Rheumatology TLP #36 2012-08 Lupus / Rheumatoid Arthritis

Before we talk about lupus and rheumatoid arthritis, this is what Bartlett Lake, AZ looks like from the back of a Streetglide.  In July.  When the thermometer on the bike is maxed out somewhere beyond the 130 F line.  Those saddlebags are actually full of water, which gets POURED onto my dew rag every few miles.  It’s seriously like riding into a hair dryer right now.

 

 

 

We’ve just published Rheumatology TLP #36  2012-08 Lupus / Rheumatoid Arthritis.  Usual rules of engagement… Pharma, buy it.  Patients, email me and i send you relevant snippets.  And as always, a big “thank you” to the Thought Leaders who contributed their wisdom.

This report is broken into two parts.  The first focuses on unmet needs in the treatment of lupus, and the second part deals with all of those pesky oral therapies in development for rheumatoid arthritis (and the usual g’mish of other indications – psoriatic arthritis, ankylosing spondylitis, Crohn’s/UC, you know the drill).  But the focus is definitely RA.

The mechanisms, and drugs discussed in RHEUM 36 are:  BAFF, CTLA4, CD20, rituximab biosimilar, CD22, anti-IFN, RNP, IL6, immunomodulator, JAK, Syk, CCR1, IP10, CXCR3, BTK, PDE4, cathepsin K, AMG-811, blisibimod, ASP015K, sifalimumab, MEDI-545, fostamatinib, abatacept, ONO-4164SC, BMS-188667SC, apremilast, AVL-292, CT-P13, GLPG0634, GS-9973, CCX354-C, GSK-143, belimumab, baricitinib, LY3009104, INCB28050, tabalumab, SCH-546738 odanacatib, atacicept, IFN-K, PS372424, GP2013, ONO-WG-307, tofacitinib, ibrutinib, PCI-32765, PRT-062607, rontalizumab, tocilizumab, RN-486, GDC-0834, TL-011,  laquinimod, TP-0829, epratuzumab, VX-509

 

But in this blog…  you’re getting LUPUS.

If you’ve been reading anything to do with hematology/oncology lately you can’t help but be struck by the changing diagnostic and treatment paradigm.  We really no longer talk about “lung cancer” or “melanoma” or some other pathology.  The game today is targeting the underlying mutational status, regardless of how that tumor then presents itself.  So what does this have to do with lupus?  A lot, actually.  Two cases in point – one that we think will be a good treatment for lupus, and one that we think will be a bad treatment for lupus.

The approach that we like are any of those anti-IFN alpha or gamma molecules that are in the pipeline.  Finally, we have a measurable prognostic marker of bad outcomes, and a targeted approach that knocks down the culprit.  There are a few of them out there – MedImmune (AstraZeneca), Genentech, Amgen and Neovacs all have slightly different approaches.

What don’t we like?  And this comes with the caveat that it’s “sexy science”… but Lupuzor (ImmuPharma) isn’t going to work.   Lupuzor is an antigen-specific peptide against U1-70 that acts as a decoy.  Now, there are some diseases, e.g. idiopathic thrombocytopenic purpura, bullous pemphigoid or pemphigus vulgaris, where there is one antigen that drives the disease, and targeting this antigen makes sense.  Our Panel views lupus as being a global defect in many different B cells (and probably others).  Thus, while they think that Lupuzor is scientifically interesting, our Panel, does not believe that taking out U1-70 alone is going to translate into a clinical benefit.  Here’s one Thought Leader’s comment:

 

“Yeah, I know a lot about Lupuzor.  I am not at all enthusiastic about Lupuzor.  So this is a peptide.  Let me disclose I have been working with this peptide in my lab for totally different reasons.  So the person who discovered this is Sylviane Muller.  Peptide derived from U1-70.  She is a world class scientist, really, really good, very thorough so I have a ton of respect for her.  However, I find it hard to believe that a peptide that is infused so infrequently is going to have any benefit in this disease.  I just don’t see it happening.  Let me just be clear.  This is supposed to be like a decoy?  Really good question.  So this peptide is derived from the U1-70 protein, which is an auto-antigen.  The thought was that this was working as antigen-specific therapy, kind of like desensitization in allergy shots, but it appears that it does not work that way at all.  So we have actually made a tetramer that has U1-70, this peptide in it and it is definitely stains a unique subset of T-lymphocytes so it does appear to be antigen specific.  She is arguing that it works as some other completely different immunomodulator that is working through some other receptor that they have some clue about what it might be.  But here you have a peptide where the mechanism of action is completely unknown.  The mechanism most of us had thought it worked through which was antigen specific inhibition none of us think that will work in lupus because there are so many autoreactive B and T cells against so many different antigens.  There is no way taking out just one of them is going to do anything. I forget how frequently they are giving it.  It is really infrequent isn’t it?  I just don’t see how this is a viable drug and I am amazed that they took this into late stage.  They are in phase 3 right?  I believe they are.  I am amazed.  I look at this and think, okay, let’s say it hits its primary endpoint how are you possibly going to market this?  You are going to take it to doctors and say we don’t know how it works, it is a peptide, but go ahead and give it anyway.  I just don’t see how that is the case.  So they have tons of really good data in mouse models.  The human data, I wasn’t that impressed with the published human data in earlier trials.  Frankly, I am surprised that they got any investor to agree to take this to phase III.  I am very unenthusiastic about this drug.  How do you really feel?  I won’t sugar coat it.  The thing about this is I really, really like Sylviane and I have a ton of respect for her as a scientist but I just don’t see where this drug makes sense. Let me just push back. What are they seeing in the mouse model?  Even if you don’t know how it is working, set that aside…  In mouse models lots of things have worked and then when they have gone into human clinical trials they haven’t worked.  They were looking at antigen-specific tolerance as the mechanism and in humans it is going to be virtually impossible to show that.  The problem with lupus is it is a global defect in many, many different B cells and probably other cell types.  So to think that let’s say you have an immune repertoire in which you have say one out of every 50,000 cells is the bad cell and you take out just that one bad cell.  The problem with lupus is that you have one out of 50,000 against U1-70 and one out of 50,000 is against histone.  Against Smith, SSA, SSB, RNP, you have all these different ones.  So how can taking just one of those out completely disrupt the thing.  It is like taking out one of the worst al-Qaeda guys.  You are going to have a whole bunch of others still around doing bad things.  Maybe that is not the best analogy.  Whereas for other diseases, I think, if you were to do this in a disease like ITP or bullous pemphigoid or pemphigus vulgaris where there is one antigen, one molecule drives the whole disease and you can get rid of that that makes sense to me, but lupus it doesn’t make sense to me.  It is really just the overall scientific rationale for the drug that I am not enthusiastic about”.

 

Categories: ankylosing spondylitis, IMMUNOLOGY, lupus, psoriatic arthritis, Rheumatoid Arthritis, rheumatology
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