Posted by Jeff Berk, BOLT International;
Short and sweet today… ALLEGRO results were presented at AAN. Laquinimod produced a 23% lower relapse rate vs placebo in relapsing remitting multiple sclerosis. While “statistically significant”, this result is a yawner (in my humble opinion).
I recently spoke with BOLT’s Multiple Sclerosis Thought Leader panel about the pros and cons of laquinimod. Here’s (some of) what they had to say:
- As of today, interferon remains 1st-line therapy for RRMS, but people hate the constant injections and flu-like symptoms. One of our Panelists, who is an ALLEGRO investigator, believes that laquinimod is as effective as fingolimod in decreasing relapses, and is much safer. He sees this oral therapy as the first that will be used 1st-line. Most of our panelists however were less enthusiastic, and while agreeing that laquinimod does have a reasonable safety profile, disagrees that it will be as effective as fingolimod. In preliminary Ph-III disclosures Teva says that laquinimod statistically significantly reduced relapse rates and it also reduced disability progression. The drug is fast tracked and we expect approval shortly after the complete Ph-III results are presented in April 2011.
“But nobody wants to be injecting these interferons or GA (gadolinium acetate; Copaxone) all the time. No they don’t. They are sick and tired of shots. They are sick and tired of flu-like symptoms. You have an occasional patient who says I am okay on this stuff, but most patients say boy you have got an oral medication, I want it; except when they hear $48,000 a year then they are not interested.
(Laquinimod cheerleader): “It is NOT less effective. Believe me, it is not. It will be easily as good as fingolimod (Gilenya). It could be better. So we don’t know yet. We really have to see the dataset before we can talk about that”.
“His premise is that even the data that we saw in the phase II trial is really under representing or understating the benefit that laquinimod is going to have in the general relapsing remitting population. I think that is a challenged design and it may under-represent what is going on. Does that give more credit to laquinimod? Theoretically it could. Again, this will be best answered when there is an active comparator”.
“I know the laquinimod better than the teriflunomide. Let’s go with that then. But I must preface with saying that even though both are likely to see approbation by the FDA I don’t see them as monotherapies. I see them actually ultimately failing to penetrate the market in a significant way until they can be shown to have benefit in combination other therapies. I am aware of the teriflunomide combination trials. I wasn’t aware that they were pushing laquinimod as a combination. No, they are not. I think that is really a criticism of the Teva development”.
“What we know is that they succeeded, at least, with the higher dose in phase II, and succeeded well enough to move into phase III”.
- Our cheerleader says that Ph-II results with laquinimod are probably understating the drug’s efficacy because the trial recruited patients with more active and aggressive disease. They all had enhancing lesions on their baseline MRI. Using a similar inclusion criterion, Copaxone in a 9-month study showed only a 35% reduction in enhancing lesions, compared to the 60% seen with laquinimod. The counter argument is that activity is good for recruiting / enriching a trial because patients who are more active on MRI will be able to be differentiated between an antiinflammatory drug and placebo. But MRI activity doesn’t predict relapse, so it doesn’t signify a group of patients with more aggressive disease. The Nay-Sayers point out that the early phase II trial showed that there was a modest effect on MRI with no effect at all on relapse and now what Teva is touting is that they did have a modest effect on relapse, based on a better effect on EDSS. But since the recruited population is not (according to the nay-sayers) at greater risk of relapse than comparable competitor trials, EDSS is not going to be predictive in a population that has such a low risk of relapse.
“Laquinimod came from obviously a drug that caused problems in clinical trials, that was the linomide. And with that issue we had a mechanism that looked very promising but a drug that created undue side effects. So was there something that we could do to the molecule to change the side effect or toxicity side of it and still maintain the mechanism? I think that is what laquinimod was supposed to do. The early phase II trial showed that there was a modest effect on MRI with no effect at all on relapse and now what we are hearing is that they did have an effect on relapse. It was modest. What is being touted is the better effect on EDSS. I don’t know that we can really say anything about EDSS in a population that has such a low risk of relapse. I think that this is where the marketing is going to spin this a little bit with laquinimod. One of the people who is most positive about laquinimod focused his comments on was he tried to suggest that the patients who were included in the laquinimod phase II trial had more active and more aggressive disease than what we typically see. I don’t have any of the data on laquinimod. So I don’t know that they can really be more active. Already the teriflunomide group was more active than either of the cladribine or fingolimod groups because the placebos had still more than half an attack a year. In either the fingolimod and cladribine studies the relapse rates for placebos were the order of about 0.3, so one attack every three years. They were really a low risk group. So the teriflunomide group was a bit more active. I don’t know at all what the laquinimod group was like. So we are splitting hairs here on these studies. You want to try to get the patients who are most active into your study because they are also the most informative. But in every study where we have looked at the patients who have and who have not had enhancing lesions or had or not had higher relapse rates coming in the various drugs work the same. So there is no added benefit of having activity. The only added benefit is that those are the patients who are most likely going to have more events and drive your efficacy measure because they are going to have the events on the placebo side and then you will have something to measure against. Whether or not they will respond to the drug I think is not the reason we look at that. It is more to load the studies with informative patients”.
“Laquinimod when you look at the phase II studies it didn’t look all that impressive. The reason being because the patients they recruited for their studies were patients who had to have an enhancing lesion on their baseline MRI. That recruits a much more active and aggressive group of MS patients. When you look at the drug in that group of patients you underestimate your drug effect. So basically with laquinimod what I can tell you the magnitude of a decrease in relapse, which I cannot tell you right now, I am sure it will be every bit as good as fingolimod”.
“Most of my panelists have not seen that kind of positive response from laquinimod yet. So most of them are saying, you know it is going to be an add-on to interferon… No, that is because they don’t know. That is because they are forgetting. Remember when you say, okay, in order to be in this study you have to have an enhancing lesion on your baseline MRI. Remember the Copaxone nine-month clinical trial where they looked at MRI? Yes. They used the same inclusion criteria for that study and what they saw was that they had about 35% decrease in enhancing lesions. Then when you looked at the results of the PreCISe study, you basically had a 75% decrease in enhancing lesions in a population of patients with much more representative RRMS. So that is the magnitude of difference that you get by using that patient population. Now with laquinimod we saw a 60% decrease in the median frequency in enhancing lesions in the phase II trial recruited using that very active population. Then what you are looking at is, again, a difference in the trial population. So basically if you have a single enhancing lesion on your MRI it predicts that you will have a higher frequency of relapses, a greater progression of disability, a greater frequency of new enhancing lesions and you are really culling the most aggressive of the most aggressive patients. So it is not too hard to imagine like an aggressive cancer, when you have an aggressive form of disease it requires much more aggressive measures to bring it under control. Interesting. The same is true here. So what I am getting at when you recruit that patient population, with aggressive disease, it is much harder to bring them under control and so you underestimate your drug effects compared to the general population”.
“I guess his comment though was that if you look at what people are using for inclusion criteria that all of the laquinimod patients had to have an enhancing lesion on their baseline MRI. Does that in any way in your mind signify a more aggressive patient population? No, it signifies a more active patient population. And what is the difference between those two words? Active means that the disease is ongoing and has activity. Those are the patients that I would select if I wanted to show a prominent response. Whereas patients who are in a phase where they are not so active you are not going to be able to show differences on MRI at least if you don’t select the activity on MRI. So it is just a question of whether you want to spend your efforts at the beginning to select patients who are likely to be beneficial for your endpoint or not. So, I don’t think it has anything to do with aggressiveness of the disease”.
- Most of our panel disagree that the patient population included in the laquinimod trials have more aggressive disease than recent or ongoing Ph-II or Ph-III trials for RRMS. The crux of the nay-sayers argument is that laquinimod’s predecessor, linomide, was also a powerful reducer of MRI inflammation, but had no effect on clinical outcome. At this point they are not willing to say anything about laquinimod’s clinical robustness until they can see larger data sets. This phase II trial was large enough to demonstrate “something”, but it had a 44% reduction in MRI active lesion development and the “30 some odd”% reduction in relapse rate is a modest effect.
“Linomide was a very powerful reducer of MRI inflammation with no effect on clinical outcome. Laquinimod is a derivative of linomide. Its anti-inflammatory effect is measured by gadolinium enhancement follows linomide effects. I don’t particularly think at this point that one can say anything about laquinimod’s clinical robustness until we see larger data sets. I think this phase II trial was large enough to demonstrate something, but it had a 44 percent reduction in MRI active lesion development and the 30 some odd percent reduction in relapse rate that is the modest effect”.
“We will have the first view from the trial probably early first quarter of next year because their data is locked until the end of December for the placebo controlled trial. The second trial has a comparator arm, but it is not an efficacy comparator. The market is obviously going to look how does laquinimod work against the back drop of Avonex? And if laquinimod cannot beat Avonex or is worse than Avonex even if it were effective against placebo then that is a very big problem. Right. I do think if laquinimod comes out with a 25 to 30 percent efficacy it has a very significant problem. It may have to demonstrate in the early patients to have some efficacy in that population”.
- Laquinimod requires no added monitoring for safety. This strongly differentiates it from fingolimod, and from its predecessor, linomide. That drug was discontinued due to fibrotic reactions, but this has not been a problem in patients on laquinimod.
“So laquinimod, at least potentially has the benefit that it has lower safety issues around it”.
“The other huge aspect of the drug is it is a very safe drug and you don’t have to monitor anything. There is really no signal for significant adverse events”.
“If those show similar effects as seen in phase II studies and nothing materializes like the linomide type of consequences. That has always been the fear that laquinimod is going to end up having some of the fibrotic reactions that were seen in linomide that killed that agent. It hasn’t materialized yet.”
- Our panel consensus is that laquinimod should be studied in combination with interferon or Copaxone, as it is not active enough on its own. Teva has not yet begun a combination program, which is going to put them at a disadvantage vs. teriflunomide; which will have combination data in about a year.
“Since we are doing immunology for the laquinimod American trial in addition to doing side study immunology, I have been able to keep up with a lot of what is going on in at least the rest of the literature about it. We have done a few little experiments on our own that are not covered by any confidentiality issues. I can only imagine that it will be a matter of just money and time before Teva allows someone to go forward and officially validate that laquinimod won’t kill you in combination with interferons or even Tysabri”.