BG-12 and its potential for the prevention of relapse in multiple sclerosis

Figures & data

Table 1 Consistency of clinical and radiological outcomes between oral therapies compared to current licensed therapies for RRMS; not from comparative studies

Trial (length years)	Relapses		Progression
	Clinical: ARR	MRI: T2/Gd-enhancing lesions	Clinical: 12 week progression	MRI: T1 black holes
BG-12 DEFINE (2)	Y, ✓	Y, ✓	Y	Y
BG-12 CONFIRM (2)	Y, ✓	Y, ✓	N, #	Y, #
Fingolimod FREEDOMS (2)	Y, ✓	Y, ✓	Y, ✓	Y, ✓
Fingolimod TRANSFORMS (1)	Y, ✓	Y, ✓	N, ✕	N, ✕
IFNβ (3)	Y, ✓	Y, ✓	N, ✕	N, ✕
GA (2)	Y, #	N, #	N, ✕	N, ✕
Natalizumab (2)	Y, ✓	Y, ✓	Y, #	N, #

Notes: Y, positive effect; N, no effect; ✓, positive effect and consistent; #, inconsistent results between outcomes; ✕, no effect in both outcomes.

Abbreviations: ARR, annualized relapse rate; MRI, magnetic resonance imaging; GA, glatiramer acetate; Gd, gadolinium; IFN, interferon; RRMS, relapsing remitting multiple sclerosis.

Figure 1 Neuroprotective mode of action: MMF on Nrf2 Phase II genes activation, such as NQO1 (NAD(P)H:quinone oxidoreductase-1) and glutathione S-transferase.

Abbreviations: ARE, antioxidant-responsive element; MMF, monomethylfumarate; Nrf2, nuclear factor E2-related factor-2; Keap1, Kelch-like ECH-associating protein-1; UL, ubiquitin; Glutat, glutathione S-transferase.

Figure 2 Anti-inflammatory mode of action: DMF on NF-kB activation.

Abbreviations: DMF, dimethylfumarate; NF-kB, nuclear factor kappa B.

Table 2 Efficacy results of BG-12 in DEFINE^84,85 and CONFIRM⁸⁶ Phase III studies

BG-12 phase III trials
At 2 years	BG-12 240 mg twice daily vs placebo		BG-12 240 mg three times daily vs placebo
Clinical outcome measure	Change	Significance	Change	Significance
DEFINE study
Relapse risk	−49%	P < 0.0001	−50%	P < 0.0001
ARR	−53%	P < 0.001	−48%	P < 0.001
Risk of confirmed disability progression	−38%	P < 0.05	−34%	P < 0.05
MRI outcome measure
Risk of new or newly enlarging T2 lesion	−85%	P < 0.0001	−74%	P < 0.0001
Patients free of new or newly enlarging T2 lesions (placebo 25%)	45%	ns	41%	ns
Odds of increased Gd-enhancing lesion activity	−90%	P < 0.0001	−73%	P < 0.0001
Patients free of Gd-enhancing lesion (placebo 62%)	93%		86%
New T1-hypointense lesions	−73%	P < 0.0001	−63%	P < 0.0001
QoL outcome measure
SF-36		P < 0.001		P < 0.0001
VAS		P = 0.003		P < 0.0001
CONFIRM study
ARR	−44%	P < 0.0001	−51%	P < 0.0001
Proportion of patients experiencing MS relapses	−34%	P < 0.003	−45%	P < 0.0001
Confirmed disability progression*	−21%	ns	−24%	ns
MRI outcome measure
Risk of new or newly enlarging T2 lesion	−71%	P < 0.0001	−73%	P < 0.0001
New T1-hypointense lesions	−57%	P < 0.0001	−65%	P < 0.0001

Note:

* At 24 weeks.

Figure 3 Reduction of ARR at 2 years by BG-12 and DMTs approved for MS treatment, as reported in Phase III clinical trials.

Note: Data obtained from different noncomparative trials.^{35–39,86,88,105}
Abbreviations: ARR, annualized relapse rate; DMT, disease-modifying treatment; MS, multiple sclerosis; BID, twice a day; TID, three times a day.

Table 3 Adverse events reported in Phase IIb⁸² and DEFINE⁸⁸ trials

	Phase IIb trial				DEFINE trial
	Placebo (65)	BG-12 120 mg once daily (64)	BG-12 120 mg three times daily (64)	BG-12 240 mg three times daily (63)	Placebo (408)	BG-12 240 mg twice daily (410)	BG-12 240 mg three times daily (416)
AEs
Flushing	6 (9%)	34 (53%)	31 (48%)	25 (40%)	20 (5%)	154 (38%)	396 (95%)
MS relapse	16 (25%)	11 (17%)	20 (31%)	12 (19%)	189 (46%)	111 (27%)	114 (27%)
Headache	7 (11%)	5 (8%)	11 (17%)	13 (21%)	80 (20%)	81 (20%)	80 (19%)
Nasopharyngitis	10 (15%)	7 (11%)	6 (9%)	7 (11%)	101 (25%)	108 (26%)	109 (26%)
Nausea	5 (8%)	1 (2%)	9 (14%)	10 (16%)	38 (9%)	53 (13%)	54 (13%)
Diarrhea	3 (5%)	6 (9%)	5 (8%)	7 (11%)	55 (13%)	62 (15%)	78 (19%)
Pruritus	5 (8%)	6 (9%)	5 (8%)	6 (10%)	19 (5%)	42 (10%)	34 (8%)
Upper abdominal pain	2 (3%)	5 (8%)	4 (6%)	9 (14%)	28 (7%)	40 (10%)	52 (13%)
Hot flushing	0	5 (8%)	1 (2%)	6 (10%)
Abdominal pain	0	2 (3%)	2 (3%)	6 (10%)	22 (5%)	46 (11%)	37 (9%)
Fatigue					54 (13%)	57 (14%)	63 (15%)
Upper respiratory tract infection					53 (13%)	63 (15%)	51 (12%)
Urinary infection					53 (13%)	55 (13%)	54 (13%)
Back pain					57 (14%)	59 (14%)	46 (11%)
Proteinuria					34 (8%)	38 (9%)	50 (12%)
Arthralgia					39 (10%)	46 (11%)	37 (9%)
Influenza					39 (10%)	34 (8%)	48 (12%)
Vomiting					24 (6%)	40 (10%)	30 (7%)
ALT < 3 × ULN					14 (3%)	26 (6%)	24 (6%)
ALT < 5 × ULN					7 (2%)	6 (1%)	10 (2%)
AST < 3 × ULN					7 (2%)	8 (2%)	8 (2%)
AST < 5 × ULN					4 (<1%)	1 (<1%)	2 (<1%)
WBC counts (<3.0 × 109/L)					1%	4%	4%
Lymphocyte counts (<0.5 × 109/L)					<1%	4%	4%
SAEs
MS relapse	5 (8%)	3 (5%)	6 (9%)	5 (8%)	60 (15%)	39 (10%)	32 (8%)
Abdominal pain	0	0	0	1 (2%)
Lower limb fracture	1 (2%)	0	0	0
Multiple sclerosis	0	1 (2%)	0	0
Pelvic inflammatory disease	0	0	1 (2%)	0
Phlebitis	0	0	1 (2%)	0
Urinary retention	0	0	0	1 (2%)
Uterine leiomyoma	1 (2%)	0	0	0
Vertigo	1 (2%)	0	0	0
Gastroenteritis					0	4 (<1%)	1 (<1%)
Gastritis					0	0	3 (<1%)
Ovarian cyst					1 (<1%)	1 (<1%)	2 (<1%)
Pneumonia					1 (<1%)	2 (<1%)	0
Basal cell carcinoma					1 (<1%)	1 (<1%)	0
Breast cancer					1 (<1%)	0	1 (<1%)
Cervix carcinoma					0	0	1 (<1%)
Transitional cell carcinoma					0	1 (<1%)	0

Abbreviations: AEs, adverse events; SAEs, serious adverse events; ALT, alanine transaminase; AST, aspartate transaminase; MS, multiple sclerosis; ULN, upper limit of normal; WBC, white blood cells.

Table 4 Relative efficacy (reduction in ARR), safety (major side effects) and ease of use (administration, day-to-day side effects) of existing and emerging therapies currently applying for a USA/EU license; not from comparative studies

Therapy	Efficacy	Safety	Ease of use
IFNβ three times dailya	30%	No long-term concerns	Injectable and systemic symptoms
GAa	30%	No long-term concerns	Daily injectable
Natalizumaba	68%	PML risk	Monthly infusion
Cladribineb	55%	Further safety data required by regulators	Intermittent oral dosing
Fingolimoda	55%	Cardiac, macula edema	Daily oral dosing
BG-12	55%	GI upset, no concerns from prior use in psoriasis	Twice daily oral dosing
Teriflunomide	30%	Minimal, no long-term data	Daily oral dosing

Notes:

a Licensed USA and EU;

b refused license in either USA or EU.

Abbreviations: ARR, annualized relapse rate; EU, European Union; IFN, interferon; GI, gastrointestinal; PML, progressive multifocal leukoencephalopathy; USA, United States of America.

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