Drugs Ther Perspect (2015) 31:213–220 DOI 10.1007/s40267-015-0222-0

ADIS DRUG CLINICAL Q&A

Interferon c-1b in chronic granulomatous disease and severe malignant osteopetrosis: a guide to its use in the USA Katherine A. Lyseng-Williamson1

Published online: 9 June 2015  Springer International Publishing Switzerland 2015

Abstract In the USA, subcutaneous interferon c-1b (Actimmune) is indicated to reduce the frequency and severity of serious infections associated with chronic granulomatous disease and delay the time to disease progression in patients with severe malignant (autosomal recessive) osteopetrosis. The mechanism of action of interferon c-1b in these conditions is complex and involves factors that are additional to the stimulation of superoxide production by phagocytes. The primary tolerability issues associated with interferon c-1b are mild to moderate fever and other flu-like symptoms, which are generally manageable with symptomatic treatment.

Adis evaluation of subcutaneous interferon c-1b in chronic granulomatous disease and osteopetrosis What are its key clinical benefits? Reduces the frequency and severity of serious infections in patients with chronic granulomatous disease Delays disease progression in patients with severe malignant (autosomal recessive) osteopetrosis Has an acceptable tolerability profile, with adverse events generally being predictable and manageable What are its key limitations? Paucity of clinical trial data, especially in patients with osteopetrosis

& Katherine A. Lyseng-Williamson [email protected] 1

Springer, Private Bag 65901, Mairangi Bay, 0754 Auckland, New Zealand

What is the rationale for using interferon c-1b in these conditions? Chronic granulomatous disease (CGD) [1–6] and congenital osteopetrosis [7–10] represent groups of rare hereditary disorders. Both disorders are associated with immunodeficiency related to deficits in the leukocyte production of superoxidase. Patients with CGD have defects in the leukocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex [1–3]. CGD has a heterogenous presentation [1–3], with X-linked and recessive forms of the disease being linked to a number of mutations in the five structural genes of the NADPH oxidase [1, 2, 4]. As NADPH oxidase is the enzyme responsible for the production of phagocyte-derived superoxide and related reactive oxygen intermediates (ROIs), defects in this enzyme lead to patients with CGD being unable to produce superoxides and ROIs in quantities that are sufficient for the normal killing of bacteria and fungi [5]. As a result, patients with CGD may frequently develop life-threatening bacterial and fungal infections, as well as a predisposition for granulomatous complications and autoimmune disorders [1, 2, 6]. Osteopetrosis is associated with increased bone density resulting from decreased bone resorption due to defects in osteoclast formation and function [7–10]. The heterogenetic disorder is associated with mutations in a number of genes involved in osteoclastic function [7, 10]. The more severe autosomal recessive form of osteopetrosis (also referred to as malignant osteopetrosis or severe malignant osteopetrosis) generally presents within the first few months of life, is associated with life-threatening complications, such as bone marrow failure, and other serious complications (e.g. changes to the bones of the skull

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resulting in blindness, deafness, facial palsy and dental problems, fractures, osteomyelitis, short stature and hypocalcaemia), and a diminished life expectancy. Patients with the relatively less severe autosomal dominant forms of the disease generally present in late childhood or adolescence, primarily have complications related to the skeleton (most commonly fractures, scoliosis, hip osteoarthritis, and osteomyelitis, but may have cranial nerve compression leading to hearing and vision loss) and generally have a normal life expectancy [7, 10]. Many osteopetrotic patients display defects in the production of leukocyte superoxide, which may result in abnormal bone resorption by osteoclasts, as normal resorption requires the presence of superoxides and ROIs [8]. The pharmacological management of these conditions includes reducing the risk of serious infections (i.e. infections that require hospitalization and/or the use of intravenous antibacterials) in patients with CGD [1, 6] and preventing disease progression in patients with severe malignant (autosomal recessive) osteopetrosis [7, 8]. As interferon c has been shown to stimulate superoxide production by phagocytes (deficits in which have been associated with both disorders), the efficacy of a recombinant human formulation of interferon c-1b has been investigated and approved in the treatment of CGD and severe malignant osteopetrosis [11, 12]. This article discusses the use of recombinant interferon c-1b to treat these conditions as approved in the USA, where the drug is marketed as Actimmune [11].

How does interferon c-1b work? The biological activity of interferon c-1b, a recombinant DNA product derived from Escherichia coli, is identical to that of natural human interferon c [13]. The activity of interferon c-1b is complex; specific effects include enhancing the oxidative metabolism of phagocytic cells (e.g. macrophages and leukocytes), providing antibody dependent cellular cytotoxicity, activating natural killer cells, and expressing Fc receptors and major histocompatibility antigens [11, 12]. The precise mechanism of action of exogenous interferon c-1b in the treatment of CGD and severe malignant osteopetrosis has not been established [11, 12], as findings from studies investigating its effects on the stimulation of superoxide production remain equivocal [1]. When treating patients with CGD and osteopetrosis with interferon c-1b, predictions of the efficacy of treatment and assessments of patient response should not be based on changes in superoxide levels [11]. In in vivo and in vitro studies in normal phagocytes, interferon c increased the production of superoxide and

ROIs via the NADPH oxidase pathway [13–16]. However, interferon c-1b did not consistently enhance defective phagocyte function in cell lines from patients with CGD in preclinical trials [17–23], and was not associated with increases in superoxide production (even in treatment responders) relative to placebo in a clinical trial in CGD patients [24]. Interferon c-1b enhanced osteoclast function in preclinical vitro studies [8, 25–28], and significantly enhanced bone resorption and leukocyte production of superoxide function in clinical studies in patients with severe malignant osteopetrosis [29, 30]. In a recent mouse model of autosomal dominant heterozygous osteopetrosis, substantial improvements in osteopetrotic phenotypes were shown with all doses of interferon c-1b; in contrast, calcitriol (at any dose) did not improve osteopetrotic phenotypes, and high doses were associated with additional increases in bone mass [31].

For whom is interferon c-1b indicated in the USA? In the USA, interferon c-1b is indicated for [11]: •

•

reducing the frequency and severity of serious infections (i.e. infections that require hospitalization and/or the use of intravenous antibacterials) in patients with CGD; delaying the time to disease progression in patients with severe malignant (autosomal recessive) osteopetrosis.

Table 1 presents a summary of the US prescribing information for interferon c-1b in these indications. Consult local prescribing information for further details.

What is the clinical efficacy of interferon c-1b? Clinical data regarding the efficacy of subcutaneous interferon c-1b in the treatment of CGD and severe malignant (autosomal recessive) osteopetrosis are limited due to the rare nature of these genetic conditions. In all studies and reports, interferon c-1b was administered subcutaneously three times weekly, with the dosage adjusted according to body surface area (BSA) [i.e. 1.5 lg/kg/dose in patients with a BSA B0.5 m2 and 50 lg/m2 in patients with a BSA [0.5 m2]. In patients with chronic granulomatous disease Interferon c-1b reduced the frequency of serious infections (defined as a clinical event requiring both hospitalization and the administration of parenteral antibacterials) in patients with CGD [24]. This result was shown in a key

215 Table 1 Prescribing summary of interferon c-1b (Actimmune) in the USA [11] What are its approved indications? Chronic granulomatous disease

To reduce the severity and frequency of serious infections

Severe malignant osteopetrosis

To delay time to disease progression

What is its recommended dosage and administration? Patients with BSA [0.5 m2 2

50 lg/m2 administered subcutaneously three times weekly

Patients with BSA B0.5 m

1.5 lg/kg/dose administered subcutaneously three times weekly

Dosage modification for severe adverse effects

Modify dosage (; dosage by 50 % or interrupt therapy until the reaction abates)

Other comments

Optimum injection sites: right and left deltoid and anterior thigh ‘Flu-like’’ symptoms (most common type of adverse experiences): may be minimized by bedtime administration; fever and headache may be prevented or partially alleviated by paracetamol (acetaminophen)

What is its availability and stability, and how should it be stored? Availability

Single-use vial containing 100 lg of interferon c-1b in 0.5 mL of solution for injection

Storage

Refrigerate at 2–8 C (36–46 F) Avoid excessive or vigorous agitation; do not shake

Stability

Discard vials that are left at room temperature for a total time of [12 h prior to use Discard any unused portion of an entered vial

What warnings and precautions should be followed with regard to hypersensitivity reactions? Patients who develop or have known hypersensitivity to IFN- c, Escherichia coliderived products or any product component

Use is contraindicated

Patients who develop acute serious hypersensitivity reactions

Discontinue treatment immediately and institute appropriate medical therapy

Patients with transient cutaneous rashes

Treatment interruption is rarely necessary

What warnings and monitoring recommendations should be followed with regard to hepatic toxicity? Liver function monitoring

Perform liver function tests prior to the beginning of and at 3-month intervals during treatment (levels of AST and/or AST may :; reversible with dosage ; or interruption) Children aged \1 year: monitor liver function monthly (: hepatic enzymes levels are more common in children aged \1 year than in older children)

What other warnings and monitoring recommendations pertain to its use? Cardiovascular disorders

Use with caution in patients with pre-existing cardiac conditions, including ischaemia, congestive heart failure and arrhythmia (such conditions may potentially be exacerbated by the acute and transient ‘flu-like’ symptoms induced by IFN- c)

Neurological disorders

Use with caution in patients with seizure disorders or compromised CNS function (; mental status, gait disturbance and dizziness have been observed with IFN- c; most abnormalities were mild and reversible within a few days of a ; in dose or IFN- c discontinuation)

Bone marrow toxicity

Use with caution in patients with myelosuppression (reversible neutropenia and thrombocytopenia have been observed during IFN- c treatment; can be severe and may be dose related) Perform haematological tests (including complete blood counts, differential and platelet counts) prior to beginning therapy and at 3-month intervals during therapy

Other laboratory tests

Perform renal function tests and urinanalysis prior to beginning therapy and at 3-month intervals during therapy

How should it be used in women who are pregnant or breast-feeding? Women who are pregnant

Use only if the potential benefit justifies the potential risk to the fetus

Women who are breast-feeding

Discontinue either breast-feeding or the drug, depending on the importance of IFN- c therapy to the mother

What potential drug interactions are associated with its use? Other potentially myelosuppressive agents

Use concomitantly with caution (: risk of bone marrow toxicity)

Drugs that are metabolised by CYP enzymes

Potential for : exposure to certain drugs (based on preclinical animal studies)

BSA body surface area, CYP cytochrome P450, IFN- c interferon c-1b, : increase(d), ; decrease(d)/reduce

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randomized, double-blind placebo-controlled 1-year trial in patients with confirmed CGD who had neutrophil superoxide production B20 % of normal, preserved renal, hepatic and haematological function and a minimum life-expectancy of 3 months, and who did not have an active infection requiring hospitalization, severe cardiac disease or a confirmed seizure disorder [24]. Baseline characteristics did not differ significantly between patients in the interferon c-1b (n = 63) and placebo (n = 65) groups of the trial [24]. Across treatment groups, the mean patient age was 14.6 years (range 1–44 years [11]), 81 % of patients were male, 67 % had an X-linked pattern of inheritance, 87 % were receiving prophylactic antibacterial therapy (i.e. trimethoprim-sulfamethoxazole or dicloxacillin) and 2 % were receiving corticosteroids (permitted only if they had previously been receiving B10 mg/day of prednisone at the same dosage for at least 1 month prior to study enrolment) [24]. The treatment period was completed by 87 % of the 128 eligible patients (57 and 54 in the interferon c-1b and placebo groups, respectively), with an average treatment duration of 8.9 months (equivalent to 95 patient-years) [24]. Following treatment for 1 year, the proportion of patients who had at least one serious infection was significantly lower with interferon c-1b than with placebo (22 vs. 46 %; p = 0.0006) [24]. Based on Kaplan–Meier analysis of the time to first serious infection (primary endpoint), a significantly greater proportion of interferon c1b than placebo recipients were free from serious infection at 1 year (77 vs. 30 %; p = 0.0006), which equates to a 67 % reduction in the relative risk of serious infection during interferon c-1b therapy [relative risk (RR) 0.33; 95 % CI 0.17–0.64] [24]. At 6 months, corresponding values were 89 vs. 72 %, indicating a progressive beneficial effect during the first year of treatment. Other endpoints that improved to a greater extent with interferon c-1b than with placebo at 1 year included the following [24]: •

•

The total number of serious infections, including recurrent events (20 vs. 56 infections; p \ 0.0001). The variability of the estimate of treatment effect was reduced by the addition of this information (RR 0.33; 95 % CI 0.20–0.56). Interferon c-1b appeared to be most effective in reducing the incidence of adenitis, abscesses, cellulitis and pulmonary infections. Total length of hospitalization for the treatment of clinical events (497 vs. 1493 days) and mean length of hospitalization (32 vs. 48 days; p = 0.02). In addition, fewer interferon c-1b than placebo recipients were hospitalized for [28 days (6 vs. 13 patients).

In subgroup analysis, interferon c-1b reduced the frequency of serious infections in patients with CGD

regardless of age, pattern of inheritance, prophylactic antibacterial use and gender [24]. The greatest benefit was shown in children aged\10 years (proportion of interferon c-1b recipients free from serious infection at 1 year was 81 % in patients aged \10 years and 73 % in those aged C10 years) [24]. The benefits of interferon c-1b in patients with CGD were maintained with long-term treatment [32]. The 1-year trial [24] was followed by open-label, uncontrolled extension study to assess the long-term clinical efficacy of interferon c-1b in patients with CGD [32]. Patients (n = 76) were observed for up to 9 years (equivalent to 328.4 patient-years of interferon c-1b treatment). During the follow-up study, there was a total of 98 serious infections, providing a rate of 0.30 serious infections per patient-year [32] (compared with 0.38 infections per patient-year in interferon c-1b recipients and 1.1 infections per patient-year in placebo recipients in the 1-year controlled trial) [24]. In subgroup analysis that stratified patients by their age at commencement of interferon c-1b therapy (i.e. B4, 5–12, 13–18 and[18 years), there was no significant between-group difference in the rate of serious infections (0.35, 0.36, 0.20 and 0.29 infections per patientyear, respectively) [32]. Interferon c-1b has also been used to treat patients with CGD in the clinical practice setting [33–37]. For example, in a retrospective review of 26 patients with CGD in a single US hospital, 24 patients were receiving treatment with interferon c-1b and prophylactic antibacterials [37]. After a mean follow-up of 9.8 years from time of diagnosis (equivalent to 3159 patient-months), 23 patients were alive without having undergone haematopoietic stem cell transplantation (HSCT). The rate of serious infections was 0.35 per patientyear, with pneumonia/lung abscess, liver abscess and brain abscess being the most commonly reported serious infections (31, 12 and 2 cases, respectively) [37]. In patients with severe malignant osteopetrosis The combination of interferon c-1b plus calcitriol delayed disease progression relative to calcitriol alone in patients with severe malignant osteopetrosis. In a small controlled trial [11], 16 patients (mean age 1.5 years; range 1 month to 8 years) were randomized to receive interferon c-1b plus calcitriol (n = 11) or calcitriol alone (n = 5). The median time to disease progression (defined as death, a significant reduction in haemoglobin or platelet counts, a serious bacterial infection requiring antibacterial treatment or a 50 dB decrease in hearing or progressive optic atrophy) was not reached in the interferon c-1b plus calcitriol group (estimated to be at least 165 days based on observed data), which was significantly longer than the median of 65 days in the calcitriol alone group (p-value not reported).

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The frequency of serious infections was also lower with interferon c-1b plus calcitriol [12]. Moreover, in a pooled analysis of this and another study (n = 24), trabecular bone volume was reduced from baseline in the majority (79 %) of patients treated with interferon c-1b with or without calcitriol for at least 6 months [11]. Treatment with interferon c-1b also significantly (p B 0.05) improved leukocyte function (as measured by superoxide production) and enhanced bone resorption and haematopoiesis (as measured by biochemical markers, bone marrow imaging and bone biopsies) in noncomparative clinical studies in patients with osteopetrosis [29, 30]. No serious infections were reported in a 6-month study in which eight paediatric patients (mean age 3 years; range 1 month to 11 years) received interferon c-1b [29]. In a longer-term study [30], 14 patients (12 children with a mean age of 4 years and 2 adults aged 25 and 30 years) received interferon c-1b for up to 18 months [30]. The clinical condition of all 11 patients treated with interferon c-1b for the full 18 months stabilized or improved [30]. In six patients with baseline infection data, the frequency of serious infections significantly (p = 0.02) decreased from a baseline rate of 5.5 per patient-year to 0.2 per patient-year [30].

What is the tolerability profile of interferon c-1b? The tolerability of subcutaneous interferon c-1b is generally acceptable in patients with CGD and severe malignant osteopetrosis, with a tolerability profile consistent with that expected with interferon treatment. In the key trial in patients with CGD, the treatmentemergent adverse effects (TEAEs) that were reported in a significantly greater proportion of interferon c-1b recipients than placebo recipients were limited to fever, headache, chills and erythema or tenderness at the injection site (Fig. 1), and were of generally of mild severity [24]. Steroid therapy to treat an inflammatory process was required by 6 % of patients in each treatment arm [24]. Few patients withdrew from interferon c-1b treatment because of a TEAE (one patient each with skin rash and worsening granulomatous colitis, and two patients with constitutional symptoms) [24]. Administration of interferon c-1b at bedtime minimized ‘flu-like’ symptoms and concomitant administration of paracetamol (acetaminophen) partially alleviated fever and headache [24]. Of note, the severity of flu-like symptoms may be reduced by initially titrating the dosage of interferon c-1b over a short 2-week period [38]. In a crossover study in 40 healthy volunteers [38], titration of interferon c-1b (i.e. 15 lg/m2 three times weekly during week 1, then 30 lg/m2 three times weekly during week 2, and then the full dosage of 50 lg/m2 three times weekly during week 3) was associated with a lower mean change from baseline in

flu-like symptom severity score at 8 h post-injection than no titration of interferon c-1b (i.e. 50 lg/m2 three times weekly during weeks 1–3); the difference between regimens was significant (p = 0.02) when adjusted for dropout and treatment length. Long-term interferon c-1b treatment was also well tolerated, with reported TEAEs generally being those expected with interferon c-1b [32]. In the long-term follow-up trial, most (73 %) TEAEs were mild or moderate in severity, with fever being the most common reported TEAE [32]. Severe TEAEs were reported in 17 % of patients, but treatment with interferon c-1b was not directly attributed to any life-threatening event. TEAEs were the reason for three (4 %) patients withdrawing from treatment (one case of recurrent exacerbations of ureteral granulomata and two cases of myalgia) [32]. Interferon c-1b is well tolerated in patients of all ages, including young children [24, 32]. When the incidence of TEAEs in the key trial in CGD was evaluated by age group, children aged B5 years had the lowest overall incidence, and those aged \10 years had a incidence of constitutional symptoms (e.g. fever, headache, chills, myalgia and fatigue) that was about half that in patients aged C10 years [24]. In the long-term follow-up study, however, there was no significant difference between children aged B12 years and those aged [12 years with regard to the overall incidence of TEAEs or the incidence of or specific TEAEs, with the exception of a borderline statistically significant higher incidence of myalgia in patient aged [12 years (0 vs. 7 events; p = 0.048) [32]. Treatment with interferon c-1b was not associated with disturbances in growth and development in the key clinical trial in patients with CGD [24] and its long-term extension study [32]. Likewise, post-marketing safety data from 37 children aged \3 years of age with CGD indicated that treatment with interferon c-1b did not affect height, weight and endocrine maturation [11]. Clinically significant TEAEs reported in interferon c-1b recipients aged \3 years include one case each of Steven-Johnson Syndrome, granulomatous colitis, urticarial and atopic dermatitis, and two cases of hepatomegaly [11]. The tolerability profile of interferon c-1b in patients with severe malignant osteopetrosis is similar to that in patients with CGD [11]. In the small noncomparative clinical studies, interferon c-1b was generally well tolerated with the most common TEAEs being transient fever and diarrhoea (severe cases of which responded to a reduction in dosage), and hypocalcaemic tetany (which responded to a 25 % increase in calcium intake) [29, 30]. As hepatic function may be affected by interferon c-1b [11], liver function tests should be performed before and during interferon c-1b therapy (Table 1). AST and/or ALT levels have been elevated by up to 25-fold from baseline

218 Fig. 1 Most commonly reported treatment-emergent adverse events in a randomized, double-blind trial of subcutaneous interferon c-1b three times weekly (n = 63) vs. placebo (n = 65) in patients with chronic granulomatous disease [24]. *p = 0.01, **p = 0.001. h indicates zero

*

Fever **

Headache Rash **

Chills

*

Injection-site erythema/tenderness Fatigue Diarrhoea

Interferon γ-1b Vomiting Placebo Weight loss Nausea Myalgia Anorexia Arthralgia Injection-site pain 0

10

20

30

40

50

60

Patients (%)

during treatment with interferon c-1b, with the incidence appearing to be higher in children aged \1 year than in those who are older [11]. Reducing the dosage of interferon c-1b or interrupting treatment reversed the elevated transaminase levels. Special precautions should be taken because of the potential risk of certain specific adverse events that have been reported with the use of interferon c-1b therapy (Table 1); these events include reversible bone marrow toxicity and, particularly with very high dosages ([10 9 the weekly recommended dosage), neurological disorders and the exacerbation of pre-existing cardiac conditions [11]. Neutralizing antibodies to interferon c-1b have not been detected in patients with CGD receiving interferon c-1b [11, 24].

What is the current clinical positioning of interferon c-1b? Subcutaneous interferon c-1b is a valuable agent to reduce the frequency and severity of serious infections associated with CGD, and delay the time to disease progression and

reduce the frequency of severe infections in patients with severe malignant (autosomal recessive) osteopetrosis. The mechanism of action of interferon c-1b in these conditions is complex and involves factors that are additional to the stimulation of superoxide production by phagocytes. Although CGD used to be associated with early fatality, it may now be effectively managed with interventions such as prophylactic treatment with interferon c-1b, antibacterials, antifungals to reduce the frequency and severity of serious infections, and curative treatment with HSCT [1, 6]. Treatment with interferon c-1b significantly reduces the frequency of serious infections in patients with all genetic types of CGD [24], with its beneficial effects being maintained with long-term therapy [32]. The management of osteopetrosis include supportive treatment of specific symptoms, prophylactic treatment with interferon c-1b and/or calcitriol to normalize bone resorption and thereby prevent disease progression, and HSCT in patients with the most severe forms of the disease [7, 8]. Relative to calcitriol alone, interferon c-1b plus calcitriol delayed disease progression [11] and reduced the frequency of serious infections [12]. These clinical results are supported by the findings of a recent mouse model of

219

dominant osteopetrosis in which substantial improvements in osteopetrotic phenotypes were shown with interferon c1b, but not with calcitriol [31]. Although calcitriol (generally in combination with a low calcium diet) has been shown to indirectly stimulate bone resorption in some patients with osteopetrosis, it provides little to no benefits with regard to improving the immunological defects associated with the disease [8]. Although TEAEs are common in patients receiving interferon c-1b, most are mild to moderate in severity, involve fever and other flu-like symptoms, and may be alleviated by prophylactic administration of paracetamol and/or administration of interferon c-1b at bedtime (Table 1). Recommendations for patient monitoring, dose modification, treatment interruption or discontinuation and other precautions (Table 1) should be followed in order to minimize the risk of hepatic toxicity and other potentially serious adverse events. Acknowledgments The manuscript was reviewed by: B.S. Katz, Northwestern University Feinberg School of Medicine, Chicago, USA; S. Saluja, Saran Ashram Hospital, Dayalbagh, Agra, India Disclosure This article was written by a salaried employee of Adis/ Springer and was not supported by any external funding. During the peer review process, the manufacturer of the agent under review was offered an opportunity to comment on the article. Changes resulting from comments received were made by the author on the basis of scientific merit.

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