchospasm and interstitial pneumonitis); metabolic (hyponatraemia and hyperglycaemia); and others (hepatic insufficiency, gastrointestinal bleeding, pancreatitis, reversible renal insufficiency and exacerbation of dermatomyositis).

6, Drug Interactions The potential for IFN'Y-Ib to interact with other drugs has not been fully evaluated. IFN'Y-I b should be cautiously adm inistered in patients with bone marrow suppression: reversible neutrop enia and hepatic enzyme increases can be dose limiting at doses greater than 250 Jlg/m 2/da y, and thrombo-

120

cytopenia and proteinuria have been seen rarely. It should be noted that the usual dosage in patients with chronic granulomatous disease is much lower than this level, usually 50 JLg/m 2 3 times daily. Animal studies using species-specific IFNI' in rodents have indicated decreases in hepatic microsomal cytochrom e P450 concentrations, suggesting a potential to decrease the metabolism of drugs degraded by this pathway.

7. Dosage and Administration The recommended dosage of IFN'Y-lb for the treatment of patients with chronic granulomatous disease is 50 JLg/m 2 (1.5 X 106 U/m 2) subcutaneously 3 times weekly for those with a body surface area greater than 0.5m 2. When body surface area is ~ 0.5m 2 , the dose should be calculated by bodyweight as 1.5 JLg/kg, also administered subcutaneously 3 times weekly. The optimum sites for injection are the right and left deltoid and anterior thigh. If any severe adverse reaction occurs the dose can be halved or therapy should be withdrawn . It is worthwhile noting a recent case report (Dorenbaum et al. 1991) of a patient whose dose was halved from 50 to 25 jLg/m 2 after 16 months' therapy , because of the appearance of significant fever, chills and headache not responding to paracetamol and diphenhydramine. Within 13 weeks from dose reduction the patient developed S. marcescens osteomyelitis, despite being relatively free of problems during long term treatment. While this is not definite evidence of an increased risk of infection during dosage reduction , it would appear to warrant further study to establish more precise dose definition for IFN'Y-l b. IFN'Y-l b is supplied as a sterile aqueous solution in single-dose vials. Vials should be stored at 2 to 8°C, and never frozen. The vial must not be vigorously shaken or left at room temperature for more than 12 hours. As the formulation does not contain preservative, once opened any unused portion of the vial should be discarded. 1FN'Y-lb is contraindicated in patients with known hypersensitivity to IFNI', E. coli-derived products or any component of the formulation.

Drugs 43 (1) 1992

Furthermore, caution should be exercised in patients with pre-existing cardiac disease (including symptoms of ischaemia, congestive heart failure or arrhythmia) as these may be exacerbated by the acute, transient · 'flu-like' or constitutional symptoms such as fever and chills, often associated with dosages 0£250 JLg/m 2/day or higher. In addition, care is required when treating patients with known seizure disorders or compromised CNS function, as adverse CNS reactions (including decreased mental status, gait disturbance and dizziness) have been observed, in particular with dosages of 250 JLg/m 2/day or higher. The effectiveness and tolerability of IFN'Y-l b have not been established in children aged less than 1 year. It is not known whether IFN'Y-l b is transferred into breast milk; as a precaution, it may be appropriate to discontinue nursing or withdraw the drug. The safety of the drug during pregnancy has not been established.

8. Place of Interferon Gamma-Ib in Therapy In the past, the only treatment for the often serious, life-threatening infections occurring in patients with chronic granulomatous disease has been a direct aggressive approach, including prompt surgical drainage of abscesses, prolonged use of systemic antimicrobial agents, and white blood cell transfusions. M6re recently, the long term use of prophylactic ant imicrobial agents, in particular cotrimoxazole, has improved the prognosis of patients by increasing thy interval between life-threatening infections. Although the future may hold some promise for correction of the underlying genetic disorder by HLA-matched bone marrow transplantation or gene therapy, serious infection currently remains a significant cause of morbidity in patients with chronic granulomatous disease and alternative prophylactic treatments are required . Clinical studies of treatment with IFN'Y-l b in various other disease states have shown an enhancement of normal phagocytic function , and preclinical studies with 1FN'Y-l b have indicated a correction in deficient phagocytic NADPH oxi-

Interferon Gamma-Ib: A Review

dase-related function in at least some patients with chronic granulomatous disease. A placebo-controlled trial was therefore undertaken with IFN-yIb in a large number of patients with chronic granulomatous disease. In this stud y, long term prophylactic treatment with a relatively low dosage of If'Nv-Ib (compared with that used in man y other disease states) led to a statistically and clinically significant reduction in the incidence of serious clinical events requiring hospitalisation. The greatest benefit of IFN-y-I b was conferred to patients aged less than 10 years, although all patients, regardless of age, pattern of genetic inheritance, prophylactic antibiotic use or sex, derived some benefit. Treatment was generally well tolerated and only rarely did adverse effects necessitate treatm ent withdrawal. Adverse clinical effects were usually mild and transient (fever, headache , chills and erythema at the injection site), and were often relieved by symptomatic treatment. The occasional more severe adverse effects associated with higher dosages ofIFN-y-1 b were not encountered. IFN-y-l b therefore offers an effective and welltolerated therapy for patients with chronic granulomatou s disease and a significant clinical advance in the treatm ent of this rare genetic disorder by improvi ng prognosis of its serious, life-threatenin g infectious man ifestations.

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