Alemtuzumab – A New Efficacy Benchmark in Relapsing–Remitting Multiple Sclerosis?

Table 1: Disease-modifying Drugs in Development for the Treatment of Multiple Sclerosis Treatment Type Indication, Administration

Phase II or III Clinical Trial Efficacy Data Method and Dose

Patient Inclusion Criteria % Relapse Reduction EDSS Score and n-values

Alemtuzumab In development for RRMS. 12mg EDSS 0–3

(MabCampath®) per day IV injection, for 5 days at Alemtuzumab pooled (n=222) month 0 and 12mg per day IV for 3 days at month 12

IFNβ-1a (n=111) 74 (p<0.001)*

Association with infusion-related cytokine release syndrome leading to fever, rash and chills during the

infusion, autoimmunity and development of immune thrombocytopenic purpura. Autoimmune thyroid-associated events were increased with alemtuzumab. Single case of glomerular basement membrane disease.62

Rituximab

In development for RRMS. 1,000mg EDSS 0–5 infusions of rituximab on days 0 and 15

Daclizumab

In development for RRMS 2mg/2 weeks (high dose), 1mg/4 weeks (low dose)

EDSS 0–5

IFNβ + placebo (n=77) IFNβ + low-dose daclizumab (n=78) IFNβ + high-dose daclizumab (n=75)

Cladribine (Mylinax®)

In development for CIS and RRMS. EDSS 0–5.5

Oral tablet up to 3.5mg/kg 1 x week Cladribine 3.5mg/kg (n=433) for 4 weeks

Placebo (n=437) 20 (p=0.04)

Rituximab (n=69) Placebo (n=35)

43 and 32** (p=0.18 and 0.31)

Infusion-associated adverse events such as chills, nausea, pruritus,

pharyngolaryngeal pain, urinary tract infection, sinusitis.75

Similar incidence of adverse events for daclizumab with or without IFNβ. With daclizumab greater incidence of nausea, urinary tract infection and upper respiratory tract infection.76

58 (p<0.001)

Lymphopenia, headache, nasopharyngitis.47

Serious adverse

events in patients receiving cladribine included infections (herpes zoster) and neoplasms (5 cases of benign uterine leiomyoma, and cases of melanoma, carcinoma of the pancreas, ovary and cervix [in situ]).

BG-12 (dimethyl In development for RRMS. fumarate)

Oral tablet 120 or 240mg 3 x per day

EDSS 0–5

BG-12 720mg (n=63) Placebo (n=65)

32 (p<0.272)

Most common adverse events were: flushing, MS relapse and headache.

Laquinimod Teriflunomide

In development for RRMS. Oral tablet 0.6mg/daily

In development for RRMS. EDSS 1–5

Laquinimod (n=106) Placebo (n=102)

EDSS ≤5.5 + ≥1 relapse in For 7 and 14mg: Oral tablet, 7mg, 14mg once daily previous year or at ≥2 32 (p=0.0978)

Adverse events significantly more frequent with BG-12 than placebo included: abdominal pain, flushing, hot flush, headache, fatigue and feeling hot. Serious adverse events more frequent with BG-12 were MS relapse, abdominal pain, pelvic inflammatory disease, phlebitis and urinary retention.48 Transient and dose-dependent increases in liver enzymes.45

No difference between teriflunomide 31.2%, 31.5% risk reduction 7mg, 14mg and placebo in serious

relapses in previous 2 years (p=0.0002 and p=0.0005) hepatic disorders (2.5, 1.9, 2.5%), ALT 1,088 patients randomised 1:1:1 to teriflunomide 7mg, 14mg or placebo

ALT = alanine transaminase; CIS = clinically isolated syndrome; EDSS = Expanded Disability Status Scale; IV = intravenous; RRMS = relapsing–remitting multiple sclerosis; ULN = upper limit of normal.

the proportion remaining free from new T2 lesions detected by MRI.26 A

disadvantage with IFNβ therapy in some patients is the development of neutralising antibodies and this is associated with reduced efficacy,27–32 particularly in patients with persistently high titres of antibodies. Such patients often benefit from switching to a non-IFNβ therapy.33

For patients who relapse despite using IFNβs or glatiramer acetate, the next treatment options are natalizumab or mitoxantrone. Both

EUROPEAN NEUROLOGICAL REVIEW

natalizumab and mitoxantrone can be highly effective in treating refractory cases of relapsing MS, but mitoxantrone is decreasingly used.14,15,34,35

>3 x ULN (6.7, 6.3, 6.7%) or serious infections or infestations (2.2, 1.6 and 2.5%) for placebo, 7 and 14mg groups.50

*p-value for difference versus placebo or versus active comparator. **% differences are for daclizumab high-dose with interferon beta (IFNβ)versus IFNβwith daclizumab low-dose versus IFNβwith placebo.

Major Safety/Tolerability Concerns in Clinical Trials

However, both of these drugs are associated with serious adverse events (AE) and therefore are generally used as second-line options, although use as first-line therapy may be warranted in selected cases.14,15,36,37

Evaluation of pooled clinical trial data has shown

that, compared with placebo, approximately 0.1% of patients treated with natalizumab for 18 months developed the rare but potentially

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