Posted by Jeff Berk, BOLT International;
I’m sitting on a Southwest flight to Chicago. I was going to rant about TSA before getting on to the psoriasis portion of this blog. But since good sarcasm only attacks those who should be able to defend themselves, and I am with each day trying to offer ever more charity to mentally retarded government employees (but I repeat myself), let me just say… (Shame on you , Jeff. Take a deep breath…. And another)… okay… as for Ms. TSA Poster-Child 2011, no hard feelings here. What’s past is past. And I’m sitting in the aisle, martini in hand, with two thin, witty, charming, SHOWERED, women sitting next to me, chatting about the surreality we just went through.
Does anybody have any GOOD weiner jokes? Bush did it?! Laura took the photo?! Ha Ha!
So yesterday’s cactus, Myrtillocactus geometrizans, can actually be seen in the left part of today’s photo of Myrtillocactus geometrizans monstrose. Monstrosae are specimens that start to develop chaotic uncontrolled growth. Some of these can survive as cuttings, and have become viable species. This monstrose doesn’t flower, and its cousin, whose photo I shared yesterday, is not in “bloom” today.
Before I get on to tofacitinib and psoriasis, I just want to thank everybody on BOLT’s Melanoma Thought Leader Panel for their referrals. And I hope to catch up with you guys at the meeting. So a little context for today is that BOLT is gearing up a bunch of new panels that will publish over the next 6-8 weeks. We just published our 13th Multiple Sclerosis TLP yesterday, and we’re just about done with Crohn’s / ulcerative colitis. Later in June we’re doing an antithrombotics / antiplatelets panel, an osteoporosis panel and… a psoriasis panel. If you actually want to hear from our panelists before the statute of limitations runs out on their comments, feel free to drop me a note. And if you’re in Chicago this week, I take my martinis straight up, usually belvedere (but I’ll slum it) with blue cheese stuffed olives.
Okay, so a few thoughts on tofacitinib’s clinical development for psoriasis from our last panel (Dec 2010 I think). PS… we talk about topical vs oral use of JAK inhibitors, and other good stuff like that, in our reports. You know, the ones that we SELL so we can pay our Thought leaders and still afford to bring you this wonderful sarcasm for free.
- Pfizer has chosen to move into Phase III in psoriasis with only 5 mg BID and 10 mg BID dosing, presumably to ensure a cleaner safety profile in its label. This risky (and risk-averse) development strategy will box tasocitinib in to competing with methotrexate and other systemic therapies, rather than displacing existing biologic agents.
“I think that the side effects that we see at this point with the tasocitinib either in the rheumatoid arthritis trials or in the more abbreviated psoriasis trials there isn’t a show stopper there. There is a little bit of decrease in hemoglobin. That I think you can blow off. You are going to maybe because it is up you are going to have the heart rates go up a bit and there are going to be some increased deaths cardiovascular wise. Of course, you have got the lipids going up and so you have got to worry about that. It depends on how they do their risk management. If they go to a dose that comes clean in clinical trials and they don’t have any problems and they have not put people on it who are over say 65 or whatever and they say well we don’t want to put the people who are extremely obese on it because we don’t want to study it in that group. I don’t know what all they are…I guess I do know what they have got in their phase III exclusion criteria, but you are going to have to go look that up. If they generate a profile that does not show side effects they are going to be able to say we are better than methotrexate and this should be the first drug of choice when you are considering methotrexate or tasocitinib.”
“The thing that I am sure you are aware of is that the thing that is going forward in phase III is not the 15 mg dose. Only the 10 mg bid dose is going forward. And is that a safety argument? Now I have got to be really dodgy here because I am chairing the DSMB on this drug as it goes forward. I can talk about anything that is out there that I know is out there. What was talked about at EADV? Safety. Okay, and what was shared in a public forum? There were issues with both lipids and hemoglobin. And they are saying dermatologists won’t tolerate any abnormalities. They aren’t even going to look at that dose in a larger trial, which I think is (a mistake). Okay, now I am giving my opinion and I shouldn’t. So you didn’t hear my opinion. I don’t know how the pills are going to come out, but in reality physicians are going to have the option of going to a higher dose or dosing more frequently. That is just becoming increasingly difficult. You are right my license will cover doses that are given for other diseases, but the people who 696.1 don’t have psoriatic arthritis, oh they shouldn’t use that dose. The payers are going to say that? The payers are going to be the barrier. And is there a dose response? Well, that is back to where your comment that is not really your comment, and it is not just you by the way. So let me just say others have said the same thing, there is a dose response. Yeah, there is a dose response. So with that unofficially said, are you going to be disappointed with the phase III trial data? Yes.”
“To go into a phase III without a phase II at that dose that is a little risky. Yeah I am surprised.”
“Anemia will be an issue (for JAK inhibitors)”
“They also reported that their hemoglobin goes down and the lipids are an issue. So they clearly have some safety signals. They said that they were only taking forward the lower dose because of this in the psoriasis trials. So in my mind they are clearly worrying about those two safety signals. Yeah you are right. But we are used to this at least with regard to the hematologic situation again from the fumaric acid esters, but only the long term data will tell how relevant this data really is. With all Fumaderm patients we are used to closely monitoring in dermatology and have adapted those or interrupted treatment because this is a drug where we know it is just temporary effects. I am not sure whether this is proven to be the case for the Pfizer product yet. But yeah I know that they tend to be more careful now for psoriasis. “
“So what was very interesting to me was that the phase II trial were done at 15 mg twice a day, so a total dose of 30 mg and yet they say they are going to do the phase III trial at 10 mg twice a day. And so I wonder about whether or not the higher dose had side effects. I fully agree because during the last EADV there was meeting with Pfizer and I was surprised by their decision. Did they talk about the side effects from the phase II trial? Yes. What were the key problems? They don’t know at the moment, but there are at least two or three side effects but I don’t know right now.”
“So I have some American panelists who say to me that going to the lower dose is really going to decrease the efficacy and that they don’t believe that the oral JAK3 will be as good as Enbrel or Humira. My experience and my guess is the same as you.”
“They talked about the 15 mg dose at EADV but they also said that they are going forward with 10 mg dose for phase III. That makes me wonder. Me too. Me too. We had a full day of meeting on that. I think that drug is quite interesting. The problem is this drug is not completely clean of side effects. It is not as clean as the biologics. They biologics do not have end organ side effect profile. What you are expecting with anti-TNF is infectious complication, etc, which is an indirect side effect, which is not an end organ type of toxicity. With methotrexate you have the liver. With cyclosporine you have the kidney. With JAK3 inhibitor you will have don’t know what. So you have diminished end organ value, which is what’s behind it. Therefore, what they want to do is to switch from 30 mg to 15 mg. I thought they were going from 30 mg a day, in other words 15 mg twice a day, and I think they were going to 10 mg twice a day. We discussed that in depth with regard to the new protocol. But it is difficult for me to give you all the details for confidentiality reasons. Basically, and I told you previously when we discussed this drug I told you that my feeling is that finally they might be going lower. I gave you negative views but now I give you very positive one. Let’s consider that here we have a very specific new mechanism of action that we have a drug which is not as spectacular as ustekinumab or briakinumab or even Humira. But we need another type of profile, different side effect profile that is probably better than methotrexate. What would you say if I come with double blind comparison between, tasocitinib and methotrexate showing that clearly tasocitinib is better than methotrexate. I would say methotrexate is a very inexpensive generic drug that you know its profile because you have used it for a hundred years. Exactly. But still tasocitinib will be one-third the price of the biologic. One third of the price? Actually the price should be 1/3 the price of a biologic. Right. The positioning of taso would be at the best like cyclosporine, not bad efficacy, acceptable side effects if you have only a decrease in hemoglobin, we can deal with it, which is less dangerous than having the kidney destroyed which is possible with methotrexate. This might well be either first line or systemic. Right, well do you really believe that Pfizer would price it at a third of the biologic? I don’t know but this is what we told them. ”
“Will the degree of body coverage, or will there be other risk factors that will suggest to you, maybe this patient is not that aggressive, their psoriasis is not that aggressive, and so you would start with tasocitinib? Well, yeah, that certainly is possible. It is an oral agent. There is still a prejudice against injections. A lot of patients prefer pills. So there will be a few of those. But again because I think we are going to be going forward with what ultimately could be less than a most effective dose, I think we are going to be struggling with how do you justify putting this on the menu. You can do it? You could come in a lot less costly.”