Laquinimod

Polman, C. et al. Neurology 2005;64:987-991

Multicenter, double-blind, randomized trial, patients with RR MS received 0.1 mg or 0.3 mg laquinimod

or placebo as three daily tablets for 24 weeks

Gadolinium-enhanced brain MRI scans were performed at screening, every eighth week during treatment, and 8 weeks after end of treatment

The primary efficacy variable was the cumulative number of active lesions over 24 weeks

Polman, C. et al. Neurology 2005;64:987-991

Figure 2. Cumulative number of active lesions (mean {+/-} SE) by visit (primary endpoint)

No statistically significant differences in the primary endpoint of active scans but there

was a strong trend (37% active in placebo, 31% in 0.1 and 21% in 0.3 group).

Polman, C. et al. Neurology 2005;64:987-991

Table 3 Statistical evaluation of the reduction in the cumulative number of active lesions at week 24

Phase III ALLEGRO Trial

2 year randomized, double blind, placebo

controlled with 1106 RRMS participants – 0.6

mg qday

Primary outcome - # confirmed relapses –

showed a 26% reduction (p=0.0024)

36% decrease in risk of progression by EDSS

(p=0.0122)

33% reduction in brain atrophy (p=0.0001)

Phase III BRAVO Trial

Comparing 0.6 mg qday with placebo

Did not reach primary endpoint of reducing

ARR (p=0.075) !

However, the laquinimod and placebo groups

had dissimilar baseline MRI measures – after

reanalysis adjusted for baseline MRI there was

21.3% reduction in ARR, 33.5% reduction in

risk of progression in EDSS and 27.5%

reduction of brain volume loss (all p<0.05)

Safety

The most common side effects have been

occasional liver enzyme elevations which are

reversible

Summary

Laquinimod has modest benefit in RRMS

Nevertheless, it is well tolerated

Teriflunomide

Oral immunomodulator with anti-inflammatory activity

Inhibits pyrimidine synthesis in T cells and other

rapidly dividing cells

Results in reduced T cell proliferation, IFN-gamma, IL-

2, IgG1, and cytostatic action on B cells

Ongoing trials – TOPIC (CIS trial) and TERACLES

(teriflunomide added to interferon or placebo)

Teriflunomide

O’Connor et al. NEUROLOGY 2006;66:894-900

Phase II, randomized, double blind, placebo controlled trial in RR (157) and SP with relapses (22)

Primary end point # combined unique active MRI lesions - Treatment with either terflunomide 7 or 14 mg/day resulted in the significant suppression of 61.1% or 61.3%, respectively (p < 0.03 or p < 0.01)

Also fewer enhancing and new T2 lesions, trend in fewer relapses and less disability

Efficacy of teriflunomide on the primary outcome measure in the phase II study.

TEMSO

Trial involving 1088 patients with multiple sclerosis, 18

to 55 years of age, with a score of 0 to 5.5 on the

Expanded Disability Status Scale

Randomly assigned (in a 1:1:1 ratio) to placebo, 7 mg of

teriflunomide, or 14 mg of teriflunomide once daily for

108 weeks

The primary end point was the annualized relapse rate,

and the key secondary end point was confirmed

progression of disability for at least 12 weeks N Engl J Med. 2011 Oct 6;365(14):1293-303.

Randomized trial of oral teriflunomide for relapsing multiple sclerosis.

O'Connor P, Wolinsky JS, Confavreux C, Comi G, Kappos L, Olsson TP, Benzerdjeb H,

Truffinet P, Wang L, Miller A, Freedman MS; TEMSO Trial Group.

TEMSO

Teriflunomide reduced the annualized relapse

rate (0.54 for placebo vs. 0.37 for teriflunomide

at either 7 or 14 mg), with relative risk

reductions of 31.2% and 31.5%, respectively

(P<0.001 for both comparisons with placebo)

The proportion of patients with confirmed

disability progression was 27.3% with placebo,

21.7% with teriflunomide at 7 mg (P=0.08), and

20.2% with teriflunomide at 14 mg (P=0.03)

TENERE

Phase II trial comparison of teriflunomide with Rebif

Two-year, randomized, rater-blinded study that

included 324 people with RR MS

No statistical superiority was observed between the

Rebif and teriflunomide arms (7mg and 14mg) on risk

of treatment failure (confirmed relapse), the primary

composite endpoint of the study

Just in – Secondary endpoints (MRI activity) were

statistically significantly different (85% reduction in

Gad + lesions at 7 mg dose; P=0.0005)

Freedman et al. 2012. Neurology 78: 1877-1885

TOWER – Just Out

Phase III randomized study of 1169 RR MS

patients assigned to either 7 mg or 14 mg

teriflunomide or placebo

Teriflunomide 14 mg reduced relapses by 36.3%

versus placebo and 7 mg by 22.3%.

Disability reduced by 31.5% in the 14 mg group.

Don’t you get tired of DUMB

acronyms ?

D – Duke

U – University

M – Marching

B - Band

Teriflunomide Adverse Events

Elevated liver enzymes (rarely serious -> withdrawal)

Low WBC’s

Alopecia

Paresthesias

Possibly UTI’s, nasopharyngitis and diarrhea

Other rare complications include neutropenia, rhabdomyalysis, and possibly trigeminal neuralgia

Possible teratogenic effect

Pregnancy should be avoided as with other similar agents

Summary of Teriflunomide

Reasonable efficacy in RR MS

Reasonable side effect profile

Pending FDA – I don’t think they have officially

filed yet

BG-12 (Dimethyl Fumarate)

BG-12 is a fumaric acid ester with

immunomodulatory properties

Demonstrated benefits in animal models of

EAE

Fumaric acid esters may decrease leukocyte

passage through the blood–brain barrier and

exert neuroprotective properties by the

activation of antioxidative pathways (Nrf-2

cellular pathway)

DEFINE

Phase III, randomized, double blind, placebo

controlled, dose comparison in 1234 patients

with RR MS

240 BID or TID vs placebo

Both BG-12 doses were associated with a

significant decrease in the proportion of patients

who relapsed at 2 years compared with placebo

(P<0.0001)

DEFINE

Both BG-12 doses were significantly superior to

placebo in reducing ARR, the number of new or

newly enlarging T2 hyperintense lesions, and the

number of new gadolinium-enhancing lesions.

The reduction in 12-week disability progression

was 38 and 34% for the twice and three-times

daily doses, respectively (P<0.05 for both).

Gold R, Kappos L, Bar-Or D, et al. Clinical efficacy of BG-12, an oral therapy,

in relapsing-remitting multiple sclerosis: data from the phase 3 DEFINE trial.

Program and abstracts of the 5th Joint Triennial Congress of the European

and Americas Committees for Treatment and Research in Multiple Sclerosis

(ECTRIMS/ACTRIMS); 19–22 October 2011; Amsterdam, The Netherlands.

CONFIRM – Preliminary Results

Phase III trial in RR MS

BG-12 met the study’s primary endpoint, significantly

reducing the annualized relapse rate by 44% for the

twice-daily (BID) dose and by 51% for the thrice-daily

(TID) dose vs placebo at 2 years

Treatment also reduced T1 lesions, T2 lesions, and the

risk for relapse, as well as the 12-week confirmed

disability progression, although this latter finding was

not statistically significant

Safety of BG-12

DEFINE results indicated that BG-12 had a

safety profile comparable to that for placebo !

Results from a phase 2b study of BG-12 (120 or

240mg three times per day) in 257 patients with

RRMS indicated that adverse events occurring

more often with BG-12 vs. placebo were

abdominal pain, flushing, and hot flush

Summary for BG-12

Good efficacy

Good adverse effects profile

Not yet filed with FDA

Overall Summary of Oral Agents

for MS Fingolimod is FDA approved for relapsing MS

and is probably a first line Rx

There are no plans to resubmit cladribine for FDA approval in MS

Teriflunomide, laquinimod and BG 12 are oral agents that likely will be submitted to the FDA soon for consideration in relapsing MS Rx

Summary

A number of treatments are on the horizon for

MS

Where they stand in terms of preference with

existing treatments is unclear at this time

Only with time, further study and experience

will we be able to determine a rational approach

to the use of current and newer treatments

The complexity of MS treatment may necessitate

referral to specialists

Emory MS Center