Hematopoietic Stem Cell Transplant: Infection Control - Episode 10
Roy Chemaly, MD: Over the years, I’ve been involved with many clinical trials for different anti- cytomegalovirus [CMV] drugs, including maribavir, which was one of the first drugs that we tested in phase 2 and phase 3 trials for the prevention of CMV disease in the stem cell transplant population. The phase 2 trial was positive. But, unfortunately, the phase 3 trial did not show a difference in primary outcome, or primary endpoint, between placebo and maribavir. Now, maribavir has been tested as a treatment option for resistant CMV infection and as preemptive therapy. So, stay tuned. Hopefully, in the future, we’ll see the results of these phase 2/phase 3 trials.
Then, after that, I was involved with the brincidofovir phase 2 and phase 3 trials. Unfortunately, the same thing happened again. The phase 2 trial results were positive. We saw a good signal that brincidofovir could prevent CMV reactivation. But, in the phase 3 trial, it did not work. We did not significantly reach the primary endpoint. This drug will probably be developed, in the future, for adenovirus infection, as a broad-spectrum antiviral drug.
I have been involved with letermovir from the beginning, when it was looked at in a phase 2 trial for the prevention of CMV reactivation or clinically significant CMV infection after allotransplant. The phase 2 trial was positive. We saw very good signals of efficacy when compared against placebo, meaning you’re comparing a prophylactic regimen versus a preemptive regimen. We also saw some signals on CMV disease, as well. So, we were very encouraged by the results of the phase 2 trial. It was moved to a phase 3 trial. This trial recently completed. It was a positive trial, meaning that it showed that letermovir prevented more CMV reactivation when you compared it to preemptive therapy—at least when you gave the drug up to week 14, which is the high-risk period. The outcome, the primary endpoint, was measured at week 24. We wanted to see if this impact or this benefit continued up to week 24, and it was a positive trial.
In the phase 3 clinical trial for letermovir, we enrolled adult allogeneic stem cell transplant recipients who were CMV-seropositive. They were randomized 2:1. They could be enrolled before or after engraftment. They were started on treatment up to week 14 and were followed to week 24 to monitor for the primary endpoint. Then, they were followed up to week 48 for serious adverse events and mortality. The primary endpoint was clinically significant CMV reactivation or CMV end-organ disease or starting preemptive therapy for CMV viral load above a certain threshold as predefined in the clinical trial. This was measured at week 24, which was 10 weeks after stopping the study drug, as I mentioned earlier, to see if it would carry the benefit after week 24. What we saw in the result was that there was less CMV reactivation in the letermovir arm when you compared it to placebo. This was true at week 14, week 24, as well as at week 48. We also found that there was a difference, numerically, in the mortality rate between the 2 arms. It was a little bit less in the letermovir arm than in the placebo arm at week 24 and week 48, as well.
Letermovir was used either in the oral form at 240 mg once a day in patients receiving cyclosporine, or 480 mg per day if the patient was receiving tacrolimus, because of the drug—drug interaction. We also could have used intravenous letermovir, which was available for the clinical trial, if the patient couldn’t take the oral regimen for some reason—especially early after transplant, when severe mucositis could occur. This, in a nutshell, is what the design and the results of the trial were. This was a good, positive trial. Now, we have an effective, safe drug to use as prophylaxis for CMV infection in our adult stem cell transplant recipients who are CMV-seropositive.
Transcript Edited for Clarity