Laquinimod. Will it become a new MS DMT

Someone asked ProfG "how can you be positive about Laquinimod when MD was rather negative?

Well the answer is simple....If we look at the effect of Laquinimod
on the relapse rate, then both ProfG and MD would agree that the influence of laquinimod is rather poor compared to other DMT on relapse rates.

In the words of ProfG "Laquinimod is a drug that does not have much effect on inflammatory MS disease activity, i.e. relapses and MRI activity (Gd-enhancing and new T2 lesions"

This is in response to the trial data

Comi G, Jeffery D, Kappos L, Montalban X, Boyko A, Rocca MA, Filippi M; ALLEGRO Study Group. Placebo-controlled trial of oral laquinimod for multiple sclerosis.N Engl J Med. 2012;366:1000-9

Vollmer TL, Sorensen PS, Selmaj K, Zipp F, Havrdova E, Cohen JA, Sasson N, Gilgun-Sherki Y, Arnold DL; BRAVO Study Group.A randomized placebo-controlled phase III trial of oral laquinimod for multiple sclerosis. J Neurol. 2014 ;261:773-83.

In both cases the reduction of relapse rate was very modest and in support of the dim view expressed by MD, both the European and US regulator did not approve laquinimod apparently on a risk:benefit exercise. 

However, it seems that the FDA wanted more data and so CONCERTO (NCT01707992was born, which is another phase III placebo verses two doses of laquinimod with over 2,000 people in the trial. This trial is massive and has over 600 people getting nothing....well OK they are getting placebo and are on a trial so they will do better than getting nothing because of the placebo effect 

However, should we ask the question about the ethics of this, as many people will undoubtedly accumulate disability as a consequence of the relapses that they have whilst on placebo and many of the people on active drug will relapse also. 

Some people will argue that people enrolled on the trial may not have had any access to any DMT and so with a 1 in 3 chance of placebo verses active is was worth it.  One of the MSers I spoke to had slipped through the DMT eligibility net due to NICE guidelines and this is why they volunteered. 

But should companies be able to get away with this?  Doing a trial against placebo is easier and cleaner and cheaper and suits them, but is it in the interests of people in the trial in  this day and age? 

Pharma are probably responding to the whims of the regulators, so they (FDA) are in part culpable. NICE complain about the costs, but in responding to regulators, pharma is having to spend millions of dollars in the drug develop process and Society bears the extra cost passed on.

There are currently over seven classes of drugs that have an impact on relapse rate and trial studies could be done to show they are not inferior to the other DMT. The company producing the laquinimod could have done a non-inferiority trial against their own DMT, so every one would be on a drug.

However, the risk here is that the new drug is inferior to the existing treatments and if showed this, it would probably be doomed. Hence the worry for laquinimod as it would be inferior in be terms of affect on relapses so many current DMT.

However ProfG was excited because of the apparent impact of laquinimod on the rate of brain atrophy, which suggests that it may neuroprotective capacity and slow brain shrinkage. This will be identified in CONCERTO

MD thinks this prospect would be exciting too.

ProfG said
" I am very impressed by the laquinimod phase 3 results. Why? Despite its weak anti-inflammatory effects laquinimod has an impact on disability progression, that appears to be independent of relapses and it slows the rate of brain atrophy. All this points to laquinimod having neuroprotective effects downstream of inflammation". 

MD thinks that this would be great and so agrees with ProfG. 
Then the question will arrive will you and take a drug and importantly will your neuro prescribe a drug that is beneficial in terms of slowing disability, but at the same time it is not stopping you from relapsing. Is the effect on disability better than could be 
achieved by other DMT that are more effective at stopping relapses.  However based on the published data it looks like a neuroprotective drug. In the beasties we have a lot of these now that don't inhibit relapse but do slow the accumulation of disability.

So will Laquinimod be beneficial for progressive MS.We shall see as there are currently trials in progressive MS (NCT02284568) and hope it works

We can also ask is there any merit of combining drugs? An immunomodulator and a neuroprotector. Well maybe there is some data already there 

Treatment of multiple sclerosis with combination of Laquinimod and Glaterimer Acetate.WO2013016684

They say that if you inject Laquinimod into EAE in mice with suboptimal dose of laquinimod and add it to a suboptimal dose of other DMT you get an better effect so this may be a way to use Laquinimod in combination with another DMT for MS. A trial will be needed 

So on its own Laquinimod may not be great at controlling relapses in MS, but it may have value in slowing the rate of progression in both relapsing MS (especially if combined with a DMT that inhibits relapsing disease) and progressive MS.

So there is no confusion. For MS you want a DMT that blocks the inflammatory response that drives relapsing MS and another to block the type of inflammation that drives progression. These may not be the same agent but they could be.