Guarded promise for adenovirus therapy

Adenovirus can cause deadly infection after hematopoietic cell transplantation (HCT). In this issue of Blood, Hiwarkar et al present data in pediatric HCT patients with adenoviremia indicating that brincidofovir, a prodrug of cidofovir, was well tolerated, demonstrated substantially more rapid virologic clearance rates compared with cidofovir, was effective even after cidofovir failure, and was efficacious even in the absence of improved lymphopenia.¹  Heretofore, we have lacked effective tools to prevent this life-threatening threat.

Cidofovir is a deoxycytidine analog that has antiviral activity against the families of double-stranded DNA viruses that are human pathogens, including adenovirus. It has clinical efficacy, most notably against cytomegalovirus (CMV) (for which it is licensed) and, to a lesser degree, adenovirus. The diphosphate metabolite of cidofovir selectively inhibits viral DNA polymerase, competitively inhibits the incorporation of deoxycytidine into viral DNA, and results in inhibition of viral DNA synthesis. However, its toxicities of myelosuppression and severe nephrotoxicity coupled with the lack of randomized trials have limited its clinical utility.

Brincidofovir is a lipid prodrug of cidofovir. The prodrug has improved oral bioavailability, allows greater cellular uptake, results in higher intracellular concentration, and has a prolonged half-life within the cell. These effects translate into brincidofovir having substantially greater antiviral activity. Brincidofovir is not a substrate of organic ion transporter 1, does not concentrate in renal tubules, and thus is not nephrotoxic, in contrast to cidofovir. Thus, with a lower toxicity profile, greater antiviral activity, and an oral formulation, brincidofovir has been greeted with great excitement as a potential treatment for CMV, adenovirus, and BK polyomavirus, all potent viral pathogens after HCT with unmet needs for more effective therapies.

The development pathway for brincidofovir seemed well in hand several years ago after a randomized trial testing placebo vs various doses of brincidofovir given weekly or twice weekly to adult CMV-seropositive HCT recipients as prophylaxis to prevent CMV viremia or disease demonstrated substantial CMV protection using a dose of 100 mg twice weekly. There was no myelosuppression or nephrotoxicity.²  The dose-limiting toxicity was diarrhea at a dose of 200 mg twice weekly.

Since then, the road has been rocky. The results of a phase 3 trial of CMV prevention were presented at the Tandem BMT meetings in 2016.³  The trial compared brincidofovir at a dose of 100 mg twice weekly to placebo, and unfortunately failed to demonstrate a lower rate of clinically significant CMV infection at week 24 after HCT.³  There was a significantly lower rate of clinically significant CMV infections at week 14 (24% vs 38%) in the brincidofovir group, but there were more infections in the 10-week follow-up period, resulting in similar rates at the end of 24 weeks (51% vs 52%; the primary endpoint). There was a substantially higher rate of diarrhea in the brincidofovir group. Many of the diarrhea events were attributed to gut graft-versus-host disease (GVHD) by the investigators, which led to initiation of steroids (eightfold higher use of corticosteroids in the brincidofovir group). Unfortunately, some (or much) of the presumed gut GVHD was likely a result of brincidofovir mucosal injury. Blinded adjudicator assessment and histologic review were not able to distinguish toxicity from gut GVHD.

There was another disappointing secondary observation in that trial: the rate of BK polyomavirus was not reduced during either treatment or follow-up phases in the brincidofovir group.

Trials with adenovirus have continued, and the report in this issue coupled with several other reports suggest a potential path forward for this drug. In a cohort of immunocompromised patients with adenovirus disease after cidofovir failure, more than two-thirds of the patients demonstrated a more than 99% drop in plasma viremia, even with profound lymphopenia.⁴  A randomized phase 2 trial compared 2 dose schedules of brincidofovir (100 mg twice weekly and 200 mg once weekly) with placebo in small groups of patients (14-16 per cohort).⁵  The twice-weekly regimen was associated with a much higher virologic response with complete clearance of viremia at 1 week in 67% compared with 29% in the once-weekly dosing group and 33% in the placebo group. There were trends to improved survival, but these were not significantly different (however, the study was underpowered to detect such differences). Unfortunately, there was also more diarrhea in the twice-weekly regimen (mostly mild to moderate) and more gut GVHD, echoing the findings in the CMV trial. Of interest, the diarrhea in the Hiwarkar study in this issue was less of a concern than in the earlier reports. The reason for this is not clear. Are children less susceptible to gut toxicity than adults (there were mixtures of adults and children in the other studies)? Does the dose (by weight) given to children result in lower drug exposure than that in adults?

What is the path forward for brincidofovir? The diarrhea/GVHD seen with brincidofovir is a legitimate concern to be addressed. One important clue as a way around this was uncovered in post hoc analyses of the CMV prevention trial.³  In patients who developed diarrhea on brincidofovir, about a third continued brincidofovir and were treated for GVHD, whereas two-thirds interrupted drug administration until symptoms abated. Both the rates of primary endpoint failure and mortality were much lower in patients who merely interrupted the drug administration rather than continuing it, and the outcomes were comparable to the rates of patients who did not develop diarrhea. Thus, a structured approach to managing diarrhea may be key to overcoming much of this problem.

Antiviral drug therapy is not the only technology that holds promise to combat adenovirus. Antiviral cellular therapies also offer hope for deadly infections from adenovirus and other DNA viruses.⁶  By addressing the underlying immune defect that puts patients at risk, cellular therapy may provide more durable control. However, the development path for cell technologies also faces formidable challenges. The unmet need for effective adenovirus therapy is important and, because of the infection’s high mortality, the challenge deserves continued efforts to get effective therapies to the clinic.