Intramuscular IFNβ-1a Research Articles

Assessment of malignancy risk in patients with multiple sclerosis treated with intramuscular interferon beta-1a: retrospective evaluation using a health insurance claims database and postmarketing surveillance data

BackgroundIntramuscular interferon beta-1a (IFNβ-1a), a multiple sclerosis (MS) therapy that has been commercially available for over a decade, provides a unique opportunity to retrospectively assess postmarketing data for evidence of malignancy risk, compared with relatively limited data available for more recently approved therapies. Postmarketing and claims data were analyzed to determine the risk of malignancy in MS patients treated with intramuscular IFNβ-1a.Materials and methodsThe cumulative reporting rates of suspected adverse drug reactions coded to malignancy in the intramuscular IFNβ-1a global safety database were compared with malignancy incidence rates in the World Health Organization GLOBOCAN database. In addition, using data from a large US claims database, the cumulative prevalence of malignancy in MS patients treated with intramuscular IFNβ-1a was compared with non-MS population controls, MS patients without intramuscular IFNβ-1a use, and untreated MS patients. Mean follow-up was approximately 3 years for all groups, ie, 3.1 years for the intramuscular IFNβ-1a group (range 0.02–6.0 years), 2.6 years for non-MS population controls (range 0–6.0 years), 2.6 years for the intramuscular IFNβ-1a nonuse group (range 0.01–6.0 years), and 2.4 years for the untreated MS group (range 0.01–6.0 years).ResultsAn estimated 402,250 patients received intramuscular IFNβ-1a during the postmarketing period. Cumulative reporting rates of malignancy in this population were consistent with GLOBOCAN incidence rates observed within the general population. The claims database included 12,894 MS patients who received intramuscular IFNβ-1a. No significant difference in malignancy prevalence was observed in intramuscular IFNβ-1a users compared with other groups.ConclusionResults from this evaluation provide no evidence of an increased risk of malignancy with intramuscular IFNβ-1a use.

Neutralizing Antibodies Are Associated with a Reduction of Interferon-β Efficacy during the Treatment of Japanese Multiple Sclerosis Patients

Multiple sclerosis (MS) is a chronic immune-mediated inflammatory demyelinating disease of the central nervous system. Interferon-β (IFN-β) has been used as the first line therapy for MS treatment in Japan, but patients treated with IFN-β may develop antibodies, known as neutralizing antibodies (NAbs), which abrogate its therapeutic effects. Intramuscular IFN-β 1a and subcutaneous IFN-β 1b are currently available in Japan, but large-scale studies evaluating the prevalence and clinical implications of NAbs against these IFN-β preparations in MS patients have only been performed in Caucasian populations. NAbs positivity has been reported to be associated with HLA-DRB1 alleles, suggesting that the positivity might differ among populations with distinct genetic backgrounds. Clinical information and sera were collected from 229 consecutive MS patients treated with IFN-β in 4 centers in Japan. Sera were tested for NAbs using a luciferase reporter gene assay. In total, 5.2% of IFN-β-1a-treated patients (4/77) and 30.3% of IFN-β-1b-treated patients (46/152) were positive for Nabs. The frequency of NAbs was highest in patients treated for 13 to 24 months. Clinical relapse and contrast-enhancing lesions in the magnetic resonance imaging increased together with NAbs titers in this group. In conclusion, the prevalence of NAbs in Japanese MS patients is similar to that in Caucasian populations and is associated with an increase in disease activity. Therefore, routine NAbs testing is recommended also in Asian populations to ensure the early identification of patients who would benefit from a change in therapy.

Injectable Multiple Sclerosis Medications

Although injection-site reactions (ISRs) occur with US Food and Drug Administration-approved injectable disease-modifying therapies (DMTs) for multiple sclerosis, there are currently few reports of real-world data on ISR management strategies or possible correlations between ISRs and patient demographics, disease characteristics, and missed injections. Patient-reported data on the use of DMTs, patient demographic and disease characteristics, missed injections, and ISR reduction strategies were collected via e-mail, a patient registry (www.ms-cam.org), and a Web-based survey. Of the 1380 respondents, 1201 (87%) indicated that they had used injectable DMTs, of whom 377 (31%) had used intramuscular (IM) interferon beta-1a (IFNβ-1a), 172 (14%) had used subcutaneous (SC) IFNβ-1a, 183 (15%) had used SC IFNβ-1b, and 469 (39%) had used glatiramer acetate (GA). The majority of respondents were older (73% were ≥40 years), female (79%), married or living with a partner (72%), white (94%), and nonsmoking (82%). Injection-site reaction incidence, grouped according to severity, varied among DMTs, with IM IFNβ-1a causing significantly (P < .001) fewer mild, moderate, or severe ISRs than the other therapies. Female sex and younger age were significantly (P < .05) associated with more moderate ISRs among users of IM IFNβ-1a, SC IFNβ-1b, and GA. Nonwhites reported severe ISRs more often than whites. For all DMTs injection-site massage and avoidance of sensitive sites were the most frequently used strategies to minimize ISRs. These data may help identify patients with characteristics associated with a higher risk for ISRs, allowing health-care professionals to provide anticipatory guidance to patients at risk for decreased adherence or discontinuation.

Voxel-wise magnetization transfer imaging study of effects of natalizumab and IFNβ-1a in multiple sclerosis

Objective: To determine the effects of intravenous natalizumab and intramuscular interferon beta-1a (IFNβ-1a) on the volume of white-matter (WM) lesions and normal appearing brain tissue (NABT) undergoing voxel-wise (VW) increases in magnetization transfer ratio (MTR) suggestive of remyelination in patients with relapsing multiple sclerosis. Methods: This prospective, open-label, single-blinded study enrolled patients with relapsing–remitting multiple sclerosis (RRMS) and relapsing secondary progressive multiple sclerosis (RSPMS) as well as a group of age/sex-matched healthy controls (n=22). Patients with multiple sclerosis were assigned to receive natalizumab monotherapy (n=77; RRMS/RSPMS) or intramuscular IFNβ-1a (n=26) as either monotherapy (RRMS) or combined with pulsed i.v. methylprednisolone, as needed (RSPMS). The primary endpoint was the two-year change in volume of NABT VWMTR, by quantifying the number of voxels that increased (suggesting remyelination) or decreased (suggesting demyelination) in their MTR value. Results: The volume of tissue undergoing increases in VWMTR was significantly larger in natalizumab compared with IFNβ-1a-treated patients (year 1: p=0.001 in NABT and p<0.006 in WM lesions; year 2: p=0.008 in NABT) and compared with healthy control subjects (year 1: p=0.05 and year 2: p=0.007 in NABT). The larger volume within NABT undergoing decreases in VWMTR was detected in multiple sclerosis patients compared with healthy controls (p<0.001), and in the IFNβ-1a group compared with the natalizumab group (year 1: p=0.05; year 2: p=0.002). One patient on natalizumab died from progressive multifocal leukoencephalopathy eight months after completing the study. Conclusion: Natalizumab may promote remyelination and stabilize demyelination in lesions and NABT in relapsing multiple sclerosis, compared with intramuscular IFNβ-1a.

Spasticity improvement in patients with relapsing–remitting multiple sclerosis switching from interferon-β to glatiramer acetate: The Escala Study

BackgroundA recent pilot study suggested spasticity improvement during glatiramer acetate (GA) treatment in multiple sclerosis (MS) patients who previously received interferon-β (IFN-β). ObjectiveTo evaluate changes in spasticity in MS patients switching from IFN-β to GA. MethodsObservational, multicentre study in patients with relapsing–remitting MS (RRMS) and spasticity switching from IFN-β to GA. The primary endpoint comprised changes on Penn Spasm Frequency Scale (PSFS), Modified Ashworth Scale (MAS), Adductor Tone Rating Scale (ATRS), and Global Pain Score (GPS) at months 3 and 6 after starting GA. ResultsSixty-eight evaluable patients were included (mean age,41.7±9.5years; female,70.6%; mean time from MS diagnosis to starting GA,7.6±5.7years). Previous treatments were subcutaneous IFN-β1a in 42.6% patients, intramuscular IFN-β1a in 41.2% and IFN-β1b in 32.4%, whose mean durations were 3.5±3.3, 2.7±2.5 and 4.4±3.6years, respectively. Statistically significant reductions in mean scores on all spasticity measurements were observed from baseline to month 3 (PSFS, 1.7±0.9 vs 1.4±0.6, p<0.01; MAS, 0.7±0.5 vs 0.6±0.5, p<0.01; highest MAS score, 1.9±0.8 vs 1.7±0.8, p<0.01; ATRS, 1.6±0.6 vs 1.4±0.6, p<0.01; GPS, 29.4±22.1 vs 24.7±19.4, p<0.01) and from baseline to month 6 (PSFS, 1.7±0.9 vs 1.3±0.6, p<0.01; MAS, 0.7±0.5 vs 0.5±0.5, p<0.01; highest MAS score, 1.9±0.8 vs 1.5±0.9, p<0.01; ATRS, 1.6±0.6 vs 1.3±0.6, p<0.01; GPS, 29.4±22.1 vs 19.1±14.8, p<0.01). ConclusionSpasticity improvement in terms of spasm frequency, muscle tone and pain can be noted after three months and prolonged for six months of GA treatment.

The prevalence of injection-site reactions with disease-modifying therapies and their effect on adherence in patients with multiple sclerosis: an observational study

BackgroundInterferon beta (IFNβ) and glatiramer acetate (GA) are administered by subcutaneous (SC) or intramuscular (IM) injection. Patients with multiple sclerosis (MS) often report injection-site reactions (ISRs) as a reason for noncompliance or switching therapies. The aim of this study was to compare the proportion of patients on different formulations of IFNβ or GA who experienced ISRs and who switched or discontinued therapy because of ISRs.MethodsThe Swiss MS Skin Project was an observational multicenter study. Patients with MS or clinically isolated syndrome who were on the same therapy for at least 2 years were enrolled. A skin examination was conducted at the first study visit and 1 year later.ResultsThe 412 patients enrolled were on 1 of 4 disease-modifying therapies for at least 2 years: IM IFNβ-1a (n = 82), SC IFNβ-1b (n = 123), SC IFNβ-1a (n = 184), or SC GA (n = 23). At first evaluation, ISRs were reported by fewer patients on IM IFNβ-1a (13.4%) than on SC IFNβ-1b (57.7%; P < 0.0001), SC IFNβ-1a (67.9%; P < 0.0001), or SC GA (30.4%; P = not significant [NS]). No patient on IM IFNβ-1a missed a dose in the previous 4 weeks because of ISRs, compared with 5.7% of patients on SC IFNβ-1b (P = 0.044), 7.1% of patients on SC IFNβ-1a (P = 0.011), and 4.3% of patients on SC GA (P = NS). Primary reasons for discontinuing or switching therapy were ISRs or lack of efficacy. Similar patterns were observed at 1 year.ConclusionsPatients on IM IFNβ-1a had fewer ISRs and were less likely to switch therapies than patients on other therapies. This study may have implications in selecting initial therapy or, for patients considering switching or discontinuing therapy because of ISRs, selecting an alternative option.

Dose titration of intramuscular interferon beta-1a reduces the severity and incidence of flu-like symptoms during treatment initiation

Background/objective:Flu-like symptoms (FLS) are common side effects of interferon beta (IFNβ) therapy and can negatively affect the willingness of patients with multiple sclerosis to initiate therapy. Although dose titration is commonly used to reduce the severity and incidence of IFNβ-related FLS during treatment initiation, these benefits have not been confirmed in a well controlled study. The objective of this randomized, dose-blinded, parallel-group study was to assess the effect of dose titration on the severity and incidence of FLS during the initial 8 weeks of once-weekly intramuscular (IM) IFNβ-1a administration.Methods:Healthy volunteers were randomized 1:1:1 to one of three IM IFNβ-1a regimens: 3-week titration (weekly quarter-dose increments over 3 weeks to full dose [30 µg]); 6-week titration (biweekly quarter-dose increments over 6 weeks to full dose); or no titration (full dose over 8 weeks). At weekly clinic visits, the severity of each FLS was rated 1 hour pre-injection and 4–6 hours and 12–15 hours post-injection. Study endpoints included post-injection change in FLS severity and post-injection FLS incidence (percentage of subjects with a ≥2-point increase in total FLS severity score) at each time point.Clinical trial registration:Clinicaltrials.gov identifier: NCT01119677.Results:Of 234 subjects enrolled, 194 (83%) completed the study. At 8 weeks, FLS severity was significantly reduced at both post-injection time points with 3-week titration (76% reduction at 4–6 hours, p < 0.001; 37% reduction at 12–15 hours; p < 0.001) and 6-week titration (50% reduction at 4–6 hours, p < 0.001; 32% reduction at 12–15 hours; p = 0.002) compared with no titration. The incidence of FLS was also significantly reduced at both time points with both titration regimens. Safety profiles for both titration regimens were consistent with the current IM IFNβ-1a label. Study limitations included that there is currently no validated assessment tool for evaluating the severity of FLS, that the study enrolled healthy volunteers, that different proportions of females were randomized to the 3-week-titration group than to the 6-week and no-titration groups, and that evaluation of the potential impact of titration on symptoms occurring substantially later after injection was not part of the study protocol.Conclusion:Dose titration during initiation of IM IFNβ-1a reduces FLS severity and incidence in healthy volunteers compared with no titration.

Subcutaneous Recombinant Interferon-β-1a (Rebif®)

Subcutaneous recombinant interferon-β-1a (SC IFNβ-1a) [Rebif®] is indicated as monotherapy for the prevention of relapses and progression of physical disability in patients with relapsing multiple sclerosis (MS). This article reviews the efficacy and tolerability of SC IFNβ-1a in this indication, with further discussion of its pharmacological properties and pertinent pharmacoeconomic studies. SC IFNβ-1a efficacy and tolerability were evaluated in randomized, double-blind, multinational trials in patients with relapsing-remitting MS (RRMS). Its efficacy was demonstrated in the 2-year PRISMS trial, as SC IFNβ-1a 22 or 44 μg three times weekly (tiw) significantly reduced relapse rates, with an ≈30% relative risk reduction compared with placebo. SC IFNβ-1a was also associated with significantly delayed progression of disability, and lower disease activity according to MRI, relative to placebo. In the 24-week EVIDENCE trial, a significantly higher proportion of SC IFNβ-1a 44 μg tiw than intramuscular IFNβ-1a (Avonex®) 30 μg once weekly recipients remained relapse free. A serum-free formulation of SC IFNβ-1a 44 μg tiw was more efficacious than placebo in preventing the development of brain lesions in the 16-week IMPROVE trial. In the 96-week REGARD trial, the efficacy of SC IFNβ-1a 44 μg tiw was not significantly different to that of glatiramer acetate for clinical endpoints, although it was associated with reduced development of brain lesions compared with glatiramer acetate, according to some MRI endpoints. In the 36-month CAMMS223 trial, alemtuzumab led to significantly lower relapse rates and risk of developing sustained disability than SC IFNβ-1a 44 μg tiw, and was generally more efficacious according to other clinical and MRI endpoints. Across trials, influenza-like symptoms, injection-site reactions, haematological disturbances and hepatic enzyme abnormalities were the most common treatment-emergent adverse events occurring with SC IFNβ-1a. In the PRISMS trial, SC IFNβ-1a 22 and 44 μg tiw recipients had more injection-site reactions than placebo recipients and, at the higher dosage, haematological disturbances and increases in ALT levels were also significantly more frequent than with placebo. Pooled data from clinical trials and postmarketing surveillance indicate that haematological and hepatic adverse events are generally asymptomatic and rarely result in treatment discontinuation. Nevertheless, some cases of serious hepatic complications have been reported. In cost-utility studies, first-line therapies for RRMS, including SC IFNβ-1a, all exceeded commonly accepted US thresholds for incremental cost per quality-adjusted life-years gained relative to symptomatic treatment. However, because of patient need and the difficulty in adequately assessing cost utility in a gradually progressive disease, these agents have been made available to many patients worldwide through special access programmes. Overall, SC IFNβ-1a has a favourable risk-benefit ratio and is a valuable first-line treatment option for patients with relapsing MS.

Fingolimod

Oral fingolimod (Gilenya™), a sphingosine 1-phosphate (S1P) receptor agonist, is the first oral agent and the first in a novel class of disease-modifying therapies (DMTs) to be approved for use in the US for the treatment of relapsing forms of multiple sclerosis (MS). In the EU, fingolimod is approved for use as a single-agent DMT in selected patients with highly-active, relapsing-remitting (RR) MS. This article reviews the pharmacological properties and clinical use of the drug in patients with RRMS. Fingolimod is rapidly converted in vivo to the active moiety S-fingolimod-phosphate, which binds with high affinity to S1P receptors, thereby sequestering lymphocytes in the lymph nodes and preventing their egress into the peripheral circulation. As a consequence, there is a reduction in the infiltration of autoaggressive lymphocytes into the CNS. Fingolimod-phosphate also acts as a functional antagonist, as its binding to S1P receptors results in their internalization and degradation, thereby downregulating S1P receptors on the lymphocyte cell surface. Since fingolimod crosses the blood : brain barrier, it also potentially acts at S1P receptors on neural cells in the CNS to mitigate neuropathological processes associated with MS. In large multinational trials in adult patients with RRMS, oral fingolimod 0.5 mg/day was more effective than oral placebo (FREEDOMS) and recommended dosages of intramuscular interferon-β (IFNβ)-1a (TRANSFORMS) in reducing the annualized relapse rate and was also generally more effective at slowing progression of neurological disability and at reducing the burden and activity of disease. Fingolimod was generally well tolerated in these trials of up to 2 years' duration, with most adverse events being manageable and of mild to moderate severity; there were two deaths from opportunistic infections, albeit these occurred with fingolimod 1.25 mg/day (higher than the recommended dosage). Limited long-term data indicated that no new safety concerns had arisen after 5 years of fingolimod treatment. However, further clinical experience is required to fully determine the long-term safety profile of fingolimod, particularly with regard to any potentially serious or life-threatening adverse events. In the absence of robust pharmacoeconomic studies and of head-to-head trials comparing fingolimod with other formulations of IFNβ and glatiramer acetate, the relative position of fingolimod with respect to other DMTs remains to be fully determined. In the meantime, given its convenient once-daily oral treatment regimen and better efficacy than intramuscular IFNβ-1a, fingolimod is a valuable emerging option for the treatment of adult patients with relapsing forms of MS.

Frequency and Magnitude of Interferon β Neutralizing Antibodies in the Evaluation of Interferon β Immunogenicity in Patients with Multiple Sclerosis

Patients with multiple sclerosis (MS) treated with interferon β (IFNβ) preparations develop varying levels of antibodies that neutralize the biological effects of IFNβ, reduce its in vivo bioavailability, and diminish its therapeutic efficacy. The aim was to determine as distinct measures of immunogenicity the occurrence (frequency) and the magnitude (level) of IFNβ neutralizing antibody (NAb) formation in a large Canadian population as a cross-sectional study of patients with MS treated in a clinical practice setting with different, equally available IFNβ products: Avonex(®) (intramuscular IFNβ-1a), Rebif(®) (subcutaneous (SC) IFNβ-1a) at 22 and 44 μg, and Betaseron(®) (SC IFNβ-1b). Over a 3-year period 3,124 serum samples from 2,711 patients with MS were submitted by neurologists in MS clinics distributed across Canada and tested for NAbs in a single independent laboratory, utilizing a quantitative, standardized NAb bioassay. NAb frequency was greatest (35%) with Rebif (SC IFNβ-1a) 44 μg and least (7.5%) with Avonex (intramuscular IFNβ-1a), whereas Betaseron (IFNβ-1b) and Rebif 22 μg were in between (22%). NAb serum levels at magnitudes considered high, ≥100 tenfold reduction units (TRU)/mL, were found in 65%-83% of patients with detectable NAbs. Nearly half (42%-47%) of NAb-positive patients given IFNβ-1a preparations had very high titers (≥ 1,000 TRU/mL), whereas only 22% of NAb-positive patients on Betaseron had titers >1,000 TRU/mL. Differences in patterns of NAb formation among the four IFNβ product-dose combinations became more evident in patients with MS when both NAb frequency and the full range of NAb titer magnitude were measured.

Adherence to Disease-Modifying Therapies in Spanish Patients with Relapsing Multiple Sclerosis: Two-Year Interim Results of the Global Adherence Project

The post-marketing international Global Adherence Project investigated adherence to disease-modifying therapy for relapsing-remitting multiple sclerosis. We report adherence data from the first 2 years in the Spanish subset of patients (n = 254 at baseline). The overall adherence rate was 85.4%. Patients taking intramuscular (IM) interferon-β (IFNβ)-1a were significantly more adherent (96.4%) compared with patients taking subcutaneous (SC) IFNβ-1a 22 µg (79.1%; p = 0.0064), SC IFNβ-1a 44 µg (79.6%; p = 0.0064) and glatiramer acetate (82.7%; p = 0.0184). At year 1 (n = 142), the overall adherence rate was 86.6%. Patients on IM IFNβ-1a were significantly more adherent than patients on SC IFNβ-1a 22 µg (93.9 vs. 66.7%; p = 0.0251). At year 2 (n = 131), the overall adherence rate was 82% (87.5% for IM IFNβ-1a, 80.0% for SC IFNβ-1a 22 µg, 77.8% for SC IFNβ-1a 44 µg, 85.2% for IFNβ-1b, and 80.0% for glatiramer acetate). In conclusion, adherence remained high among all disease-modifying therapies over the first 2 years of the study and was significantly higher for IM IFNβ-1a, at visit 1, compared with SC IFNβ-1a.

Gender effects on intramuscular interferon beta-1a in relapsing–remitting multiple sclerosis: analysis of 1406 patients

Background: We aimed to evaluate effects of gender on efficacy and safety of intramuscular (IM) interferon beta (IFNβ)-1a in patients with relapsing–remitting MS (RRMS) or clinically isolated syndromes (CIS) characteristic of early MS. Methods: Pooled data from 1406 (1027 women; 379 men) patients enrolled in five clinical studies of IM IFNβ-1a were analyzed. One analysis examined data for all patients treated with IM IFNβ-1a from all studies. Separate analyses were conducted of pooled IM IFNβ-1a-treated groups from all studies and pooled IFNβ-1a-treated and placebo-treated patients from the placebo-controlled studies. Outcome measures included time to first relapse, annualized relapse rate, time to disability progression, number of gadolinium-enhanced lesions, adverse events, laboratory evaluations, and neutralizing antibodies. Results: All efficacy assessments indicated similar treatment effects of IM IFNβ-1a in men and women with no significant treatment-by-gender interactions. Women reported more headaches, urinary tract infections, and depression in the analysis; however, these were also common in women who received placebo. Men reported more frequent flu-like symptoms in the placebo-controlled studies only. There were no other differences in the safety profile of IM IFNβ-1a between men and women. Conclusions: We conclude that no significant gender-related differences were found in the efficacy and safety of IM IFNβ-1a in patients with RRMS or CIS.

Persistence and adherence to disease modifying drugs among patients with multiple sclerosis

Objective:This retrospective database study aimed to evaluate the adherence of multiple sclerosis (MS) patients on immunomodulatory treatments using claims data, and to identify differences between compliance and persistency measurements in the context of this disease.Methods:Continuously enrolled MS patients treated with subcutaneous IFNβ-1b (Betaseron), subcutaneous IFNβ-1a (Rebif), intramuscular IFNβ-1a (Avonex), and subcutaneous glatiramer acetate (Copaxone).) were identified from the PharMetrics patient-centric database, and all information related to patient demographics and pharmacy claims for the drugs of interest were extracted.Outcome measures:The main outcomes were treatment switches and discontinuations for patients initiated on the drugs of interest. Various compliance and persistency metrics including the proportion of days covered, treatment prevalence at 6-monthly time points after initiation, and the continuous time on drug were also examined.Results:A total of 6134 MS patients were started on one of the four drugs of interest. The number of patients switching or discontinuing therapy rose over the study period. The proportion of patients switching was similar between study drugs, by the different metrics, with the highest switch rates for subcutaneous IFNβ-1b and the lowest for subcutaneous glatiramer acetate. Discontinuation rates were highest for subcutaneous IFNβ-1b and lowest for intramuscular IFNβ-1a. Regression models showed that intramuscular IFNβ-1a and subcutaneous IFNβ-1a had similar and higher persistency compared to subcutaneous IFNβ-1b and subcutaneous glatiramer acetate.Conclusions:Although treatment switching and discontinuation is common in MS patients, there is some noticeable variability between drugs and across measures of persistency and adherence. Also, claims data do not allow distinguishing between clinical patterns of MS, direct estimation of disease severity and observation of care that occurs outside of insurance coverage, and results need to be cautiously interpreted. The compliance to the various MS drugs was 80% or higher at all times for all four drugs. The highest rate of treatment persistency existed in the intramuscular IFNβ-1a initiator group, while subcutaneous IFNβ-1b was associated with a significantly lower persistence (p < 0.0001).

Efficacy of intramuscular interferon beta-1a in patients with clinically isolated syndrome: analysis of subgroups based on new risk criteria

Approximately 85% of multiple sclerosis (MS) cases begin as clinically isolated syndromes (CIS). Results from the Controlled High-Risk Subjects Avonex® Multiple Sclerosis Prevention Study (CHAMPS) demonstrated that, in patients with CIS, treatment with intramuscular (IM) interferon beta-1a (IFNβ-1a) 30 μg once weekly delayed conversion to clinically definite MS (CDMS) in the total population and in subgroups based on presenting syndromes and baseline magnetic resonance imaging (MRI) characteristics. Changes to clinical and MRI risk classification of presenting symptoms in recent studies prompted reanalysis of CHAMPS data. Presenting syndromes were assessed using a derived algorithm that stratifies patients into mono- or multifocal categories based on functional system scores. The ability of IM IFNβ-1a to delay progression to CDMS in subgroups based on clinical presentation and MRI characteristics was assessed. Reanalysis of CHAMPS patients showed that 30% could be classified by clinical criteria as having multifocal disease at baseline. IM IFNβ-1a initiated at a first demyelinating attack delayed CDMS in monofocal patients (P = 0.0013), patients with or without gadolinium-enhancing lesions (P = 0.0007, P = 0.0405) and patients with at least nine T2 lesions at baseline (P = 0.0044). These data confirm that IM IFNβ-1a delays conversion to CDMS in patients with CIS.

Cost effectiveness and budget impact of natalizumab in patients with relapsing multiple sclerosis

ABSTRACTBackground: Disease-modifying therapy (DMT) is the largest single-cost item that contributes to the total per-patient cost of multiple sclerosis (MS), a disabling disorder of the central nervous system. Natalizumab is the most recent DMT to be approved for the treatment of relapsing MS and may be an attractive alternative to interferon beta and glatiramer acetate (GA).Objectives: To determine from the perspective of a United States payer (1) the incremental cost effectiveness of natalizumab compared with other DMTs and (2) the budgetary impact of utilization of natalizumab for the treatment of relapsing MS.Methods: A combined cost effectiveness and budget impact model was developed. Model inputs were drug acquisition costs (wholesale acquisition cost), costs of drug administration and monitoring, costs of treating relapses, anticipated reduction in relapse rates after 2 years of therapy, and estimated market utilization of natalizumab. Outcomes included total 2-year costs of therapy per patient, costs per relapse avoided for each treatment, and overall 2-year costs to the health plan and per member per month (PMPM) costs. Drug acquisition costs are in 2008 US dollars, and all other costs were inflated to 2008 US dollars when necessary. Univariate sensitivity analyses were performed to determine the model inputs with the greatest influence on the cost per relapse avoided for natalizumab.Results: The overall 2-year cost of therapy per patient was $72 120 for natalizumab, $56 790 for intramuscular (IM) interferon beta-1a (IFNβ-1a), $56 773 for IFNβ-1b, $57 180 for GA, and $58 538 for subcutaneous (SC) IFNβ-1a. The cost per relapse avoided was lowest for natalizumab at $56 594, followed by $87 791 for IFNβ-1b, $93 306 for IM IFNβ-1a, $96 178 for SC IFNβ-1a, and $103 665 for GA. The incremental cost-effectiveness ratios of natalizumab relative to IM IFNβ-1a, IFNβ-1b, GA, and SC IFNβ-1a were $23 029, $24 452, $20 671, and $20 403 per additional relapse avoided, respectively. An increase in natalizumab utilization to 9% resulted in an increase of approximately $61 760 in total 2-year costs to a hypothetical health plan of 1 million members, or a $0.003 PMPM incremental cost. Univariate sensitivity analyses indicated that the model inputs with the most influence on cost per relapse avoided for natalizumab were the weighted average number of relapses before treatment and the anticipated relative relapse rate reduction.Conclusions: Natalizumab was the most cost-effective therapy as measured by total cost per relapse avoided, not withstanding a higher drug acquisition cost versus other DMTs. Entry of natalizumab to the market is likely to result in a minimal increase in health-plan costs on a PMPM basis. Limitations of the study include the use of a surrogate measure, relapse avoided, as an outcome measure; also, adverse events were not included in the model.

Efficacy and tolerability of intramuscular interferon beta-1a compared with subcutaneous interferon beta-1a in relapsing MS: results from PROOF

ABSTRACTObjective: Benefits from interferon beta (IFNβ) treatment in patients with multiple sclerosis are affected by many factors, including sustained clinical efficacy, acceptable tolerability, adherence to therapy, and the development of neutralizing antibodies (NAbs). The Prospective and Retrospective Long-Term Observational Study of Avonex and Rebif (PROOF) was designed to compare the relative efficacy and tolerability of the two IFNβ-1a products for up to 5 years.Methods: PROOF compared the relative efficacy and tolerability of intramuscular (IM) IFNβ-1a (Avonex) 30 µg once weekly (n= 69) and subcutaneous (SC) IFNβ-1a (Rebif) 44 µg three times per week (n= 67). The duration of the retrospective portion of the study was 12–24 months. Due to slow enrollment, PROOF ended earlier than planned and the final duration of the prospective portion of the study was 6 months. Therefore, between 18 and 30 months of efficacy and tolerability data were available for analysis.Results: After controlling for baseline disability level, Expanded Disability Status Scale (EDSS) scores revealed no statistically significant differences between the treatment groups during the prospective portion of the study, with sustained disability progression similar in both groups (25.8% IM IFNβ-1a 30 µg once weekly vs. 26.7% SC IFNβ-1a 44 µg three times per week). Relapse rates were similar in the groups, as were MRI endpoints of brain parenchymal fraction, T1 lesion volume, T2 lesion volume, number of new/enlarging T2 lesions, and gadolinium-enhancing (Gd+) lesion volume and count. Treatment groups differed in frequency of NAbs, with 19% of patients treated with SC IFNβ-1a 44 µg three times per week NAb+ compared with none treated with IM IFNβ-1a 30 µg once weekly. More NAb+ patients compared with NAb– patients had disability progression (40.0% vs. 27.8%, p= NS), new or enlarging T2 lesions at the end of treatment (63.6% vs. 40.7%, p= 0.003), and Gd+ lesions after 12–24 months of treatment (36.4% vs. 15%, p= 0.001). The IFNβ-1a products had comparable tolerability. However, fewer patients treated with IM IFNβ-1a 30 µg once weekly had injection-site reactions (2.9% vs. 6.0%). Limitations of this study include its design and sample size, both of which hinder detection of differences in efficacy between IFNβ-1a treatments.Conclusions: The results of the present study show that the two IFNβ-1a products have comparable efficacy and differing immunogenicity.

Methylprednisolone, Mycophenolate Mofetil, or Cyclophosphamide as Combination Therapy With Interferon Beta-1a in Patients With Multiple Sclerosis: Retrospective Study

Currently approved disease-modifying therapies for multiple sclerosis (MS) are only partially effective. This study evaluated the efficacy and safety of combination therapy with intramuscular (IM) interferon beta (IFNβ)-1a (Avonex) in patients with disease that progressed despite treatment. A retrospective chart review of all patients from the MS Center of Atlanta, Georgia, was performed (N ≈1300). Eligible patients had a diagnosis of relapsing MS, were treated with IM IFNβ-1a for ≥12 months before initiation of combination therapy, and were on combination therapy for active disease. In addition, patient records must have contained data on relapses, Expanded Disability Status Scale (EDSS) scores, magnetic resonance imaging (MRI) scans, laboratory values, and adverse events. Patients were identified who had been treated with the following in addition to IM IFNβ-1a: pulse corticosteroids only (n = 25), pulse corticosteroids plus mycophenolate mofetil (n = 8), and pulse corticosteroids plus cyclophosphamide (n = 13). The annualized relapse rate was significantly reduced by all three treatments compared with monotherapy (all P ≤.01). For all three groups, no significant improvement was observed with combination therapy compared with monotherapy on evaluations of stable EDSS scores and MRI scans. Three serious adverse events were noted, with two considered related to study medication: one with mycophenolate mofetil (abnormal liver function test results resolved with discontinuation of drug) and one with cyclophosphamide (white blood cell count decrease resolved by withholding one dose). These data suggest that combination therapy is a viable option for the treatment of active MS.

Interferon-β1a: a once-weekly immunomodulatory treatment for patients with multiple sclerosis

Multiple sclerosis (MS) is a chronic demyelinating disease of the CNS. The most common form of MS at onset, relapsing–remitting disease, is defined not by pathological features but by unpredictable periods of acute or subacute neurological worsening, followed by gradual improvement over weeks to months, often with residual neurological deficits. Evidence from serial magnetic resonance imaging studies in relapsing–remitting disease reveals significant inflammation, demyelination and axonal loss occurring both during and between relapses. Disease-modifying agents, such as interferon (IFN)-β1a, reduce the frequency of relapse by 30% in well established relapsing patients, reduce the risk of a second attack by 50% in high-risk patients, following a first attack, and reduce the number and volume of magnetic resonance imaging lesions. Intramuscular IFN-β1a is effective in delaying disability progression and brain atrophy. The relationship between response to therapy and pathological subtype of MS is unknown. This review summarizes key findings of Phase III clinical trials, extension studies and postmarketing trials, demonstrating the efficacy and safety of intramuscular IFN-β1a. Results demonstrating the negative impact of anti-IFN-β neutralizing antibodies on clinical efficacy are also addressed. Finally, expert commentary regarding the treatment of MS with IFN-β therapy and future strategies to augment intramuscular IFN-β1a efficacy by combination treatment with other agents is presented.

MxA protein induction in MS patients treated with intramuscular IFNβ-1a

MxA protein production in peripheral blood leukocytes is a valuable marker to evaluate biologic effects of interferon-beta (IFNbeta) therapy in multiple sclerosis (MS) patients. The three IFNbeta preparations available in the treatment of MS differ with respect to antigenicity and biologic activity. We studied prospectively the induction of MxA protein and the development of binding (BAb) and neutralising antibodies (NAb) in nine relapsing-remitting MS (RRMS) patients during one year of intramuscular IFNbeta -1a (Avonex) treatment. Another nine RRMS patient treated with Avonex for 1-3.5 years were also included. The results were compared with our earlier published data of subcutaneous IFNbeta-1a (Rebif). None of these 18 patients developed NAb but three of the long-term patients developed BAb. The baseline MxA protein levels rose but the induction was weaker compared to Rebif. The stimulation index (MxA after/before IFNbeta-1a injection) remained elevated. Weekly intramuscular dosing of IFNbeta-1a provides a sustained effect on lymphocytes but differences in leukocyte stimulation may underlie some of the differences between IFNbeta therapies.

The effects of intramuscular interferon beta-Ia in patients at high risk for development of multiple sclerosis: A post hoc analysis of data from CHAMPS

Background: In the Controlled High Risk Subjects Avonex® Multiple Sclerosis Prevention Study (CHAMPS), intramuscular (IM) interferon beta-1a (IFNβ-1a) delayed the development of clinically definite multiple sclerosis (CDMS) in patients with a single demyelinating event who had magnetic resonance imaging (MRI) evidence of previous subclinical disease activity (defined as ≥2 T2-weighted hyperintense lesions, 1 of which was periventricular or ovoid, on unenhanced MRI scans). Objective: This post hoc analysis was conducted to assess the effects of IM IFNβ-1a on delaying the development of CDMS in a subgroup of CHAMPS patients who met a more stringent definition of high risk than was used in that trial. Methods: Patients from the overall CHAMPS population were included in the present analysis if they had ≥9 T2-weighted hyperintense lesions and ≥1 gadolinium-enhanced lesion on the baseline MRI scan. The cumulative probability of developing CDMS in each treatment group was calculated using the Kaplan-Meier product-limit method and compared using the log-rank test. The actual proportions of patients who developed CDMS in each treatment group were calculated and compared using the chi-square test. Results: Ninety-one patients met the more stringent definition of high risk and were included in the subgroup analysis. Fifty-one patients (56.0%) received IFNβ-1a 30 μg IM once weekly and 40 (44.0%) received placebo. Baseline demographic and clinical characteristics were similar between the 2 groups. Seventy-four patients (81.3%) were female, 80 (87.9%) were white, and the mean age was 33.0 years. Overall, IM IFNβ-1a reduced the rate of development of CDMS by 66% compared with the placebo group ( P = 0.002, log-rank test) over the 3-year follow-up period. At 2 years, the Kaplan-Meier estimate of the cumulative probability of developing CDMS was 21% in the IM IFNβ-1a group and 56% in the placebo group, representing a 63% reduction in risk for CDMS with IFNβ-1a ( P = 0.002, log-rank test). The results based on the actual proportions of patients developing CDMS were similar to the Kaplan-Meier estimates. Conclusions: The results of this subgroup analysis are compatible with IM IFNβ-1a reducing the risk of a second demyelinating event in patients meeting the more stringent definition of high risk. Although the treatment effect of IFNβ-1a was significant in both the overall CHAMPS population (44% risk reduction vs placebo; P = 0.002) and in this high-risk subgroup (66%), the results of the present analysis suggest that the magnitude of treatment benefit with IFNβ-1a may be greater in patients with more disease activity, as measured by MRI parameters.