REVIEWER: Dr. Mark S. Freedman, Director, Multiple Sclerosis Research Unit, The Ottawa Hospital, Ottawa, Canada
Redefining therapeutic efficacy
Conclusions
New data on novel and emerging therapies were the centrepiece of the 2014 joint meeting of the Americas and European Committee for Research and Treatment of Multiple Sclerosis (ACTRIMS/ECTRIMS), with results suggesting that clinical standards are being redefined for optimal disease control in relapsing-remitting multiple sclerosis (RRMS).
Of growing importance are no evidence of disease activity (NEDA), generally defined as no relapses, no EDSS progression and no MRI activity (enhancing T1 or new/enlarging T2 lesions); and early brain atrophy, which has been shown to be highly prognostic of disability progression and cognitive impairment in RRMS (Minneboo et al. J NeurolNeurosurg Psychiatry 2008;79:917-923; Calabrese et al. Arch Neurol 2009;66:1144-1150; Tauhid et al. ECTRIMS 2014; abstract P016).Cognitive change is highly prevalent in MS. An analysis of the London database reported that 69% of newly-diagnosed RRMS patients (average age 36.9 years, median EDSS 2.0) had some cognitive dysfunction. The most common impairment was seen on the Symbol Digit Modalities Test (37.5%), which evaluates processing speed and working memory (Morrow et al. ECTRIMS 2014; abstract P160).
Long-term data are only available for the first-generation injectable disease-modifying therapies (DMTs). To date, their modest short-term efficacy does not appear to translate to substantial benefits over the disease course. In the 16-year follow-up of the IFNb-1b pivotal trial, the likelihood of reaching EDSS 6.0 for patients with >80% drug exposure was 35.7% compared to 38.65 with < 10% drug exposure; differences were not significant (Ebers et al. J Neurol Neurosurg Psychiatry 2010;81:907-912). It should be noted that only 28 of 260 patients (11%) received >80% drug exposure. A retrospective analysis of MS patients in the B.C. database reported that IFNb use was not associated with a reduction in disability progression compared to untreated contemporary or historical controls (Shirani et al. JAMA 2012;308:247-256).
Long-term data are lacking for second-generation agents, but the hope is that their greater potency will result in long-term benefits. A recent analysis found that patients with breakthrough disease on a first-line injectable are at higher risk of more relapses or progression (Freedman et al. ECTRIMS 2014; abstract P046). Moreover, an estimated 10-36% of patients will present with aggressive MS at onset (Menon et al. ECTRIMS 2014; abstract P227). Thus, a substantial proportion of patients would be expected to be at high risk of ongoing disease activity during treatment with a first-line therapy. An important goal of management is to promptly identify patients with a suboptimal response and provide more optimal therapy.
After initiating treatment, of particular importance is ongoing disease activity, which has been shown to be predictive of worse outcomes. For example, MSBase group reported that high annualized relapse rates (ARR), especially relapse activity early in the treatment course, were highly predictive of EDSS change at five- and eight-year follow-up (Spelman et al. ECTRIMS 2014; abstract P771). Similar results were obtained by the Barcelona group. In a 12-year prospective follow-up study of patients receiving IFNb, persistent disease activity in the first two years of treatment was predictive of severe long-term disability worsening, defined as 5-point worsening in EDSS, wheelchair, or onset of SPMS (Rio et al. ECTRIMS 2014; abstract P285). This supports previous findings that frequent relapses in the first two years are prognostic of a shorter time to reach key disability endpoints (Scalferi et al. Brain 2010; 133; 1914-1929).
An emerging method of assessing treatment efficacy is NEDA, which provides a composite measure of ongoing disease activity. In the CLIMB study of patients with CIS/RRMS on injectable therapies, NEDA showed good positive predictive values for EDSS change < 0.5 points at seven-year follow-up (71.7% at year 1, 79.3% at year 2) (Rotstein et al. ECTRIMS 2014; abstract P763). Up to 15% of patients in the placebo arm of randomized trials have been shown to achieve NEDA at one year (Havrdova et al. Lancet Neurol 2009; 8:254-60), but NEDA rates typically decline to < 10% by year 2 (Havrdova 2009; Havrdova et al. AAN 2013; abstract P07.106).
The highest NEDA rate with IFNb in head-to-head trials was seen in the TRANSFORMS trial (34% at 1 year with IFNb-1a IM vs. 46% with fingolimod) (Cohen et al. N Engl J Med 2010;362:402-15). NEDA rates at two years were 14-27% with IFNb-1a SC in the CARE-MS trials (vs. 32-39% with alemtuzumab) (Cohen et al. Lancet 2012;380:1819-28; Coles et al. Lancet 2012;380:1829-39), and 12% with glatiramer acetate in the CONFIRM trial (vs. 18% with dimethyl fumarate 240 mg BID) (Fox et al. N Engl J Med 2012;367:1087-97). Moreover, these comparative data suggest improved control of inflammatory disease activity with more potent agents, with over one-third of patients achieving NEDA in the first two years of therapy when treated with the infusion agents natalizumab and alemtuzumab, or fingolimod.
Redefining therapeutic efficacy
According to new data from extension and observational studies, second-line therapies are highly effective in reducing clinical and radiological disease activity. In the first long-term follow-up study of natalizumab, continuous treatment was associated with a low risk of disability worsening over a six-year period compared to stopping treatment (6% vs. 39%) (Prosperini et al. ECTRIMS 2014; abstract P292). However, the analysis has several limitations. Patients remaining on study would have self-selected for treatment response. Those who discontinued were likely to have experienced significant clinical worsening, a known complication associated with natalizumab withdrawal (Schaaf et al. Expert Rev Neurother 2011;11:1247-50). Moreover, 66% of patients interrupted or discontinued natalizumab during the observation period, primarily due to concerns about the risk of progressive multifocal leukoencephalopathy (PML) with continued exposure to the drug. Clinical trials with active controls have not been performed so comparative data are lacking.
In an analysis of the subset of patients with highly active disease in the CARE-MS I trial, alemtuzumab (12 mg/day x 5 days followed by a three-day course a year later) significantly reduced early disease activity compared to subcutaneous IFNb-1a (Krieger et al. ECTRIMS 2014; abstract P088). In year 2, ARR was 0.20 with alemtuzumab and 0.40 with IFNb-1a; the proportion of patients relapse-free was 76.2% and 50.4%, respectively (hazard ratio 0.40). Patients in the alemtuzumab group were also more likely to be free of enhancing T1 lesions (90.3% vs. 66.1%), new/enlarging T2 lesions (71.2% vs. 45.6%), and hypointense T1 lesions (“black holes”; 90.4% vs. 68.4%). While there was not a substantial difference in NEDA in this group with highly active disease (25.5% vs. 20.0%), the change in brain parenchymal fraction was reduced 32.1% at two years with alemtuzumab compared to IFNb-1a, indicating an important reduction in brain volume loss.
Disease activity remained low during the CARE-MS I extension (Coles et al. ECTRIMS 2014; abstract P090). Most patients (73%) did not require additional drug after the two courses of treatment in the two-year core study. In year 3, 64% of patients on continuous alemtuzumab were disease activity-free, defined as no clinical or MRI activity and no six-month sustained accumulation of disability for the one-year cross-sectional analysis (Havrdova et al. ECTRIMS 2014; abstract FC1.4). ARR remained low in years 3 (0.19) and 4 (0.14) (Coles 2014). Mean EDSS scores remained below baseline values (-0.16 in years 0-2, -0.09 in years 3-4) throughout the four years, with 79.3% demonstrating stable or improved EDSS scores in year 4. Among patients initially randomized to IFNb-1a, ARR was reduced 69% (0.39 to 0.12) after switching to alemtuzumab.
Similar efficacy was seen in the two-year extension of the CARE-MS II trial, which enrolled patients with ongoing disease activity while on prior therapy. Overall, 68% of patients in the alemtuzumab group did not require further treatment (Hartung et al. ECTRIMS 2014; abstract P043). In year 3, 55% of patients on continuous alemtuzumab were disease activity-free (Havrdova 2014). ARR remained low throughout the study period (0.26 in years 0-2, 0.24 in years 0-4). EDSS scores remained below pre-treatment values, with 67% demonstrating stable or improved EDSS scores over the four-year period (Hartung 2014).
MRI results were presented separately for the first year of the extension (Barkhof et al. ECTRIMS 2014; abstract P075; Fisher et al. ECTRIMS 2014; abstract P103). Although 80% of patients were not re-treated in year 3, 86.5% of patients were free of enhancing T1 lesions and 69.0% were free of new/enlarging T2 lesions on the annual scan. The median annual rate of brain volume loss slowed over time: -0.48% in year 0-1, -0.22% in year 1-2, and -0.10% in year 2-3.
Improvements were also seen in patient quality of life (Moreau et al. ECTRIMS 2014; abstract P044). In year 3, SF-36 physical and mental component summary scores were stable or improved in 82% and 73% of patients, respectively. The four-year cumulative incidence of thyroid adverse effects was 37.5% in the CARE-MS I extension, and 34.7% in the CARE-MS II extension, with the incidence peaking in year 3 and declining thereafter (Coles 2014; Hartung 2014). The cumulative incidence of immune thrombocytopenia purpura (ITP) was 1.1% in the CARE-MS I extension and 2.5% in CARE-MS II. Overall, 1.3% of patients in CARE-MS I and 4.1% in CARE-MS II withdrew due to adverse effects.
Earlier use of more potent agents has also been shown to have a beneficial effect on the rate of brain atrophy. An analysis of phase III trials of fingolimod examined the amount of brain volume loss in placebo-treated patients at the end of the core study period (Haring et al. ECTRIMS 2014; abstract P081). Patients in the continuous fingolimod groups took an additional 13.6-14.6 months to reach that degree of brain volume loss during the FREEDOMS/FREEDOMS II extensions. The amount of time gained versus IFNb-1a in the TRANSFORMS study was 5.6 months with continuous fingolimod. In LONGTERMS, the open-label extension of phase II and III trials of fingolimod, a comparison of patients on continuous fingolimod versus placebo-fingolimod showed that mean percentage brain volume change (PBVC) was significantly lower at all time points from month 12 to month 72 (Radue et al. ECTRIMS 2014; abstract P439). Higher atrophy rates were associated with an increased risk of disability. Thus, delaying treatment is associated with an early loss of brain volume that is not regained, underscoring the importance of prompt, effective treatment.
The impact of different therapies on the rate of brain volume loss may not be immediately apparent, but more effective disease control appears to produce a more sustained benefit over time. A new meta-analysis compared the impact of first- and second-line therapies on brain atrophy for up to 48 months (Branger et al. ECTRIMS 2014; abstract P543). First-line therapies were the IFNb drugs, glatiramer acetate, teriflunomide, dimethyl fumarate and laquinimod. Second-line therapies were natalizumab, alemtuzumab, fingolimod and daclizumab. The analysis included 35 studies (n=17,770). The time periods studied were 0-48 months, and 12-48 months (to account for pseudoatrophy). Over the 48-month period, the annualized rate of brain volume loss was -0.23% with second-line agents, -0.42% with first-line agents, and -0.50% with placebo; differences were significant between second-line agents and placebo. Over months 12-48, the annual rate of brain atrophy was -0.10% with second-line agents, -0.46% with first-line agents, and -0.55% with placebo. Second-line agents were significantly superior to first-line agents and placebo. Second-line agents were also more effective when the analysis was limited to studies that evaluated atrophy using SIENA and brain parenchymal fraction.
The disease course in MS is characterized by immune dysfunction throughout the CNS that results in extensive demyelination and axonal loss. The accelerated rate of brain volume change in RRMS is associated with early cognitive impairment and progressive neurological deficits, loss of employment and higher rates of morbidity and mortality.
The expanding armamentarium of disease-modifying agents now enables clinicians to intervene more effectively. A high proportion of patients switched to second-line agents will demonstrate a substantial reduction in disease activity, with many achieving NEDA in the crucial early period during which treatments can provide the most benefit with respect to disease control, longer-term functioning and quality of life. While the predictive value of NEDA on outcomes must be validated in long-term studies, the impact of second-line agents in slowing the rate of brain volume loss suggests that cognitive dysfunction may be reduced and the onset of progressive MS may be delayed with an early, more aggressive approach to therapy.