Expert Opinion on Drug Safety
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Dimethyl fumarate for treating relapsing multiple sclerosis William Sheremata , Andrew D Brown & Kottil W Rammohan To cite this article: William Sheremata , Andrew D Brown & Kottil W Rammohan (2015) Dimethyl fumarate for treating relapsing multiple sclerosis, Expert Opinion on Drug Safety, 14:1, 161-170, DOI: 10.1517/14740338.2015.977251 To link to this article: http://dx.doi.org/10.1517/14740338.2015.977251
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Drug Safety Evaluation
Dimethyl fumarate for treating relapsing multiple sclerosis
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William Sheremata†, Andrew D Brown & Kottil W Rammohan †
University of Miami, Miller School of Medicine, Department of Neurology, Miami, FL, USA
1.
Introduction
2.
Mechanisms of action
3.
Clinical applications
4.
Safety evaluation of DMF
5.
Conclusion
6.
Expert opinion
7.
Authors note
Introduction: Outcomes of two large double-blind placebo-controlled studies of oral dimethyl fumarate (DMF) in multiple sclerosis (MS) provided the basis for its marketing approval as Tecfidera by the US FDA in early 2013 and the European Medicines Agency in February 2014. The safety of DMF is complemented by experience in the use of an oral mixture of fumaric acid esters, including DMF for psoriasis (Fumaderm; DMF and monoethyl fumarate [DMF-MEF]) licensed in Germany in 1994. Areas covered: This article reviews the pivotal trials leading to the approval of DMF for MS and the pharmacological literature related to the extensive use of oral fumaric acid esters for psoriasis over the last quarter century. Anecdotal reports of serious adverse reactions to DMF-MEF are also reviewed in this report. Expert opinion: DMF is generally safe and well tolerated. Flushing and gastrointestinal side effects are relatively common for the approved DMF dose but are ordinarily mild and self-limited. No increase in malignancies has been reported despite theoretical concerns. Although progressive multifocal encephalopathy has been reported anecdotally in 5 of > 196,000 patient-years of experience with fumaric acid esters, none of the 65,000 DMF MS patients treated in the first year has been affected. Appendix to the abstract: Subsequent to the acceptance of this article for publication, the manufacturer has notified physicians of the death of one patient from PML complicating use of DMF in the DEFINE study extension (ENDORSE). This does not alter the expert opinion rendered regarding the safety of DMF. We await the outcomes and recommendations from the ongoing investigation into this case. Keywords: dimethyl fumarate, fumarate, lymphopenia, monoethyl fumarate, multiple sclerosis, neuroprotection, nuclear factor (erythroid-derived-2)-like 2, progressive multifocal encephalopathy Expert Opin. Drug Saf. (2015) 14(1):161-170
1.
Introduction
Multiple sclerosis (MS) is ordinarily a relapsing-remitting neurological disorder at its outset, with unpredictable clinical manifestations due to multifocal inflammatory demyelinating disease of the optic nerves, brain and spinal cord [1,2]. Despite the tendency of exacerbations to remit early in the illness, MS is arguably the most common cause of chronic disability in young adults, affecting approximately one per thousand of the population in the USA [2]. It occurs most commonly in people of European descent with women affected twice as commonly than men [3]. In the last two decades, a succession of drugs has been approved for MS. The first four injected subdermally are of similar, modest, effectiveness [4]. In order of their regulatory approval they are: IFN-b1b; Betaseron, 1993 [5,6] IFN-b1a; Avonex 30 µg once weekly in 1996 [7,8]; glatiramer acetate (GA/Copaxone) in 1997 [9,10] and in 2002 in the USA; IFN-b1a 44 µg three times weekly (Rebif) [11,12]. More potent agents administered intravenously, and with a greater risk of serious adverse experience (SAE), have also been approved. Mitoxantrone (Novantrone) was 10.1517/14740338.2015.977251 © 2015 Informa UK, Ltd. ISSN 1474-0338, e-ISSN 1744-764X All rights reserved: reproduction in whole or in part not permitted
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Box 1. Drug summary. Drug name (generic) Phase (for indication under discussion) Indication (specific to discussion) Pharmacology description/mechanism of action Route of administration Chemical structure
Dimethyl fumarate Launched EU, USA and ROW 2013 Relapsing-remitting forms of multiple sclerosis Transcription factor nuclear factor (erythroid-derived-2)-like 2 stimulant ± other mechanisms Oral O
CH3 O
O H3C
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Pivotal trial(s)
O
[21,22]
Pharmaprojects -- copyright to Citeline Drug Intelligence (an Informa business). Readers are referred to Pipeline (http://informa-pipeline.citeline.com) and Citeline (http://informa.citeline.com).
approved in 2000 [13,14] and natalizumab (Tysabri) in 2004 [15,16]. Oral agents have now arrived, the first fingolimod (Gilenya) in 2010 [17,18] followed by teriflunomide (Aubagio) in 2012 [19,20] and dimethyl fumarate (DMF/ Tecfidera) in 2013 [21-23]. Although not powered for efficacy, the Determination of the Efficacy and Safety of Oral Fumarate IN Relapsing-Remitting MS (DEFINE) trial showed GA to be somewhat less effective than DMF but both drugs were equally safe [21,24]. Despite some concerns [25-30], one expert (SL Hauser) evaluated DMF is as a somewhat more effective and safer new oral agent for the management of MS1 [4]. Discussion of recently published reports is presented in this communication. 2.
Mechanisms of action
DMF/C6H804 is an ester of fumaric acid (trans-butenedioic acid; molecular mass of 144.13) (Box 1). Fumaric acid is derived from succinic acid in the citric acid (Krebs) cycle [31,32]. Both fumaric acid and DMF are odorless white crystalline powders. The half-life for DMF is 12 min and is 36 h for monomethyl fumarate (MMF), its primary metabolic product [33]. In 1959, a German chemist, Walter Schweckendiek, proposed fumaric acid as a treatment for psoriasis, hypothesizing psoriasis resulted from fumaric acid deficiency [30]. Orally, fumaric acid is poorly absorbed but fumaric acid esters are rapidly absorbed and achieve good bioavailability [31,33]. Following successful clinical trials in psoriasis, a preparation of DMF and 3-monoethylfumarae salts (Fumaderm; DMF and monoethyl fumarate [DMF-MEF]) was approved in Germany in 1994)2. 1 Based on ‘personal’, non-scientific meta-analysis, as practicing physicians typically do. 2
The most recent communication from Biogen-Idec, just received, indicate that the company in referring to the Fumaderm product sold in Europe, recommends use the generic term “Fumarate mixture”.
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The company has referred to the product as ‘dimethyl fumarate and monoethyl fumarate/DMF-MEF’ in communication with the FDA and for other legal matters in the USA. Improved neurological status of two MS patients with psoriasis, a Th1-mediated disorder, receiving MEF led to the first successful therapeutic trial of DMF in MS [23,34]. Numerous in vitro and ex vivo studies, as well as in vivo experiments, have not fully defined the mechanisms of action of DMF [34-49]. A review summarized the known properties of fumarates on T cells, with information largely derived from studies in psoriasis, rather than MS [31]. Nearly all patients experience a decrease in circulating T cells, with a 50% decrease in CD4+ cells reported in the cutaneous inflammatory infiltrate [23,24,48]. Investigations have also shown that MMF rapidly deprives astrocytes of glutathione leading to increased production of ‘Th2’ cytokines, IL-4 and IL-5 by stimulated T cells, with no effect on ‘Th1’ cytokines (i.e., a shift from a Th1 to a Th2 functional profile) [45]. In its FDA-regulatory filing, the manufacturer hypothesized that activation of the nuclear factor (erythroid-derived2)-like 2 (Nrf2) antioxidant pathway by DMF is the mechanism by which DMF exerts its neuroprotective and anti-inflammatory effects in the CNS [36-43,45-47]. This Nrf2 pathway is involved in the cellular response to oxidative stress. Administration of MMF is known to induce Nrf2 activation in vitro within cells transfected with rat Keap-1, a protein that binds to Nrf2. This inhibits proteolysis of Nrf2, resulting in translocation of Nrf2 to the nucleus and the subsequent induction of antioxidant response genes. In the rat malonate-induced striatal lesion experimental model, oral DMF administration leads to an increase in MMF not only in plasma, but in cerebrospinal fluid and brain, also [40,50]. The neuroprotective impact in experimental demyelinating disease induced by cuprizone/rapamycin is further evidence of drug entry and neuroprotection in the CNS [40]. In the chronic mouse experimental autoimmune
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Dimethyl fumarate
encephalomyelitis (EAE) model in vivo, oral administration of DMF induces transcriptional stress markers of Nrf2 activation with decreased injury to myelin and axons [38,44]. In the Nrf2 knockout mouse these benefits of DMF are abrogated [38]. Recently, another mechanism of action of MMF has been shown. Chen et al. have shown that MMF may mediate benefit in a MOG-induced model of EAE via its affinity for the hydroxycarboxylic acid receptor 2 (HCA2, GRP109A). They showed that MMF ameliorates EAE in wild-type mice but fails to do so in HCA2--/-- knockout mice [49]. The reported neuropathological findings in this model are unusual because of the heavy infiltration of polymorphonuclear cells in the spinal cord of these animals, but suggest induction of Th17 cells. The presence of neutrophils in the CNS lesions is not seen in MS, and is not a feature found in most EAE models [2,38,44]. Fumaric acid esters appear capable of acting both in the CNS and peripherally [35-47]. Following oral administration of DMF in animals and humans, plasma levels of DMF are low to undetectable [50]. However, radiolabelled drug administered to long rats is widely distributed, including the brain, reaching the highest levels at 30 min [50]. At 72 h, radioactivity is still present all tissues, including brain. The hydrolysis product (MMF) is detectable in the plasma of animals and humans and is the drug-related compound quantitated in pharmacological studies to assess systemic drug exposure. Metabolic products of MMF are eventually exhaled in the form of CO2 and H2O [31,50]. Adaptive immune responses have been the primary focus in MS research. Litjens et al. in 2004 reported that MMF, the major metabolic product of DMF, affects polarization of monocytes and dendritic cells (DC), playing a pivotal role in T-cell activation [41]. Mature DC stimulated with lipopolysaccharide (primed) and then cultured with MMF, produce reduced levels of IL-12 and IL-10. However, co-culture of DC (primed or not) with Th1 cells and MMF decreased IFN-g production (and induced activation of macrophages in the periphery and CNS microglial cells [41]. Ghoreschi et al. showed fumarate-induced glutathione depletion furthers development of type II DC [42]. This leads to an anti-inflammatory response consisting of an induction of IL-4-producing Th2 cells, making IL-10 instead of IL-12 and IL-23 (constituting a shift from either a Th1 or Th17 type of immune to a Th2 response). More recently, Peng et al. have reported that DMF inhibits DC maturation via NK-kB and extracellular signal-regulated kinase 1 and 2 [43]. This in turn results in a reduction of IL-12 and IL-6 production. Importantly, this inhibition of cytokine production is associated with the suppression of both Th1 and Th17 T-cell differentiation. Schilling et al., in 2006, showed treatment with either DMF or MMF reduced macrophage entry into the spinal cord early in mouse chronic EAE [44]. Wilms et al. observed that in vitro DMF inhibits both microglial and astrocytic inflammation by suppressing NO, IL-1b, TNF-a and IL-6 production [45].
Importantly, this study documented the induction of increased ‘alternatively activated (M2) macrophages and microglia cells’. Their findings suggest the neuroprotective effects of DMF may be due in part to the ability of DMF to impact innate immunity within the CNS, inhibiting expression of the multiple neuro-inflammatory mediators in the brain of MS. More recently, Linker et al. documented evidence of a diminished innate immune response consisting of a reduction of glial activation in both white and gray matter in the late phase of illness in response to DMF treatment [38,51]. Preservation of myelin and axons was documented in these treated animals. They concluded that fumaric acid esters exert neuroprotective effects dependent on function of the Nrf2 oxidative stress response pathway in the CNS [38,39]. 3.
Clinical applications
The Phase IIb study of DMF in relapsing-remitting MS using brain MRI showed a reduction of new gadolinium-enhancing lesions, new or enlarging T2-hyperintense lesions and new T1-hypoinense lesions at week 24 associated with a trend to relapse rate reduction [48]. This reduction of new T1-hypointense lesions following T2-hyperintense lesions was interpreted as evidence of a neuroprotective effect. The subsequent pivotal DEFINE and Comparator and an Oral Fumarate in Relapsing-Remitting Multiple Sclerosis (CONFIRM) studies led to regulatory approval. Both of these studies compared two doses of DMF, 240 mg twice and 240 mg thrice daily [21,22]. GA was also used as a comparator in the CONFIRM trial, but the study was not powered statistically to demonstrate efficacy [21]. The DEFINE study documented a significant reduction in the proportion of patients on DMF relapsing over 2 years versus placebo [22]. In the group receiving the approved twice-daily dose, 27% experienced relapses, versus 46% on placebo -- a 49% reduction in the risk of relapse (p < 0.0001). All secondary outcomes were also met in the DMF groups. Surrogate measures included a significant impact on disease activity detected by brain MRI. The proportion of those who progressed over 2 years at the approved twice-daily dose of DMF was 16% compared with 27% for placebo -- a 38% reduction (p = 0.005). In the CONFIRM trial, a significant reduction in annualized MS relapse rates was seen in DMF-treated groups versus placebo [21]. For the twice-daily dose group, relapse rate was reduced by 44% versus placebo. Significant reductions in disease activity in the DMF groups versus placebo were found by MRI, and in the proportion of patients relapsing. However, disability progression was not reduced significantly in the CONFIRM trial [21]. This was attributed to an unexpected and unusually low rate of relapse in the placebo recipients. A pre-specified analysis of the combined DEFINE and CONFIRM study results revealed a significant 32% decrease in the risk confirmed progression with the approved twice-daily DMF dose at 24 weeks (p = 0.0034), with a
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similar decreased risk for 54 weeks (p = 0.0278) [52]. A highly significant reduction in new and enlarging T2 and gadolinium-enhancing T1 lesions with DMF signified an associated decrease in the inflammatory component of the illness.
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4.
Safety evaluation of DMF
The incidence of adverse events (AEs) was similar in the CONFIRM (87 -- 94%) and DEFINE studies (95 -- 96%). Study withdrawal was similar among all groups in both studies (10% for placebo, 12% for DMF and 10% for GA in the CONFIRM study; and 13% for placebo and 16% for DMF in the DEFINE study) [21,22]. Table 1 shows all AEs for the approved 240 mg twice-daily dosage [21,22]. Those unique for DMF in both the pivotal Phase III studies consisted mainly of flushing and gastrointestinal events following drug administration [21,22]. The most common AEs associated with DMF versus placebo are flushing (40 vs 6%) and gastrointestinal events including abdominal pain (18 vs 10%), diarrhea (14 vs 11%) and nausea (12 vs 9%). Although self-limited, lasting a few weeks, they led to drug discontinuation in 4% patients on DMF versus < 1% on placebo. Laboratory abnormalities included elevations in hepatic transaminases and a transient increase in mean eosinophil counts during the first 2 months. A decrease in white blood cell count with lymphopenia occurred over the first year of drug use, and then plateaued. A 12% decrease of white blood cells with a 32% decrease in lymphocytes occurred in the first year of the CONFIRM trial [21]. The findings (decreases of 10 and 28%) were similar in the DEFINE trial. Notably, 6% of subjects had a marked reduction of lymphocytes to below 500 cell/mm3 but no increase in opportunistic infections occurred. In the combined results of the two studies, at study conclusion lymphocyte counts were depressed by 28.2% on DMF and 17.9% 4 weeks after stopping drug. A decrease in lymphocytes, regardless of cause, particularly to < 500 cell/mm3 is a recognized risk factor for progressive multifocal leukoencephalopathy (PML) [24,27-29,53]. DMF and MEF is approved in Germany for only short-term treatment of psoriasis (6 months). The guideline recommends checking leukocyte counts every 2 -- 3 months, and drug withdrawal if the count remains below 3000/mm3 or the lymphocyte count is below 500/mm3 [29]. No patient in whom these guidelines were observed has developed PML [29]. In the USA, the guideline for the use of DMF is to repeat leukocyte counts every 6 months. Pregnancy A class C designation for risk associated with use of DMF in pregnancy was assigned based on the absence of data. The drug has not been studied in pregnancy and it is not known if it is present in breast milk. Its use during pregnancy and nursing should be discouraged. A registry is compiling 4.1
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pregnancy outcome reports but no concerns have arisen. Animal studies showed rabbits receiving very high doses have increased spontaneous abortions [50]. Malignancies No increase in malignancies was seen in the DMF recipients in the CONFIRM study. One placebo recipient was found to have a malignant tumor (breast) and four in the glatiramer group had malignancies (one each: basal cell carcinoma, cervical carcinoma, endometrial cancer and thyroid cancer). In the DEFINE study, two malignancies occurred in each study group. One DMF patient treated with twice-daily DMF and one placebo recipient were found to have a renal cell carcinoma. Although mice and rats given high doses of oral DMF for up to 2 years had an increase in kidney tumors, no increase in such malignancies has been seen in humans. Proteinuria occurs in 1 -- 10% of drug recipients. It should be monitored but drug discontinuation has not been necessary [21,22]. Activation of Nrf2 by DMF raises theoretical considerations concerning the risk of malignant disease [54]. Activation of Nrf2 has been postulated to potentially increase growth of nascent breast cancer and other tumors, or lead to oncogenesis de novo. However, no evidence has accumulated to support such concerns with the use of DMF. It should be pointed out that while oncogenes may induce Nrf2 to protect the tumor, prior activation might protect against tumor growth [54]. 4.2
Infection There was no increased incidence of infection in DMF recipients in the Phase II and Phase III studies, nor in post-market surveillance [21,22,55]. However, five cases of PML have been reported from > 196,000 patient-years of experience with DMFMEF [24-30]. Of the > 65,000 patients placed on DMF during the year following regulatory approval worldwide, one post-natalizumab patient with high JC virus antibody titer developed PML shortly after switching to DMF [24]. The mixture of fumarates licensed in Germany (DMFMEF) contains 56% DMF as well as 44% MEF [29]. In contrast, Tecfidera contains DMF as the sole active component [21,22,24]. At presentation of the fifth case of PML, Gold et al. suggested that MEF is the specific risk factor for PML in the product licensed in Germany [24]. Regardless, these cases represent a very small incidence of PML from the large collected experience with psoriasis. The sole case of PML is an MS patient receiving DMF who had recognized risk factors for PML. This patient was identified from the increasingly large population of MS patients that is approximately one-third the size of the experience with psoriasis [56]. 4.3
5.
Conclusion
It is concluded that DMF is a safe and effective addition to the oral armamentarium of drugs for the reduction of the
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Table 1. Adverse reaction in study 1 and 2 reported for Tecfidera 240 mg b.i.d. at 2% higher incidence than placebo.
Blood and lymphatic system disorders Lymphopenia Gastrointestinal disorders Abdominal pain Diarrhea Nausea Vomiting Dyspepsia Vascular disorders Flushing Skin and subcutaneous tissue disorders Pruritus Rash Erythema Investigations Albumin urine present Aspartate aminotransferase increased
Tecfidera n = 769 (%)
Placebo n = 771 (%)
2
65,000 patients prescribed the medication in the first year of marketing worldwide. However, anecdotal reports of six cases from approximately a quarter million patients treated with DMF-MEF for psoriasis is a very low risk, the association cannot be dismissed. Continued use of DMF will require appropriate vigilance. Putting the issues of gastrointestinal side effects, occurrence of flushing and PML in perspective, it may be concluded that DMF is a safe and effective addition to the oral armamentarium of drugs for the reduction of the risk of relapse in MS. 7.
Authors note
Report of a PML Case October 20, 2014. Biogen-Idec has notified all investigators that a MS patient that participated in the DEFINE study and entered the ENDORSE study has has died from PML. The patient had been randomized to the placebo arm of the study; then subsequently she received DMF for 4.5 years and had lymphocyte counts less than 500 cell/l for more than 3.5 years. The report of one case of PML occurring in the 2650 randomized study subjects from the pivotal DEFINE and CONFIRM studies of DMF is concerning. This report
identifies a risk of PML complicating the use of DMF without concurrent use of MEF and without prior exposure to natalizumab. The common risk factor for PML amongst the fumarate mixture treated psoriasis patients and this DMF study subject is a drug induced severe reduction of lymphocytes to levels less than 500 cells. Despite this report, the risk for PML associated with DMF appears relatively small although the actual risk remains to be determined. The opinion expressed in the review remains unaltered; rational vigilance and prospective data collection are recommended. In the interim, awaiting direction from the FDA, it is suggested that CD4 counts be obtained on a 2-3 monthly basis with planned dosage reduction or drug withdrawal if CD4 counts fall below 500, as suggested by Gold [24].
Acknowledgements The authors thank Biogen-Idec editorial staff for having provided a fact-check review of this manuscript. The generic term for the German product marketed as Fumaderm in Europe is designated as ‘monoethyl fumarate’, although dimethyl fumarate constitutes 56% of the product and monoethyl fumarate 44%. In the USA, it is designated as ‘dimethyl fumarate and monoethyl fumarate’. The authors have abbreviated this generic designation as ‘DMF-MEF’.
Declaration of interest KW Rammohan and W Sheremata have received research grants from the NIH, Biogen-Idec, Hoffman-La Roche, Novartis, Teva, GlaxoSmithKline, and EMD Serono through their University. KW Rammohan has also received compensation from Biogen-Idec, Teva, EMD Serono, Hoffman-La Riche, Novartis and Genzyme. W Sheremata has received honoraria for consultation from Biogen-Idec and Questcor, and will receive an honorarium from Bayer. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
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Affiliation
William Sheremata†1 MD FRCPC FACP FAAN, Andrew D Brown2,3 MD & Kottil W Rammohan4 MD † Author for correspondence 1 Emeritus Professor of Neurology, University of Miami, Miller School of Medicine, Department of Neurology, 1120 NW 14th Street, Miami, FL 33136, USA E-mail: [email protected] 2 Fellow in Multiple Sclerosis, Florida International University, Department of Neurology, Miami, FL 33136, USA 3 University of Miami, Miller School of Medicine, 1120 NW 14th Street, Miami, FL 33136, USA 4 Professor of Clinical Neurology, University of Miami, Miller School of Medicine, Department of Neurology, 1120 NW 14th Street, Miami, FL 33136, USA
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ISSN: 1474-0338 (Print) 1744-764X (Online) Journal homepage: http://www.tandfonline.com/loi/ieds20
Dimethyl fumarate for treating relapsing multiple sclerosis William Sheremata , Andrew D Brown & Kottil W Rammohan To cite this article: William Sheremata , Andrew D Brown & Kottil W Rammohan (2015) Dimethyl fumarate for treating relapsing multiple sclerosis, Expert Opinion on Drug Safety, 14:1, 161-170, DOI: 10.1517/14740338.2015.977251 To link to this article: http://dx.doi.org/10.1517/14740338.2015.977251
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Drug Safety Evaluation
Dimethyl fumarate for treating relapsing multiple sclerosis
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William Sheremata†, Andrew D Brown & Kottil W Rammohan †
University of Miami, Miller School of Medicine, Department of Neurology, Miami, FL, USA
1.
Introduction
2.
Mechanisms of action
3.
Clinical applications
4.
Safety evaluation of DMF
5.
Conclusion
6.
Expert opinion
7.
Authors note
Introduction: Outcomes of two large double-blind placebo-controlled studies of oral dimethyl fumarate (DMF) in multiple sclerosis (MS) provided the basis for its marketing approval as Tecfidera by the US FDA in early 2013 and the European Medicines Agency in February 2014. The safety of DMF is complemented by experience in the use of an oral mixture of fumaric acid esters, including DMF for psoriasis (Fumaderm; DMF and monoethyl fumarate [DMF-MEF]) licensed in Germany in 1994. Areas covered: This article reviews the pivotal trials leading to the approval of DMF for MS and the pharmacological literature related to the extensive use of oral fumaric acid esters for psoriasis over the last quarter century. Anecdotal reports of serious adverse reactions to DMF-MEF are also reviewed in this report. Expert opinion: DMF is generally safe and well tolerated. Flushing and gastrointestinal side effects are relatively common for the approved DMF dose but are ordinarily mild and self-limited. No increase in malignancies has been reported despite theoretical concerns. Although progressive multifocal encephalopathy has been reported anecdotally in 5 of > 196,000 patient-years of experience with fumaric acid esters, none of the 65,000 DMF MS patients treated in the first year has been affected. Appendix to the abstract: Subsequent to the acceptance of this article for publication, the manufacturer has notified physicians of the death of one patient from PML complicating use of DMF in the DEFINE study extension (ENDORSE). This does not alter the expert opinion rendered regarding the safety of DMF. We await the outcomes and recommendations from the ongoing investigation into this case. Keywords: dimethyl fumarate, fumarate, lymphopenia, monoethyl fumarate, multiple sclerosis, neuroprotection, nuclear factor (erythroid-derived-2)-like 2, progressive multifocal encephalopathy Expert Opin. Drug Saf. (2015) 14(1):161-170
1.
Introduction
Multiple sclerosis (MS) is ordinarily a relapsing-remitting neurological disorder at its outset, with unpredictable clinical manifestations due to multifocal inflammatory demyelinating disease of the optic nerves, brain and spinal cord [1,2]. Despite the tendency of exacerbations to remit early in the illness, MS is arguably the most common cause of chronic disability in young adults, affecting approximately one per thousand of the population in the USA [2]. It occurs most commonly in people of European descent with women affected twice as commonly than men [3]. In the last two decades, a succession of drugs has been approved for MS. The first four injected subdermally are of similar, modest, effectiveness [4]. In order of their regulatory approval they are: IFN-b1b; Betaseron, 1993 [5,6] IFN-b1a; Avonex 30 µg once weekly in 1996 [7,8]; glatiramer acetate (GA/Copaxone) in 1997 [9,10] and in 2002 in the USA; IFN-b1a 44 µg three times weekly (Rebif) [11,12]. More potent agents administered intravenously, and with a greater risk of serious adverse experience (SAE), have also been approved. Mitoxantrone (Novantrone) was 10.1517/14740338.2015.977251 © 2015 Informa UK, Ltd. ISSN 1474-0338, e-ISSN 1744-764X All rights reserved: reproduction in whole or in part not permitted
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Box 1. Drug summary. Drug name (generic) Phase (for indication under discussion) Indication (specific to discussion) Pharmacology description/mechanism of action Route of administration Chemical structure
Dimethyl fumarate Launched EU, USA and ROW 2013 Relapsing-remitting forms of multiple sclerosis Transcription factor nuclear factor (erythroid-derived-2)-like 2 stimulant ± other mechanisms Oral O
CH3 O
O H3C
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Pivotal trial(s)
O
[21,22]
Pharmaprojects -- copyright to Citeline Drug Intelligence (an Informa business). Readers are referred to Pipeline (http://informa-pipeline.citeline.com) and Citeline (http://informa.citeline.com).
approved in 2000 [13,14] and natalizumab (Tysabri) in 2004 [15,16]. Oral agents have now arrived, the first fingolimod (Gilenya) in 2010 [17,18] followed by teriflunomide (Aubagio) in 2012 [19,20] and dimethyl fumarate (DMF/ Tecfidera) in 2013 [21-23]. Although not powered for efficacy, the Determination of the Efficacy and Safety of Oral Fumarate IN Relapsing-Remitting MS (DEFINE) trial showed GA to be somewhat less effective than DMF but both drugs were equally safe [21,24]. Despite some concerns [25-30], one expert (SL Hauser) evaluated DMF is as a somewhat more effective and safer new oral agent for the management of MS1 [4]. Discussion of recently published reports is presented in this communication. 2.
Mechanisms of action
DMF/C6H804 is an ester of fumaric acid (trans-butenedioic acid; molecular mass of 144.13) (Box 1). Fumaric acid is derived from succinic acid in the citric acid (Krebs) cycle [31,32]. Both fumaric acid and DMF are odorless white crystalline powders. The half-life for DMF is 12 min and is 36 h for monomethyl fumarate (MMF), its primary metabolic product [33]. In 1959, a German chemist, Walter Schweckendiek, proposed fumaric acid as a treatment for psoriasis, hypothesizing psoriasis resulted from fumaric acid deficiency [30]. Orally, fumaric acid is poorly absorbed but fumaric acid esters are rapidly absorbed and achieve good bioavailability [31,33]. Following successful clinical trials in psoriasis, a preparation of DMF and 3-monoethylfumarae salts (Fumaderm; DMF and monoethyl fumarate [DMF-MEF]) was approved in Germany in 1994)2. 1 Based on ‘personal’, non-scientific meta-analysis, as practicing physicians typically do. 2
The most recent communication from Biogen-Idec, just received, indicate that the company in referring to the Fumaderm product sold in Europe, recommends use the generic term “Fumarate mixture”.
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The company has referred to the product as ‘dimethyl fumarate and monoethyl fumarate/DMF-MEF’ in communication with the FDA and for other legal matters in the USA. Improved neurological status of two MS patients with psoriasis, a Th1-mediated disorder, receiving MEF led to the first successful therapeutic trial of DMF in MS [23,34]. Numerous in vitro and ex vivo studies, as well as in vivo experiments, have not fully defined the mechanisms of action of DMF [34-49]. A review summarized the known properties of fumarates on T cells, with information largely derived from studies in psoriasis, rather than MS [31]. Nearly all patients experience a decrease in circulating T cells, with a 50% decrease in CD4+ cells reported in the cutaneous inflammatory infiltrate [23,24,48]. Investigations have also shown that MMF rapidly deprives astrocytes of glutathione leading to increased production of ‘Th2’ cytokines, IL-4 and IL-5 by stimulated T cells, with no effect on ‘Th1’ cytokines (i.e., a shift from a Th1 to a Th2 functional profile) [45]. In its FDA-regulatory filing, the manufacturer hypothesized that activation of the nuclear factor (erythroid-derived2)-like 2 (Nrf2) antioxidant pathway by DMF is the mechanism by which DMF exerts its neuroprotective and anti-inflammatory effects in the CNS [36-43,45-47]. This Nrf2 pathway is involved in the cellular response to oxidative stress. Administration of MMF is known to induce Nrf2 activation in vitro within cells transfected with rat Keap-1, a protein that binds to Nrf2. This inhibits proteolysis of Nrf2, resulting in translocation of Nrf2 to the nucleus and the subsequent induction of antioxidant response genes. In the rat malonate-induced striatal lesion experimental model, oral DMF administration leads to an increase in MMF not only in plasma, but in cerebrospinal fluid and brain, also [40,50]. The neuroprotective impact in experimental demyelinating disease induced by cuprizone/rapamycin is further evidence of drug entry and neuroprotection in the CNS [40]. In the chronic mouse experimental autoimmune
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Dimethyl fumarate
encephalomyelitis (EAE) model in vivo, oral administration of DMF induces transcriptional stress markers of Nrf2 activation with decreased injury to myelin and axons [38,44]. In the Nrf2 knockout mouse these benefits of DMF are abrogated [38]. Recently, another mechanism of action of MMF has been shown. Chen et al. have shown that MMF may mediate benefit in a MOG-induced model of EAE via its affinity for the hydroxycarboxylic acid receptor 2 (HCA2, GRP109A). They showed that MMF ameliorates EAE in wild-type mice but fails to do so in HCA2--/-- knockout mice [49]. The reported neuropathological findings in this model are unusual because of the heavy infiltration of polymorphonuclear cells in the spinal cord of these animals, but suggest induction of Th17 cells. The presence of neutrophils in the CNS lesions is not seen in MS, and is not a feature found in most EAE models [2,38,44]. Fumaric acid esters appear capable of acting both in the CNS and peripherally [35-47]. Following oral administration of DMF in animals and humans, plasma levels of DMF are low to undetectable [50]. However, radiolabelled drug administered to long rats is widely distributed, including the brain, reaching the highest levels at 30 min [50]. At 72 h, radioactivity is still present all tissues, including brain. The hydrolysis product (MMF) is detectable in the plasma of animals and humans and is the drug-related compound quantitated in pharmacological studies to assess systemic drug exposure. Metabolic products of MMF are eventually exhaled in the form of CO2 and H2O [31,50]. Adaptive immune responses have been the primary focus in MS research. Litjens et al. in 2004 reported that MMF, the major metabolic product of DMF, affects polarization of monocytes and dendritic cells (DC), playing a pivotal role in T-cell activation [41]. Mature DC stimulated with lipopolysaccharide (primed) and then cultured with MMF, produce reduced levels of IL-12 and IL-10. However, co-culture of DC (primed or not) with Th1 cells and MMF decreased IFN-g production (and induced activation of macrophages in the periphery and CNS microglial cells [41]. Ghoreschi et al. showed fumarate-induced glutathione depletion furthers development of type II DC [42]. This leads to an anti-inflammatory response consisting of an induction of IL-4-producing Th2 cells, making IL-10 instead of IL-12 and IL-23 (constituting a shift from either a Th1 or Th17 type of immune to a Th2 response). More recently, Peng et al. have reported that DMF inhibits DC maturation via NK-kB and extracellular signal-regulated kinase 1 and 2 [43]. This in turn results in a reduction of IL-12 and IL-6 production. Importantly, this inhibition of cytokine production is associated with the suppression of both Th1 and Th17 T-cell differentiation. Schilling et al., in 2006, showed treatment with either DMF or MMF reduced macrophage entry into the spinal cord early in mouse chronic EAE [44]. Wilms et al. observed that in vitro DMF inhibits both microglial and astrocytic inflammation by suppressing NO, IL-1b, TNF-a and IL-6 production [45].
Importantly, this study documented the induction of increased ‘alternatively activated (M2) macrophages and microglia cells’. Their findings suggest the neuroprotective effects of DMF may be due in part to the ability of DMF to impact innate immunity within the CNS, inhibiting expression of the multiple neuro-inflammatory mediators in the brain of MS. More recently, Linker et al. documented evidence of a diminished innate immune response consisting of a reduction of glial activation in both white and gray matter in the late phase of illness in response to DMF treatment [38,51]. Preservation of myelin and axons was documented in these treated animals. They concluded that fumaric acid esters exert neuroprotective effects dependent on function of the Nrf2 oxidative stress response pathway in the CNS [38,39]. 3.
Clinical applications
The Phase IIb study of DMF in relapsing-remitting MS using brain MRI showed a reduction of new gadolinium-enhancing lesions, new or enlarging T2-hyperintense lesions and new T1-hypoinense lesions at week 24 associated with a trend to relapse rate reduction [48]. This reduction of new T1-hypointense lesions following T2-hyperintense lesions was interpreted as evidence of a neuroprotective effect. The subsequent pivotal DEFINE and Comparator and an Oral Fumarate in Relapsing-Remitting Multiple Sclerosis (CONFIRM) studies led to regulatory approval. Both of these studies compared two doses of DMF, 240 mg twice and 240 mg thrice daily [21,22]. GA was also used as a comparator in the CONFIRM trial, but the study was not powered statistically to demonstrate efficacy [21]. The DEFINE study documented a significant reduction in the proportion of patients on DMF relapsing over 2 years versus placebo [22]. In the group receiving the approved twice-daily dose, 27% experienced relapses, versus 46% on placebo -- a 49% reduction in the risk of relapse (p < 0.0001). All secondary outcomes were also met in the DMF groups. Surrogate measures included a significant impact on disease activity detected by brain MRI. The proportion of those who progressed over 2 years at the approved twice-daily dose of DMF was 16% compared with 27% for placebo -- a 38% reduction (p = 0.005). In the CONFIRM trial, a significant reduction in annualized MS relapse rates was seen in DMF-treated groups versus placebo [21]. For the twice-daily dose group, relapse rate was reduced by 44% versus placebo. Significant reductions in disease activity in the DMF groups versus placebo were found by MRI, and in the proportion of patients relapsing. However, disability progression was not reduced significantly in the CONFIRM trial [21]. This was attributed to an unexpected and unusually low rate of relapse in the placebo recipients. A pre-specified analysis of the combined DEFINE and CONFIRM study results revealed a significant 32% decrease in the risk confirmed progression with the approved twice-daily DMF dose at 24 weeks (p = 0.0034), with a
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similar decreased risk for 54 weeks (p = 0.0278) [52]. A highly significant reduction in new and enlarging T2 and gadolinium-enhancing T1 lesions with DMF signified an associated decrease in the inflammatory component of the illness.
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4.
Safety evaluation of DMF
The incidence of adverse events (AEs) was similar in the CONFIRM (87 -- 94%) and DEFINE studies (95 -- 96%). Study withdrawal was similar among all groups in both studies (10% for placebo, 12% for DMF and 10% for GA in the CONFIRM study; and 13% for placebo and 16% for DMF in the DEFINE study) [21,22]. Table 1 shows all AEs for the approved 240 mg twice-daily dosage [21,22]. Those unique for DMF in both the pivotal Phase III studies consisted mainly of flushing and gastrointestinal events following drug administration [21,22]. The most common AEs associated with DMF versus placebo are flushing (40 vs 6%) and gastrointestinal events including abdominal pain (18 vs 10%), diarrhea (14 vs 11%) and nausea (12 vs 9%). Although self-limited, lasting a few weeks, they led to drug discontinuation in 4% patients on DMF versus < 1% on placebo. Laboratory abnormalities included elevations in hepatic transaminases and a transient increase in mean eosinophil counts during the first 2 months. A decrease in white blood cell count with lymphopenia occurred over the first year of drug use, and then plateaued. A 12% decrease of white blood cells with a 32% decrease in lymphocytes occurred in the first year of the CONFIRM trial [21]. The findings (decreases of 10 and 28%) were similar in the DEFINE trial. Notably, 6% of subjects had a marked reduction of lymphocytes to below 500 cell/mm3 but no increase in opportunistic infections occurred. In the combined results of the two studies, at study conclusion lymphocyte counts were depressed by 28.2% on DMF and 17.9% 4 weeks after stopping drug. A decrease in lymphocytes, regardless of cause, particularly to < 500 cell/mm3 is a recognized risk factor for progressive multifocal leukoencephalopathy (PML) [24,27-29,53]. DMF and MEF is approved in Germany for only short-term treatment of psoriasis (6 months). The guideline recommends checking leukocyte counts every 2 -- 3 months, and drug withdrawal if the count remains below 3000/mm3 or the lymphocyte count is below 500/mm3 [29]. No patient in whom these guidelines were observed has developed PML [29]. In the USA, the guideline for the use of DMF is to repeat leukocyte counts every 6 months. Pregnancy A class C designation for risk associated with use of DMF in pregnancy was assigned based on the absence of data. The drug has not been studied in pregnancy and it is not known if it is present in breast milk. Its use during pregnancy and nursing should be discouraged. A registry is compiling 4.1
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pregnancy outcome reports but no concerns have arisen. Animal studies showed rabbits receiving very high doses have increased spontaneous abortions [50]. Malignancies No increase in malignancies was seen in the DMF recipients in the CONFIRM study. One placebo recipient was found to have a malignant tumor (breast) and four in the glatiramer group had malignancies (one each: basal cell carcinoma, cervical carcinoma, endometrial cancer and thyroid cancer). In the DEFINE study, two malignancies occurred in each study group. One DMF patient treated with twice-daily DMF and one placebo recipient were found to have a renal cell carcinoma. Although mice and rats given high doses of oral DMF for up to 2 years had an increase in kidney tumors, no increase in such malignancies has been seen in humans. Proteinuria occurs in 1 -- 10% of drug recipients. It should be monitored but drug discontinuation has not been necessary [21,22]. Activation of Nrf2 by DMF raises theoretical considerations concerning the risk of malignant disease [54]. Activation of Nrf2 has been postulated to potentially increase growth of nascent breast cancer and other tumors, or lead to oncogenesis de novo. However, no evidence has accumulated to support such concerns with the use of DMF. It should be pointed out that while oncogenes may induce Nrf2 to protect the tumor, prior activation might protect against tumor growth [54]. 4.2
Infection There was no increased incidence of infection in DMF recipients in the Phase II and Phase III studies, nor in post-market surveillance [21,22,55]. However, five cases of PML have been reported from > 196,000 patient-years of experience with DMFMEF [24-30]. Of the > 65,000 patients placed on DMF during the year following regulatory approval worldwide, one post-natalizumab patient with high JC virus antibody titer developed PML shortly after switching to DMF [24]. The mixture of fumarates licensed in Germany (DMFMEF) contains 56% DMF as well as 44% MEF [29]. In contrast, Tecfidera contains DMF as the sole active component [21,22,24]. At presentation of the fifth case of PML, Gold et al. suggested that MEF is the specific risk factor for PML in the product licensed in Germany [24]. Regardless, these cases represent a very small incidence of PML from the large collected experience with psoriasis. The sole case of PML is an MS patient receiving DMF who had recognized risk factors for PML. This patient was identified from the increasingly large population of MS patients that is approximately one-third the size of the experience with psoriasis [56]. 4.3
5.
Conclusion
It is concluded that DMF is a safe and effective addition to the oral armamentarium of drugs for the reduction of the
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Table 1. Adverse reaction in study 1 and 2 reported for Tecfidera 240 mg b.i.d. at 2% higher incidence than placebo.
Blood and lymphatic system disorders Lymphopenia Gastrointestinal disorders Abdominal pain Diarrhea Nausea Vomiting Dyspepsia Vascular disorders Flushing Skin and subcutaneous tissue disorders Pruritus Rash Erythema Investigations Albumin urine present Aspartate aminotransferase increased
Tecfidera n = 769 (%)
Placebo n = 771 (%)
2
65,000 patients prescribed the medication in the first year of marketing worldwide. However, anecdotal reports of six cases from approximately a quarter million patients treated with DMF-MEF for psoriasis is a very low risk, the association cannot be dismissed. Continued use of DMF will require appropriate vigilance. Putting the issues of gastrointestinal side effects, occurrence of flushing and PML in perspective, it may be concluded that DMF is a safe and effective addition to the oral armamentarium of drugs for the reduction of the risk of relapse in MS. 7.
Authors note
Report of a PML Case October 20, 2014. Biogen-Idec has notified all investigators that a MS patient that participated in the DEFINE study and entered the ENDORSE study has has died from PML. The patient had been randomized to the placebo arm of the study; then subsequently she received DMF for 4.5 years and had lymphocyte counts less than 500 cell/l for more than 3.5 years. The report of one case of PML occurring in the 2650 randomized study subjects from the pivotal DEFINE and CONFIRM studies of DMF is concerning. This report
identifies a risk of PML complicating the use of DMF without concurrent use of MEF and without prior exposure to natalizumab. The common risk factor for PML amongst the fumarate mixture treated psoriasis patients and this DMF study subject is a drug induced severe reduction of lymphocytes to levels less than 500 cells. Despite this report, the risk for PML associated with DMF appears relatively small although the actual risk remains to be determined. The opinion expressed in the review remains unaltered; rational vigilance and prospective data collection are recommended. In the interim, awaiting direction from the FDA, it is suggested that CD4 counts be obtained on a 2-3 monthly basis with planned dosage reduction or drug withdrawal if CD4 counts fall below 500, as suggested by Gold [24].
Acknowledgements The authors thank Biogen-Idec editorial staff for having provided a fact-check review of this manuscript. The generic term for the German product marketed as Fumaderm in Europe is designated as ‘monoethyl fumarate’, although dimethyl fumarate constitutes 56% of the product and monoethyl fumarate 44%. In the USA, it is designated as ‘dimethyl fumarate and monoethyl fumarate’. The authors have abbreviated this generic designation as ‘DMF-MEF’.
Declaration of interest KW Rammohan and W Sheremata have received research grants from the NIH, Biogen-Idec, Hoffman-La Roche, Novartis, Teva, GlaxoSmithKline, and EMD Serono through their University. KW Rammohan has also received compensation from Biogen-Idec, Teva, EMD Serono, Hoffman-La Riche, Novartis and Genzyme. W Sheremata has received honoraria for consultation from Biogen-Idec and Questcor, and will receive an honorarium from Bayer. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
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Affiliation
William Sheremata†1 MD FRCPC FACP FAAN, Andrew D Brown2,3 MD & Kottil W Rammohan4 MD † Author for correspondence 1 Emeritus Professor of Neurology, University of Miami, Miller School of Medicine, Department of Neurology, 1120 NW 14th Street, Miami, FL 33136, USA E-mail: [email protected] 2 Fellow in Multiple Sclerosis, Florida International University, Department of Neurology, Miami, FL 33136, USA 3 University of Miami, Miller School of Medicine, 1120 NW 14th Street, Miami, FL 33136, USA 4 Professor of Clinical Neurology, University of Miami, Miller School of Medicine, Department of Neurology, 1120 NW 14th Street, Miami, FL 33136, USA
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