CCR1 Antagonists for Rheumatoid Arthritis?

Some of our Thought leaders participated in a workshop recently, where the value of developing chemokine receptor antagonists for rheumatoid arthritis was one of the topics of conversation.  The overwhelming consensus of that working group was that the evidence doesn’t support further interest.

Actually, the minority position has some merit, and we think that it’s premature to pull the plug on the bathtub with the CCR1 baby still in it.  At least for CCX-354 (ChemoCentryx / GlaxoSmithKline).  Modeling with CCX-354, MLN-3897 and CP-481,715 accurately predicts that the critical PK/PD aspect of CCR1 antagonism is hitting a high enough level of receptor occupancy.  This is probably above 97%.  ChemoCentryx believes that they can achieve this level in their Ph-II rheumatoid arthritis trial using 100 mg b.i.d. or 200 mg b.i.d. doses.  Here’s what one of our Thought Leaders had to say:

 

“Now we come back to ChemoCentryx because they have done some modeling with the original study that we did and they made the compounds and everything and also for the CCR1 antagonist from Millennium that we tested.  I can mention this because they presented this at the latest ACR meeting as a poster.  They predict based on their modeling that our phase I clinical trial ten years with the Pfizer compound should have resulted in biological and clinical effect as it did.  And they also predict based on the modeling that the study with the millennium compound should have been negative, which it was.  This paper has now been accepted in the Pharmacology Journal.  It supports the notion that CCR1 is actually a good target but that it has been difficult to develop the right drugs that leads to sufficient levels of receptor occupancy to translate the effect into clinical improvement.  I was looking on clinicaltrials.gov and I think that the ChemoCentryx they are talking about 100 mg b.i.d. and a 200 mg b.i.d. in the clinical trial that they are running now.  It suggests to me that they are very conscious of the dose or they are being very conscious of looking for a dose necessary to keep high enough pharmacologic concentration to have the degree of blockade.  Now I am not sure if you guys know whether or not there is a cut off, say 90 percent or 95 percent or 98 percent blockade. We believe it should certainly be higher than 95 and probably higher than 97 percent and probably 24 hours a day.  And ChemoCentryx believes that they have reached that and that they can do this with the compound that is in the clinical trial at this moment.

Categories: IMMUNOLOGY, Rheumatoid Arthritis
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