Posted by Jeff Berk, BOLT International;
Have you been missing your cactus photo? Here ya go.
Blogging today from Charles de Gaulle. Here’s a shout out to Guilhem Bousquet. Nicest Frenchman I know. Pretty good oncologist to boot. Il a été longtemps, mon ami! Thank you for the tour of your city.
So today I’m going to transition from myeloma, malignant bone disease, to boring old osteoporosis. BOLT International’s Osteoporosis Thought Leader panel has convened more than 50 times over the past 15 years. As a group we’ve seen a lot of changes. In the mid-90’s, almost to a person, if you asked a Panelist about the concept of combining a SERM and estrogen you’d get comments like “throwing fuel on the fire (stimulating breast cancer)”, “been there, done that with tamoxifen and it doesn’t work”, etc. (Someone told me that “etc” is what you say when you know there’s another example but you can’t think of it at the moment).
Well, now that alendronate’s generic, the only peeps who are still espousing good things about oral bisphosphonates are Teva and Warner-Chilcott. And a few of my Panelists who are up in arms over the overreaction of just about everybody to frozen bone (which, by the way, you never see when using a bisphosphonate for multiple myeloma, even though there you see a ton of osteonecrosis of the jaw.), gastric upset, ONJ (which is just NOT a problem in the non-metastatic setting), ETC.
Here’s the point:
- By default, SERMs are making a comeback; with the caveat that in highly price regulated markets (UK comes to mind) it doesn’t make commercial sense to launch a new SERM. But the pendulum is clearly swinging toward starting younger women (without cardiovascular risk factors) on something other than a potent antiresorptive – and SERMs fit that bill.
“What also has happened is we become more selective about who we give that to. The younger osteoporotic patient, yes, the osteopenic patient, the person who just has borderline osteoporosis we are less likely to want to give a bisphosphonate to. So yes we are looking more at the SERMs”.
“So you take a holiday, some other people said switch to a SERM or something like that. Usually not, no. Usually it is stop the medicine for a period of time because when you have been on one of these drugs for ten years you don’t need to usually resume another antiresorptive right away. You see for a year or two off of therapy you see generally pretty good stability of bone in the spine, maybe a little less at the hip, but not usually substantial. And as a result when we stop it we usually don’t immediately start something else.
“Are you seeing any uptick in SERM usage? I have increased my SERM use. I haven’t seen any of the data, the IMF data. I don’t believe there was an uptick that I saw, but I have increased my use of it and I would envision there would be a little more SERM use”.
“So some have said I am starting younger patients with low BMD on a SERM rather than straight to a bisphosphonate. I would agree with that. I have said this before and I think both the new SERMs I think would have a useful clinical role. We don’t think we are going to get them in the UK. We certainly haven’t gotten them yet. I think there was a stand up at the meeting and, of course, SERMs have always been popular in Spain and Portugal, I think particularly Spain. So they had a stand up. I can’t even remember what it was. It was bazedoxifene I think is available in Spain. I think it is a useful drug, yeah. We have discussed the lasofoxifene data and I think those data are good. And it is just in the UK we understand that we may well never see them. What is the basis for it not coming through in the UK? I presume they just don’t think they are going to see a proper market. But whether that means they just won’t promote it but it will be available I don’t know. But we have heard absolutely nothing more. I would use them for sure. I think they would be useful, particularly with some of the beneficial non-skeletal effects. The more convincing signal, albeit it may be in the longer term or post-hoc analyses but you have got some nonvertebral fracture signal; at least some, which you didn’t have with raloxifene. Of course, one of the uses we proposed for raloxifene and did it for a while, was to follow on from other treatments. So for example HRT, and now you would say, right, you can have your bisphosphonate for five years. Beyond five years the evidence that you can really significantly continue to reduce fracture risk is not so convincing. There is a bit of data for vertebral and very little for nonvertebral beyond five years. So I will give you the five years of bisphosphonate and then I will switch to something else. That something else might very logically be one of the new SERMs. I would strongly consider adopting that approach and you could say, by the way, it will reduce your risk of breast cancer, etc. I think it is potentially a useful treatment both following on and as a new treatment, a first treatment for a fair number of patients. I would certainly consider it. And also the younger patients, you have got people in their fifties and what have you. You don’t necessarily want to commit them to long-term bisphosphonates. They may not have had fractures. You may be thinking more prevention, the osteopenics. I am sure there is a big market in it. They perceive the UK market to be quite unfavorable obviously”.
Raloxifene Teva (Teva)
- Lilly has told some panelists that they believe that they can successfully hold off Raloxifene Teva from reaching the US market until 2014. Thus, Lilly is going to invest more money into marketing Evista because they have a little longer shelf life before they get the generic competition.
“The concern has been for the US about the introduction of a generic raloxifene from Teva, but the Lilly folks reassure me they have been successful in court to hold it off to 2014 they think. So they are going to probably invest more money in marketing into Evista because they have a little longer shelf life before they get the generic”.
Evista (raloxifene; Lilly)
“I am going to go with Evista in position number three. We did the original MORE trial and even though there is absence of any evidence of nonvertebral fracture efficacy, I think it probably works very well if we studied the right patient population. By all rights, the Evista demographics should skew a little bit younger. It doesn’t in real practice but it should. But if you look at an agent that has relatively few side effects, prevents breast cancer and does a credible job of protecting bone I think it is a good treatment agent”.
Viviant / Aprela (bazedoxifene +/- estrogen TSEC; Pfizer)
- Bazedoxifene will launch in Italy in the next few months. It is already approved in Spain and Japan. This will be the only SERM on the Italian market.
“So how does a drug like bazedoxifene get prescribed in Italy? That will be interesting. It is getting into the market in the next couple of months. It is going to get into the market just like all the other drugs for prevention of fracture through primary care. And in fact, we are so surprised that this happens for bazedoxifene but is not happened for denosumab. Why not? You tell me. If you have more information I would be pleased to know. They are still deciding if denosumab is a drug that has to be prescribed by hospital people or by general practitioners. And just in the time they are discussing this almost a year has passed. Well that is the story of recruitment in Italy. Who is going to get to prescribe bazedoxifene? Probably the company will market that with gynecologists. So it will be a gynecologist’s drug. So this is going to happen. That the drug will be prescribed by gynecologists and will be mostly let’s say surrogate of estrogen. You know why, because we don’t have raloxifene. Raloxifene was totally abandoned by Lilly here. So in Italy we don’t have a SERM. Interesting. Italy is very strange you know. Just the classical situation is quite unique in many ways”.
- Most panelists are more enthusiastic about Aprela (bazedoxifene TSEC; the combination with low dose estrogen) than they are about Viviant. This is not driven by the SERM alone, as raloxifene is viewed as a better SERM. But the combination may offer physicians a safer way to prescribe estrogen for menopausal symptoms. One panelist said that Pfizer is filing the combination now, so we estimate that by ASBMR 2012 Aprela should launch in the US.
“The third was bazedoxifene plus estrogen. So the question there then becomes is this really the same thing as estrogen without progesterone? And the answer may be yes. And if it is estrogen without progesterone because the bazedoxifene is essentially doing what the progesterone would have done you may very well get moderate antifracture efficacy as well as some real benefits in terms of the miseries of menopausal symptoms. So while I don’t see it as the world’s greatest bone drug, it could if it turns out to be adequately safe and we won’t know that for a long time, it could turn out to be sort of estrogen without the problems. Which to me seemed like it fit in very well in that early patient with low bone mass? Yeah, it is really funny because bazedoxifene is sort of a not very exciting SERM. I mean it is no better than Evista. Estrogen still scares people and it may well be that even though it is estrogen together with bazedoxifene that the average patient is going to be scared to death. The patient who is terrified of taking estrogen who took it, who loved it, but is terrified of ever taking it again because everybody she knows has breast cancer may be equally terrified to touch something that has the word estrogen in it. So even though it may be in principal great stuff and there certainly are going to be women who miss their estrogen terribly who would love to go back on estrogen for relief of symptoms and who are convince that because it has got bazedoxifene instead of progesterone in the package their risk of breast cancer is not as high because they are going to believe the data, which seemed believable, that in the WHI the women on estrogen only without progesterone because they did hysterectomies were not at increased risk of breast cancer. If we can convince ourselves that estrogen with bazedoxifene is safe for the breast and makes you feel good and is adequate for bone in lots of people who simply want to stop bone loss it could be terrific. But just as people are terrified by atypical fractures, which are probably pretty rare they are go not be nervous about estrogen. People are so risk averse. They are so frightened of side effects; both patients and doctors”.
“The other sweet spot may I point out to you is the SERMs. I just got asked to review the seven years bazedoxifene experience. So SERMs are going out long-term too. I would argue that if the woman doesn’t have vasomotor symptoms I should feel comfortable with keeping her on SERMs for seven years or so. We got long-term data now with SERMs. So there are other drugs. Is bazedoxifene being prescribed in the US right now? No, bazedoxifene, I did the launch in Spain and I did the launch in Japan. That is why I was in Japan”.
“SERMs if we can get one that shows nonvertebral risk reduction as lasofoxifene did, except lasofoxifene is going nowhere as far as I know, if we had a better SERM, yes, it is a milder drug. I just saw a woman who is 64 who in 1996 when she went through menopause was put on estrogen and Fosamax. In 2006 they were both stopped. It was ridiculous and she should never have been put on Fosamax. So what do we do with her now? She has got a T-score of the spine of -2.5 having lost bone in the five years she stopped these drugs. I am putting her on Evista. She has T-scores of the hip that are mildly low. I am not worried about her breaking her hip. I am worried about spine fractures. This is a great choice for her. When she gets a whole lot older I can put her back on a bisphosphonate because she will have been away from it for a long time. They go away. Once you stop doesn’t mean never again, it means time off. So that is not the answer to your question”.
“Pfizer Wyeth was reluctant to introduce bazedoxifene in a marketplace that we thought by 2012 would have Raloxifene Teva, Teva’s SERM, but there is a bigger window. What I am hearing between the lines is the preferences for the US because SERMs haven’t had great penetration because they increase vasomotor symptoms to introduce tissue selective estrogen receptor complex; Premarin and bazedoxifene in the US. They are actually submitting an NDA right now, the FDA with the data. Yeah that has been a while coming also. I think the US will not see bazedoxifene alone but it will see TSEC (tissue selective estrogen complex). So let’s assume that they get filed by ASBMR and put eight months onto it so some time in 2012 we should have bazedoxifene plus estrogen available. Right, yes. How is that going to compete against Evista, against raloxifene? Well I haven’t seen the TSEC post-hoc data but the data I presented in Japan, you have seen my post-hoc nonvert data is suggestive that in five years it is trending 0.06. There is a suggestion of nonvert efficacy. But clarify for me, that is for the monotherapy correct? That is right. I have no idea what is going on with TSEC. I am not privy to the data. But the big issue for me is the safety, at least the preclinical data I know pretty well. If you add raloxifene and estrogen breast cancer cells they multiple. If you add bazedoxifene and estrogen to breast cancer cells they don’t multiply. There is pretty good preclinical data that bazedoxifene plus estrogen should be safe for the breast, but I really want to see really at a granular level the safety data.
“Given the clinical data that you have seen for bazedoxifene and lasofoxifene in a fantasy world since you are probably not going to get either one, but if you could only have one which one would you take? It probably would be lasofoxifene. If you look at the whole package that is what I would choose. So you take the higher efficacy with a little bit higher cardiovascular risk? Yeah, I think I would. I am biased. I am a bone doctor. That is fine. We love you anyway”.