Comparison of efficacy and safety of oral agents for the treatment of relapsing–remitting multiple sclerosis

Figures & data

Table 1 Mechanism of action of three oral agents

Drugs	Mechanism of action
Fingolimod^Citation1	Binds to the SP1 receptor by sequestering lymphocytes in the lymph nodes
Teriflunomide^Citation2^–^Citation4	Prevents pyrimidine biosynthesis in activated lymphocytes by inhibiting DHODH. As a consequence, it reduces the proliferation of activated B and T lymphocytes
Dimethyl fumarate^Citation6	Provides neuroprotective and cytoprotective effects by upregulating Nrf2

Abbreviations: DHODH, dihydro-orotate dehydrogenase; Nrf2, nuclear factor erythroid 2-derived factor 2; SP1, sphingosine 1 phosphate.

Table 2 Outcomes from Phase III studies: fingolimod, teriflunomide, and dimethyl fumarate at their respective recommended doses

	Fingolimod 0.5 mg	Teriflunomide 14 mg	Dimethyl fumarate 240 mg BID
Characteristics of Phase III studies	FREEDOMS,^Citation13 FREEDOMS II^Citation20: randomized, double-blind, placebo-controlled studies of RRMS TRANSFORMS^Citation18: randomized, double-blind, study versus active comparator IFN β 1a of RRMS	TEMSO^Citation26, TOWER^Citation28: randomized, double-blind, placebo-controlled studies of RRMS	DEFINE^Citation33: randomized, double-blind, placebo-controlled studies of RRMS CONFIRM^Citation34: randomized, double-blind study versus placebo, with also an active reference comparator rater-blinded GA of RRMS
Relative reduction of ARR (compared to placebo or active comparator)	FREEDOMS^Citation13: 54% TRANSFORMS^Citation18: 52% FREEDOMS II^Citation20: 48%	TEMSO^Citation26: 31.5% TOWER^Citation28: 36.3%	DEFINE^Citation33: 53% CONFIRM^Citation34: 44%
Reduction of CDP	FREEDOMS^Citation13: 30% TRANSFORMS^Citation18: 29% FREEDOMS II^Citation20: 17%	TEMSO^Citation26: 29.8% TOWER^Citation28: 31.5%	DEFINE^Citation33: 38% CONFIRM^Citation34: 21%

Abbreviations: ARR, annualized relapse rate; BID, two times daily; CDP, confirmed disability progression; GA, glatiramer acetate; IFN β 1a, interferon beta 1a; RRMS, relapsing–remitting multiple sclerosis.

Table 3 Frequency, incidence, and severity data of AEs of fingolimod

	Fingolimod
Incidence of all AEs in:  FREEDOMS^Citation13  TRANSFORMS^Citation18  FREEDOMS II^Citation20	0.5 mg	1.25 mg	Placebo
	94.4% 86% 98%	94.2% 90.5% 97%	92.6% 91.6% 97%
Frequent AEs	Respiratory infections, headache, alterations in liver enzymes
Overall severity of AEs	Mild to moderate
Reactions that caused interruption of the treatment	Elevated ALT levels

Abbreviations: AEs, adverse events; ALT, alanine aminotransferase.

Table 4 Frequency, incidence, and severity data of AEs of teriflunomide

	Teriflunomide
Incidence of all AEs in:  TEMSO^Citation26  TOWER^Citation28	7 mg	14 mg	Placebo
	89.1% 84%	90.8% 86%	87.5% 83%
Frequent AEs	Diarrhea, nausea, headache, elevated ALT levels, and decreased hair density
Overall severity of AEs	Mild to moderate
Reactions that caused interruption of the treatment	Elevated ALT levels, neutropenia, hair thinning, and nausea

Abbreviations: AEs, adverse events; ALT, alanine aminotransferase.

Table 5 Frequency, incidence, and severity data of AEs of dimethyl fumarate

	Dimethyl fumarate
Incidence of all AEs in:  DEFINE^Citation33  CONFIRM^Citation34	240 mg BID	240 mg TID	Placebo	GA
	96% 94%	95% 92%	95% 92%	Not included* 87%
Frequent AEs	Flushing and gastrointestinal events
Overall severity of AEs	Mild to moderate
Reactions that caused interruption of the treatment	Flushing, nausea, and diarrhea

Note:

* The DEFINE study did not include GA.

Abbreviations: AEs, adverse events; BID, two times daily; GA, glatiramer acetate; TID, three times daily.

Table 6 Cardiovascular events of fingolimod, teriflunomide, and dimethyl fumarate

	Fingolimod 0.5 mg, 1.25 mg, placebo	Teriflunomide 7 mg, 14 mg, placebo	Dimethyl fumarate 240 mg BID, TID, placebo, GA
Bradycardia	FREEDOMS^Citation13: 2.1%, 3.3%, 0.7% TRANSFORMS^Citation18: 0.5%, 2.4%, 0 FREEDOMS II^Citation20: 1%, 2%, 1%	No reports	No reports
First-degree AV block	FREEDOMS^Citation13: 0.5%, 1.2%, 0.5% TRANSFORMS^Citation18: 0.2%, 0.5%, 0 FREEDOMS II^Citation20: 1%, 2%, 1%	No reports	No reports
Second-degree AV block	FREEDOMS^Citation13: 0, 0.2%, 0.2% TRANSFORMS^Citation18: 0.2%, 0.7%, 0 FREEDOMS II^Citation20: 1%, 0, <0.5%	No reports	No reports
Increased blood pressure	FREEDOMS^Citation13: 6.1%, 6.3%, 3.8% TRANSFORMS^Citation18: 3.7%, 5%, 1.9% FREEDOMS II^Citation20: 9%, 13%, 3%	TEMSO^Citation26: 5.4%, 5%, 3.1% TOWER^Citation28: 5%, 5%, 2%	No reports
Flushing	No reports	No reports	DEFINE^Citation33: 38%, 32%, 5%* CONFIRM^Citation34: 31%, 24%, 4%, 2%

Note:

* There are only three results shown because the DEFINE study did not include GA.

Abbreviations: AV, atrioventricular; BID, two times daily; TID, three times daily; GA, glatiramer acetate.

Table 7 Hematochemical abnormalities and infections caused by fingolimod, teriflunomide, and dimethyl fumarate

	Fingolimod 0.5 mg, 1.25 mg, placebo	Teriflunomide 7 mg, 14 mg, placebo	Dimethyl fumarate 240 mg BID, TID, placebo, GA
Increased ALT levels	FREEDOMS^Citation13: 8.5%, 12.5%, 1.7% TRANSFORMS^Citation18: 6.5%, 5.7%, 1.9% FREEDOMS II^Citation20: 8%, 10%, 2%	TEMSO^Citation26: 12%, 14.2%, 6.7% TOWER^Citation28: 11%, 14%, 8%	DEFINE^Citation33: 6%, 6%, 3%* CONFIRM^Citation34: 6%, 6%, 6%, 7% (≥3 ULN)
Lymphopenia	FREEDOMS^Citation13: 3.5%, 5.4%, 0.5% TRANSFORMS^Citation18: 0.2%, 1%, 0 FREEDOMS II^Citation20: 8%, 10%, 0	TEMSO^Citation26: not available TOWER^Citation28: 13%, 13%, 7%	DEFINE^Citation33: 4%, 4%, 1% (at 1 year, 28% reductions for 240 mg BID and TID)* CONFIRM^Citation34: 5%, 4%, 1% (at 1 year, 32% reductions for 240 mg BID, 28% for 240 mg TID)
Upper respiratory infections	FREEDOMS^Citation13: 49.9%, 48%, 50.5% TRANSFORMS^Citation18: 7.2%, 8.6%, 6.3% FREEDOMS II^Citation20: 52%, 51%, 52%	TEMSO^Citation26: no increase found TOWER^Citation28: 9%, 9%, 11%	DEFINE^Citation33: not available CONFIRM^Citation34: 10%, 14%, 9%, 8%
Herpes virus infections	FREEDOMS^Citation13: 8.7%, 5.8%, 7.9% TRANSFORMS^Citation18: 2.1%, 5.5%, 2.8% FREEDOMS II^Citation20: 8%, 10%, 5%	No increase found	No increase found

Note:

* There are only three results shown because the DEFINE study did not include GA.

Abbreviations: ALT, alanine aminotransferase; BID, two times daily; TID, three times daily; GA, glatiramer acetate.

Table 8 Tumor incidence of fingolimod, teriflunomide, and dimethyl fumarate

Type of cancer	Fingolimod 0.5 mg, 1.25 mg, placebo	Teriflunomide 7 mg, 14 mg, placebo	Dimethyl fumarate 240 mg BID, TID, placebo, GA
Basal cell carcinoma	FREEDOMS^Citation13: 0.9%, 0.7%, 0.2% TRANSFORMS^Citation18: 0.7%, 0.5%, 0.2% FREEDOMS II^Citation20: 3%, 2%, 1%	No case	DEFINE^Citation33: <1%, 0, <1%* CONFIRM^Citation34: 0, 0, 0, 1 case
Bowen’s disease	FREEDOMS^Citation13: 0, 0.2%, 0 TRANSFORMS^Citation18, FREEDOMS II^Citation20: no case	No case	No case
Breast cancer	FREEDOMS^Citation13: 0, 0.2%, 0.7% TRANSFORMS^Citation18: 0.5%, 0.5%, 0 FREEDOMS II^Citation20: 0.5%, 0.5%, 0	TEMSO^Citation26: 0, 0, 0.3% TOWER^Citation28: no case	DEFINE^Citation33: 0, <1%, <1%* CONFIRM^Citation34: 0, 0, 1 case, 0
Cervical carcinoma	FREEDOMS^Citation13: 0, 0, 0.2% TRANSFORMS^Citation18, FREEDOMS II^Citation20: no case	TEMSO^Citation26: 0, 0.3%, 0.3% TOWER^Citation28: no case	DEFINE^Citation33: 0, <1%, 0* CONFIRM^Citation34: 0, 0, 0, 1 case
Melanoma	FREEDOMS^Citation13: 0, 0.2%, 0.2% TRANSFORMS^Citation18: 0.7%, 0, 0 FREEDOMS II^Citation20: 0.7%, 0, 0	No case	No case
Squamous cell carcinoma	FREEDOMS^Citation13, TRANSFORMS^Citation18: no case FREEDOMS II^Citation20: <0.5%, 1%, 1%	No case	No case
Thyroid cancer	FREEDOMS^Citation13, TRANSFORMS^Citation18: no case FREEDOMS II^Citation20: <0.5%, 0, <0.5%	TEMSO^Citation26: 0, 0, 0.3% TOWER^Citation28: 0, 0, 0.3%	DEFINE^Citation33: no case CONFIRM^Citation34: 0, 0, 0, 1 case
Lymphoma Endometrial carcinoma	No case No case	No case No case	No case DEFINE^Citation33: no case CONFIRM^Citation34: 0, 0, 0, 1 case
Transitional cell carcinoma	No case	No case	DEFINE^Citation33: <1%, 0, 0* CONFIRM^Citation34: no case

Note:

* There are only three results shown because the DEFINE study did not include GA.

Abbreviations: BID, two times daily; GA, glatiramer acetate; TID, three times daily.

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