Posted by Jeff Berk, BOLT International;
So my GF thinks that the only reason I write this blog is to make you, dear reader, look at my cactus photos. For today, and only for today, I’ll stipulate that this is true. Therefore, upon you I foist this image of a Soehrensia uebelmanniana in bloom. Maybe not such a big deal to you, but I’ve killed all the rest of his brothers and sisters, and this is the first time said beast has ever flowered. It was a sort of hot day today in the desert, and by noon this flower fried and died.
Okay, so on to multiple myeloma. Today’s blog is in response to an email I got from a Japanese reader (who first, my heart goes out to you guys. And second, like it needs to be said, your English is a lot better than my Japanese! I assume you had some help from Google translation, but hey, that’s what it’s there for). Anyway, I have a lot of pharma clients who are active in this space. It’s an extremely fertile area for development of small molecules and biologicals for two reasons. First, there is a huge unmet need for treatment of relapsed/refractory disease. And second, the evolution of molecular understanding of the disease has reached a point where there are a plethora of viable ways to treat. We last spoke with BOLT’s Multiple Myeloma Thought Leader panel just after ASH 2010. I could go on and on about the therapies that we’ll be seeing in 2012 and beyond. But tonight, in honor of my Sushi Bros, I’m going to share the Panel’s thoughts on Actimid (pomalidomide). So here goes…
- Celgene will file Actimid for use in lenalidomide relapsed/refractory MM during 2H2011. The company is actively differentiating Actimid by positioning it as the go-to drug in Revlimid failures. They are not letting investigators run 1st-line studies with pomalidomide. With Actimid as the go-to drug for lenalidomide failures, it will be thalidomide that is pushed aside. FDA is probably going to require PFS data, meaning that response rate in the LEN rel/ref patient cohort is not going to suffice for approval of Actimid.
Pomalidomide (+ low dose DEX) Responses in Rel/Ref MM:
“That data remains strong. That space has not changed. It is not commercially available but they will probably look for an approval some time next year. I wonder if they can get it approved based on just responses on lenalidomide failures. I don’t think so. I think they are going to have to do a randomized trial, but we will see. Celgene does not want to position it in competition to lenalidomide. Right. So the idea that we are going to get pomalidomide up front studies at this moment in time is probably unlikely. Cannibalism. There is no reason for them to do that. Yeah. And it is what it is. The data that we have is the data that we will get”.
“I think pomalidomide in a lenalidomide world is huge because I think what you are going to see is that lenalidomide is used up front and in truth the pomalidomide will start to go right into lenalidomide failure where as thalidomide currently will sort of increasingly get pushed sideways. Pomalidomide is awesome. It is quite frankly in my experience the best of thalidomide and the best of Revlimid put into one to be perfectly honest with you. I am pretty sure you did this other presentation that really tickled me and that was the combination of thalidomide and Revlimid overcoming thalidomide resistance. To me I don’t get why you would do that. I would stick with pomalidomide. The bottom line is thalidomide is toxic and it is unpredictable. So combining Revlimid and thalidomide, I mean yeah sure if you are stuck and you can’t get pomalidomide I suppose you could do it. But you know what that is actually a neat little thought because if you can’t get pomalidomide that is what I might do if I was looking to overdrive resistance to either of the two alone and I was stuck. I would use low dose Revlimid and low dose thalidomide”.
“You know Celgene is trying to give a role to pomalidomide as basically third, so another agent in patients resistant to lenalidomide. This is the role of pomalidomide. Pomalidomide is a little bit more effective than lenalidomide. That has some other side effects like hematologic toxicity. But I think what will be very much the use of pomalidomide will be, again, in those kind of niche that we were talking about before for carfilzomib and HDAC inhibitor. This would be the perfect agent to use if you want something or in condition where lenalidomide is already completely resistant. Probably with time pomalidomide will move earlier on”.
“I think the first usage is going to be in patients who have relapsed after Revlimid and after Velcade. So it would be third line therapy. Whether they are refractory to Revlimid or not, I think we will have to wait and see how the studies will end up being done. But I am sure they would be the patients who are exposed to Revlimid. I don’t expect a study being done that compares directly to Revlimid. And in absence to that they will be Revlimid exposed patient. An easier study would be a nonrandomized study to take Revlimid refractory patient and show the drug works. But that is again many ifs and buts and FDA in the middle”.
“Pomalidomide is clearly working in lenalidomide failure and indeed in Velcade failure. The pomalidomide data are frankly to my mind anyway much more impressive than carfilzomib. So the pomalidomide data, what is the mechanism? Why do you think it is working so much better than lenalidomide? I think there are a couple of points to make. I think that if you look at it from a molecular point of view – it sort of just dawned on me as I was looking at the molecular structures – it is the best of thalidomide and the best Revlimid because it combines the carbonyl and amine in the phthaloyl ring. Everyone said “what about combining thalidomide and Revlimid? Wouldn’t that be an exciting trial?” The reality is the pomalidomide does exactly that as one agent. Interesting. I think that it is really interesting drug. I think it clearly works thalidomide failure. That was never a question. But the fact that it is working so consistently in Revlimid failure is really unexpected. I don’t think any of us expected to see that strength of signal. You mentioned carfilzomib as it being oversold. I think that is the challenge for carfilzomib. When you have got single agent response rates from pomalidomide of 35 to 40 percent in combination, I should say, even with dexamethasone in the face of true lenalidomide and true Velcade failure, that is an impressive signal. And it is extremely well tolerated too, which is the other message. I think pomalidomide is probably going to be the next FDA approved IMiD. I don’t think it is going to be too long. I think it could be within the next couple of years. Carfilzomib, I think will probably get an approval as well, probably in the same sort of time frame. But I think pomalidomide is moving very quickly forward”.
“I am wondering at the end of the day how are you going to really practice. So you have a patient who is relapsing from a CR with a minimal monoclonal peak. Your first choice is probably going to be Revlimid because it is oral and you may or may not give them dexamethasone. So now you have something that is going to make them respond 80 percent of the time. So you get another year out of it, a year-and-a-half, and they are relapsing again. And then you say are you going to add perifosine, are you going to add HuLuc? You are probably not. You are probably going to say let me give them Velcade. And then you are going to say, okay, I am going to give them Velcade. Do I give them Velcade single agent or do I give them Velcade with one of these new partners? That may be where it fits, particularly in patients with symptomatic relapses. So by that point we are looking at basically a fourth line kind of therapy? Correct. So they will probably get some degree of response but a short period of time and there are going to be a lot more toxicities. And if pomalidomide becomes available then you can say guess who is going to be the default? It is going to be pomalidomide. A lot of it is going to be it depends how they market the drug and whether pomalidomide is on the market or not”.
- Pomalidomide is an iterative improvement over lenalidomide, increasing the CR rate by about 20%. It does seem to have a much better safety profile – less fatigue, hematotoxicity (and no increase in neuropathy) vs LEN.
“Honestly speaking, I am not looking also at the data. Some people are saying, well, pomalidomide is completely different. In my opinion if you look at the efficacy lenalidomide stays at thalidomide as pomalidomide stays at lenalidomide. So every time you increase the efficacy a little bit with the novel agent but you are not really changing the world because you are not doubling the CR rate where basically increase of 15 to 20 percent, a response rate with the newer agent. So the efficacy is not changing the world. It is better, but it is not dramatically better and that this is the perfect agent and I think Celgene will do everything possibly to position that agent in that respect. It is the perfect agent to use in lenalidomide resistant patient”.
“I am currently treating two patients with Pom/adromycine/dex and I can see that tolerability is really excellent. They do not have any of these adverse effects that are associated with Len. No neurotoxicity, no hematoxicity and no fatigue. So it is really outstanding how those patients are doing who are receive P/A/D. So I think there is no real medical reason for holding Pom for the majority of myeloma subjects. I think if we look into the upfront data that was presented it was really very interesting. And it should be continued to be further developed. But I think it will not happen as long as lenalidomide has any success in the earlier lines of treatment”.
“The pomalidomide data when I looked at responses in lenalidomide refractory patients, it seemed like there was 25 or perhaps 30 percent response rate. Close to that. That seemed very good to me. It is good. I think it is good. I think pomalidomide data are not new actually. There was a paper recently published by Mayo Clinic on pomalidomide and I think that will be in a range of 20 to 25 percent in lenalidomide resistance. I think those are good data. I think it is very encouraging. I don’t think pomalidomide is a different mechanism. I think it is just a more potent drug. I think that honestly when you look at the side effects of pomalidomide, at least by what was published from Mayo, it doesn’t look like the side effects will be overwhelming compared to lenalidomide. So my feeling is that pomalidomide could actually start replacing Revlimid as mainstay treatment”.
“I would certainly think that if it was on the list to be picked I would put it as number one for me. I think its activity demonstrated by two studies presented, Gertz and Martha Lacy clearly suggests it is a very active drug, number one. Number two, it has shown clear efficacy in real refractory setting in patients who are refractory to lenalidomide. 30% response in that setting. I personally had patients who were refractory to everything and got the drug and responded. So there is a clear signal about its activity and activity that is superior than Revlimid. And it’s tolerated quite well. It is the same toxicity that we see with Revlimid. A little bit more here and there, but I think it is very clearly effective drug. I think from those angles, both convenience of dosing – oral dosing and efficacy I think it has really good potential. I would think that is the number one new drug that I would watch for going forward and I really look forward to using it. Truthfully in current setting, and this is confidential what I am saying, but my personal bias about it is that I think we all are, and not just me personal, but my colleagues here too. We are clearly distressed that the drug is not available for the patients who are right now relapsing and dying. It looks so promising. I think it is a good drug. That would be my first pick”.
- Pomalidomide is going to be a direct threat to carfilzomib because of the high response rate being seen with Celgene’s drug in bortezomib failures.
“You mentioned carfilzomib as it being oversold. I think that is the challenge for carfilzomib. When you have got single agent response rates from pomalidomide of 35 to 40 percent in combination, I should say, even with dexamethasone in the face of true lenalidomide and true Velcade failure, that is an impressive signal. And it is extremely well tolerated too, which is the other message. I think pomalidomide is probably going to be the next FDA approved IMiD. I don’t think it is going to be too long. I think it could be within the next couple of years. Carfilzomib, I think will probably get an approval as well, probably in the same sort of time frame. But I think pomalidomide is moving very quickly forward”.
- Low-dose pomalidomide is marginally effective in the treatment for anemia associated with JAK2V617F-positive myelofibrosis. Best results reported at ASH 2010 were in the absence of marked splenomegaly. Combined response rate using IWG-MRT criteria was 25% (95% CI, 16-34%) and ranged between 11% and 42% among the four treatment arms. Response appears to be predicted by early drug-induced basophilia. Pomalidomide also appears to improve thrombocytopenia in most subjects with baseline platelets <100 x 10e9/L but is not active in controlling disease-associated splenomegaly. Grade 3/4 adverse events (regardless of attribution) included anemia (10%), thrombocytopenia (9%), leukopenia (9%), fatigue (7%), dyspnea (5%), thrombosis (4%), diarrhea (4%) and hyperglycemia (4%).
“Pomalidomide is not yet commercially available. They have to do the study looking at pomalidomide for Revlimid failures. That is going to be their licensing trial. So pomalidomide is not going to be on the market probably for one or two years unless they get the myelofibrosis indication. If they get the myelofibrosis indication similar to what happen when Revlimid was approved for MDS but not for myeloma, I would say that many people won’t have access to pomalidomide unless they have myelofibrosis because it won’t be reimbursed”.