Advances in the treatment of relapsing–remitting multiple sclerosis: the role of pegylated interferon β-1a

Figures & data

Table 1 Disease Modifying Therapies approved by Health Canada for the treatment of Multiple Sclerosisa

DMT: Trademark	Indication	Dosage	Clinical Trial	Efficacyb	Safetyc,d	Mechanism of Actione
First line
					Common to all interferonβ	Common to all interferonβ
Interferonβ-1b Betaseron^® Extavia^®	CIS, RRMS, SPMS w/relapses	250 µg SC; QAD 250 µg SC; QAD	IFNβ MSSG^Citation22	34%	– injection site rxn – flu-like symptoms – decreased blood cell counts – increased LFT	– decrease in pro-inflammatory and increase anti-inflammatory cytokine profiles – inhibition of Th1 cell proliferation – downregulation of antigen presentation by B cells and glial cells in CNS – reduce entry of immune cells into the CNS, most likely through inhibition of MMPs – increase expression of neurotrophic factors
Interferonβ-1a Avonex^® Rebif^®	CIS, RRMS, SPMS w/relapses	30 µg IM; QW 22 µg SC; TIW 44 µg SC; TIW	MSCRG^Citation23 PRISMS^Citation24 PRISMS^Citation24	18% 27% 33%
PEG-Interferonβ Plegridy^®	RRMS	125 µg SC; Q2W	ADVANCE^Citation25	36%
Glatiramer acetate Copaxone^®	CIS, RRMS	20 mg SC; QD	CMSSG^Citation26 CONFIRM^Citation27	29% 29%	– injection site rxn – post-injection rxn (flushing, chest pain, dyspnea)	– shifts from pro-inflammatory Th1/Th17 to anti-inflammatory Th2 response – regulation of monocytes, dendritic & B cells – increase expression of neurotrophic factors
Teriflunomide Aubagio^®	RRMS	14 mg PO; QD	TEMSO^Citation30 TOWER^Citation29	32% 36%	– GI symptoms – decreased blood cell counts – increased LFT	– dihydroorotate dehydrogenase inhibitor; reduces synthesis of pyrimidine nucleotides – reduced proliferation of activated T cells – shifts from pro-inflammatory Th1/Th17 to anti-inflammatory Th2 response
Dimethyl fumarate Tecfidera^®	RRMS	240 mg PO; BD	DEFINE^Citation28 CONFIRM^Citation27	53% 44%	– flushing – GI symptoms – decreased blood cell counts – strong allergic rxn, including anaphylaxisd – PMLd	– shifts from pro-inflammatory Th1/Th17 to anti-inflammatory Th2 response – cytoprotective effects through Nrf2 – modulation of NF-κB activity
Second line
Fingolimod Gilenya^®	RRMS	0.5 mg PO; QD	FREEDOMS^Citation40 FREEDOMS-II^Citation39	54% 48%	– bradycardia – decreased blood cell counts – infection – skin cancerd – PMLd	– S1P receptor agonist; internalization and degradation – inhibits egress of activated lymphocytes from lymph node – modulate astrocyte function
Natalizumab Tysabri^®	RRMS	300 mg IV; Q4W	AFFIRM^Citation41	68%	– infusion rxn – PML	– humanized mAb that binds α4 integrin – blocks interaction with VCAM-1 preventing migration of activated lymphocytes into CNS
Alemtuzumab Lemtrada^®	RRMS	0.5 mg IV; 5 consecutive days in year 1, then 3 consecutive days in year 2	CARE MS-I^Citation42 CARE MS-II^Citation42	55% 49% (vs IFNβ-1a)	– infusion rxn – infection – thyroid disorders – secondary autoimmunity	– humanized mAb that binds CD52 – depletion of CD52-expressing lymphocytes through antibody-mediated cytolysis

Notes:

a an additional DMT, daclizumab (humanized mAb that binds CD25) marketed as Zinbryta^®, was approved by Health Canada for treatment of RRMS in December 2016 while manuscript was in print;

b efficacy reported as % reduction in relapse rate compared to placebo, except for alemtuzumab (compared to IFNβ-1a), in Phase III clinical trials;

c reported in Phase III clinical trials, except indicated as

d recently reported by Health Canada (http://www.hc-sc.gc.ca; accessed January 14, 2017);⁴²

e proposed mechanisms based on known pharmacology and/or current evidence from clinical trials and animal models.⁵³

Abbreviations: BD, twice daily; CIS, clinically isolated syndrome; CNS, central nervous system; DMT, disease modifying therapy; GI, gastrointestinal; IFN, interferon; IM intramuscular; IV, intravenous; LFT, liver function tests; mAb; monoclonal antibody; MMP, matrix metalloproteinase; MS, multiple sclerosis; NF-κβ, nuclear factor-kappa β; Nrf2, nuclear factor-erythroid 2-related factor 2; PEG, polyethylene glycol; PO, per oral; PML, progressive multifocal leukoencephalopathy ; QAD, once every other day; QD, once daily; QW, once weekly; Q2W, once every 2 weeks; Q4W, once every 4 weeks; RRMS, relapsing-remitting MS; rxn, reaction; S1P, sphingosine-1-phosphate; SC, subcutaneous; SPMS, secondary progressive MS; TIW, three times weekly; VCAM-1, vascular cell adhesion molecule 1.

Table 2 Summary of PRISMS, INCOMIN, EVIDENCE and ADVANCE trials

PRISMS^Citation24 – Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis
Inclusion criteria	Clinically definite RRMS for ≥1 year; ≥2 relapses in preceding 2 years, and baseline EDSS scores of 0–5
Exclusion criteria	Previous systemic treatment with IFNs, lymphoid irradiation or cyclophosphamide or with other immunomodulatory or immunosuppressive therapy in previous 12 months
Intervention	IFNβ-1a (Rebif^®) 22 or 44 µg SC TIW or placebo
Primary outcome	Relapse rate over the course of 2-year study
Summary of results	Relapse rates were reduced by 27% in the 22 µg IFNβ-1a intervention and 33% in the 44 µg IFNβ-1a intervention group compared to placebo group. IFNβ-1a interventions were also associated with an increased proportion of patients remaining relapse free, decreased change in EDSS scores and decreased time to first progression. MRI end points showed a decrease in total burden of disease (ΔT2 lesion volume), number of new/newly enlarging T2 lesions and number of T1 Gd-enhancing lesions with IFNβ-1a treatment compared to placebo. High-dose treatment (44 µg) showed more favorable outcomes compared to low-dose treatment (22 µg)
INCOMIN^Citation31 – Independent Comparison of Interferon
Inclusion criteria	Clinically definite RRMS; ≥2 clinically documented relapses during the preceding 2 years with no relapse (and no corticosteroid treatment) for at least 30 days before study entry and baseline EDSS score of 1–3.5
Exclusion criteria	Previous systemic treatment with IFNβ or treatment with other immunosuppressive or immunomodulatory drugs (except corticosteroids)
Intervention	IFNβ-1b (Betaseron^®) 250 µg SC QAD or IFNβ-1a (Avonex^®) 30 µg IM QW
Primary outcome	Proportion of patients who remained relapse free over the course of 2-year study
Summary of results	In the IFNβ-1b SC intervention group, 49% of patients remained relapse free compared to 33% in the IFNβ-1a IM intervention group. IFNβ-1b treatment was also associated with a decrease in ARR and 6-month sustained progression in EDSS. MRI end points showed an increase in the proportion of patients remaining free from new T2 lesions, remaining free from T1 Gd-enhancing lesions and showing no MRI activity with IFNβ-1b SC compared to IFNβ-1a IM treatment
EVIDENCE^Citation32 – Evidence of Interferon Dose-response-European North American Comparative Efficacy
Inclusion criteria	Clinically confirmed RRMS; ≥2 relapses in previous 2 years and baseline EDSS score of 0–5.5
Exclusion criteria	Previous treatment with IFNβ
Intervention	IFNβ-1a (Rebif^®) 44 µg SC TIW or IFNβ-1a (Avonex^®) 30 µg IM QW
Primary outcome	Proportion of patients who remained relapse free at ≥48 weeks
Summary of results	In the IFNβ-1a SC TIW intervention group, 56% of patients remained relapse free compared to 48% in the IFNβ-1a IM QW intervention group. IFNβ-1a SC TIW was also associated with a decrease in ARR and time to first relapse, but no difference was observed in EDSS progression. MRI end points showed a decrease in the number of new or enlarging T2 lesions in the IFNβ-1a SC TIW compared to the IFNβ-1a IM QW treatment
ADVANCE^Citation25 – Pegylated Interferon beta-1a for Relapsing–Remitting Multiple Sclerosis
Inclusion criteria	RRMS; ≥2 relapses in previous 3 years with at least one relapse in previous 12 months and baseline EDSS score of 0–5
Exclusion criteria	Progressive MS, previous treatment with IFNβ for >4 weeks or discontinuation <6 months before baseline
Intervention	PEG-IFNβ-1a Plegridy^® 125 µg SC Q2W or Q4W or placebo
Primary outcome	ARR at 48 weeks
Summary of results	ARR were reduced by 36% in the PEG-IFN Q2W and 28% in the PEG-IFN Q4W intervention groups compared to the placebo group. PEG-IFNβ interventions were also associated with an increased proportion of patients remaining relapse free and a decreased proportion of patients showing 12-week sustained EDSS progression. MRI end points showed a decrease in total burden of disease (ΔT2 lesion volume), number of new/newly enlarging T2 lesions and number of T1 Gd-enhancing lesions with PEG-IFNβ treatment compared to placebo. More frequent injections (Q2W) showed more favorable outcomes compared to low-frequency injections (Q4W)

Abbreviations: ARR, annualized relapse rate; EDSS, expanded disability status scale; IFNβ, interferon beta; IM, intramuscular; MS, multiple sclerosis; PEG, polyethylene glycol; QAD, once every other day; QW, once weekly; Q2W, once every 2 weeks; Q4W, once every 4 weeks; RRMS, relapsing–remitting MS; MRI, magnetic resonance imaging; SC, subcutaneous; TIW, three times weekly.

Figure 1 Schematic depicting the role of PEG-IFNβ therapy in MS.

Notes: (A) In MS, pro-inflammatory cytokines stimulate CD4+ cells to proliferate and differentiate into Th1 and Th17 effector cells. Activated T cells express VLA-4, which interacts with VCAM-1 on endothelial cells, to facilitate crossing the BBB. In the CNS, auto-reactive T cells and macrophages result in damage to the myelin sheath, axons and neurons. Inflammatory demyelinating lesions result in the clinical presentation of MS. (B) IFNβ is conjugated to PEG to increase the molecule’s serum concentration and half-life. Proposed actions of IFNβ include modulating cytokine milieu to favor anti-inflammatory pathways, which inhibits expansion of Th1/Th17 and promotes expansion of Th2 cells. Down-regulation of VLA-4 and inhibition of MMP-9 reduce migration of activated T cells into CNS. (C) Linking of anti-VCAM-1 antibodies to the PEG tail may enhance IFNβ anti-inflammatory actions by 1) blocking interaction of leukocytes expressing VLA-4 with VCAM-1 and 2) increasing local concentration of PEG-IFNβ at BBB.
Abbreviations: BBB, blood–brain barrier; CNS, central nervous system; IFNβ, interferon beta; M, macrophage; MMP, matrix metalloproteinase; MS, multiple sclerosis; PEG, polyethylene glycol; PEG-IFNβ, pegylated interferon β; TIMP-1, tissue inhibitor of metalloproteinase-1; VCAM-1, vacular cell adhesion molecule 1; VLA-4, very late activation antigen-4.

Table 3 Comparison of currently available data on interferon β-1a and pegylated interferon β-1a

	IFNβ-1a aPRISMS: 2-year study^Citation24			PEG-IFNβ-1a aADVANCE: 1-year study ^Citation5
Administration	Placebo SC; TIW	22 µg SC; TIW	44 µg SC; TIW	Placebo SC; Q2W	125 µg SC; Q2W	125 µg SC; Q2W
Number of patients enrolled	187 (170)	189 (167)	184 (165)	500 (456)	512 (438)	500 (438)
% Completed treatment	91	88	90	91	86	88
Clinical outcomes
Relapse rateb	2.56	1.82	1.73	0.40	0.26	0.29
% reduction of relapse rate vs placebo	–	27	33	–	36	28
% relapse free (1 year)	22	37	45	71	81	78
Disability progressionc	0.48	0.23	0.24	0.105	0.068	0.068
MRI outcomes
Burden of diseased	10.9%	−1.2%	−3.8%	0.77 cm^3	−0.26 cm^3	0.06 cm^3
T2 new/enlarging lesions	4.5	1.3	0	10.9	3.6	7.9
T1 Gd-enhancing lesions	8.0	1.4	1.3	1.4	0.2	0.9
New active lesionse	10.6	2.1	1.3	11.2	3.7	7.3
NAbs	–	Anti-IFN: 23.8%	Anti-IFN: 12.5%	–	Anti-IFN: <1%f anti-PEG: 6%f	Anti-IFN: <1%f anti-PEG: 8%f
Adverse events (%)g
Injection-site reactions	22	61	62	7	62	56
Influenza-like illness	24	25	27	13	47	47
Headache	44	47	45	33	44	41
Fatigue	16	14	19	10	10	11
Myalgia	8	13	14	6	19	19
Fever	6	13	12	15	45	44
Abnormal blood cell counts
Leukopenia	2	4	8	1	7	4
Lymphopenia	4	5	13	3	5	4
Elevated liver enzymes
Alanine aminotransferase	1	5	7	1	2	2
Aspartate aminotransferase	1	2	3	1	1	1
Adverse events resulting in discontinuation	1	3	5	1	5	5
Pharmacokinetics^Citation62
AUCh	–	12 IU⋅h/mL	71.6 IU⋅h/mL	–	24.5 ng⋅h/mL	23.5 ng⋅h/mL
Cmax	–	1.3 IU/mL	12.8 IU/mL	–	221 pg/mL	202 pg/mL
Tmax (h)	–	1–2	0.25	–	35.9	35.1
half-life (h)	–	n.a.	12.8	–	62.8	56.8

Notes:

a Comparison of placebo-controlled studies; no head-to-head trials have directly compared IFNβ-1a to PEG-IFNβ-1a.

b Defined as number of relapses over 2-year study period (PRISMS) or ARR at 48 weeks (ADVANCE).

c Defined as change in EDSS over duration of study (PRISMS) or proportion of patients with 12-week sustained progression in EDSS ≥1.0 (ADVANCE).

d Defined as change in total in T2 lesion volume from baseline (PRISMS, mm²; ADVANCE, cm³).

e Defined as the sum of T1 Gd-enhancing and new or newly enlarging T2 lesions (PRISMS, clinically unique; ADVANCE new active).

f Reported at 2 years.¹²²

g PRISMS reported adverse events in first 3 months of therapy and ADVANCE reported adverse events over the full 48 weeks.

h Measured over 8 h for 22 µg IFNβ-1a and measured over 168 h for 44 µg IFNβ-1a and 125 µg PEG-IFNβ-1a. C_max, maximum serum concentration; T_max, time to reach C_max.

Abbreviations: ARR, annualized relapse rate; AUC, area under curve; EDSS, Expanded Disability Status Scale; IFN, interferon; Q2W, once every 2 weeks; MRI, magnetic resonance imaging; n.a., not available; NAbs, neutralizing antibodies; PEG, polyethylene glycol; SC, subcutaneous; TIW, three times weekly.

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