J Neurol (2003) 250 [Suppl 4]: IV/9–IV/14
`DOI 10.1007/s00415-003-1403-7
`
`Luca Durelli
`
`Dose and frequency of
`interferon treatment matter
`INCOMIN and OPTIMS
`
`■ Abstract Three different inter-
`feron beta (IFNβ) products are cur-
`rently approved for the treatment
`of patients with relapsing-remit-
`ting multiple sclerosis (RRMS).
`However, the recommended
`method of administration, the
`dosage and the frequency of ad-
`ministration differ widely between
`each of the three products. Al-
`though controlled clinical trials
`have demonstrated the efficacy of
`both alternate-day IFNβ-1b
`(Betaferon®/Betaseron®) and once-
`weekly IFNβ-1a (AvonexTM) com-
`pared with placebo, it is likely that
`patient compliance, efficacy and
`tolerability are affected by the
`dosage regimen used.
`There are several issues to con-
`sider. Once-weekly administration
`may be associated with fewer ad-
`verse events and greater conve-
`nience, and it has been suggested
`that this may increase compliance.
`
`Professor Luca Durelli, MD (쾷)
`Department of Neuroscience
`University of Turin
`Turin, Italy
`Tel.: +39-011/6633634
`E-Mail: luca.durelli@unito.it
`
`Conversely, frequent administra-
`tion may be associated with in-
`creased overall efficacy. There is a
`convincing pharmacological ratio-
`nale indicating that frequent dos-
`ing, with an interval of less than
`72 h, is necessary to sustain the ac-
`tivity of intracellular molecular
`signalling pathways responsible for
`regulating IFNβ-induced gene ex-
`pression. However, there was a
`need to explore the overall effec-
`tiveness of the two administration
`protocols in a comparative trial.
`The INCOMIN (Independent
`Comparison of Interferon) study
`compared clinical and magnetic
`resonance imaging (MRI) efficacy
`of IFNβ-1b 250 μg (8 MIU) subcu-
`taneously (s. c.) on alternate days
`and IFNβ-1a 30 μg (6 MIU) intra-
`muscularly (i. m.) once weekly in
`patients with RRMS. INCOMIN
`demonstrated convincingly that
`clinical and MRI outcome mea-
`sures were significantly better in
`the IFNβ-1b-treated group. Blinded
`MRI evaluation confirmed the clin-
`ical results. Despite some limita-
`tions of the study design, imposed
`by the ethical and practical chal-
`
`lenges of conducting comparative
`trials of injectable therapies, the
`concordance of the clinical and
`MRI findings indicate that fre-
`quently administered IFNβ-1b re-
`duced evidence of disease activity
`more effectively than once-weekly
`administered IFNβ-1a, with the
`clinical benefits for patients be-
`coming more pronounced over
`time.
`Given that the response to IFNβ
`appears to be dose dependent, the
`question that might be asked is
`whether greater efficacy can be ob-
`tained by increasing doses beyond
`those currently approved. OPTIMS
`(Optimization of Interferon dose
`for MS) is currently examining the
`safety and efficacy of a dose of
`IFNβ-1b that is higher than any
`currently marketed IFNβ. While
`OPTIMS is still underway, prelimi-
`nary safety analyses indicate that
`higher doses are well tolerated.
`
`■ Key words interferon beta-1b ·
`interferon beta-1a · clinical trial ·
`relapsing-remitting · multiple
`sclerosis · relapse
`
`JON 1403
`
`IFNβ-1b (Betaferon®/Betaseron®) is administered sub-
`cutaneously (s. c.) every other day at a dose of 250 μg (8
`MIU). The other two are IFNβ-1a products, one admin-
`istered intramuscularly (i. m.) once weekly (Avonex™)
`at a dose of 30 μg (6 MIU), the other s. c. three times a
`week (Rebif®) at a dose of 22 (6 MIU) or 44 μg (12 MIU).
`
`Introduction
`
`There are three interferon beta (IFNβ) products cur-
`rently approved for the treatment of relapsing-remitting
`multiple sclerosis (RRMS). One product containing
`
`Merck 2020
`TWi v Merck
`IPR2023-00049
`
`

`

`IV/10
`
`The efficacy of all three IFNβ products has been
`demonstrated in patients with RRMS in randomised
`clinical trials [5–7, 10, 11, 14]. Beneficial effects have
`been observed on relapse-related measures of disease
`and on magnetic resonance imaging (MRI) outcomes,
`compared with placebo. However, questions regarding
`the optimal dose and administration frequency, and the
`duration of treatment remain unanswered.
`Many patients are currently treated with once-weekly
`IFNβ – the perceived increase in convenience from fewer
`injections each week may be thought to increase the
`likelihood of compliance, although there is no published
`evidence to date to support this hypothesis. The re-
`quirement for prolonged treatment, particularly if dis-
`ease stabilisation has occurred, could also push patients
`towards fewer weekly doses, again for reasons of conve-
`nience. However, any perceived increased convenience
`may be gained at the expense of efficacy.
`Clinical and pharmacological evidence to date sug-
`gests that the efficacy of IFNβ is dosage dependent [5–9,
`14, 16]. There is also evidence that simply increasing the
`dose is insufficient – more frequent administration is re-
`quired [1,13,14].Until recently,no data from direct com-
`parisons of the different IFNβ formulations to support
`the superiority of high dose and frequent administration
`have been available.However,two studies comparing dif-
`ferent IFNβ products, INCOMIN (Independent Compa-
`rison of Interferons) [2] and EVIDENCE (Evidence
`for Interferon Dose Effect: European-North American
`Comparative Efficacy) [9] have now been published. In
`addition,the findings from INCOMIN have been further
`extended to examine the possibility of reducing the IFNβ
`dose from every other day to once weekly in patients with
`RRMS and stable disease. These studies, together with
`other ongoing trials, will help to answer the question of
`the most appropriate IFNβ dose and frequency to use.
`This paper will provide an overview of the studies and the
`other evidence relating to these questions of dose and ad-
`ministration frequency.
`
`The rationale for high-dose therapy
`
`There is a body of evidence from a number of clinical
`and pharmacological studies indicating that clinical and
`biological responses are greater at higher IFNβ doses. A
`study comparing the biological effects of i. m. IFNβ-1a
`once weekly and s. c. IFNβ-1b every other day demon-
`strated a significant increase in the levels of several bio-
`logical markers in favour of more frequent/higher dos-
`ing [17].Levels of MxA,neopterin,β2-microglobulin and
`interleukin (IL)-10 were maintained at a high level
`throughout the 1-week study period with IFNβ-1b,
`while after a single dose of i. m. IFNβ-1a, they typically
`returned to baseline within 5 days of administration.
`Rothuizen et al. [13] studied the immunological effects
`
`of IFNβ (the interferon-induced inhibition of pro-in-
`flammatory cytokine production) by administering a
`weekly IFNβ dose of 66 μg to healthy volunteers, either
`as a single once-weekly dose, or as three separate 22 μg
`doses given during the week. The biological activity of
`IFNβ, as assessed by the inhibition of cytokine produc-
`tion, increased by as much as threefold when the IFNβ
`dose was administered three times weekly.
`Clinical studies comparing different treatment regi-
`mens of IFNβ consistently demonstrate the greater effi-
`cacy of the higher dose [5, 6, 8, 11]. The original pivotal
`study of IFNβ-1b, which examined the efficacy of 50 and
`250 μg every other day indicated significant benefits in
`relapse rate and MRI parameters for the 250 μg dose
`compared with both placebo and the 50 μg dose. In the
`case of the 50 μg dose, only the effect on relapse rate was
`significant relative to placebo [5, 6, 10]. Data from the
`PRISMS (Prevention of Relapses and Disability by Inter-
`feron beta-1a Subcutaneously in MS) trial examining
`the efficacy of s. c. IFNβ-1a indicated a significant bene-
`fit for the higher dose (44 μg) and a lower dose (22 μg)
`given three times weekly, compared with placebo [11].
`Both doses had significant effects on relapse rate,time to
`first relapse, the proportion of patients remaining re-
`lapse free and time to disability progression. There were
`also significant reductions in MRI burden of disease and
`new lesion development. For each outcome measure,
`there were dose-related increases in effect, although
`only with the MRI parameters did these become signif-
`icant [11].
`When once-weekly s. c. IFNβ-1a (44 and 22 μg) was
`assessed in the OWIMS (Once-Weekly Interferon for
`MS) study, significantly greater effects on MRI measures
`were seen using the higher dose compared with either
`the lower dose or placebo. However, no significant clin-
`ical effects were observed relative to placebo [14].
`The data from both PRISMS [9] and the original piv-
`otal trial of IFNβ-1b [5], together with data from the
`Multiple Sclerosis Collaborative Research Group trial of
`once-weekly i. m. IFNβ-1a [7] were recently compared
`using evidence-based medicine measures and an intent-
`to-treat analysis [3]. Three evidence-based medicine
`measures were used for comparison – number needed to
`treat (NNT), relative risk (RR) and absolute risk reduc-
`tion (ARR). Although all three studies demonstrated
`significant improvements in relapse-related and MRI
`measures of disease relative to placebo [5–7, 10, 11], only
`the analyses from the pivotal study of IFNβ-1b and
`PRISMS were based on the ITT population [5, 6, 10, 11].
`Analyses based on the ITT population include data from
`all patients who begin therapy, regardless of whether
`they remain in the study, therefore providing a more ac-
`curate assessment of drug effects. The results of this
`comparison showed that significant reductions in re-
`lapse rates and MRI measures of disease were obtained
`only with frequently administered regimes, and that
`
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`

`IV/11
`
`lapse free and the primary MRI outcome measure was
`the proportion of patients remaining free from new T2
`lesions. The clinical evaluations were unblinded; how-
`ever, MRI evaluations were performed in a blinded fash-
`ion. The INCOMIN study demonstrated that the higher
`dose frequently administered IFNβ-1b was superior to
`once weekly IFNβ-1a [2].
`Significant benefits were seen in clinical outcomes,
`including the primary clinical outcome measure, the
`proportion of patients remaining relapse free (51 % ver-
`sus 36 %, P < 0.036), and many of the secondary clinical
`outcome measures [2] (Fig. 1). The MRI results con-
`firmed the clinical results.The proportion of patients re-
`maining free of new T2 lesions was significantly in-
`creased relative to IFNβ-1a (55 % patients remaining
`free of new T2 lesions versus 26 %, respectively,
`P < 0.0003). Secondary MRI outcomes were also signifi-
`cantly improved in the IFNβ-1b-treated group [2]. The
`incidence of adverse events was similar between the two
`treatment groups with the exception of injection-site re-
`actions, which were significantly higher in IFNβ-1b-
`treated patients, most likely associated with the 3.5-fold
`greater number of injections administered [2].
`A second study, EVIDENCE, compared the efficacy of
`three-times-weekly s. c. IFNβ-1a (44 μg) with once-
`weekly i. m. IFNβ-1a (30 μg) over 48 weeks [9]. The re-
`sults of this study demonstrated significantly greater
`clinical and MRI benefit for the more frequently admin-
`istered treatment, both confirming the results seen in
`INCOMIN and providing further data in support of the
`rationale for higher dose, frequent administration of
`IFNβ [9].
`
`once-weekly dosing failed to produce any significant ef-
`fects [3].
`When taken together, the results from these studies
`and analyses indicate that higher doses are more effec-
`tive. This observation has been echoed by the Thera-
`peutics and Technology Assessment Subcommittee of
`the American Academy of Neurology, which, in a recent
`report on disease modifying therapies, suggested that
`there was evidence to support a clinically relevant dose-
`response relationship for IFNβ [4]. However, there is
`also evidence that simply increasing dose while main-
`taining once-weekly administration is insufficient to
`significantly increase efficacy [1] – more frequent ad-
`ministration may also be needed.
`While there is obviously an emerging pattern in the
`clinical trials performed to date, the comparison of dif-
`ferent studies performed at different times and on dif-
`ferent cohorts is problematic at best. The only way to es-
`tablish the most effective dose and administration
`regimen is to perform direct comparative studies on the
`different IFNβ preparations. Until recently, no such
`comparative clinical studies of different IFNβ doses and
`administration schedules had been performed. IN-
`COMIN was designed to provide answers to the ques-
`tion of the most appropriate IFNβ dose and frequency of
`administration [2].
`
`INCOMIN
`
`INCOMIN was a prospective, randomised, 2-year study
`comparing IFNβ-1b (250 μg s. c.) administered every
`other day and IFNβ-1a (30 μg i. m.) administered once
`weekly in 188 patients with RRMS. The study was car-
`ried out independently of the pharmaceutical industry,
`with support from the Italian Ministry of Health and the
`Italian MS Society [2]. The primary clinical outcome
`measure was the proportion of patients remaining re-
`
`a)
`
`b)
`
`Fig. 1 INCOMIN primary outcome measures, a clinical, b MRI. Both are significantly improved with IFNβ-1b treatment compared to once-weekly IFNβ-1a
`
`

`

`IV/12
`
`The consequences of reducing IFNβ dose –
`the Dose Reduction Study
`
`Both INCOMIN and EVIDENCE support the notion that
`high-dose, frequently administered IFNβ is the more ef-
`fective treatment for RRMS [2, 9]. However, MS is a
`chronic disease, requiring equally long-term treatment.
`Faced with the prospect of multiple injections each week
`for the foreseeable future, many patients might wish to
`reduce the dose and frequency of administration, in the
`hope of improved convenience, if they have achieved
`disease stability.
`A further study was designed to test whether patients
`achieving disease stabilisation using IFNβ-1b (250 μg
`s. c. every other day) could maintain their clinical bene-
`fit if switched to once-weekly IFNβ-1a (30 μg i. m.)
`(Fig. 2).
`Some of the patients who participated in INCOMIN
`with definite RRMS and stable disease (defined as no re-
`lapses or progression of no more than 0.5 points in the
`previous 24 months, and no MRI activity in the last 12
`months) who had been receiving IFNβ-1b for at least 36
`months were included in the study. Patients were ran-
`domised either to continue receiving IFNβ-1b, or to
`gradually reduce the dose of IFNβ until they were re-
`
`ceiving once-weekly i. m. IFNβ-1a (30 μg), then followed
`for 12 months.
`Patients remaining on IFNβ-1b did significantly
`better than those receiving once-weekly IFNβ-1a. The
`number of patients remaining relapse free, the annual
`relapse rate and MRI outcome measures were all signif-
`icantly better in those continuing to receive IFNβ-1b
`every other day (Fig. 3). The data from this study sup-
`port the concept that not only are high dose and fre-
`quent administration important determinants of re-
`sponse, but also that, in order to maintain the clinical
`and MRI benefits, high-dose, high-frequency adminis-
`tration must be maintained.
`
`The tolerability of higher doses – OPTIMS
`
`As we have seen,the evidence obtained to date would ap-
`pear to support the assertion that a regimen of high,
`multiple-weekly doses of IFNβ is more effective than
`once-weekly dosing [2, 9]. There is also evidence indi-
`cating that a dose-response relationship for IFNβ exists
`[5, 6, 8, 10, 11]. Not all patients respond optimally to the
`approved doses of IFNβ currently marketed and, given
`the above observations, it is reasonable to ask whether
`
`Fig. 2 The Dose Reduction Study – trial design
`
`a)
`
`b)
`
`Fig. 3 High-frequency IFNβ-1b must be maintained in order to ensure continued treatment benefits for both a clinical and b MRI outcomes
`
`

`

`using IFNβ doses higher than those currently approved
`could generate an improved response in these patients.
`There is some evidence from a pilot study that treatment
`responses to IFNβ-1b extend beyond the currently ap-
`proved dose. In this study, IFNβ-1b was given to patients
`at doses of up to 500 μg. While none of the patients re-
`ceiving this higher dose experienced relapses during the
`study period, adverse events – in the absence of any
`titration or forms of prophylaxis – meant that the ma-
`jority had to be switched to a lower dose [8].
`Since completion of this pilot study, much has been
`learned regarding the management of adverse events.
`While IFNβ is well tolerated, with a good safety profile,
`a number of adverse events are associated with therapy
`with these drugs. Typically, skin reactions (rash, ery-
`thema, pain) and flu-like symptoms (fever, chills,
`headache) predominate, and may be worse at the higher
`doses [15]. However, these adverse events can now be
`managed very effectively. Skin reactions can be reduced
`by measures that include injection-site rotation, and the
`use of automated injection systems [15]. Flu-like reac-
`tions become less frequent over time, and can also be
`managed with non-steroidal anti-inflammatory drugs
`(NSAIDs) or ibuprofen [12].Gradually titrating the drug
`over a period of several weeks, to achieve the therapeu-
`tic dose, is also effective.
`Given that adverse events can now be managed more
`effectively, there has been a greater focus on the use of
`doses above those currently approved, with the aim of
`increasing the number of patients benefiting from
`IFNβ-treatment. The first study designed to look at the
`question of higher dose therapy is the OPTIMS (OPTi-
`mization of Interferon for MS) study, which is investi-
`gating the use of 375 μg (12 MIU) IFNβ-1b administered
`s. c. every other day (Fig. 4). OPTIMS is a multicentre
`randomised 12-month study with a planned enrolment
`of 230 patients with RRMS.Patients will receive the stan-
`dard IFNβ-1b dose for a 6-month run-in period, during
`which time they will undergo monthly MRI scans.Those
`patients assessed as responding optimally to the ap-
`proved dose will continue with IFNβ-1b at the approved
`
`Fig. 4 The OPTIMS study – trial design
`
`IV/13
`
`dose. Those patients with a sub-optimal response, as as-
`sessed by relapses, or the presence of new or enlarging
`T2 or Gd-enhancing lesions, will be randomised to re-
`ceive either the standard treatment (250 μg), or 375 μg
`(12 MIU) IFNβ-1b s. c. every other day. All patients will
`then be followed for a further 6 months. It is hoped that
`a total of 100 sub-optimal responders and 100 normal
`responders will be recruited.
`To date, some patients have completed the full year in
`the study, enabling comparison of adverse events in the
`two dose groups. Currently, the incidence of adverse
`events is no higher in the higher dose group, indicating
`that the higher dose is as well tolerated as the approved
`dose.
`
`Conclusions
`While IFNβ has been shown to be effective in the treat-
`ment of RRMS, the question of the optimal dose and fre-
`quency of administration remains a controversial one.
`Data from a number of different studies indicate that the
`response to IFNβ is dose dependent.
`Data from INCOMIN and EVIDENCE suggest that
`frequent administration of IFNβ, several times per
`week, coupled with a high dose offers significantly bet-
`ter clinical and MRI benefits compared to once-weekly
`schedules. In addition, an extension of the INCOMIN
`study has shown that this treatment must be main-
`tained, even after long periods of disease stability, in or-
`der to maintain these benefits. These data indicate that
`not only should patients receive frequent, high-dose
`IFNβ treatment in order to achieve the greatest clinical
`effect, but also that this therapy must be maintained in
`order to sustain this treatment benefit. Reducing dose to
`once-weekly IFNβ-1a may offer perceived benefits in
`terms of convenience, but this preference has a clinical
`cost.
`Finally, it may also be possible to increase the IFNβ
`doses currently used in order to increase the number of
`patients benefiting from treatment. Several studies are
`
`

`

`IV/14
`
`currently ongoing to investigate this possibility, but
`there are no efficacy data at present. However, the initial
`safety analysis from OPTIMS suggests that higher IFNβ
`doses are well tolerated. Other studies to investigate the
`possibility of using higher than approved IFNβ doses
`are planned.
`
`■ Acknowledgements I would acknowledge all members of
`INCOMIN and OPTIMS Trial Study Groups without whom this re-
`view would not have been possible, and P. Littlebury, PhD, Senior Ed-
`itor, PAREXEL MMS Europe Ltd.
`
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