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Letermovir for CMV Prophylaxis in Transplant Patients

Panelists: Harry Erba, MD, PhD, University of Alabama at Birmingham; Roy Chemaly, MD, MPH, MD Anderson Cancer Center; Mark Levis, MD, PhD, Sidney Kimmel Comprehensive Cancer Center
Published: Thursday, Feb 02, 2017


Transcript:

Harry Erba, MD, PhD:
I think what we’ve done is talked about our general approach. And what I’m learning from you today is that it would be really great to have some prophylactic measures. But let me make sure I understand: you don’t prophylax patients. You don’t need to prophylax patients who have CMV-negative recipients, is that right?

Mark Levis, MD, PhD: Correct. They’re CMV-negative into negative.

Harry Erba, MD, PhD: Both negative.

Mark Levis, MD, PhD: Negative into negative, yes. But that’s actually not common.

Harry Erba, MD, PhD: Yes, it’s not common. Let’s move on then.

Mark Levis, MD, PhD: The only thing I would comment on, and particularly in the cord blood, is the use of valacyclovir at a high dose is thought, perhaps, to have some data.

Roy Chemaly, MD, MPH: Yes, there are some data. They can’t delay the high dose.

Mark Levis, MD, PhD: It’s an enormous dose.

Roy Chemaly, MD, MPH: Yes, 2 g/3 times a day. But there are some data showing maybe it will work against CMV.

Harry Erba, MD, PhD: But, fortunately, Dr. Chemaly, you have done some further work in this area with a new antiviral agent that may be potentially used in the future in prophylaxis. Do you want to tell us more about that?

Roy Chemaly, MD, MPH: So, we conducted a phase II trial on letermovir versus placebo in allogeneic transplant recipients, trying to prevent CMV from reactivation. We enrolled around 131 patients, and it was a dose-escalation study, as well, versus placebo. It met the primary endpoint. It prevented around 50% of CMV reactivation when compared to placebo in the highest dose, which was 240 mg once a day. And they took it from time of engraftment up to day 100. So, say, week 12 to week 14, they have been on the study drug and it worked very nicely. We didn’t see much of a safety signal from the drug, plus all SAEs or AEs were compared with the placebo. There was no evidence of myelotoxicity or nephrotoxicity that you worry about in this patient population or even liver toxicity, based on this phase II trial.

Harry Erba, MD, PhD: It was a randomized phase II trial.

Roy Chemaly, MD, MPH: It was randomized, placebo-controlled, yes, in the phase II. This was back in 2014. After that, because of these encouraging results and the positive result, we went ahead, and we moved forward with the phase III trial with more than 500 patients. I think it was around 540, if I remember well. And enrollment was completed. We have that out—it’s publicly available now through a press release—where it met the primary endpoint of 224. What’s interesting, what we found, is that you treat patients or we put them on prophylaxis versus placebo until week 14. After that, you stop the study drug and you continue monitoring them to week 24 and see how many will have reactivation over that time period. And it was much less on the letermovir than on the placebo arm. So, it met the primary endpoint and it was a positive trial. But it’s still under analysis, and hopefully, we’ll hear more about it.

Mark Levis, MD, PhD: And in the phase II, it was about a 70% overall reduction in the risk of reactivation. What is that holding in this stage?

Roy Chemaly, MD, MPH: It’s around between 50% and 70%, I would say. It depends on the dose that you look at and also what we did in the phase II. So, they had some patients who had early reactivation and they were enrolled in the study. If you remove these patients who had already reactivated before the study drug, actually it was 100% effective, the 240 mg.

Mark Levis, MD, PhD: How early had they reactivated?

Roy Chemaly, MD, MPH: It was pretty early. Actually, it was around day 20, I would say.

Mark Levis, MD, PhD: Yes. I was going to say I’m not sure we even begin screening until then.

Roy Chemaly, MD, MPH: But, now, these days, actually, the practice is changing a little bit because of the sensitive PCR. So, we’re starting to treat early on, and you start seeing some reactivation even before engraftment.

Harry Erba, MD, PhD: And when you stop the study drug, I’m sure you looked at what the reactivation rate was like after that, right?

Roy Chemaly, MD, MPH: Yes. It was also much less on the letermovir versus the placebo.

Harry Erba, MD, PhD: Oh, it was still less?

Roy Chemaly, MD, MPH: Until week 24, yes.

Harry Erba, MD, PhD: Oh, that’s interesting. But it brings up a drug approval question that I’m going to add, because, to me, what I’ve heard so far—in terms of treating active CMV—is you don’t even know when to start your treatment. The drugs you have are toxic, and I think I heard you say very few people are dying of CMV infection anymore.

Mark Levis, MD, PhD: Well, we are treating. Because we remember all those patients dying, we, at my institution, leap on a positive result and they’re hammered with the toxic treatment.

Roy Chemaly, MD, MPH: This is the problem with CMV viremia. Although any viremia, as I mentioned earlier, puts patients at disadvantage for survival still.

Mark Levis, MD, PhD: The sheer cost of this when we have to add valganciclovir or ganciclovir to these patients, transfusion goes up. Everything just goes haywire.

Harry Erba, MD, PhD: I know. You’re preaching to the choir. I understand, but at the end of the day, how are we going to get this? It sounds like a drug that patients need, that clinicians need for their patients based on this toxicity profile and efficacy in terms of decreasing reactivation. And we understand, when reactivation occurs, how sick these people get, all of the cost utilizations. But you didn’t quite tell me yet that we know that survival is worse.

Mark Levis, MD, PhD: So, that comes down to the diagnostic testing, right?

Harry Erba, MD, PhD: OK, but let me ask you, is the endpoint going to be survival or is it going to be reactivation? This is my question.

Roy Chemaly, MD, MPH: It was mainly a reactivation, clinically significant.

Harry Erba, MD, PhD: That one for the randomized phase II?

Roy Chemaly, MD, MPH: Even phase III. Actually, it was mainly prophylaxis or the occurrence of clinical significance in CMV viremia in necessitating antiviral therapy. So, it wasn’t survival, but the secondary endpoint was survival.

Mark Levis, MD, PhD: A validated assay, molecular assay, something we’ve longed for in our field.

Harry Erba, MD, PhD: Oh, that’s why we can’t do it in AML.

Mark Levis, MD, PhD: So, you can’t wrap your mind around this. I actually have that in infectious disease.

Harry Erba, MD, PhD: That’s right. I understand you actually have a validated assay. OK, well, that’s good for patients because that’s the point I was trying to get.

Roy Chemaly, MD, MPH: Right. You put in CMV viremia, and so many toxic drugs can be given to patients. If only we had a good safe oral drug that you can give to your patient during their high-risk period.

Transcript Edited for Clarity
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Transcript:

Harry Erba, MD, PhD:
I think what we’ve done is talked about our general approach. And what I’m learning from you today is that it would be really great to have some prophylactic measures. But let me make sure I understand: you don’t prophylax patients. You don’t need to prophylax patients who have CMV-negative recipients, is that right?

Mark Levis, MD, PhD: Correct. They’re CMV-negative into negative.

Harry Erba, MD, PhD: Both negative.

Mark Levis, MD, PhD: Negative into negative, yes. But that’s actually not common.

Harry Erba, MD, PhD: Yes, it’s not common. Let’s move on then.

Mark Levis, MD, PhD: The only thing I would comment on, and particularly in the cord blood, is the use of valacyclovir at a high dose is thought, perhaps, to have some data.

Roy Chemaly, MD, MPH: Yes, there are some data. They can’t delay the high dose.

Mark Levis, MD, PhD: It’s an enormous dose.

Roy Chemaly, MD, MPH: Yes, 2 g/3 times a day. But there are some data showing maybe it will work against CMV.

Harry Erba, MD, PhD: But, fortunately, Dr. Chemaly, you have done some further work in this area with a new antiviral agent that may be potentially used in the future in prophylaxis. Do you want to tell us more about that?

Roy Chemaly, MD, MPH: So, we conducted a phase II trial on letermovir versus placebo in allogeneic transplant recipients, trying to prevent CMV from reactivation. We enrolled around 131 patients, and it was a dose-escalation study, as well, versus placebo. It met the primary endpoint. It prevented around 50% of CMV reactivation when compared to placebo in the highest dose, which was 240 mg once a day. And they took it from time of engraftment up to day 100. So, say, week 12 to week 14, they have been on the study drug and it worked very nicely. We didn’t see much of a safety signal from the drug, plus all SAEs or AEs were compared with the placebo. There was no evidence of myelotoxicity or nephrotoxicity that you worry about in this patient population or even liver toxicity, based on this phase II trial.

Harry Erba, MD, PhD: It was a randomized phase II trial.

Roy Chemaly, MD, MPH: It was randomized, placebo-controlled, yes, in the phase II. This was back in 2014. After that, because of these encouraging results and the positive result, we went ahead, and we moved forward with the phase III trial with more than 500 patients. I think it was around 540, if I remember well. And enrollment was completed. We have that out—it’s publicly available now through a press release—where it met the primary endpoint of 224. What’s interesting, what we found, is that you treat patients or we put them on prophylaxis versus placebo until week 14. After that, you stop the study drug and you continue monitoring them to week 24 and see how many will have reactivation over that time period. And it was much less on the letermovir than on the placebo arm. So, it met the primary endpoint and it was a positive trial. But it’s still under analysis, and hopefully, we’ll hear more about it.

Mark Levis, MD, PhD: And in the phase II, it was about a 70% overall reduction in the risk of reactivation. What is that holding in this stage?

Roy Chemaly, MD, MPH: It’s around between 50% and 70%, I would say. It depends on the dose that you look at and also what we did in the phase II. So, they had some patients who had early reactivation and they were enrolled in the study. If you remove these patients who had already reactivated before the study drug, actually it was 100% effective, the 240 mg.

Mark Levis, MD, PhD: How early had they reactivated?

Roy Chemaly, MD, MPH: It was pretty early. Actually, it was around day 20, I would say.

Mark Levis, MD, PhD: Yes. I was going to say I’m not sure we even begin screening until then.

Roy Chemaly, MD, MPH: But, now, these days, actually, the practice is changing a little bit because of the sensitive PCR. So, we’re starting to treat early on, and you start seeing some reactivation even before engraftment.

Harry Erba, MD, PhD: And when you stop the study drug, I’m sure you looked at what the reactivation rate was like after that, right?

Roy Chemaly, MD, MPH: Yes. It was also much less on the letermovir versus the placebo.

Harry Erba, MD, PhD: Oh, it was still less?

Roy Chemaly, MD, MPH: Until week 24, yes.

Harry Erba, MD, PhD: Oh, that’s interesting. But it brings up a drug approval question that I’m going to add, because, to me, what I’ve heard so far—in terms of treating active CMV—is you don’t even know when to start your treatment. The drugs you have are toxic, and I think I heard you say very few people are dying of CMV infection anymore.

Mark Levis, MD, PhD: Well, we are treating. Because we remember all those patients dying, we, at my institution, leap on a positive result and they’re hammered with the toxic treatment.

Roy Chemaly, MD, MPH: This is the problem with CMV viremia. Although any viremia, as I mentioned earlier, puts patients at disadvantage for survival still.

Mark Levis, MD, PhD: The sheer cost of this when we have to add valganciclovir or ganciclovir to these patients, transfusion goes up. Everything just goes haywire.

Harry Erba, MD, PhD: I know. You’re preaching to the choir. I understand, but at the end of the day, how are we going to get this? It sounds like a drug that patients need, that clinicians need for their patients based on this toxicity profile and efficacy in terms of decreasing reactivation. And we understand, when reactivation occurs, how sick these people get, all of the cost utilizations. But you didn’t quite tell me yet that we know that survival is worse.

Mark Levis, MD, PhD: So, that comes down to the diagnostic testing, right?

Harry Erba, MD, PhD: OK, but let me ask you, is the endpoint going to be survival or is it going to be reactivation? This is my question.

Roy Chemaly, MD, MPH: It was mainly a reactivation, clinically significant.

Harry Erba, MD, PhD: That one for the randomized phase II?

Roy Chemaly, MD, MPH: Even phase III. Actually, it was mainly prophylaxis or the occurrence of clinical significance in CMV viremia in necessitating antiviral therapy. So, it wasn’t survival, but the secondary endpoint was survival.

Mark Levis, MD, PhD: A validated assay, molecular assay, something we’ve longed for in our field.

Harry Erba, MD, PhD: Oh, that’s why we can’t do it in AML.

Mark Levis, MD, PhD: So, you can’t wrap your mind around this. I actually have that in infectious disease.

Harry Erba, MD, PhD: That’s right. I understand you actually have a validated assay. OK, well, that’s good for patients because that’s the point I was trying to get.

Roy Chemaly, MD, MPH: Right. You put in CMV viremia, and so many toxic drugs can be given to patients. If only we had a good safe oral drug that you can give to your patient during their high-risk period.

Transcript Edited for Clarity
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