Actemra / RoActemra (tocilizumab; anti-IL6) East and West

Posted by Jeff Berk, BOLT International;

I spent the day yesterday writing blogs.  Just kidding.  It was too nice of a day in Paris to do anything other than skate the city.   So I zipped to-and-fro for 6 hours.  Until my calves were bleeding like a rare steak.  Paris is really laid out well for skating.  Not too hilly, opulent beauty (must’ve been nice to be a “Loiue the Something-Teenth” back in the day), and while I’m not that big, my blades and I do have more mass than the things that the taxi drivers are in.  So I win on collisions.  While Rollerblading I noticed some stark differences between living in Arizona and Paris.  For instance:  In Arizona they’ll stink-eye you if you leave your dog poo on the sidewalk.  Not to worry, though.  I have good aim and the actual contact surface of a skate wheel leaves some room to maneuver.  (Segue to) Here’s today’s cactus flower.  I have no idea what kind this is.  It’s not any of the usual suspects.



Okay, so back to differences between Europe (yes, I just expanded from Paris to all of Europe) and the States; this time in relation to Actemra (tocilizumab; Roche / Chugai)  According to BOLT’s Rheumatology Thought Leader panel, there are two aspects of Actemra’s profile that are viewed differently on each side of the Atlantic.  The Europeans are less accepting of the IV dose than the Americans; although US payers are starting to balk at reimbursing physicians, so there will over time be less incentive to run infusion clinics.  But because there is only an infusion available, the European sales have been below Roche/Chugai’s expectations.  The other difference is that the Americans are more worried about elevated lipids than their European counterparts.


“The point of view on tocilizumab is a little bit different from the American colleagues and we always discuss it at the top new therapies in April and very interesting background of rheumatology or medicine you have already formed your view on new drugs.  But that is just an interesting scientific discussion.  Before we move on I want to capture that.  How are the Europeans looking differently at IL-6 inhibition than the Americans are? There are two reasons.  The negative reason is people here do want to have subcutaneous injections much more than infusions.  As far as I know, more American patients accept infusions for whatever reason.  The second thing is the side effects are the positive side for tocilizumab.  The side effect is moderate elevation of cholesterol levels, it is not being discussed here as a problem at all.  And there is a little bit of a neutropenia, nobody has seen really severe forms.  It is also not much of a problem.  The potential side effects will it drive drug into a certain direction.  On the other side, because of this only infusion option sales here are much less than expected.  So that is what the Roche or the Chugai people tell us.  Do I have problems with the drug?  No”.


“The problem of tocilizumab, or Actemra, is I think more the problem of just getting it as an infusion, at least in Europe, than the side effects.  As soon as it is available in subcutaneous form and the trials are running most likely it will be a first line as with anti-TNF inhibitor in Europe”.


“I would like to see tocilizumab licensed as subcutaneous”.




Actemra (tocilizumab) will have an extremely hard time moving into a 1st-line role because of its label.  As it is, patients have to fail at least two anti-TNF agents, and then compete with either abatacept or rituximab for next-line use.  Within a year, the drug will also have to contend with orally available tasocitinib.  Other limitations to tocilizumab uptake have been the iv dose form (which costs the payers between $100-$400) and having to monitor for the increase in cholesterol; which is probably going to be a class effect for all drugs that impair the IL-6 pathway.  Unless Roche gets a 1st-line indication, based on showing at least non-inferiority to anti-TNF therapy on radiographic progression and signs-and-symptoms, not even the arrival of sub-q dose form (2012/early 2013 in the US) is going to help.


“Comments from other US-based rheumatologists have been that tocilizumab uptake has been pretty slow.  What is your personal experience? We use it.  Because of its label, we are restricted obviously after you fail a TNF.  We certainly use it before rituximab.  I think it is a pretty good drug actually and it works pretty fast.  We have obviously a greater experience with abatacept because it has been around longer.  I think personally its use is only going to increase over time as rheumatologists become more comfortable with the lipid issue.  If they can get their label changed I think will really help them.  If they can’t get their label changed then in the US the uptake is going to be less than 10 percent because that is where their refractory market is.  Is the IV formulation what is holding them back? No.  I think what is holding them back is the fact that they can’t be used until you fail another biologic.  If you go on anti-TNF 50 or 60 percent of those patients are going to do pretty well and probably not have to switch.  So you are dealing in with like a funnel.  So you are on the other side of the funnel now and you are basically batting it out with other TNFs and abatacept and rituximab in a market that is slowly expanding, but not as big at the end of the tube as it is at the beginning of the funnel.  I think that is the problem they have”.


“What has your actual in the field experience been with tocilizumab?  Where are you using the drug if any place? I am using it in patients who have tried and failed a TNF inhibitor.  The drug works well there.  It is a good drug.  However, it does require intravenous infusions once-a-month and that is a bit of a pain for guys like me who don’t have their own infusion center.  And I do have to monitor cholesterol which is something I don’t have to monitor with other products.  It is not that big of a deal but it does affect the way many of my colleagues approach the drug”.

“I will tell you I right now have no experience with anything related to IL-6 inhibition.  I think it is being used very sparingly and I am not aware of anyone in our clinic who has been using it at all.  Why the limitation? I think because there are so many other drugs that are already further ahead.  So typically we cycle through at least two of the TNF inhibitors and then go to CTLA-4 IG or Orencia and then either think about an IL-6 inhibitor or rituximab is the next line of therapy.  I just don’t think there are that many patients who are making it all the way through all of them”.


“The uptake has been relatively slow here and that somewhat surprised me and it surprised some of my colleagues because the efficacy of this drug is quite good.  I think the concern is the cholesterol elevation and is that going to translate into long-term increased cardiovascular risk, which we all really know is two to three times that of the general population, and I don’t think anybody knows that.  The cytopenias, the liver function studies, certainly this drug doesn’t have the safety that an anti-TNF drug does, and I don’t see it replacing it despite the efficacy studies that were presented.  But I see it perhaps moving in on abatacept and Rituxan as second line behind TNF.  So your comment was that the uptake is slower? It is slower than what we anticipated.  Of course, most of the data originally came out of Japan, moved to Europe and so on.  But even the uptake in Europe has been slower than what I think they anticipated.  So what is it going to take, if anything, for Genentech to be able to turn it around?  What data are they going to need to provide you or what sort of repositioning are they going to need to make? I think they are going to continue to hound on the efficacy that it may be a better drug than anti-TNF from an efficacy standpoint and turning off radiographic progression as well as symptoms and signs”.





It will take Roche through 2011 to complete the sub-q trials with tocilizumab, and then it will take another year to register the drug.  The US launch should therefore be late 2012/early 2013.  The launch in Germany is expected in 2012.  Timing is thus very similar for tocilizumab sub-q and abatacept sub-q.  The efficacy profile for the sub-q is similar to the iv.


“Still the most interesting part of this subject is that the subcutaneous work, specifically in Germany because the people have to go to work as in the US they don’t like to come to the infusion base because then they have problems with their employer.  And the other side, see the good effects of tocilizumab so they will be happy if they can get it subcutaneously.  When will that be available in Germany? When the study results would be nice to have it in 2011, but I rather guess it could become 2012”.



“The more interesting thing is, and that might be at least for Europe the key thing to happen in the future if the subcutaneous form of tocilizumab is as effective as tocilizumab intravenously.  If this happens then this is a true challenge for all the TNF inhibitors”.


“Right now IL-6 from Roche, tocilizumab is moving forward their subcutaneous version.  Is the limitation on tocilizumab going to be the IV form? In other words, are they really dependent on the subcutaneous to become competitive with Enbrel and Humira? I think so.  When do you think that is going to be available? The studies are being done now.  So it takes them a year and a half to do the studies and then a year to register so at best I think you are talking about 2013”.


“In terms of timing, which will be available first to you, a subcutaneous Orencia or a subcutaneous RoActemra? I can’t tell.  I think both of them are pretty much at equal pace because I saw the presentation.  I think both companies, especially Roche will work very hard because they have a very successful drug with RoActemra and as soon as it comes out subcutaneously it will make a tremendous difference.  I think they are going to work very hard to make that available very soon”.



“What I saw there was very encouraging.  Basically, it was of course no surprise, they have the same efficacy as the IV drug”.




Payers in both the US and Europe are the primary driver for development of the sub-q dose.  The cost of administering an IV are between $100-$400, according to rheumatologists our Osteoporosis Thought Leaders.  Germany has recently dropped the iv reimbursement to about $2 (that’s not a typo), which strongly encourages physicians to switch to sub-q delivery.  The rest of Europe will soon follow.  Roche must have the sub-q for tocilizumab if they want to keep Actemra from becoming a 3rd-tiered biological, behind anti-TNF and either abatacept or rituximab (in Europe).  Once Pfizer launches tofacitinib (tasocitinib), the need for tocilizumab sub-q will become even more acute.  Finally, Roche needs a sub-q dose of tocilizumab to mitigate the infusion site reactions reported in the clinical trials; although we note below that the real-world experience has been a lower frequency and severity of adverse events.


“The advantage for both Orencia and for Roche is that with the pushback from IV therapy from a payer standpoint, having subcutaneous treatment may offer them some advantage.  The disadvantage will be for patients who are on Medicare D but that may be changing with the healthcare law anyway.  So from an efficacy standpoint subcutaneous therapy is going to offer nothing above IV for either of those molecules.  It will offer less risk for Roche of an infusion reaction potentially.  For BMS infusion reactions don’t occur with Orencia anyway.  So their major advantage is going to be potentially from a commercial standpoint and with regard to payer issues.  We do know in the US that there are now payers that are third tiering Remicade because it is an IV therapy.  So subcutaneous treatment tends to be more preferable from a commercial and managed care standpoint”.


“In Germany it is very easy because currently we get for an infusion less than two dollars because we get a lump sum for each patient coming in and if a patient gets ultrasound, infusion or whatever the health insurance companies don’t care.  We just get a lump sum for a quarter of a year it could be like 40 dollars or something.  It varies a little bit from state to state in Germany.  We recently we got up to 100 Euros per infusion.  But for the next quarter on we will get less than 2 dollars.  So that immediately tells you that there is a strong incentive to change from IV drugs to subcutaneous because it is by no means cost effective to have an infusion clinic anymore.  Now this is quite different in some other countries.  I know that because the way their system is set up you can generate money, either by the pharmacy, because the pharmacy gets a bargain price from the company but charges the health insurance company that regular price.  The difference between regular price and rebate you can then split between the pharmacy of your hospital and between the institution.  What country are you specifically thinking of? I think it is so in Austria and potentially Britain I think.  But that also may change because of course the health insurance companies find out and they don’t like this system very much because they would like to pay the less amount right away.  So in Germany it is very clear that if you want to have a successful drug you have got to go for subcutaneous drug unless it has a very, very special feature which you cannot get otherwise.  Actemra would be much more successful in Germany if it were to be delivered subcutaneous.



“How will the pharmacoeconomics work?  What impact will that have on the German physician? That is a topic which can’t be answered right now because, as you know, our Minister of Health has decided to test the pharmacoeconomic basis of the biologics right in this month.  There is a specific institute that is investigating this.  Three of the top sellers of all drugs in Germany are TNF inhibitors and they have to save money.  It might get to the point that the company has to reduce their price forced by the Ministry and then a lot of things will be different.  But this question for Germany cannot be answered right now because of our pricing system”.

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