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Immunomodulatory therapies for relapsing-remitting multiple sclerosis: monoclonal antibodies, currently approved and in testing Expert Rev. Clin. Pharmacol. 8(3), 283–296 (2015)
Jessica Craddock1 and Silva Markovic-Plese*1,2 1 Department of Neurology, University of North Carolina at Chapel Hill, 105 Mason Farm Road, Chapel Hill, NC 27599, USA 2 Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, 105 Mason Farm Road, Chapel Hill, NC 27599, USA *Author for correspondence: Tel.: +1 919 966 3701 [email protected]
Relapsing–remitting multiple sclerosis (RRMS), a CNS inflammatory demyelinating disease, is one of the most prevalent causes of chronic disability in young adults. Studies of the disease pathogenesis have identified multiple therapeutic targets. The number of approved disease modifying therapies has almost doubled within the past 5 years, which creates a challenge for medical professionals to stay abreast of their use in everyday practice. This manuscript provides an overview of available injectable, oral, and intravenous therapies for RRMS, and offers guidance in selecting an appropriate therapy. Focus is on the recently approved and emerging monoclonal antibody therapies, because they offer more selective and superior therapeutic efficacy compared with injectable and oral disease modifying therapies. We discuss the outlook for monoclonal antibodies and their role in RRMS treatment in the future. KEYWORDS: alemtuzumab . daclizumab . mechanism of action . monoclonal antibody . natalizumab . ocrelizumab .
ofatumamab
.
relapsing remitting multiple sclerosis
Epidemiological studies have reported an increased incidence and prevalence of multiple sclerosis (MS) over the past decades. There are about 200 new cases diagnosed in the USA each week and approximately 2.5 million MS patients worldwide. MS is a CNS disease characterized by an autoimmune/inflammatory response, myelin and axonal loss [1], which can result in a significant disability [2,3]. IFN-b-1b was approved by the US FDA as the first disease-modifying therapy (DMT) for relapsing–remitting (RR) MS in 1993 [4]. Following the first-line therapies, including various forms of IFN-b and glatiramer acetate (GA) in the 1990s [5], mitoxantrone was approved in 2002 for the aggressive forms of MS and for patients who had failed the first-line therapies [6]. Recent approval of several oral DMTs with new mechanisms of action (MOAs) and similar or superior efficacy has dramatically changed the treatment options for patients with RRMS [7]. Emerging treatments with monoclonal antibodies (mAbs) has resulted in informahealthcare.com
10.1586/17512433.2015.1036030
more selective and superior therapeutic efficacy [8], with natalizumab as the most effective available therapy [9], followed by the recently approved alemtuzumab [10] and ongoing Phase III clinical trials with anti-B cell therapies and the anti-IL-2 receptor alpha mAb (daclizumab) in progress. The goal of this manuscript is to provide an overview of the available first-line injectable, oral, and secondline therapies for RRMS, and discuss the efficacy, safety, and tolerability of recently introduced and currently tested mAbs, and their future therapeutic use. We will primarily focus on the pivotal clinical trials for US FDA-approved therapies for RRMS, discussing study design, efficacy and tolerability results in comparison to placebo. It is important to emphasize that the design of clinical trials for MS therapies has evolved over the past 20 years, introducing new measures of disease activity and therapeutic efficacy. There are only several head-to-head comparison studies [11–13]. We will focus primarily on
2015 Informa UK Ltd
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Craddock & Markovic-Plese
the placebo-controlled studies to provide a basis for the comparison of clinical efficacy, imaging results, and safety data, which will allow us to provide suggestions regarding therapeutic algorithms that can be used in current practice for the approved therapies, while awaiting approval of additional treatments. Several of them are mAbs in the final stages of Phase III clinical testing. A discussion of study designs and efficacy data, focusing on the relapse rate, disability and MRI readouts, as well as the most relevant information on the adverse events for each approved medication will provide an informative overview of the complex and extensive data on the new DMTs for RRMS. Currently approved therapies for RRMS First-line injectable therapies IFN-b-1b
The first DMT approved for RRMS was IFN-b-1b, approved in 1993 [4]. Its MOA are still not completely elucidated, but include inhibition of inflammatory cell migration across the blood–brain barrier, modification of inflammatory cytokines (inhibition of IL-12/IFN-g/IL-17-A [14] and induction of IL-10), inhibition of MHC class II expression on antigen presenting cells, and reconstitution of deficient endogenous IFN-b secretion and signaling [15]. The results of the pivotal placebocontrolled trial compared the effect of IFN-b-1b 8 million international units (MIU) and 1.6 MIU subcutaneous (S.Q.) injection every other day with placebo (ratio 1:1:1) over 2 years in 372 patients with active RRMS (mean baseline expanded disability status scale [EDSS] 2.8–3.0 for the various subgroups, at least two exacerbations in the previous 2 years). There was a decrease in the annual relapse rate (ARR; placebo 1.27, 8 MIU 0.84, 34% reduction; p = 0.0001), whereas EDSS did not change significantly [4]. Yearly brain MRI studies revealed an 80% decrease in the number of active scans in treated patients. Reported side effects were flu-like syndrome that decreased after 3 months, elevated liver enzymes, injection site reactions, and mild intermittent lymphopenia, neutropenia and anemia. The 8 MIU dose was approved for the treatment of RRMS. Further randomized controlled trials have found depression and suicide infrequently associated with IFN-b-1b. Rarely, congestive heart failure, severe hepatotoxicity, and autoimmune hepatitis were reported with its use. Additional controlled clinical trials have documented injection site necrosis, and at least 5% more frequently than placebo headache, hypertonia, insomnia, pain, rash, abdominal pain, and asthenia. IFN-b-1b is currently available as Betaseron and Extavia brands. They have the same active ingredient, but they are not considered interchangeable. Of note, Extavia has been approved in Europe for the treatment of RRMS, early MS, and secondary progressive MS with relapses. IFN-b-1a (intramuscular)
In 1996, the MS Collaborative Research Group designed a clinical trial to assess the ability of IFN-b-1a (30 mg 284
intramuscular [I.M.] weekly) in 301 patients with active RRMS (baseline EDSS 2.3–2.4) to decrease the accumulation of disability over 2 years [16]. Patients were administered IFN-b-1a for up to 104 weeks and compared with placebo. IFN-b-1a is glycosylated and less immunogenic in comparison with IFN-b-1b. The primary outcome was time to sustained disability progression of at least 1 point in EDSS, persisting for at least 6 months, which was significantly delayed in the IFN-b-1a-treated patients (p = 0.02). The ARR was 0.82 for placebo and 0.67 for treated patients, with a relative reduction of 18.3%; p = 0.04 (TABLE 1). MRI results at 2 years revealed no significant change in T2 lesion volume and a decrease in the number of Gd-enhancing lesions (p = 0.05) in the IFN-b-1atreated patients in comparison with placebo. Only 4% of the patients discontinued the IFN-b-1a due to adverse events, which included flu-like symptoms, muscle aches, headache, chills, fever and anemia. Both treatment arms included adverse events of injection site reactions, depression and menstrual disorders. There was a greater incidence of depression in the treatment group, 20% compared with placebo 13%, but this difference was not statistically significant. Neutralizing antibody (NAB) presence was found in 15 of the IFN-b-1a-treated patients. Similar to IFN-b-1b, with additional controlled trials there have been reports of severe hepatic injury, including hepatic failure. During the post-marketing period, there have been cases of congestive heart failure in patients with no known risk factors, rare pancytopenia, thrombocytopenia and autoimmune diseases, including idiopathic thrombocytopenic purpura, hyperthyroid and hypothyroid disease, and even rare cases of autoimmune hepatitis. It is recommended to periodically check complete blood count (CBC) with differential counts, platelets, chemistry panel and liver function studies. IFN-b-1a (S.Q.)
In 1998, the PRISMS trial assessed the efficacy and dose-effect of IFN-b-1a administered at 22 mg and 44 mg S.Q. in comparison with placebo in 560 active RRMS patients over 2 years [17] and demonstrated a dose-dependent decrease in ARR (32% decrease in comparison with placebo, in the 44 mg group; p < 0.005). The time to sustained progression was longer (p < 0.005) and the T2 lesion load was significantly decreased (p < 0.0001) in the 44 mg treatment group. The side effect profile was similar to the other IFN preparations, and the incidence of depression did not differ between the IFN-b-1a and placebo-treated patients (21–28%). Both 44 and 22 mg doses were approved as a treatment for RRMS. Pegylated IFN-b-1a
Although the IFNs showed moderate efficacy in suppressing disease activity and an excellent safety profile, their frequent parenteral administration was a challenge to many patients. All manufacturers now provide disposable autoinjectors that simplify administration, and a new preparation of pegylated IFN-b-1a [18] has decreased the frequency of administration to Expert Rev. Clin. Pharmacol. 8(3), (2015)
Trial/ study
Treatment arms
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MSCRG
PRISMS
ADVANCE
CMSSG
IFN-b 1a I.M.
IFN-b-1a S.Q.
Pegylated IFN-b-1a S.Q.
Glatiramer acetate
FREEDOMS
386 F 174 M
1071 F 441 M
22 mg S.Q. t.i.w. 44 mg S.Q. t.i.w. Placebo
125 mg S.Q. every 2 weeks 125 mg S.Q. every month Placebo
1.25 mg daily 0.5 mg daily IFNb-1a 30 mg I.M. placebo
689 F 583 M
184 F 67 M
221 F 80 M
30 mg I.M. weekly Placebo
20 mg S.Q. daily Placebo
259 F 113 M
1.6 MIU S.Q. q.o.d. 8 MIU S.Q. q.o.d. Placebo
Sex
1272
251
1512
560
301
372
n
2.4 2.3 2.5
2.8 2.4
2.5 2.5 2.4
2.5 2.5 2.4
2.4 2.3
2.9 3.0
Mean EDSS baseline
0.16 (60%) p < 0.01 0.18 (55%) p < 0.01 0.4
1.19 (29.2%) p = 0.007 1.68
0.26 (35%) p < 0.0007 0.29 (28%) p < 0.01 0.4
1.82 (28.9%) p < 0.005 1.73 (32.4%) p < 0.005 2.56
0.67 (18.3%) p = 0.04 0.82
1.17 (7.8%) p = 0.01 0.84 (33.9%) p = 0.0001 1.27
ARR (percent reduction) p value vs placebo
0.17 (32%) p = 0.02 0.18 (28%) p = 0.02 0.29
0.22 (12%) p > 0.05 0.25
0.07 (38%) p = 0.04 in both groups 0.1
0.29 (22%) p = 0.07 0.26 (30%) p = 0.03 0.38
0.22 (37.2%) p = 0.02 0.35
0.28 (0%) 0.20 (28.6%) p = 0.16
Disability accumulation (percent reduction) p value vs placebo
1.25 mg: Reduced number of the T2 lesions (p < 0.001) Reduced number of the lesions (p < 0.001) 0.5 mg: Reduced number of the T2 lesions (p < 0.001) Reduced number of the lesions (p < 0.001)
Gd-enhancing
new/enlarged
Gd-enhancing
new/enlarged
65% decrease in the number of new T2 lesions and Gd-enhancing and hypointense T1 lesions (all p < 0.0001) in q 2 week group
67% decrease 78% decrease in the number of new T2 lesions
52% decrease in the number of Gd-enhancing lesions
80% reduction in the number of active scans (scans with new or enlarging T2 lesions)
Percent reduction in brain MRI lesions
Bradycardia Macular edema Herpes infections
Injection site reaction Systemic reaction
Flu-like symptoms
Flu-like symptoms
Flu-like symptoms
Flu-like symptoms
Key adverse events
ARR: Annualized relapse rate, Disability accumulation (in EDSS); b.i.d.: Twice daily; EDSS: Expanded disability status scale; Gd: Gadolinium; I.M: Intramuscular; I.V.: Intravenous; n: total number; q.o.d.: Every other day; S.Q.: Subcutaneous; t.i.d.: Three times daily; t.i.w.: Three times a week.
Fingolimide
First-line oral therapies
MSSG
IFN-b-1b S.Q.
First-line injectable therapies
Active drug
Table 1. Approved first- and second-line therapies for relapsing–remitting multiple sclerosis.
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285
286
Flushing GI irritation Leukopenia
Cardiotoxicity Leukemia
71% decrease in the number of new/ enlarging T2 lesions in BID dose 57% decrease in the number of hypointense T1 lesions in all groups vs placebo
Significantly reduced number of T2 lesions (p = 0.03) and Gdenhancing lesions (p = 0.02)
0.13 (21% ) p = 0.25 0.13 (24%) p = 0.20 0.16 (7%) p = 0.70 0.17
0.08 (63.6%) p = 0.036 0.22
0.22 (44%) p < 0.001 0.20 (51%) p < 0.001 0.29 (29%) p = 0.01 0.40
0.35 (65.7%) p = 0.001 1.02 188 5 mg/m2 I.V. every 3 months 12 mg/m2 I.V. every 3 months Placebo MIMS Mitoxantrone
Second-line infusion therapy
98 F 90 M
2.6 2.5 2.6 1417 993 F 424 M CONFIRM Dimethyl fumarate
240 mg b.i.d. 240 mg t.i.d. Glatiramer acetate 20 mg S.Q. daily Placebo
1088 785 F 303 M 7 mg daily 14 mg daily Placebo TEMSO Teriflunomide
First-line oral therapies
ARR: Annualized relapse rate, Disability accumulation (in EDSS); b.i.d.: Twice daily; EDSS: Expanded disability status scale; Gd: Gadolinium; I.M: Intramuscular; I.V.: Intravenous; n: total number; q.o.d.: Every other day; S.Q.: Subcutaneous; t.i.d.: Three times daily; t.i.w.: Three times a week.
Hepatotoxicity 39.4% and 67.4% reduction in total T2 lesion volume Decreased number of the Gd-enhancing lesions (p < 0.001) 0.22 (23.7%) p = 0.08 0.20 (29.8%) p = 0.03 0.27 0.37 (31.2%) p < 0.001 0.37 (31.5%) p < 0.001 0.54
n Sex
2.68 2.67 2.68
4.6 4.5 4.7
Key adverse events Percent reduction in brain MRI lesions Disability accumulation (percent reduction) p value vs placebo Mean EDSS baseline
ARR (percent reduction) p value vs placebo
Craddock & Markovic-Plese
Treatment arms Trial/ study Active drug
Table 1. Approved first- and second-line therapies for relapsing–remitting multiple sclerosis (cont.).
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twice a month. Recently approved pegylated IFN-b-1a has a biologically inert polyethylene glycol group attached to the interferon molecule, improving its pharmacokinetic and pharmacodynamic properties. The Phase III clinical trial ADVANCE tested this preparation at 125 mg S.Q. every other week or every month against placebo in 1516 RRMS patients [19]. After 1 year, ARR (0.4 for placebo, 0.26 for every 2 weeks, 0.29 for every 4 weeks; p = 0.0007, p = 0.01) and the proportion of patients with disability progression (placebo 0.1, every 2 weeks and 4 weeks 0.07; p = 0.04, p = 0.02) were significantly lower in both treatment groups than in placebo. After 1 year of placebo, patients were randomized to IFN-b-1a treatment. The number of new or enlarging T2 lesions, as well as the number of new Gdenhancing lesions was lower in patients treated every other week (a 67 and 86% decrease, respectively, both p < 0.0001) than in the patients treated once a month. This preparation was less immunogenic than IFN-b-1a I.M. (less than 1% patients had neutralizing antibodies [NAB]). The adverse events were mild to moderate, so the medication was recently added to the available therapies for RRMS. The incidence of depression and suicide was similar to placebo. There was a higher incidence of asymptomatic increase in liver transaminases and injection site reactions. The incidence of significant lymphopenia, neutropenia and thrombocytopenia was less than 1%. Glatiramer acetate
This first-line therapy was approved in 1996, following a pivotal study of GA injection at 20 mg S.Q. daily in 250 RRMS patients, and showed an ARR reduction of 29% and no significant inhibition of disability progression in comparison with the placebo (TABLE 1) [5]. The MRI effect was delayed and less prominent than with IFN-b, which was attributed to GA’s different MOAs, whereby GA induced an immunoregulatory Th2-mediated cell responses [20]. The medication has been widely used due to its outstanding safety profile. A transient, self-limited systemic reaction Expert Rev. Clin. Pharmacol. 8(3), (2015)
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Immunomodulatory therapies for relapsing remitting MS
following the injection occurred in 15–20% of patients, including palpitations, chest tightness and dyspnea, but was not considered a contraindication for the continuation of the medication’s use, as the reaction is typically not recurring and is not associated with cardiac disease. However, in additional placebo-controlled trials, 15% of patients experienced at least one episode of transient chest pain compared with 8% of placebo. In addition, 2.5% of treated groups experienced lipoatrophy, and in post-marketing evaluations, skin necrosis has rarely been described. This year, a less frequent 40 mg three times a week S.Q. administration was approved. It is considered as effective as the daily administration [21]. Oral therapies Fingolimod
Several oral DMTs have come to market over the past 4 years. Fingolimod was the first, introduced in 2010. It has a new mechanism of action, serving as a functional antagonist of the sphingosine-1-phosphate type 1 receptor and inducing its internalization on lymphocytes, resulting in their sequestration in the lymph nodes. A 24-month double-blind, placebo-controlled trial was completed with 1033 active RRMS patients randomly assigned at ratio 1:1:1 to either a daily dose of fingolimod at 1.25 mg or 0.5 mg, or placebo [22]. The ARR was significantly lower in both fingolimod groups, with 0.18 in the low dose compared with 0.16 in the high dose, and 0.4 in the placebo group, a relative reduction of 55 and 60%, respectively, both p < 0001. The cumulative probability of disability progression, confirmed after 3 months, was 18% in the 0.5 mg group and 28% in the 1.25 mg group in comparison with placebo. There were significantly fewer new or enlarging T2 lesions and Gd-enhancing lesions on brain MRI scans of the treated patients at 24 months (p < 0.001). A 30% decrease in atrophy measures was already detected at 6 months and maintained until the end of the study. Adverse reactions resulting in discontinuation of therapy included dyspnea, urticaria, vasodilation, and hypersensitivity reactions. In regards to dyspnea, there has also been an associated dose-dependent reduction in forced expiratory volume at 1 s (FEV1) and diffusion lung capacity. The changes in FEV1 appear to be reversible with fingolimod discontinuation. Additional adverse effects reported to date include hypertension and rare cases of posterior reversible encephalopathy syndrome. The most concerning adverse events were bradycardia, atrioventricular block and macular edema. Peripheral blood lymphocyte counts were decreased by an average of 73% from baseline and an increase in alanine aminotransferase (ALT) levels to three times the upper limit of normal was detected in 8.5% of patients. Thus, increased efficacy in comparison with the first-line therapy was associated with a new profile of more serious adverse events, which requires prescreening of patients before they can receive this treatment. Since there were two fatal herpes infections in TRANSFORMS study comparing the efficacy of fingolimod to IFN-b-1a I.M. at the 1.25 mg dose [23], serological evidence for the effective informahealthcare.com
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vaccination against varicella zoster virus is required before starting this treatment. A 0.5 mg dose was approved for RRMS, and the current ASSESS study is testing the efficacy and safety of lower dose (0.25 mg) in comparison with the currently approved dose. Teriflunomide
Oral teriflunomide was released in 2012. It has a new mechanism of action, namely, inhibition of dihydroorotate dehydrogenase, a mitochondrial enzyme involved in DNA replication. It reversibly reduces T cell and B cell activation and proliferation. The TEMSO study was conducted over 108 weeks in 1088 active RRMS patients assigned to 7 or 14 mg, or placebo [24]. The results indicated a significant reduction in the relapse rate with 0.54 in placebo versus 0.37 in teriflunomide at either dose at 2 years, 31% reduction; p < 0.001. Disability progression was significantly reduced only by the high dose (by 29.8%; p = 0.03; TABLE 1). In addition, there were significantly fewer new or enlarging T2 lesions (p = 0.03) and Gdenhancing lesions (p < 0.001) compared with placebo, but no difference in the brain atrophy. Diarrhea, nausea and hair thinning were more common with teriflunomide, and an ALT increase was detected in 54% patients on the low dose, requiring monthly liver function test monitoring for the first 6 months of treatment. However, the incidence of ALT greater than three-times the upper limit of normal was similar across all groups. Animal studies have identified a teratogenic risk, so the medication is contraindicated in pregnant women and women taking this medication should use contraception. Teriflunomide’s effect is reversible following medication withdrawal and faster elimination can be induced (4 or 8 g cholestyramine t.i.d., or 50 g activated charcoal b.i.d.). A serum level of £0.02 mg/ml is considered to have minimal effects on a fetus and is the goal of accelerated elimination, which typically takes 11 days but may be completed even faster. Without accelerated elimination, clearance can last up to 2 years. Besides pregnancy, accelerated elimination is required if a patient wants to become pregnant, father a child, has a drug-induced liver disease, or if it is clinically desired. Long-term use of its precursor leflunomide in patients with rheumatoid arthritis since 1998 has demonstrated a good safety profile, however, there were two documented cases of progressive multifocal leukoencephalopathy (PML), which has not been reported in RRMS patients. Dimethyl fumarate
The most recent oral DMT that has been approved in 2013 is dimethyl fumarate. This is an antioxidant with an antiinflammatory effect mediated through activation of the nuclear factor erythroid-derived 2-like (Nrf2) pathway. In the Phase III CONFIRM randomized trial, after the first DEFINE Phase III clinical trial [25], 1417 active RRMS patients were assigned to 240 mg b.i.d. or 240 mg t.i.d. GA, or placebo [12]. At the end of the 2-year study, there was a significant reduction in the relapse rate at both doses compared with placebo (51 and 44% 287
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reduction, respectively, both p < 0.001). Unlike the DEFINE study, which showed a significant effect on reduced disability progression with both doses (38 and 34%, respectively, p < 0.01), disability progression was not significantly different between the groups. There was a reduction in the mean number of new or enlarging T2 lesions (71% in b.i.d. dose; p < 0.001) as well as T1 hypointense lesions (57%; p < 0.001) in all groups compared with placebo. Adverse events that were more common with dimethyl fumarate included flushing, gastrointestinal (GI) upset, upper respiratory tract infections and erythema, which had the highest incidence in the first month and decreased thereafter. Overall, the medication was well tolerated. Flushing and GI events were mild and treatment discontinuation was documented in low percentages: flushing 4% in b.i.d. group and 2% in t.i.d. group, nausea and diarrhea 2% in t.i.d. group. There was documented resolution of the adverse events even if the medication was continued. Additional significant adverse effects included a mean decrease in lymphocyte counts by 30% in the first year, which typically remained stable. In controlled clinical trials, 6% of patients developed lymphopenia < 0.5 109/l versus 95%) of CD19+ peripheral B cells, that persisted up to 24 weeks. The numbers were reconstituted up to 30% of the baseline values at 48 weeks. Although the majority (78%) of patients experienced infusion-associated adverse events within 24 h, including headache, general pain, pruritus and rash, the treatment was not associated with increased incidence of infection, and patients retained their capacity to mount an immune response upon receiving vaccination. The manufacturers of rituximab decided not to pursue FDA approval, but to focus on the humanized anti-CD20 mAb ocrelizumab. In comparison with rituximab, ocrelizumab is less 289
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immunogenic and associated with more antibody-dependent instead of complement-mediated cytolytic effects. The results of a Phase II randomized placebo-controlled multicenter trial on 218 active RRMS patients were released in 2011 [36]. The primary objective was to investigate the effect of ocrelizumab on the number and volume of Gd-enhancing lesions. The patients were randomly assigned to either 600 or 2000 mg iv. infusion of ocrelizumab, IFN-b-1a 30 mg I.M. weekly or placebo. The total study period was 24 weeks. The ocrelizumab group was infused on days 1 and 15 for the first cycle and then again in 6 months. The placebo group and IFN-b-1a group were given ocrelizumab during the second cycle. At week 24, there was a significantly reduced number of Gd-enhancing lesions in both the high (96% reduction; p < 0.0001) and low dose ocrelizumab group (89% reduction; p < 0.0001), as compared with placebo. There was also a significant reduction in the ARR at week 24 in the 600 and 2000 mg group (80 and 73%, respectively). In an open-label extension phase, patients initially randomized to placebo and IFN-b-1a received one infusion cycle of ocrelizumab, and reached a similar low disease activity (based on MRI). The number of adverse events was similar between the groups, however, one patient in the high dose ocrelizumab group died from an acute onset thrombotic microangiopathy. The most common adverse events included urinary and respiratory tract infection, headache, nausea, chills and oral herpes. There was no evidence of the rebound disease activity, even after B cell repletion. With these encouraging data, ocrelizumab entered Phase III trials, which are expected to be completed in 2015. The human anti-CD20 mAb ofatumumab was also recently tested at lower doses (100, 300 and 700 mg) in a Phase II study and confirmed to induce a strong inhibition of number of Gd-enhancing lesions by 99.8% at 24 weeks in comparison with placebo [37]. An additional Phase II study is testing lower doses (3–60 mg) and subcutaneous instead of intravenous administration. The results are pending with estimated completion in June 2015 [38]. Very strong and early inhibition of brain lesion formation and clinical disease activity, as well as good tolerability, are likely to lead to the approval of ocrelizumab for the treatment of RRMS patients in the near future. Daclizumab, anti-IL-2Ra mAb
Daclizumab is a humanized IgG1 mAb directed against the IL-2Ra chain of the high affinity IL-2 receptor, which was expected to block activated CD25+ T cells. However, it was found to induce the expansion of CD56high NK cells with immunoregulatory function and cytotoxicity against activated autologous CD4+ T cells [39]. It is administered as once a month using S.Q. injection. The most common adverse events include transient elevation in liver enzymes, infections, and mild-to-moderate cutaneous rashes that may be local or generalized. There have been no cases of PML. Daclizumab has been approved for the prevention of allograft rejection after kidney transplantation. Investigations of its use in RRMS began with multiple case series. CHOICE was the first randomized 290
double-blind, placebo-controlled Phase II clinical trial evaluating the safety and efficacy of two doses (1 and 2 mg/kg) when added to IFN-b-1a [40]. Two hundred and thirty patients with at least 1-year MRI stability on IFN-b-1a were randomly assigned to high dose (iv. at 2 week intervals), low dose (iv. every 4 weeks), or placebo (S.Q. every 2 weeks) over 1 year in addition to IFN-b-1a. The outcome was a reduction in the number of Gd-enhancing lesions by 72% in the high-dose daclizumab group (TABLE 2). There was no significant difference in ARR and EDSS score or change in volume of T2 lesions at 6 months. Tolerability was good with most common adverse events including gastrointestinal disorders, skin and subcutaneous tissue disorders, injection site reaction, headache and infections. Fourteen (18%) patients in the IFN-b and low-dose daclizumab group had rash compared with six (8%) in the IFN-b and placebo group and six (8%) in the IFN-b and high-dose daclizumab group. Nausea occurred in 19% of patients on IFN-b with high-dose daclizumab as compared with 9% with low-dose and IFN-b and 8% with placebo and IFN-b. Only five patients discontinued treatment because of adverse events. Four of these patients were in the treatment group with daclizumab and these events included headache, pyrexia, rash and raised liver enzymes. In 2013, Gold et al. [41] have released the results of their randomized, placebo-controlled Phase II trial, SELECT, using a new formulation of daclizumab (DAC HYP) with the same amino acid sequence but with a change in the glycosylation profile, which was less immunogenic. There were 621 patients randomly assigned to either high-dose (300 mg) or low-dose (150 mg) monotherapy every 4 weeks or placebo. The study was conducted over 52 weeks. Outcomes included 50% reduced ARR (0.21, 0.23 and 0.46 for 150 mg, 300 mg, and placebo, respectively), and a higher proportion of relapse-free patients (p < 0.001) and a 57% decreased confirmed disability progression at 52 weeks for the 150 mg arm (TABLE 2). The daclizumab-treated group had an increased number of infections and cutaneous reactions including rash, as compared with placebo. The daclizumab-treated group had a greater number of patients with liver enzyme levels up to five-times the upper limit of normal. One patient died due to the complications of infection. The extension Phase IIb study revealed a 59% ARR reduction in patients randomized to placebo for 1 year and then treated with daclizumab, and a 50% decrease in the proportion of patients with disability progression. The efficacy of daclizumab was sustained through the second year, as supported by stable ARRs and further diminished MRI measures of disease activity, with the number of Gd-enhancing lesions below the baseline values. NK CD56high cells were monitored during this trial. Interestingly, there was an increase from median baseline of 8 cells per ml to 40 cells per ml at the end of treatment, correlating with treatment effect. In addition, both CD4 and CD8 cell counts decreased by 7–10%. Safety was similar to the initial study, except for one death due to autoimmune hepatitits. More patients discontinued treatment secondary to adverse Expert Rev. Clin. Pharmacol. 8(3), (2015)
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Trial/ study
Treatment arms
CAREMSI
CAREMSII
Alemtuzumab
Alemtuzumab
Phase II
Ofatumumab
100 mg I.V. week 0 and 2 300 mg I.V. week 0 and 2 700 mg I.V. week 0 and 2 Placebo
300 mg I.V.on day 1 and 15 of cycle (600 mg) 1000 mg I.V. on day 1 and 15 of cycle (2000 mg) IFN-b-1a 30 mg I.M. every week Placebo 38
2.4 3.1 2.6
3.5 3.4 3.1 3.2
2.7 2.7
2.0 2.0
2.3 2.3
Mean EDSS baseline
0.13 (80%) p = 0.0005 0.17 (73%) p = 0.0014 0.36 (44%) p = 0.07 0.64
0.26 (49.4%) p < 0.0001 0.52
0.18 (54.9%) p < 0.001 0.39
0.23 (68.5%) p < 0.001 0.73
ARR (percent reduction) (p value vs placebo)
0.13 (42%) p = 0.008 0.21
0.08 (30%) p = 0.22 0.11
0.17 (42%) p < 0.001 0.29
Disability accumulation (percent reduction) p value vs placebo
Infusion Reaction
Infusion Reaction
99.8% decrease in the number of Gd-enhancing lesions
Secondary autoimmunity (thyroid disease, ITP)
Secondary autoimmunity (thyroid disease, ITP)
Infusion reaction PML
Key adverse events
600 mg: 89% decrease in the number of Gd-enhancing lesions 2000 mg: 96% reduction in the number of Gd-enhancing lesions
Reduced number of the new/enlarging T2 lesions (p < 0.0001) and Gd-enhancing lesions (p < 0.0001)
Reduced number of the new/enlarging T2 lesions (p < 0.04); reduced number of the Gd-enhancing lesions (p < 0.0001) and Reduced total brain volume loss by 40%
83% decrease in the number of new/enlarging T2 lesions 92% decrease in the number of Gd-enhancing lesions
Percent reduction in number or volume of MRI lesions
ARR: Annualized relapse rate, Disability accumulation (in EDSS); EDSS: Expanded disability status scale; Gd: Gadolinium; I.M: Intramuscular; I.V.: Intravenous; n: total number; q.o.d.: Every other day; S.Q.: Subcutaneous; t.i.w.: Three times a week.
Phase II
Ocrelizumab
628
22 F 16 M
532 F 96 M
12 mg I.V. 3 days per year 24 mg I.V. 3 days per year IFN-b-1a 44 mg S.Q. t.i.w.
578
218
365 F 213 M
12 mg I.V. 3 days per year 24 mg I.V. 3 days per year IFN-b-1a 44 mg S.Q. t.i.w.
942
n
141 F 77 M
660 F 282 M
Sex
300 mg I.V. every 4 weeks Placebo
Future monoclonal antibodies
AFFIRM
Natiluzumab
Approved monoclonal antibodies
Active drug
Table 2. Monoclonal antibody therapies in relapsing–remitting multiple sclerosis.
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291
292
Rash Transient elevation of liver enzymes
Rash Transient elevation of liver enzymes
72% decrease in the number of Gd-enhancing lesions with 2 mg/kg dose
70% decrease 79% decrease in the number of Gd-enhancing lesions 0.11 (57%) p = 0.021 0.15 (43%) p = 0.091 0.25 0.21 (54%) p < 0.001 0.23 (50%) p < 0.001 0.46 621 150 mg S.Q. every 4 weeks 300 mg S.Q. every 4 weeks Placebo SELECT
402 F 219 M
3.0 3.0 3.0 230 112 F 118 M IFN-b-1a 30 mg I.M. + 1 mg/kg I.V. every 4 weeks IFN- b-1a 30 mg I.M. + 2 mg/kg I.V. every 2 weeks IFN-b-1a 30 mg IM every week + Placebo CHOICE Daclizumab
Future monoclonal antibodies
2.8 2.7 2.7
0.2 7 (34%) p = 0.30 0.29 (30%) p = 0.35 0.41
ARR (percent reduction) (p value vs placebo) Mean EDSS baseline n
ARR: Annualized relapse rate, Disability accumulation (in EDSS); EDSS: Expanded disability status scale; Gd: Gadolinium; I.M: Intramuscular; I.V.: Intravenous; n: total number; q.o.d.: Every other day; S.Q.: Subcutaneous; t.i.w.: Three times a week.
Key adverse events Disability accumulation (percent reduction) p value vs placebo
Percent reduction in number or volume of MRI lesions
Craddock & Markovic-Plese
Sex Treatment arms Trial/ study Active drug
Table 2. Monoclonal antibody therapies in relapsing–remitting multiple sclerosis (cont.).
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events in the daclizumab group (15; 3.6%) compared with placebo (2;
Review
Immunomodulatory therapies for relapsing-remitting multiple sclerosis: monoclonal antibodies, currently approved and in testing Expert Rev. Clin. Pharmacol. 8(3), 283–296 (2015)
Jessica Craddock1 and Silva Markovic-Plese*1,2 1 Department of Neurology, University of North Carolina at Chapel Hill, 105 Mason Farm Road, Chapel Hill, NC 27599, USA 2 Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, 105 Mason Farm Road, Chapel Hill, NC 27599, USA *Author for correspondence: Tel.: +1 919 966 3701 [email protected]
Relapsing–remitting multiple sclerosis (RRMS), a CNS inflammatory demyelinating disease, is one of the most prevalent causes of chronic disability in young adults. Studies of the disease pathogenesis have identified multiple therapeutic targets. The number of approved disease modifying therapies has almost doubled within the past 5 years, which creates a challenge for medical professionals to stay abreast of their use in everyday practice. This manuscript provides an overview of available injectable, oral, and intravenous therapies for RRMS, and offers guidance in selecting an appropriate therapy. Focus is on the recently approved and emerging monoclonal antibody therapies, because they offer more selective and superior therapeutic efficacy compared with injectable and oral disease modifying therapies. We discuss the outlook for monoclonal antibodies and their role in RRMS treatment in the future. KEYWORDS: alemtuzumab . daclizumab . mechanism of action . monoclonal antibody . natalizumab . ocrelizumab .
ofatumamab
.
relapsing remitting multiple sclerosis
Epidemiological studies have reported an increased incidence and prevalence of multiple sclerosis (MS) over the past decades. There are about 200 new cases diagnosed in the USA each week and approximately 2.5 million MS patients worldwide. MS is a CNS disease characterized by an autoimmune/inflammatory response, myelin and axonal loss [1], which can result in a significant disability [2,3]. IFN-b-1b was approved by the US FDA as the first disease-modifying therapy (DMT) for relapsing–remitting (RR) MS in 1993 [4]. Following the first-line therapies, including various forms of IFN-b and glatiramer acetate (GA) in the 1990s [5], mitoxantrone was approved in 2002 for the aggressive forms of MS and for patients who had failed the first-line therapies [6]. Recent approval of several oral DMTs with new mechanisms of action (MOAs) and similar or superior efficacy has dramatically changed the treatment options for patients with RRMS [7]. Emerging treatments with monoclonal antibodies (mAbs) has resulted in informahealthcare.com
10.1586/17512433.2015.1036030
more selective and superior therapeutic efficacy [8], with natalizumab as the most effective available therapy [9], followed by the recently approved alemtuzumab [10] and ongoing Phase III clinical trials with anti-B cell therapies and the anti-IL-2 receptor alpha mAb (daclizumab) in progress. The goal of this manuscript is to provide an overview of the available first-line injectable, oral, and secondline therapies for RRMS, and discuss the efficacy, safety, and tolerability of recently introduced and currently tested mAbs, and their future therapeutic use. We will primarily focus on the pivotal clinical trials for US FDA-approved therapies for RRMS, discussing study design, efficacy and tolerability results in comparison to placebo. It is important to emphasize that the design of clinical trials for MS therapies has evolved over the past 20 years, introducing new measures of disease activity and therapeutic efficacy. There are only several head-to-head comparison studies [11–13]. We will focus primarily on
2015 Informa UK Ltd
ISSN 1751-2433
283
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the placebo-controlled studies to provide a basis for the comparison of clinical efficacy, imaging results, and safety data, which will allow us to provide suggestions regarding therapeutic algorithms that can be used in current practice for the approved therapies, while awaiting approval of additional treatments. Several of them are mAbs in the final stages of Phase III clinical testing. A discussion of study designs and efficacy data, focusing on the relapse rate, disability and MRI readouts, as well as the most relevant information on the adverse events for each approved medication will provide an informative overview of the complex and extensive data on the new DMTs for RRMS. Currently approved therapies for RRMS First-line injectable therapies IFN-b-1b
The first DMT approved for RRMS was IFN-b-1b, approved in 1993 [4]. Its MOA are still not completely elucidated, but include inhibition of inflammatory cell migration across the blood–brain barrier, modification of inflammatory cytokines (inhibition of IL-12/IFN-g/IL-17-A [14] and induction of IL-10), inhibition of MHC class II expression on antigen presenting cells, and reconstitution of deficient endogenous IFN-b secretion and signaling [15]. The results of the pivotal placebocontrolled trial compared the effect of IFN-b-1b 8 million international units (MIU) and 1.6 MIU subcutaneous (S.Q.) injection every other day with placebo (ratio 1:1:1) over 2 years in 372 patients with active RRMS (mean baseline expanded disability status scale [EDSS] 2.8–3.0 for the various subgroups, at least two exacerbations in the previous 2 years). There was a decrease in the annual relapse rate (ARR; placebo 1.27, 8 MIU 0.84, 34% reduction; p = 0.0001), whereas EDSS did not change significantly [4]. Yearly brain MRI studies revealed an 80% decrease in the number of active scans in treated patients. Reported side effects were flu-like syndrome that decreased after 3 months, elevated liver enzymes, injection site reactions, and mild intermittent lymphopenia, neutropenia and anemia. The 8 MIU dose was approved for the treatment of RRMS. Further randomized controlled trials have found depression and suicide infrequently associated with IFN-b-1b. Rarely, congestive heart failure, severe hepatotoxicity, and autoimmune hepatitis were reported with its use. Additional controlled clinical trials have documented injection site necrosis, and at least 5% more frequently than placebo headache, hypertonia, insomnia, pain, rash, abdominal pain, and asthenia. IFN-b-1b is currently available as Betaseron and Extavia brands. They have the same active ingredient, but they are not considered interchangeable. Of note, Extavia has been approved in Europe for the treatment of RRMS, early MS, and secondary progressive MS with relapses. IFN-b-1a (intramuscular)
In 1996, the MS Collaborative Research Group designed a clinical trial to assess the ability of IFN-b-1a (30 mg 284
intramuscular [I.M.] weekly) in 301 patients with active RRMS (baseline EDSS 2.3–2.4) to decrease the accumulation of disability over 2 years [16]. Patients were administered IFN-b-1a for up to 104 weeks and compared with placebo. IFN-b-1a is glycosylated and less immunogenic in comparison with IFN-b-1b. The primary outcome was time to sustained disability progression of at least 1 point in EDSS, persisting for at least 6 months, which was significantly delayed in the IFN-b-1a-treated patients (p = 0.02). The ARR was 0.82 for placebo and 0.67 for treated patients, with a relative reduction of 18.3%; p = 0.04 (TABLE 1). MRI results at 2 years revealed no significant change in T2 lesion volume and a decrease in the number of Gd-enhancing lesions (p = 0.05) in the IFN-b-1atreated patients in comparison with placebo. Only 4% of the patients discontinued the IFN-b-1a due to adverse events, which included flu-like symptoms, muscle aches, headache, chills, fever and anemia. Both treatment arms included adverse events of injection site reactions, depression and menstrual disorders. There was a greater incidence of depression in the treatment group, 20% compared with placebo 13%, but this difference was not statistically significant. Neutralizing antibody (NAB) presence was found in 15 of the IFN-b-1a-treated patients. Similar to IFN-b-1b, with additional controlled trials there have been reports of severe hepatic injury, including hepatic failure. During the post-marketing period, there have been cases of congestive heart failure in patients with no known risk factors, rare pancytopenia, thrombocytopenia and autoimmune diseases, including idiopathic thrombocytopenic purpura, hyperthyroid and hypothyroid disease, and even rare cases of autoimmune hepatitis. It is recommended to periodically check complete blood count (CBC) with differential counts, platelets, chemistry panel and liver function studies. IFN-b-1a (S.Q.)
In 1998, the PRISMS trial assessed the efficacy and dose-effect of IFN-b-1a administered at 22 mg and 44 mg S.Q. in comparison with placebo in 560 active RRMS patients over 2 years [17] and demonstrated a dose-dependent decrease in ARR (32% decrease in comparison with placebo, in the 44 mg group; p < 0.005). The time to sustained progression was longer (p < 0.005) and the T2 lesion load was significantly decreased (p < 0.0001) in the 44 mg treatment group. The side effect profile was similar to the other IFN preparations, and the incidence of depression did not differ between the IFN-b-1a and placebo-treated patients (21–28%). Both 44 and 22 mg doses were approved as a treatment for RRMS. Pegylated IFN-b-1a
Although the IFNs showed moderate efficacy in suppressing disease activity and an excellent safety profile, their frequent parenteral administration was a challenge to many patients. All manufacturers now provide disposable autoinjectors that simplify administration, and a new preparation of pegylated IFN-b-1a [18] has decreased the frequency of administration to Expert Rev. Clin. Pharmacol. 8(3), (2015)
Trial/ study
Treatment arms
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MSCRG
PRISMS
ADVANCE
CMSSG
IFN-b 1a I.M.
IFN-b-1a S.Q.
Pegylated IFN-b-1a S.Q.
Glatiramer acetate
FREEDOMS
386 F 174 M
1071 F 441 M
22 mg S.Q. t.i.w. 44 mg S.Q. t.i.w. Placebo
125 mg S.Q. every 2 weeks 125 mg S.Q. every month Placebo
1.25 mg daily 0.5 mg daily IFNb-1a 30 mg I.M. placebo
689 F 583 M
184 F 67 M
221 F 80 M
30 mg I.M. weekly Placebo
20 mg S.Q. daily Placebo
259 F 113 M
1.6 MIU S.Q. q.o.d. 8 MIU S.Q. q.o.d. Placebo
Sex
1272
251
1512
560
301
372
n
2.4 2.3 2.5
2.8 2.4
2.5 2.5 2.4
2.5 2.5 2.4
2.4 2.3
2.9 3.0
Mean EDSS baseline
0.16 (60%) p < 0.01 0.18 (55%) p < 0.01 0.4
1.19 (29.2%) p = 0.007 1.68
0.26 (35%) p < 0.0007 0.29 (28%) p < 0.01 0.4
1.82 (28.9%) p < 0.005 1.73 (32.4%) p < 0.005 2.56
0.67 (18.3%) p = 0.04 0.82
1.17 (7.8%) p = 0.01 0.84 (33.9%) p = 0.0001 1.27
ARR (percent reduction) p value vs placebo
0.17 (32%) p = 0.02 0.18 (28%) p = 0.02 0.29
0.22 (12%) p > 0.05 0.25
0.07 (38%) p = 0.04 in both groups 0.1
0.29 (22%) p = 0.07 0.26 (30%) p = 0.03 0.38
0.22 (37.2%) p = 0.02 0.35
0.28 (0%) 0.20 (28.6%) p = 0.16
Disability accumulation (percent reduction) p value vs placebo
1.25 mg: Reduced number of the T2 lesions (p < 0.001) Reduced number of the lesions (p < 0.001) 0.5 mg: Reduced number of the T2 lesions (p < 0.001) Reduced number of the lesions (p < 0.001)
Gd-enhancing
new/enlarged
Gd-enhancing
new/enlarged
65% decrease in the number of new T2 lesions and Gd-enhancing and hypointense T1 lesions (all p < 0.0001) in q 2 week group
67% decrease 78% decrease in the number of new T2 lesions
52% decrease in the number of Gd-enhancing lesions
80% reduction in the number of active scans (scans with new or enlarging T2 lesions)
Percent reduction in brain MRI lesions
Bradycardia Macular edema Herpes infections
Injection site reaction Systemic reaction
Flu-like symptoms
Flu-like symptoms
Flu-like symptoms
Flu-like symptoms
Key adverse events
ARR: Annualized relapse rate, Disability accumulation (in EDSS); b.i.d.: Twice daily; EDSS: Expanded disability status scale; Gd: Gadolinium; I.M: Intramuscular; I.V.: Intravenous; n: total number; q.o.d.: Every other day; S.Q.: Subcutaneous; t.i.d.: Three times daily; t.i.w.: Three times a week.
Fingolimide
First-line oral therapies
MSSG
IFN-b-1b S.Q.
First-line injectable therapies
Active drug
Table 1. Approved first- and second-line therapies for relapsing–remitting multiple sclerosis.
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285
286
Flushing GI irritation Leukopenia
Cardiotoxicity Leukemia
71% decrease in the number of new/ enlarging T2 lesions in BID dose 57% decrease in the number of hypointense T1 lesions in all groups vs placebo
Significantly reduced number of T2 lesions (p = 0.03) and Gdenhancing lesions (p = 0.02)
0.13 (21% ) p = 0.25 0.13 (24%) p = 0.20 0.16 (7%) p = 0.70 0.17
0.08 (63.6%) p = 0.036 0.22
0.22 (44%) p < 0.001 0.20 (51%) p < 0.001 0.29 (29%) p = 0.01 0.40
0.35 (65.7%) p = 0.001 1.02 188 5 mg/m2 I.V. every 3 months 12 mg/m2 I.V. every 3 months Placebo MIMS Mitoxantrone
Second-line infusion therapy
98 F 90 M
2.6 2.5 2.6 1417 993 F 424 M CONFIRM Dimethyl fumarate
240 mg b.i.d. 240 mg t.i.d. Glatiramer acetate 20 mg S.Q. daily Placebo
1088 785 F 303 M 7 mg daily 14 mg daily Placebo TEMSO Teriflunomide
First-line oral therapies
ARR: Annualized relapse rate, Disability accumulation (in EDSS); b.i.d.: Twice daily; EDSS: Expanded disability status scale; Gd: Gadolinium; I.M: Intramuscular; I.V.: Intravenous; n: total number; q.o.d.: Every other day; S.Q.: Subcutaneous; t.i.d.: Three times daily; t.i.w.: Three times a week.
Hepatotoxicity 39.4% and 67.4% reduction in total T2 lesion volume Decreased number of the Gd-enhancing lesions (p < 0.001) 0.22 (23.7%) p = 0.08 0.20 (29.8%) p = 0.03 0.27 0.37 (31.2%) p < 0.001 0.37 (31.5%) p < 0.001 0.54
n Sex
2.68 2.67 2.68
4.6 4.5 4.7
Key adverse events Percent reduction in brain MRI lesions Disability accumulation (percent reduction) p value vs placebo Mean EDSS baseline
ARR (percent reduction) p value vs placebo
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Treatment arms Trial/ study Active drug
Table 1. Approved first- and second-line therapies for relapsing–remitting multiple sclerosis (cont.).
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twice a month. Recently approved pegylated IFN-b-1a has a biologically inert polyethylene glycol group attached to the interferon molecule, improving its pharmacokinetic and pharmacodynamic properties. The Phase III clinical trial ADVANCE tested this preparation at 125 mg S.Q. every other week or every month against placebo in 1516 RRMS patients [19]. After 1 year, ARR (0.4 for placebo, 0.26 for every 2 weeks, 0.29 for every 4 weeks; p = 0.0007, p = 0.01) and the proportion of patients with disability progression (placebo 0.1, every 2 weeks and 4 weeks 0.07; p = 0.04, p = 0.02) were significantly lower in both treatment groups than in placebo. After 1 year of placebo, patients were randomized to IFN-b-1a treatment. The number of new or enlarging T2 lesions, as well as the number of new Gdenhancing lesions was lower in patients treated every other week (a 67 and 86% decrease, respectively, both p < 0.0001) than in the patients treated once a month. This preparation was less immunogenic than IFN-b-1a I.M. (less than 1% patients had neutralizing antibodies [NAB]). The adverse events were mild to moderate, so the medication was recently added to the available therapies for RRMS. The incidence of depression and suicide was similar to placebo. There was a higher incidence of asymptomatic increase in liver transaminases and injection site reactions. The incidence of significant lymphopenia, neutropenia and thrombocytopenia was less than 1%. Glatiramer acetate
This first-line therapy was approved in 1996, following a pivotal study of GA injection at 20 mg S.Q. daily in 250 RRMS patients, and showed an ARR reduction of 29% and no significant inhibition of disability progression in comparison with the placebo (TABLE 1) [5]. The MRI effect was delayed and less prominent than with IFN-b, which was attributed to GA’s different MOAs, whereby GA induced an immunoregulatory Th2-mediated cell responses [20]. The medication has been widely used due to its outstanding safety profile. A transient, self-limited systemic reaction Expert Rev. Clin. Pharmacol. 8(3), (2015)
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following the injection occurred in 15–20% of patients, including palpitations, chest tightness and dyspnea, but was not considered a contraindication for the continuation of the medication’s use, as the reaction is typically not recurring and is not associated with cardiac disease. However, in additional placebo-controlled trials, 15% of patients experienced at least one episode of transient chest pain compared with 8% of placebo. In addition, 2.5% of treated groups experienced lipoatrophy, and in post-marketing evaluations, skin necrosis has rarely been described. This year, a less frequent 40 mg three times a week S.Q. administration was approved. It is considered as effective as the daily administration [21]. Oral therapies Fingolimod
Several oral DMTs have come to market over the past 4 years. Fingolimod was the first, introduced in 2010. It has a new mechanism of action, serving as a functional antagonist of the sphingosine-1-phosphate type 1 receptor and inducing its internalization on lymphocytes, resulting in their sequestration in the lymph nodes. A 24-month double-blind, placebo-controlled trial was completed with 1033 active RRMS patients randomly assigned at ratio 1:1:1 to either a daily dose of fingolimod at 1.25 mg or 0.5 mg, or placebo [22]. The ARR was significantly lower in both fingolimod groups, with 0.18 in the low dose compared with 0.16 in the high dose, and 0.4 in the placebo group, a relative reduction of 55 and 60%, respectively, both p < 0001. The cumulative probability of disability progression, confirmed after 3 months, was 18% in the 0.5 mg group and 28% in the 1.25 mg group in comparison with placebo. There were significantly fewer new or enlarging T2 lesions and Gd-enhancing lesions on brain MRI scans of the treated patients at 24 months (p < 0.001). A 30% decrease in atrophy measures was already detected at 6 months and maintained until the end of the study. Adverse reactions resulting in discontinuation of therapy included dyspnea, urticaria, vasodilation, and hypersensitivity reactions. In regards to dyspnea, there has also been an associated dose-dependent reduction in forced expiratory volume at 1 s (FEV1) and diffusion lung capacity. The changes in FEV1 appear to be reversible with fingolimod discontinuation. Additional adverse effects reported to date include hypertension and rare cases of posterior reversible encephalopathy syndrome. The most concerning adverse events were bradycardia, atrioventricular block and macular edema. Peripheral blood lymphocyte counts were decreased by an average of 73% from baseline and an increase in alanine aminotransferase (ALT) levels to three times the upper limit of normal was detected in 8.5% of patients. Thus, increased efficacy in comparison with the first-line therapy was associated with a new profile of more serious adverse events, which requires prescreening of patients before they can receive this treatment. Since there were two fatal herpes infections in TRANSFORMS study comparing the efficacy of fingolimod to IFN-b-1a I.M. at the 1.25 mg dose [23], serological evidence for the effective informahealthcare.com
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vaccination against varicella zoster virus is required before starting this treatment. A 0.5 mg dose was approved for RRMS, and the current ASSESS study is testing the efficacy and safety of lower dose (0.25 mg) in comparison with the currently approved dose. Teriflunomide
Oral teriflunomide was released in 2012. It has a new mechanism of action, namely, inhibition of dihydroorotate dehydrogenase, a mitochondrial enzyme involved in DNA replication. It reversibly reduces T cell and B cell activation and proliferation. The TEMSO study was conducted over 108 weeks in 1088 active RRMS patients assigned to 7 or 14 mg, or placebo [24]. The results indicated a significant reduction in the relapse rate with 0.54 in placebo versus 0.37 in teriflunomide at either dose at 2 years, 31% reduction; p < 0.001. Disability progression was significantly reduced only by the high dose (by 29.8%; p = 0.03; TABLE 1). In addition, there were significantly fewer new or enlarging T2 lesions (p = 0.03) and Gdenhancing lesions (p < 0.001) compared with placebo, but no difference in the brain atrophy. Diarrhea, nausea and hair thinning were more common with teriflunomide, and an ALT increase was detected in 54% patients on the low dose, requiring monthly liver function test monitoring for the first 6 months of treatment. However, the incidence of ALT greater than three-times the upper limit of normal was similar across all groups. Animal studies have identified a teratogenic risk, so the medication is contraindicated in pregnant women and women taking this medication should use contraception. Teriflunomide’s effect is reversible following medication withdrawal and faster elimination can be induced (4 or 8 g cholestyramine t.i.d., or 50 g activated charcoal b.i.d.). A serum level of £0.02 mg/ml is considered to have minimal effects on a fetus and is the goal of accelerated elimination, which typically takes 11 days but may be completed even faster. Without accelerated elimination, clearance can last up to 2 years. Besides pregnancy, accelerated elimination is required if a patient wants to become pregnant, father a child, has a drug-induced liver disease, or if it is clinically desired. Long-term use of its precursor leflunomide in patients with rheumatoid arthritis since 1998 has demonstrated a good safety profile, however, there were two documented cases of progressive multifocal leukoencephalopathy (PML), which has not been reported in RRMS patients. Dimethyl fumarate
The most recent oral DMT that has been approved in 2013 is dimethyl fumarate. This is an antioxidant with an antiinflammatory effect mediated through activation of the nuclear factor erythroid-derived 2-like (Nrf2) pathway. In the Phase III CONFIRM randomized trial, after the first DEFINE Phase III clinical trial [25], 1417 active RRMS patients were assigned to 240 mg b.i.d. or 240 mg t.i.d. GA, or placebo [12]. At the end of the 2-year study, there was a significant reduction in the relapse rate at both doses compared with placebo (51 and 44% 287
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reduction, respectively, both p < 0.001). Unlike the DEFINE study, which showed a significant effect on reduced disability progression with both doses (38 and 34%, respectively, p < 0.01), disability progression was not significantly different between the groups. There was a reduction in the mean number of new or enlarging T2 lesions (71% in b.i.d. dose; p < 0.001) as well as T1 hypointense lesions (57%; p < 0.001) in all groups compared with placebo. Adverse events that were more common with dimethyl fumarate included flushing, gastrointestinal (GI) upset, upper respiratory tract infections and erythema, which had the highest incidence in the first month and decreased thereafter. Overall, the medication was well tolerated. Flushing and GI events were mild and treatment discontinuation was documented in low percentages: flushing 4% in b.i.d. group and 2% in t.i.d. group, nausea and diarrhea 2% in t.i.d. group. There was documented resolution of the adverse events even if the medication was continued. Additional significant adverse effects included a mean decrease in lymphocyte counts by 30% in the first year, which typically remained stable. In controlled clinical trials, 6% of patients developed lymphopenia < 0.5 109/l versus 95%) of CD19+ peripheral B cells, that persisted up to 24 weeks. The numbers were reconstituted up to 30% of the baseline values at 48 weeks. Although the majority (78%) of patients experienced infusion-associated adverse events within 24 h, including headache, general pain, pruritus and rash, the treatment was not associated with increased incidence of infection, and patients retained their capacity to mount an immune response upon receiving vaccination. The manufacturers of rituximab decided not to pursue FDA approval, but to focus on the humanized anti-CD20 mAb ocrelizumab. In comparison with rituximab, ocrelizumab is less 289
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immunogenic and associated with more antibody-dependent instead of complement-mediated cytolytic effects. The results of a Phase II randomized placebo-controlled multicenter trial on 218 active RRMS patients were released in 2011 [36]. The primary objective was to investigate the effect of ocrelizumab on the number and volume of Gd-enhancing lesions. The patients were randomly assigned to either 600 or 2000 mg iv. infusion of ocrelizumab, IFN-b-1a 30 mg I.M. weekly or placebo. The total study period was 24 weeks. The ocrelizumab group was infused on days 1 and 15 for the first cycle and then again in 6 months. The placebo group and IFN-b-1a group were given ocrelizumab during the second cycle. At week 24, there was a significantly reduced number of Gd-enhancing lesions in both the high (96% reduction; p < 0.0001) and low dose ocrelizumab group (89% reduction; p < 0.0001), as compared with placebo. There was also a significant reduction in the ARR at week 24 in the 600 and 2000 mg group (80 and 73%, respectively). In an open-label extension phase, patients initially randomized to placebo and IFN-b-1a received one infusion cycle of ocrelizumab, and reached a similar low disease activity (based on MRI). The number of adverse events was similar between the groups, however, one patient in the high dose ocrelizumab group died from an acute onset thrombotic microangiopathy. The most common adverse events included urinary and respiratory tract infection, headache, nausea, chills and oral herpes. There was no evidence of the rebound disease activity, even after B cell repletion. With these encouraging data, ocrelizumab entered Phase III trials, which are expected to be completed in 2015. The human anti-CD20 mAb ofatumumab was also recently tested at lower doses (100, 300 and 700 mg) in a Phase II study and confirmed to induce a strong inhibition of number of Gd-enhancing lesions by 99.8% at 24 weeks in comparison with placebo [37]. An additional Phase II study is testing lower doses (3–60 mg) and subcutaneous instead of intravenous administration. The results are pending with estimated completion in June 2015 [38]. Very strong and early inhibition of brain lesion formation and clinical disease activity, as well as good tolerability, are likely to lead to the approval of ocrelizumab for the treatment of RRMS patients in the near future. Daclizumab, anti-IL-2Ra mAb
Daclizumab is a humanized IgG1 mAb directed against the IL-2Ra chain of the high affinity IL-2 receptor, which was expected to block activated CD25+ T cells. However, it was found to induce the expansion of CD56high NK cells with immunoregulatory function and cytotoxicity against activated autologous CD4+ T cells [39]. It is administered as once a month using S.Q. injection. The most common adverse events include transient elevation in liver enzymes, infections, and mild-to-moderate cutaneous rashes that may be local or generalized. There have been no cases of PML. Daclizumab has been approved for the prevention of allograft rejection after kidney transplantation. Investigations of its use in RRMS began with multiple case series. CHOICE was the first randomized 290
double-blind, placebo-controlled Phase II clinical trial evaluating the safety and efficacy of two doses (1 and 2 mg/kg) when added to IFN-b-1a [40]. Two hundred and thirty patients with at least 1-year MRI stability on IFN-b-1a were randomly assigned to high dose (iv. at 2 week intervals), low dose (iv. every 4 weeks), or placebo (S.Q. every 2 weeks) over 1 year in addition to IFN-b-1a. The outcome was a reduction in the number of Gd-enhancing lesions by 72% in the high-dose daclizumab group (TABLE 2). There was no significant difference in ARR and EDSS score or change in volume of T2 lesions at 6 months. Tolerability was good with most common adverse events including gastrointestinal disorders, skin and subcutaneous tissue disorders, injection site reaction, headache and infections. Fourteen (18%) patients in the IFN-b and low-dose daclizumab group had rash compared with six (8%) in the IFN-b and placebo group and six (8%) in the IFN-b and high-dose daclizumab group. Nausea occurred in 19% of patients on IFN-b with high-dose daclizumab as compared with 9% with low-dose and IFN-b and 8% with placebo and IFN-b. Only five patients discontinued treatment because of adverse events. Four of these patients were in the treatment group with daclizumab and these events included headache, pyrexia, rash and raised liver enzymes. In 2013, Gold et al. [41] have released the results of their randomized, placebo-controlled Phase II trial, SELECT, using a new formulation of daclizumab (DAC HYP) with the same amino acid sequence but with a change in the glycosylation profile, which was less immunogenic. There were 621 patients randomly assigned to either high-dose (300 mg) or low-dose (150 mg) monotherapy every 4 weeks or placebo. The study was conducted over 52 weeks. Outcomes included 50% reduced ARR (0.21, 0.23 and 0.46 for 150 mg, 300 mg, and placebo, respectively), and a higher proportion of relapse-free patients (p < 0.001) and a 57% decreased confirmed disability progression at 52 weeks for the 150 mg arm (TABLE 2). The daclizumab-treated group had an increased number of infections and cutaneous reactions including rash, as compared with placebo. The daclizumab-treated group had a greater number of patients with liver enzyme levels up to five-times the upper limit of normal. One patient died due to the complications of infection. The extension Phase IIb study revealed a 59% ARR reduction in patients randomized to placebo for 1 year and then treated with daclizumab, and a 50% decrease in the proportion of patients with disability progression. The efficacy of daclizumab was sustained through the second year, as supported by stable ARRs and further diminished MRI measures of disease activity, with the number of Gd-enhancing lesions below the baseline values. NK CD56high cells were monitored during this trial. Interestingly, there was an increase from median baseline of 8 cells per ml to 40 cells per ml at the end of treatment, correlating with treatment effect. In addition, both CD4 and CD8 cell counts decreased by 7–10%. Safety was similar to the initial study, except for one death due to autoimmune hepatitits. More patients discontinued treatment secondary to adverse Expert Rev. Clin. Pharmacol. 8(3), (2015)
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Trial/ study
Treatment arms
CAREMSI
CAREMSII
Alemtuzumab
Alemtuzumab
Phase II
Ofatumumab
100 mg I.V. week 0 and 2 300 mg I.V. week 0 and 2 700 mg I.V. week 0 and 2 Placebo
300 mg I.V.on day 1 and 15 of cycle (600 mg) 1000 mg I.V. on day 1 and 15 of cycle (2000 mg) IFN-b-1a 30 mg I.M. every week Placebo 38
2.4 3.1 2.6
3.5 3.4 3.1 3.2
2.7 2.7
2.0 2.0
2.3 2.3
Mean EDSS baseline
0.13 (80%) p = 0.0005 0.17 (73%) p = 0.0014 0.36 (44%) p = 0.07 0.64
0.26 (49.4%) p < 0.0001 0.52
0.18 (54.9%) p < 0.001 0.39
0.23 (68.5%) p < 0.001 0.73
ARR (percent reduction) (p value vs placebo)
0.13 (42%) p = 0.008 0.21
0.08 (30%) p = 0.22 0.11
0.17 (42%) p < 0.001 0.29
Disability accumulation (percent reduction) p value vs placebo
Infusion Reaction
Infusion Reaction
99.8% decrease in the number of Gd-enhancing lesions
Secondary autoimmunity (thyroid disease, ITP)
Secondary autoimmunity (thyroid disease, ITP)
Infusion reaction PML
Key adverse events
600 mg: 89% decrease in the number of Gd-enhancing lesions 2000 mg: 96% reduction in the number of Gd-enhancing lesions
Reduced number of the new/enlarging T2 lesions (p < 0.0001) and Gd-enhancing lesions (p < 0.0001)
Reduced number of the new/enlarging T2 lesions (p < 0.04); reduced number of the Gd-enhancing lesions (p < 0.0001) and Reduced total brain volume loss by 40%
83% decrease in the number of new/enlarging T2 lesions 92% decrease in the number of Gd-enhancing lesions
Percent reduction in number or volume of MRI lesions
ARR: Annualized relapse rate, Disability accumulation (in EDSS); EDSS: Expanded disability status scale; Gd: Gadolinium; I.M: Intramuscular; I.V.: Intravenous; n: total number; q.o.d.: Every other day; S.Q.: Subcutaneous; t.i.w.: Three times a week.
Phase II
Ocrelizumab
628
22 F 16 M
532 F 96 M
12 mg I.V. 3 days per year 24 mg I.V. 3 days per year IFN-b-1a 44 mg S.Q. t.i.w.
578
218
365 F 213 M
12 mg I.V. 3 days per year 24 mg I.V. 3 days per year IFN-b-1a 44 mg S.Q. t.i.w.
942
n
141 F 77 M
660 F 282 M
Sex
300 mg I.V. every 4 weeks Placebo
Future monoclonal antibodies
AFFIRM
Natiluzumab
Approved monoclonal antibodies
Active drug
Table 2. Monoclonal antibody therapies in relapsing–remitting multiple sclerosis.
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Immunomodulatory therapies for relapsing remitting MS
Review
291
292
Rash Transient elevation of liver enzymes
Rash Transient elevation of liver enzymes
72% decrease in the number of Gd-enhancing lesions with 2 mg/kg dose
70% decrease 79% decrease in the number of Gd-enhancing lesions 0.11 (57%) p = 0.021 0.15 (43%) p = 0.091 0.25 0.21 (54%) p < 0.001 0.23 (50%) p < 0.001 0.46 621 150 mg S.Q. every 4 weeks 300 mg S.Q. every 4 weeks Placebo SELECT
402 F 219 M
3.0 3.0 3.0 230 112 F 118 M IFN-b-1a 30 mg I.M. + 1 mg/kg I.V. every 4 weeks IFN- b-1a 30 mg I.M. + 2 mg/kg I.V. every 2 weeks IFN-b-1a 30 mg IM every week + Placebo CHOICE Daclizumab
Future monoclonal antibodies
2.8 2.7 2.7
0.2 7 (34%) p = 0.30 0.29 (30%) p = 0.35 0.41
ARR (percent reduction) (p value vs placebo) Mean EDSS baseline n
ARR: Annualized relapse rate, Disability accumulation (in EDSS); EDSS: Expanded disability status scale; Gd: Gadolinium; I.M: Intramuscular; I.V.: Intravenous; n: total number; q.o.d.: Every other day; S.Q.: Subcutaneous; t.i.w.: Three times a week.
Key adverse events Disability accumulation (percent reduction) p value vs placebo
Percent reduction in number or volume of MRI lesions
Craddock & Markovic-Plese
Sex Treatment arms Trial/ study Active drug
Table 2. Monoclonal antibody therapies in relapsing–remitting multiple sclerosis (cont.).
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Review
events in the daclizumab group (15; 3.6%) compared with placebo (2;
