Posted by Jeff Berk; BOLT International
So I don’t post as often as I’d like. Read between the lines…
The Lord’s great “GRACE” test.
I’m a guest in my own home.
Will they EVER leave?!
BOLT International published our 33rd installment of our Rheumatology Thought Leader Panel a couple of weeks ago; sort of just in time for the upcoming American College of Rheumatology meeting. We try to run our “Fantasy Formulary” exercise every year, but we didn’t do so in 2010. Thus, Rheum TLP #33 gave us a chance to compare the kind of new therapies for a broad spectrum of rheumatic indications (rheumatoid arthritis, lupus, psoriatic arthritis, osteoarthritis, ankylosing spondylitis, osteoarthritis, gout, vasculitis, and some minor indications) to the survey we ran last in 2009. Needless to say there were some dramatic changes.
In 2009 the top ten drugs that our Panel (US + EU) felt were going to “change the world” were:
To be clear, there was a fair amount of diversity in the responses of our European and American Panelists in 2009. And we received very different top-ten lists from each side of the pond again in 2011.
I obviously want my Dark-Siders (you Pharma Lurkers know who you are) to buy Rheum TLP #33, so I’m not going to share any of the quantitative results in this blog. I’ll have the report posted on BOLT’s “Buy Now” page this weekend and you can just put it on your credit card. For you TEA Partiers, you’ll be supporting a dyed-in-the-wool capitalist. And for you OWS-ers, you’ll be deficit spending; which is just what keynesian mental midgets, barry hussein, paul krugman and who could ever forget, robert reich want you to be doing. I know, I know. I better watch what I say or else barry will drop a Kamikazi (the word is capitalized as a sign of respect) drone on my house. Well if it will also get those guests to finally leave… (Get it? “Read between the lines”? I’m a guest in my own home? At this point I’m down with whatever it takes to get them to leave!)
Anyway, instead of the highly valuable data tables and analysis that you’ll find in BOLT’s Rheumatology Thought Leader Panel #33, I’m sharing a section of the section on IL-17’s future in the hands of the rheumatology community.
IL17 (AIN-457/secukinumab/Novartis; ixekizumab / Lilly, AMG-827/Amgen)
- New class, moving into Ph-III
“At the end of the day I don’t know whether IL-17 is going to reach the market or not but they are certainly the next closest one. They are moving into phase III studies now. They are from a different class. Will they offer us anything above and beyond what we have now? I think that remains to be seen”.
- Best efficacy to date in psoriasis (Amgen AMG-827). Then ankylosing spondylitis (secukinumab), then psoriatic arthritis. RA results have been less impressive. AS is highly driven by TH-17, so it makes sense that an IL-17 inhibitor should work in this disease. Amgen’s receptor antagonist has shown better results thus far in psoriasis. Amgen claims that this is due to blocking all IL17, not just A or F. However, notably, Amgen has discontinued their RA program because of lackluster results.
“So the top three on your list are all IL-17 molecules? Right. And then my obvious interest in them amongst your panel has to do with a pretty deep knowledge of how effective they are in psoriasis. Thus may keen interest in seeing how they do in psoriatic arthritis and ankylosing spondylitis, which is my sort of bent. I listed Amgen’s first because I am extremely impressed with their psoriasis data, and maybe this is brain washing, but they do emphasize the point that as an inhibitor of the receptor they are capturing the gamut of IL-17 molecules and not just A or F or what have you. So I am particularly interested in that. They did, as you know, call a halt to their rheumatoid program because of lackluster results. So to that extent it is not going to have quite the broad appeal as if it had a great response in rheumatoid disease. But still I think it is going to be a very interesting group of agents. And then the other thing that goes along with it is the fact that the safety profile I have seen so far looks pretty darn good. There is a little bit of neutropenia, and obviously the same issues with serious infection that any of the other agents have, but they don’t have these special niche side effects like cholesterol and LFTs with the IL-6 inhibitors and JAK inhibitors and the problem of the particular opportunistic infections like you have with the anti-TNFs or the MS issue like you have with the anti-TNFs”.
“We discussed this recently at a major conference, but apparently there was a press release by Novartis saying that anti-IL-6 didn’t work in ankylosing spondylitis. So that appears to be public domain. It may have also been the case with Aventis. I am not sure. So surprisingly or not surprisingly, it is a different mechanism of disease in ankylosing spondylitis compared to rheumatoid arthritis. So if you look at the rheumatoid arthritis, glucocorticoids really have a lot. In ankylosing spondylitis you have to give grams of prednisone until you see something. So the pathway of inflammation apparently is quite different in AS compared to RA. And luckily for the patient anti-TNF appeared to attack part of pathways relevant in both diseases while IL-6 may be different here. This is similar to the anti-IL-1, which has some effect in rheumatoid arthritis but also no affect at all in ankylosing spondylitis. So it is a different disease, and in ankylosing spondylitis my third favorite drug might work, this is IL-17 directed therapy. And is that because the ankylosing spondylitis is TH17 driven? It looks like it. Basically you have to do the trial. And some data have come out with regard to anti-IL-17. I don’t know if they will be presented at the ACR. I don’t think so because the ACR abstracts are already out. You may have seen them already. So that could be a good target in ankylosing spondylitis where the disease might be more IL-17 driven rather than IL-6 driven. There is a tremendous medical need in anti-TNF resistant psoriatic arthritis and ankylosing spondylitis. These might be diseases that might be targeted by anti-IL-17. Obviously there are no data yet, at least not that I know of, but since there is such a need, and unfortunately, apparently otherwise they wouldn’t have abandoned the trial, anti-IL-6 didn’t meet that. So we are desperately looking for a second biologic and that could potentially be secukinumab”.
“And I haven’t heard either of those groups (Novartis, Lilly) pulling out of RA. No, and that is only because they are probably not as smart as Amgen in that regard because clearly there are going to be a whole bunch of drugs out there that work better in RA than the Novartis and Lilly drugs. Is there a difference in activity you are seeing with the IL-17 inhibitors and ankylosing spondylitis? Only from that one trial that I think we already discussed. Do you have a mechanistic reason why there would be a difference? Between RA and the spondys, sure. I think the spondys are more driven by TH-17 cell pathway mechanism and I think that this drug is more targeted in that arena”.
“I am not very excited about IL-17 right now in rheumatoid arthritis. I am very excited about IL-17 blockade in ankylosing spondylitis. I think IL-17 blockade in AS is particularly exciting, not for RA but spondylitis based upon the early data to date. What is different about the pathophysiology of ankylosing spondylitis that accounts for the difference in efficacy that is being seen? I don’t know that I can tell you what. From a bone standpoint it makes a lot of sense why IL-17 blockade would work in AS, but we don’t have any bone data. It is all signs and symptoms data. Why it would be better in AS than RA, we have other drugs that don’t work fairly well in AS but work in RA. This would be the first that I can recall that works in AS and not rheumatoid arthritis”.
“I think I saw better results in psoriasis trials and better results in ankylosing spondylitis trials than I did in RA. Is it really worth pushing one of these drugs for RA? I think it is a good question. Certainly, the drugs will first have their approval in skin so they will be approved in psoriasis. And then the question is do you want to try to get psoriatic arthritis and ankylosing spondylitis and RA as part of your lifecycle management or do you just sort of say no we are done. I think to that end, each company is going to take a different strategy moving forward. And some will go for RA and some will not.
“Maybe antibodies which block IL-17. I have always thought that was likely to turn out to be an important approach. I would probably go for that. When I push my panelists as to what indications they all kind of squinch their faces and say we thought RA but that doesn’t look that good. So I hear ankylosing spondylitis, I hear certainly the derm applications. Frankly I don’t understand why but I accept the fact as enough people have said to me the results in ankylosing spondylitis look really good. But what is the difference between that and RA in terms of physiology that would make an anti-IL-17 be an effective AS drug but not RA? It is a separate set of joints and we know very, very little. We have very little understanding of why certain joints tend to be attacked in one condition than in another condition. I still think it may have a part to play and I haven’t rule out for use in rheumatoid yet either”.
“I think of three competitors; Novartis, Lilly and Amgen. Has anybody distinguished themselves in the IL-17 space yet? Not so far as I am aware”.
- Will need a biomarker to identify patients with TH17 driven disease.
“I think if this drug class is going to be effective…
Oops… The Free-Meter just expired…