- Email: [email protected]
Interferon beta-1b
Interferon beta-1b
Background
Mechanism of action
Multiple sclerosis (MS) affects between 1 and 1-25 million persons world wide.’ Prevalence rates in the USA and Europe range from 15 to 145 per 100 000. Disease susceptibility seems to be influenced by genetic determinants, distance of residence from the equator, and possibly by age of exposure to certain infectious agents. 2,3 Patients with MS experience various neurological symptoms including disturbances of vision, coordination, sensation, gait, and endurance, and of bowel, bladder, and sexual function. The clinical course is unpredictable, with recurrent attacks (exacerbations) that are often punctuated or followed by more insidious progression of functional impairment. The socioeconomic consequences of the disease are considerable-eg, between 1981 and 1982, 75-85% of MS patients in the USA, the UK, and Australia were unemployed, and these individuals are at particular risk of social isolation.4-6 The cause of MS remains unknown. Convergent lines of immunological, genetic, and epidemiological evidence suggest that tissue injury results from a misdirected immune response to one or more myelin antigens. Results of therapeutic trials with immunomodulatory agents support this concept since treatments that augment immune function have exacerbated disease activity, whereas immunosuppressive and immunomodulating treatments have produced modest clinical benefits.’ Limited efficacy, troublesome side-effects, and toxicity associated with existing treatments have spurred researchers to develop better disease-modifying therapies. The rationale for investigating interferons as potential disease-modifying agents in MS arose from: (a) their antiviral and immunomodulatory properties; (b) their limited toxicity during clinical use;9 and (c) the observation that cells isolated from patients with MS have deficient production of both type I (interferon alpha and interferon beta) and type II (interferon gamma) interferons.lo Recombinant (synthesised in cell cultures programmed with interferon genes) interferons have greater appeal as potential therapies than their natural (purified from cell cultures stimulated to produce interferon) counterparts because of their greater purity and availability. Recombinant interferon beta-lb (Betaseron, Berlex Laboratories) is the first biological drug tested in phase III clinical trials to reduce significantly both the rate of MS-related exacerbations and the number of new lesions detected on serial magnetic resonance imaging (MRI) scans.",12 These findings led to the expedited approval of this agent in July, 1993, for the treatment of ambulatory relapsing-remitting MS patients in the USA. Other recombinant interferon beta products for use in MS are also being developed (Biogen; Ares-Serono).
Interferon
UCSF/Mount Zion Multiple Sclerosis Center, 1600 Divisadero, San Francisco, CA 94115-1610, USA (D E Goodkin MD)
beta-lb
is
synthetic analogue (165 Da) of recombinant human interferon beta produced in Escherichia coli. The analogue differs from native interferon beta in that it: (a) is not produced in mammalian cells; (b) is not glycosylated; (c) has a serine substitution for cysteine at position 17; and (d) lacks the N-terminal methionine. Despite these aminoacids,
a
18 500
differences interferon beta-lb binds to the same receptor sites as native interferon beta.’3 Receptor binding is thought to initiate the biological effects of the analogue. Although the mechanisms by which interferon beta-lb produces therapeutic benefits are unknown, several drug-related activities may be relevant to the immunopathogenesis of MS.14 The analogue inhibits viral replication,15 and is a potent antiproliferative agent. 16 Among its immunomodulatory activities are the ability to increase (a) cytotoxicity of natural killer cells," (b) phagocytic activity of macrophages;18 (c) antibodydependent cytotoxicity of polymorphonuclear leucocytes and killer cells;19 (d) expression and shedding of human leucocyte antigens and tumour-associated antigens;19 and (e) suppressor cell function in vitro.2O Additionally, the drug reduces interferon gamma secretion by activated lymphocytes, production of tumour necrosis factor by macrophages, and expression of interferon-gammainduced class II major histocompatibility antigens on antigen-presenting glial cells.
Clinical
phamacokinetics
Intensive investigation of the pharmacokinetics of interferon beta-lb has been hampered by the lack of an accurate assay for determination of drug concentrations in biological fluids. There is no information on the pharmacokinetics of the dose that has been used clinically, and we do not know whether hepatic or renal dysfunction interferes with elimination.
Efficacy Natural fibroblast interferon beta was originally administered intrathecally to 20 MS patients in a randomised placebo-controlled but unblinded pilot study.2’ The intrathecal route was chosen because it was uncertain whether interferon would cross the blood brain barrier. Fewer exacerbations were experienced by the actively treated patients, and this encouraging result was subsequently confirmed in a randomised double-blind trial. 22 Two identical placebo-controlled phase III clinical trials of subcutaneously administered interferon beta-lb conducted simultaneously in the USA and Canada have also documented treatment benefits in actively treated ambulatory relapsing-remitting MS patients. 11,12 The pooled results from these studies deserve careful scrutiny. 372
independently ambulatory subjects
were
recruited, 1057
least two medically documented acute exacerbations during the 2 years before enrolment. Participants were assigned randomly to one of three treatment groups: (a) placebo, (b) low-dose interferon beta-lb (1-6 million IU); or (c) high-dose interferon betaIb (8-0 million IU). Each treatment was self-administered subcutaneously every other day for 2-3 years. Treatment groups were well matched for various demographic and disease characteristics. Primary endpoints were exacerbation rate and the proportion of patients remaining free from exacerbations. Exacerbations were each
patient having
defined
as
at
"the appearance of
a
new
symptom
or
worsening of old symptoms, attributable to MS; accompanied by an appropriate neurological abnormality; lasting at least 24 hours in the absence of fever; and preceded by stability or improvement for at least 30 days". The high-dose group experienced a 34% reduction in annual on-study exacerbation rate compared with placebo-treated patients during the first 2 years of the study. The proportion of patients who were exacerbation free 2 years after initiating therapy was also significantly greater in the high dose interferon-treated patients. Neutralising antibodies to interferon beta-lb were detected at some time during the study in 11% of the placebo-treated group, 47% of the low-dose drug group, and 45% of the high-dose group. There was no relation between the presence of neutralising antibodies and exacerbation severity or time between exacerbations. Although this study was well designed and showed a measurable treatment effect, there were procedural limitations. An intention-to-treat analysis was planned but not truly accomplished for the primary outcome measures. 65 patients discontinued treatment before 2 years and 123 patients before 3 years. Data from these patients and from those who were withdrawn from the study were censored. Inexplicably, more patients were available for follow-up after 3 years than after 2 years. Additionally, about 20% of the patients who reported exacerbations during the first 2 years did not have neurological verification of their exacerbations within the time required by the protocol. This is worrying since patients receiving interferon were more likely to experience side-effects and their knowledge of treatment assignment might have resulted in biased reporting of exacerbations. Moreover, if one eliminates from the analysis the patients without neurological verification of exacerbations according to protocol, there is no longer a significant difference in exacerbation rates between the treatment groups. Finally, about 25% of the patients in this study experienced sustained progression of disability during 3 years of clinical follow-up, but the proportions of patients experiencing sustained progression of disability did not differ significantly between the treatment groups. Overall, the ultimate clinical significance of the modest reduction in exacerbation rates in the actively treated patients remains uncertain. This study is the first phase III clinical trial to show convincingly an active treatment-related difference in serial MRI activity. 12 The placebo group showed a 17-1%
increase in mean lesion area over 3 years vs a 6-2% decrease in the high-dose interferon group (p=0-002). Subgroup analysis of 52 patients who underwent serial MRI scans every 6 weeks for 2 years showed a 75% reduction in the rate of new lesion formation in the highdose treatment group compared with placebo. These MRI results, as well as the size and multicentre design, 1058
this study from other clinical trials which, in the absence of serial MRI monitoring, have shown similar reductions in exacerbation rates.23,24 The MRI data, used as a surrogate outcome measure in this trial, were pivotal in the deliberations of the Food and Drug Administration (FDA) that ultimately led to the expedited approval of interferon beta-lb for use in ambulatory relapsingremitting MS patients in the USA. FDA approval for marketing of the drug was contingent upon documentation of additional clinical data supporting the drug’s efficacy "within a reasonable amount of time". So far, there are still no convincing clinical data to support the notion that the reduction in new MRI activity observed in MS patients treated with interferon beta-lb translates into a reduction in measurable progression of sustained disability. The results from a double-blind placebo-controlled randomised phase III trial of weekly intramuscular recombinant interferon beta with the Biogen product are anticipated soon, and will be of considerable interest since the primary outcome measure is time to sustained treatment failure as measured by the Kurtzke Expanded Disability Status Scale score. The design of this study relegates exacerbation rates to the status of a secondary outcome measure because of the poor correlation between exacerbation rates and sustained progression of disability. There are other important differences between the Biogen and Berlex studies. The Biogen recombinant product, which is expressed by a mammalian cell line, is glycosylated and is otherwise identical to naturally occurring interferon beta. Interferon beta-lb is expressed by bacterial cells, is not glycosylated, lacks the N-terminal methionine found in the native molecule, and has a serine substitution for cysteine at position 17. These structural differences may explain the observation that neutralising antibodies were found in 45% of the high-dose interferon beta-lb group" and in only 3% of patients treated with the Biogen product. 25 Whether neutralising antibodies will have any effect on dose, route of administration, efficacy, or tolerance of the products is unknown. A separate multicentre study of a recombinant interferon beta in relapsing and secondary progressive MS is being conducted in Europe, Canada, and Australia. The design of this study, sponsored by Ares-Serono, has not been published and results will not be available for at least 2 years.
distinguish
Adverse reactions Treatment with interferon beta-lb is well tolerated. Patient attrition from the phase III trials was attributed to side-effects in 5 of 111 patients in the low-dose group and in 10 of 124 in the high-dose group. Reasons for withdrawal due to treatment effects were: abnormal liver enzymes (3 patients), injection site pain (3), fatigue (3), and cardiac arrhythmia, allergic reaction, nausea, headache, "flu syndrome", confusion, and "felt sick"
(1 each). Adverse reactions and
laboratory abnormalities that are
with interferon beta-lb than significantly with placebo are listed in the table. Additional adverse reactions reported during routine postmarketing surveillance conducted by the manufacturer include transient paralysis, hemiparesis, loss of leg strength, and profound weakness without fever within 5 hours of initiating treatment. The frequency and duration of these adverse reactions have not been determined adequately. more common
ALT=alanine amnotransferase; AST=aspartate aminotransferase.
Table: Adverse reactions and
laboratory abnormalities
Drug interactions There is very little information about drug interactions with interferon beta-lb. In 3 cancer patients treatment with doses of 0-8-71-0 million IU led to a dosedependent inhibition of antipyrine elimination,26 and an unconfirmed report suggests that the drug may inhibit the metabolism of zidovudine in AIDS patients.27 The effect of alternate-day administration of 8-0 million IU on the metabolism of commonly prescribed symptomatic therapies for MS (eg, lioresal, tricyclic antidepressants, oxybutinin, amantadine) is unknown.
Clinical
use
Indications and procedure Interferon beta-lb is administered subcutaneously every other day at a recommended dose of 8-0 million IU. The cost is about US$10 000 a year. Injection supplies and a training videotape have been prepared by Berlex to help patients. Experience suggests that this education session is most effectively conducted in an office or clinic setting by an experienced nurse or physician who observes the patient self-administer the first dose. Interferon beta-lb should be started only after documentation of normal haemoglobin, complete and differential white blood cell counts, platelet count, and routine blood biochemical tests including liver function tests. These tests should also be monitored every third month after starting therapy because of the hepatic and haematological toxicity (table). Rotation of injection sites seems to diminish skin reactions, and flu-like symptoms can be reduced by administration of oral paracetamol or non-steroidal anti-
inflammatory drugs. Interferon beta-lb has been licensed for marketing in the USA only for the treatment of clinically definite, ambulatory, relapsing-remitting MS patients between the ages of 18 and 50. Although the task of identifying such patients might seem easy, experience gained from reviewing the records of patients seeking entry into clincial trials has shown that many patients tend to overestimate the number of exacerbations they have experienced. A pretreatment attack rate has not been specified for approved use of the drug, but an accurate assessment of this rate is essential to realistic therapeutic expectations. Patients should understand that the 34% reduction in attack frequency in the study participants was found only in a trial in which all patients experienced two or more medically documented attacks in the preceding 2 years. Overall clinical judgment will
ultimately guide individual treatment decisions, but doctors enthusiasm for prescribing drug therapy should probably be related directly to the documented exacerbation frequency before treatment and inversely to the severity of functional impairment at the time treatment is being entertained. A practice advisory for using and discontinuing interferon beta-lb therapy has been discussed by an advisory committee to the American Academy of Neurology but has not been widely circulated. Until widely accepted guidelines are published it is appropriate to consider discontinuing drug therapy in the following clinical situations: (a) steady progression of disability for 6 months; (b) annual exacerbation rate during therapy exceeding annual pretreatment exacerbation rate; (c) depression or suicidal ideation; (d) non-compliance; (e) severe adverse reaction; and (/) pregnancy. Although interferon beta-lb has been approved only for ambulatory relapsing-remitting patients between the ages of 18 and 50, there is no reason to assume that there is any biological difference between these individuals and MS patients with a relapsing-progressive clinical course or those who are older than 50 years. There is a feeling that patients who occasionally use devices to help them walk or even non-ambulatory patients with frequent exacerbations may benefit from interferon, but there are no data from randomised controlled trials to support this notion. However, a remaining concern is that side-effects in marginally ambulatory patients may produce more noticeable negative functional consequences than in individuals with lesser degrees of disability. The role of interferon beta-lb in patients whose clinical course has been progressive since onset (primary progressive MS) remains unexplored. It would be unwise to entertain drug use in this clinically, pathologically, and radiologically distinct groups of patients28 until data from controlled clinical trials are available. Contraindications The effects of interferon beta-lb on fertility and reproduction are unknown. The drug has abortifacient activity and should not be given to pregnant women. Although there are no data on excretion of the drug in human milk, use by nursing mothers is discouraged because of a potential adverse reaction in their infants. Safety and efficacy in children under the age of 18 have not been established. Precautions 1 suicide and 4 attempted suicides were reported among 372 study patients during the 3-year trial period. All 5 patients received interferon beta-lb and no attempted suicides were reported in patients receiving placebo. Patients to be treated with the drug should be told about the side-effects of depression and suicidal ideation. Patients who become depressed should be monitored closely and therapy should be stopped if necessary.
Therapeutic potential Recombinant beta interferons may have a use in several other therapeutic areas: (a) patients with isolated idiopathic optic neuritis, brainstem syndromes, or myelopathy who additionally have focally abnormal T2weighted or gadolinium-enhanced brain MRI scans and so are at increased risk of MS; (b) non-ambulatory 1059
MS patients; (c) relapsing MS patients who are older than 50 years; (d) patients with primary progressive MS; and (e) combination therapies with cytokines or other agents. Some examples of potentially effective combination therapies include transforming growth factor beta, which would theoretically augment the inhibitory effect of interferon beta on class II major histocompatibility antigen expression on astrocytes, and soluble tumour necrosis factor alpha receptor which would complex circulating tumour necrosis factor and thereby prevent this pro-inflammatory cytokine from enhancing inflammation at the site of MS plaque development. In addition, anti-adhesion molecule therapy (eg, anti-integrin) might block lymphocyte-endothelial cell interaction in the post-capillary venule and prevent activated lymphocytes from gaining entry to the site of MS plaque formation, and recombinant growth factor therapy might enhance central nervous system
relapsing
remyelination.
References 1 2
3
4
5
6
7
8
9
10
Dean G. How many people in the world have multiple sclerosis? Neuroepidemiology 1994; 13: 1-7. Kurtzke JF. Epidemiologic evidence for multiple sclerosis as an
infection. Clin Microbiol Rev 1993; 6: 382-427. National Center for Health Statistics. Current estimates from the health interview survey, United States, 1989. Vital and health statistics, series 10, no 176. DHHS pub no (PHS) 90-1504. Public health service. Washington, DC: US Government Printing Office, 1990. Gulick EE, Yam M, Touw MM. Work performance by persons with multiple sclerosis: conditions that impede or enable the performance of work. Int J Nurs Stud 1989; 26: 301-11. Maybery CP, Brown CR. Social relationships, knowledge and adjustment to multiple sclerosis. J Neurol Neurosurg Psychiatry 1984; 47: 372-76. Colville PL. Rehabilitation. In: Hallpike JF, Adams CWM, Tourtellotte WW, eds. Multiple sclerosis: pathology, diagnosis, and management. Baltimore: Williams and Wilkins, 1983: 631-54. Rudick RA, Goodkin DE, eds. Treatment of multiple sclerosis: trial design, results and future perspectives. London: Springer-Verlag, 1992. Stiehm ER, Kronenberg LH, Rosenblatt HM, et al. Interferon: immunobiology and clinical significance. Ann Intern Med 1982; 96: 80-93. Merigan TC, Rand KH, Polland RB, et al. Human leucocyte interferon for the treatment of herpes zoster in patients with cancer.
N Engl J Med 1978; 298: 981-87. Neighbor PA, Bloom BR. Absence of virus-induced lymphocyte
1060
suppression and interferon production in multiple sclerosis. Proc Natl Acad Sci USA 1979; 76: 476-80. 11 The IFN&bgr; Multiple Sclerosis Study Group. Interferon beta-lb is effective in relapsing-remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. Neurology 1993; 43: 655-61. 12 Paty DW, Li DKB, UBC MS/MRI Study Group, IFN&bgr; Multiple Sclerosis Study Group. Interferon beta 1-b is effective in relapsingremitting multiple sclerosis. II. MRI analysis results of a multicenter, randomized, double-blind, placebo-controlled trial. Neurology 1993; 43: 662-67. 13 Thompson MR, Zhang Z, Fournier A, et al. Characterization of human beta-interferon-binding sites on human cells. J Biol Chem 1985; 260: 563-67. 14 Steinman L. Autoimmune disease. Sci Am 1993; 269: 106-15. 15 Mark D, Drummond R, Creasey A, et al. A synthetic mutant of interferon beta for clinical trial. In: Kishida T, ed. Proceedings of the International Symposium on Interferons, Japan, 1984: 167-72. 16 Borden EC, Hogan TF, Voelkel J. Comparative antiproliferative activity in vitro of natural interferons alfa and beta for diploid and transformed human cells. Cancer Res 1982; 42: 4948-53. 17 Herberman RR, Ortaldo JR, Bonnard GD Augmentation by interferon of human natural and antibody-dependent cell-mediated cytotoxicity. Nature 1979; 277: 221-23. 18 Huang KY, Donahoe RM, Gordon FB, et al. Enhancement of phagocytosis by interferon-containing preparations. Infect Immun 1971; 4: 581-88. 19 Giacomini P, Aguzzi A, Pestka S, et al. Modulation of recombinant DNA leukocyte (alfa) and fibroblast (beta) interferons on the expression and shedding of HL- and tumor-associated antigens by human melanoma cells. J Immunol 1984; 133: 1649-55. 20 Noronha A, Toscas A, Jensen MA. Interferon beta augments suppressor cell function in multiple sclerosis. Ann Neurol 1990; 27: 207-10. 21 Jacobs L, O’Malley J, Freeman A, et al. Intrathecal interferon reduces exacerbations of multiple sclerosis. Science 1981; 214: 1026-28. 22 Jacobs L, Salazar AM, Herndon R, et al. Intrathecally administered natural human fibroblast interferon reduces exacerbations of multiple sclerosis: results of a multicenter, double-blind study. Arch Neurol 1987; 44: 589-95. 23 Yudkin PL, Ellison GW, Ghezzi A, et al. Overview of azathioprine treatment in multiple sclerosis. Lancet 1991; 338: 1051-55. 24 Bornstein MB, Miller A, Slagel S, et al. A pilot trial of COP I in exacerbating-remitting multiple sclerosis. N Engl J Med 1987; 317: 408-14. 25 Jacobs L, Cookfair D, Rudick R, et al. A phase III trial of intramuscular recombinant beta interferon as treatment for multiple sclerosis: current status. Ann Neurol 1993; 34: 310. 26 Blaschke TF, Homing SJ, Merigan TC, et al. Recombinant betaserinterferon inhibits antipyrine clearance in man. Clin Res 1985; 33: 19A. 27 Nokta M, Loh JP, Douidar SM, et al. Metabolic interaction of recombinant interferon beta and zidovudine in AIDS patients. J Interferon Res 1991; 11: 159-64. 28 Thompson AJ, Kermode AG, Wicks D, et al. Major differences in the dynamics of primary and secondary progressive multiple sclerosis. Ann Neurol 1991; 29: 53-62.
Background
Mechanism of action
Multiple sclerosis (MS) affects between 1 and 1-25 million persons world wide.’ Prevalence rates in the USA and Europe range from 15 to 145 per 100 000. Disease susceptibility seems to be influenced by genetic determinants, distance of residence from the equator, and possibly by age of exposure to certain infectious agents. 2,3 Patients with MS experience various neurological symptoms including disturbances of vision, coordination, sensation, gait, and endurance, and of bowel, bladder, and sexual function. The clinical course is unpredictable, with recurrent attacks (exacerbations) that are often punctuated or followed by more insidious progression of functional impairment. The socioeconomic consequences of the disease are considerable-eg, between 1981 and 1982, 75-85% of MS patients in the USA, the UK, and Australia were unemployed, and these individuals are at particular risk of social isolation.4-6 The cause of MS remains unknown. Convergent lines of immunological, genetic, and epidemiological evidence suggest that tissue injury results from a misdirected immune response to one or more myelin antigens. Results of therapeutic trials with immunomodulatory agents support this concept since treatments that augment immune function have exacerbated disease activity, whereas immunosuppressive and immunomodulating treatments have produced modest clinical benefits.’ Limited efficacy, troublesome side-effects, and toxicity associated with existing treatments have spurred researchers to develop better disease-modifying therapies. The rationale for investigating interferons as potential disease-modifying agents in MS arose from: (a) their antiviral and immunomodulatory properties; (b) their limited toxicity during clinical use;9 and (c) the observation that cells isolated from patients with MS have deficient production of both type I (interferon alpha and interferon beta) and type II (interferon gamma) interferons.lo Recombinant (synthesised in cell cultures programmed with interferon genes) interferons have greater appeal as potential therapies than their natural (purified from cell cultures stimulated to produce interferon) counterparts because of their greater purity and availability. Recombinant interferon beta-lb (Betaseron, Berlex Laboratories) is the first biological drug tested in phase III clinical trials to reduce significantly both the rate of MS-related exacerbations and the number of new lesions detected on serial magnetic resonance imaging (MRI) scans.",12 These findings led to the expedited approval of this agent in July, 1993, for the treatment of ambulatory relapsing-remitting MS patients in the USA. Other recombinant interferon beta products for use in MS are also being developed (Biogen; Ares-Serono).
Interferon
UCSF/Mount Zion Multiple Sclerosis Center, 1600 Divisadero, San Francisco, CA 94115-1610, USA (D E Goodkin MD)
beta-lb
is
synthetic analogue (165 Da) of recombinant human interferon beta produced in Escherichia coli. The analogue differs from native interferon beta in that it: (a) is not produced in mammalian cells; (b) is not glycosylated; (c) has a serine substitution for cysteine at position 17; and (d) lacks the N-terminal methionine. Despite these aminoacids,
a
18 500
differences interferon beta-lb binds to the same receptor sites as native interferon beta.’3 Receptor binding is thought to initiate the biological effects of the analogue. Although the mechanisms by which interferon beta-lb produces therapeutic benefits are unknown, several drug-related activities may be relevant to the immunopathogenesis of MS.14 The analogue inhibits viral replication,15 and is a potent antiproliferative agent. 16 Among its immunomodulatory activities are the ability to increase (a) cytotoxicity of natural killer cells," (b) phagocytic activity of macrophages;18 (c) antibodydependent cytotoxicity of polymorphonuclear leucocytes and killer cells;19 (d) expression and shedding of human leucocyte antigens and tumour-associated antigens;19 and (e) suppressor cell function in vitro.2O Additionally, the drug reduces interferon gamma secretion by activated lymphocytes, production of tumour necrosis factor by macrophages, and expression of interferon-gammainduced class II major histocompatibility antigens on antigen-presenting glial cells.
Clinical
phamacokinetics
Intensive investigation of the pharmacokinetics of interferon beta-lb has been hampered by the lack of an accurate assay for determination of drug concentrations in biological fluids. There is no information on the pharmacokinetics of the dose that has been used clinically, and we do not know whether hepatic or renal dysfunction interferes with elimination.
Efficacy Natural fibroblast interferon beta was originally administered intrathecally to 20 MS patients in a randomised placebo-controlled but unblinded pilot study.2’ The intrathecal route was chosen because it was uncertain whether interferon would cross the blood brain barrier. Fewer exacerbations were experienced by the actively treated patients, and this encouraging result was subsequently confirmed in a randomised double-blind trial. 22 Two identical placebo-controlled phase III clinical trials of subcutaneously administered interferon beta-lb conducted simultaneously in the USA and Canada have also documented treatment benefits in actively treated ambulatory relapsing-remitting MS patients. 11,12 The pooled results from these studies deserve careful scrutiny. 372
independently ambulatory subjects
were
recruited, 1057
least two medically documented acute exacerbations during the 2 years before enrolment. Participants were assigned randomly to one of three treatment groups: (a) placebo, (b) low-dose interferon beta-lb (1-6 million IU); or (c) high-dose interferon betaIb (8-0 million IU). Each treatment was self-administered subcutaneously every other day for 2-3 years. Treatment groups were well matched for various demographic and disease characteristics. Primary endpoints were exacerbation rate and the proportion of patients remaining free from exacerbations. Exacerbations were each
patient having
defined
as
at
"the appearance of
a
new
symptom
or
worsening of old symptoms, attributable to MS; accompanied by an appropriate neurological abnormality; lasting at least 24 hours in the absence of fever; and preceded by stability or improvement for at least 30 days". The high-dose group experienced a 34% reduction in annual on-study exacerbation rate compared with placebo-treated patients during the first 2 years of the study. The proportion of patients who were exacerbation free 2 years after initiating therapy was also significantly greater in the high dose interferon-treated patients. Neutralising antibodies to interferon beta-lb were detected at some time during the study in 11% of the placebo-treated group, 47% of the low-dose drug group, and 45% of the high-dose group. There was no relation between the presence of neutralising antibodies and exacerbation severity or time between exacerbations. Although this study was well designed and showed a measurable treatment effect, there were procedural limitations. An intention-to-treat analysis was planned but not truly accomplished for the primary outcome measures. 65 patients discontinued treatment before 2 years and 123 patients before 3 years. Data from these patients and from those who were withdrawn from the study were censored. Inexplicably, more patients were available for follow-up after 3 years than after 2 years. Additionally, about 20% of the patients who reported exacerbations during the first 2 years did not have neurological verification of their exacerbations within the time required by the protocol. This is worrying since patients receiving interferon were more likely to experience side-effects and their knowledge of treatment assignment might have resulted in biased reporting of exacerbations. Moreover, if one eliminates from the analysis the patients without neurological verification of exacerbations according to protocol, there is no longer a significant difference in exacerbation rates between the treatment groups. Finally, about 25% of the patients in this study experienced sustained progression of disability during 3 years of clinical follow-up, but the proportions of patients experiencing sustained progression of disability did not differ significantly between the treatment groups. Overall, the ultimate clinical significance of the modest reduction in exacerbation rates in the actively treated patients remains uncertain. This study is the first phase III clinical trial to show convincingly an active treatment-related difference in serial MRI activity. 12 The placebo group showed a 17-1%
increase in mean lesion area over 3 years vs a 6-2% decrease in the high-dose interferon group (p=0-002). Subgroup analysis of 52 patients who underwent serial MRI scans every 6 weeks for 2 years showed a 75% reduction in the rate of new lesion formation in the highdose treatment group compared with placebo. These MRI results, as well as the size and multicentre design, 1058
this study from other clinical trials which, in the absence of serial MRI monitoring, have shown similar reductions in exacerbation rates.23,24 The MRI data, used as a surrogate outcome measure in this trial, were pivotal in the deliberations of the Food and Drug Administration (FDA) that ultimately led to the expedited approval of interferon beta-lb for use in ambulatory relapsingremitting MS patients in the USA. FDA approval for marketing of the drug was contingent upon documentation of additional clinical data supporting the drug’s efficacy "within a reasonable amount of time". So far, there are still no convincing clinical data to support the notion that the reduction in new MRI activity observed in MS patients treated with interferon beta-lb translates into a reduction in measurable progression of sustained disability. The results from a double-blind placebo-controlled randomised phase III trial of weekly intramuscular recombinant interferon beta with the Biogen product are anticipated soon, and will be of considerable interest since the primary outcome measure is time to sustained treatment failure as measured by the Kurtzke Expanded Disability Status Scale score. The design of this study relegates exacerbation rates to the status of a secondary outcome measure because of the poor correlation between exacerbation rates and sustained progression of disability. There are other important differences between the Biogen and Berlex studies. The Biogen recombinant product, which is expressed by a mammalian cell line, is glycosylated and is otherwise identical to naturally occurring interferon beta. Interferon beta-lb is expressed by bacterial cells, is not glycosylated, lacks the N-terminal methionine found in the native molecule, and has a serine substitution for cysteine at position 17. These structural differences may explain the observation that neutralising antibodies were found in 45% of the high-dose interferon beta-lb group" and in only 3% of patients treated with the Biogen product. 25 Whether neutralising antibodies will have any effect on dose, route of administration, efficacy, or tolerance of the products is unknown. A separate multicentre study of a recombinant interferon beta in relapsing and secondary progressive MS is being conducted in Europe, Canada, and Australia. The design of this study, sponsored by Ares-Serono, has not been published and results will not be available for at least 2 years.
distinguish
Adverse reactions Treatment with interferon beta-lb is well tolerated. Patient attrition from the phase III trials was attributed to side-effects in 5 of 111 patients in the low-dose group and in 10 of 124 in the high-dose group. Reasons for withdrawal due to treatment effects were: abnormal liver enzymes (3 patients), injection site pain (3), fatigue (3), and cardiac arrhythmia, allergic reaction, nausea, headache, "flu syndrome", confusion, and "felt sick"
(1 each). Adverse reactions and
laboratory abnormalities that are
with interferon beta-lb than significantly with placebo are listed in the table. Additional adverse reactions reported during routine postmarketing surveillance conducted by the manufacturer include transient paralysis, hemiparesis, loss of leg strength, and profound weakness without fever within 5 hours of initiating treatment. The frequency and duration of these adverse reactions have not been determined adequately. more common
ALT=alanine amnotransferase; AST=aspartate aminotransferase.
Table: Adverse reactions and
laboratory abnormalities
Drug interactions There is very little information about drug interactions with interferon beta-lb. In 3 cancer patients treatment with doses of 0-8-71-0 million IU led to a dosedependent inhibition of antipyrine elimination,26 and an unconfirmed report suggests that the drug may inhibit the metabolism of zidovudine in AIDS patients.27 The effect of alternate-day administration of 8-0 million IU on the metabolism of commonly prescribed symptomatic therapies for MS (eg, lioresal, tricyclic antidepressants, oxybutinin, amantadine) is unknown.
Clinical
use
Indications and procedure Interferon beta-lb is administered subcutaneously every other day at a recommended dose of 8-0 million IU. The cost is about US$10 000 a year. Injection supplies and a training videotape have been prepared by Berlex to help patients. Experience suggests that this education session is most effectively conducted in an office or clinic setting by an experienced nurse or physician who observes the patient self-administer the first dose. Interferon beta-lb should be started only after documentation of normal haemoglobin, complete and differential white blood cell counts, platelet count, and routine blood biochemical tests including liver function tests. These tests should also be monitored every third month after starting therapy because of the hepatic and haematological toxicity (table). Rotation of injection sites seems to diminish skin reactions, and flu-like symptoms can be reduced by administration of oral paracetamol or non-steroidal anti-
inflammatory drugs. Interferon beta-lb has been licensed for marketing in the USA only for the treatment of clinically definite, ambulatory, relapsing-remitting MS patients between the ages of 18 and 50. Although the task of identifying such patients might seem easy, experience gained from reviewing the records of patients seeking entry into clincial trials has shown that many patients tend to overestimate the number of exacerbations they have experienced. A pretreatment attack rate has not been specified for approved use of the drug, but an accurate assessment of this rate is essential to realistic therapeutic expectations. Patients should understand that the 34% reduction in attack frequency in the study participants was found only in a trial in which all patients experienced two or more medically documented attacks in the preceding 2 years. Overall clinical judgment will
ultimately guide individual treatment decisions, but doctors enthusiasm for prescribing drug therapy should probably be related directly to the documented exacerbation frequency before treatment and inversely to the severity of functional impairment at the time treatment is being entertained. A practice advisory for using and discontinuing interferon beta-lb therapy has been discussed by an advisory committee to the American Academy of Neurology but has not been widely circulated. Until widely accepted guidelines are published it is appropriate to consider discontinuing drug therapy in the following clinical situations: (a) steady progression of disability for 6 months; (b) annual exacerbation rate during therapy exceeding annual pretreatment exacerbation rate; (c) depression or suicidal ideation; (d) non-compliance; (e) severe adverse reaction; and (/) pregnancy. Although interferon beta-lb has been approved only for ambulatory relapsing-remitting patients between the ages of 18 and 50, there is no reason to assume that there is any biological difference between these individuals and MS patients with a relapsing-progressive clinical course or those who are older than 50 years. There is a feeling that patients who occasionally use devices to help them walk or even non-ambulatory patients with frequent exacerbations may benefit from interferon, but there are no data from randomised controlled trials to support this notion. However, a remaining concern is that side-effects in marginally ambulatory patients may produce more noticeable negative functional consequences than in individuals with lesser degrees of disability. The role of interferon beta-lb in patients whose clinical course has been progressive since onset (primary progressive MS) remains unexplored. It would be unwise to entertain drug use in this clinically, pathologically, and radiologically distinct groups of patients28 until data from controlled clinical trials are available. Contraindications The effects of interferon beta-lb on fertility and reproduction are unknown. The drug has abortifacient activity and should not be given to pregnant women. Although there are no data on excretion of the drug in human milk, use by nursing mothers is discouraged because of a potential adverse reaction in their infants. Safety and efficacy in children under the age of 18 have not been established. Precautions 1 suicide and 4 attempted suicides were reported among 372 study patients during the 3-year trial period. All 5 patients received interferon beta-lb and no attempted suicides were reported in patients receiving placebo. Patients to be treated with the drug should be told about the side-effects of depression and suicidal ideation. Patients who become depressed should be monitored closely and therapy should be stopped if necessary.
Therapeutic potential Recombinant beta interferons may have a use in several other therapeutic areas: (a) patients with isolated idiopathic optic neuritis, brainstem syndromes, or myelopathy who additionally have focally abnormal T2weighted or gadolinium-enhanced brain MRI scans and so are at increased risk of MS; (b) non-ambulatory 1059
MS patients; (c) relapsing MS patients who are older than 50 years; (d) patients with primary progressive MS; and (e) combination therapies with cytokines or other agents. Some examples of potentially effective combination therapies include transforming growth factor beta, which would theoretically augment the inhibitory effect of interferon beta on class II major histocompatibility antigen expression on astrocytes, and soluble tumour necrosis factor alpha receptor which would complex circulating tumour necrosis factor and thereby prevent this pro-inflammatory cytokine from enhancing inflammation at the site of MS plaque development. In addition, anti-adhesion molecule therapy (eg, anti-integrin) might block lymphocyte-endothelial cell interaction in the post-capillary venule and prevent activated lymphocytes from gaining entry to the site of MS plaque formation, and recombinant growth factor therapy might enhance central nervous system
relapsing
remyelination.
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