Background: Adenovirus (AdV) infection is an important cause of morbidity and mortality after hematopoietic cell transplant (HCT). Cidofovir is often used off-label to treat AdV viremia but does not lead to resolution of viremia without T cell immune reconstitution [1Hiwarkar P. Amrolia P. Sivaprakasam P. et al.Brincidofovir is highly efficacious in controlling adenoviremia in pediatric recipients of hematopoietic cell transplant.Blood. 2017; 129: 2033-2037Crossref PubMed Scopus (70) Google Scholar]. Brincidofovir (BCV) is an investigational antiviral with high potency in vitro against all AdV subtypes. BCV was evaluated as a treatment for AdV infection or disease in pediatric allogeneic HCT recipients in the AdVise trial (CMX001-304; NCT02087306); primary analyses were previously presented [2Prasad V. Papanicolaou G.A. Marón G.M. et al.Treatment of Adenovirus Infection in Allogeneic Hematopoietic Cell Transplant Patients with Brincidofovir: Final 36 Week Results from the AdVise Trial. BMT Tandem, Orlando FL2017Google Scholar]. Herein we further analyze the effect of BCV on AdV viral burden in the subgroup of pediatric HCT patients with clinically significant AdV viremia (≥1000 copies/mL) within 100 days of transplant, and examine the correlation of viral burden with clinical outcome. Methods: In the AdVise trial, patients were treated with oral BCV 2 mg/kg (up to 100 mg) twice weekly for 12 weeks and followed for 36 weeks post-first dose. AdV viremia outcomes were assessed at multiple time points, including clearance of viremia, reductions in viremia, time to clearance, time undetectable, time under 1000 copies/mL, and viral burden measured as area under the viremia-time curve (AUC) and time-averaged area under the viremia-time curve (AAUC). Associations between these viral responses and mortality were examined. Results: Of the 100 pediatric allo HCT patients enrolled in the AdVise trial, 40 presented with AdV viremia ≥1000 copies/mL within 100 days of transplant. Thirty-four (85%) cleared the virus on BCV, with a median (IQR) time to clearance of 22 (15, 38) days. Twenty-one (53%) of these 40 patients were alive at Week 36. Mean (SD) Week 12 AAUC was 2.4 (.5) log10 c/mL in patients alive at Week 36 versus 3.3 (1.7) log10 c/mL in patients who died prior to Week 36 (see Figure 1; Satterthwaite t-test P = .038). Baseline AdV viremia was positively correlated with AAUC (R2 = .30). Conclusions: Rapid declines in AdV viral load, clearance of AdV, and reductions in AdV viral burden were observed in pediatric allogeneic HCT recipients treated with BCV. Viral responses were associated with improved survival. These data support continued development of BCV as the first potential therapeutic for AdV.

Brincidofovir (BCV, CMX001) is an orally available, long-acting, broad-spectrum antiviral that has been evaluated in healthy subjects in Phase I studies and in hematopoietic cell transplant recipients and other immunocompromised patients in Phase II/III clinical trials for the prevention and treatment of cytomegalovirus and adenovirus infections. BCV has also shown in vitro activity against orthopoxviruses such as variola (smallpox) virus, and is under advanced development as a treatment for smallpox under the US FDA's 'Animal Rule'. The anticipated treatment regimen for smallpox is a total weekly dose of 200 mg administered orally for 3 consecutive weeks. To assess the benefit-to-risk profile of BCV for the treatment of smallpox, we evaluated short-term safety data associated with comparable doses from Phase I studies and from adult and pediatric subjects in the cytomegalovirus and adenovirus clinical programs. When administered at doses and durations similar to that proposed for the treatment of smallpox, BCV was generally well tolerated in both adults and pediatric subjects. The most common adverse events were mild gastrointestinal events and asymptomatic, transient, and reversible elevations in serum transaminases. The data presented herein indicate a favorable safety profile for BCV for the treatment of smallpox, and support its continued development for this indication.

Adenovirus infection in immunocompromised patients contributes to significant morbidity and mortality, especially after allogeneic hematopoietic cell transplantation (HCT). Brincidofovir (BCV, CMX001) is an orally bioavailable lipid conjugate of cidofovir that has in vitro activity against adenoviruses and other double stranded DNA viruses. This randomized placebo-controlled phase II trial evaluated pre-emptive treatment with BCV for the prevention of adenovirus disease in pediatric and adult allogeneic HCT recipients with asymptomatic adenovirus viremia. Allogeneic HCT recipients with adenovirus viremia were randomized 1:1:1 to receive oral BCV 100 mg (2 mg/kg if < 50 kg) twice weekly (BIW), BCV 200 mg (4 mg/kg if < 50 kg) once weekly (QW), or placebo for 6 to 12 weeks, followed by 4 weeks of post-treatment follow-up. For randomization, subjects were stratified by screening absolute lymphocyte count (< 300 cells/mm(3) versus >= 300 cells/mm(3)). Assignment to BCV or placebo was double blinded; dose frequency was unblinded. The primary endpoint was the proportion of subjects experiencing treatment failure, defined as either progression to probable or definitive adenovirus disease or confirmed increasing adenovirus viremia (>= 1 log(10) copies/mL) during randomized therapy. Between June 2011 and December 2012, 48 subjects were randomized to the BCV BIW (n = 14), BCV QW (n = 16), or placebo (n = 18) groups. The proportion of subjects with treatment failure in the BCV BIW group was 21% (odds ratio, .53; 95% confidence interval [CI], .11 to 2.71; P =.45), 38% (odds ratio, 1.23; 95% CI, .30 to 5.05, P =.779) in the BCV QW group, and 33% in the placebo group. All-cause mortality was lower in the BCV BIW (14%) and BCV QW groups (31%) relative to the placebo group (39%), but these differences were not statistically significant. After 1 week of therapy, 8 of 12 subjects (67%) randomized to BCV BIW had undetectable adenovirus viremia (< 100 copies/mL), compared with 4 of 14 subjects (29%) randomized to BCV QW and 5 of 15 subjects (33%) randomized to placebo. In a post hoc analysis of subjects with viremia >= 1000copies/mL at baseline, 6 of 7 BCV BIW subjects (86%) achieved undetectable viremia compared with 2 of 8 placebo subjects (25%; P =.04). Early treatment discontinuation because of adverse events was more common in subjects treated with BCV than with placebo. Diarrhea was the most common event in all groups (57% BCV BIW, 38% BCV QW, 28% placebo), but it led to treatment discontinuation in only 1 subject receiving BCV QW. Events diagnosed as acute graft-versus-host disease, primarily of the gastrointestinal tract, were more frequent in the BCV BIW group (50%) than in the BCV QW (25%) and placebo (17%) groups. There was no evidence of myelotoxicity or nephrotoxicity in BCV-treated subjects. The results of this trial confirm the antiviral activity of BCV against adenoviruses. Further investigation is ongoing to define the optimal treatment strategy for HCT recipients with serious adenovirus infection and disease. (c) 2017 American Society for Blood and Marrow Transplantation.

Background: AdV is an important cause of mortality after HCT. Disseminated AdV disease is associated with 50-80% mortality, typically within 60 days of diagnosis. Brincidofovir (BCV), an investigational antiviral, has high in vitro potency against all AdV subtypes. Herein we describe outcomes in 158 allo HCT pts treated with BCV. Methods: Pediatric (peds, <18 y) and adult allo HCT pts received oral BCV 100 mg (2 mg/kg if <50 kg) twice weekly for 12 wks. Cohort A had asymptomatic viremia or localized infection (n = 65; 23 adults, 42 peds); Cohort B had disseminated disease (n = 93; 35 adults, 58 peds). Results: Median (IQR) BCV treatment duration was 81 days (39-108) in peds and 49 days (18-81) in adults. Median time from HCT to 1st BCV dose was 59 days in peds and 99 days in adults. In peds, 51% received the 1st dose within 60 days of HCT (28% in adults), while 33% received the 1st dose 90 or more days after HCT (57% in adults). Prior IV cidofovir use was 53% in peds and 29% in adults. At baseline, 78 peds (78%) and 49 adults (84%) had AdV viremia in plasma (median 3.2 and 4.8 log10 copies/mL, respectively) (Table 1).Table 1Association between AdV Virologic Response and Survival at Week 36Definition of ResponderPeds (N=100)Adults (N=58)Proportion of Responders*Denominator: Pts with baseline AdV viremia still on study at wk 4 or wk 6.Mortality in:Proportion of Responders*Denominator: Pts with baseline AdV viremia still on study at wk 4 or wk 6.Mortality in:RespondersNon-respondersRespondersNon-respondersCohort A (asymptomatic or localized infection; N=65)≥2log10 drop in viremia or ND at wk 481%21/2629%6/2140%2/554%7/1343%3/783%5/6ND at wk 668%17/2529%5/1725%2/862%8/1350%4/880%4/5Cohort B (disseminated disease; N=93)≥2log10 drop in viremia or ND at wk 484%36/4331%11/36†P < 0.05 vs. non-responders, Cox model for time to death.71%5/750%13/2662%8/13†P < 0.05 vs. non-responders, Cox model for time to death.92%12/13ND at wk 668%28/4125%7/28†P < 0.05 vs. non-responders, Cox model for time to death.54%7/1342%10/2450%5/10†P < 0.05 vs. non-responders, Cox model for time to death.93%13/14ND, no detectable viremia.* Denominator: Pts with baseline AdV viremia still on study at wk 4 or wk 6.† P < 0.05 vs. non-responders, Cox model for time to death. Open table in a new tab ND, no detectable viremia. All-cause mortality was lower in peds (42%) vs. adults (69%) at wk 36. AdV–associated mortality was 8% at day 90 and 12% at wk 36 in peds. Assessment of enrollment period as a covariate demonstrated a period effect with lower mortality in Cohort B peds enrolled in the last quartile (21%) compared to those enrolled at the beginning of the study (67%); differences were less pronounced in adults (63% 4th quartile vs. 78% 1st quartile). BCV was discontinued due to AEs in 22% of peds and 29% of adults; GI AEs were the most common (7% and 14%, respectively). Conclusions: Rapid declines in AdV viremia were observed in the majority of allo HCT pts treated with BCV. Survival was higher in pts with virologic response to BCV. These differences were statistically significant in both adults and peds. Virologic response and survival were higher in peds, compared to adults. Late mortality in peds was driven by competing risks rather than AdV. These data support continued development of BCV as the first potential therapeutic for AdV, especially in the peds population.

AdV is associated with significant morbidity and mortality. No drug is currently approved for AdV. BCV is an orally available lipid-conjugate of cidofovir (CDV) that has demonstrated promise as preemptive therapy in allo HCT patients (pts) with asymptomatic AdV viremia (VL) in a Phase 2 study. The pilot portion of a Phase 3 BCV study for AdV (CMX001-304, AdVise Study; NCT02087306) was initiated in MAR2014. Preliminary results for 26 subjects enrolled through 15JUL2014 are described (data cut-off 12SEP2014). All subjects receive open-label BCV 100 mg (≥ 50 kg) or 2 mg/kg (< 50 kg) twice a week. For the 26 subjects, median age = 6.5 y (range: 0-29), 58% < 12 y; 20 allo HCT pts (16 with disseminated disease), 4 solid organ transplant pts and 2 chemotherapy pts; median VL in plasma by quantitative polymerase chain reaction (PCR) at baseline (BL) 4.8 log10c/mL (range: undetectable [< 2 log10; < LOD] to > 10 log10) (n = 23); 46% were AdV positive in respiratory secretions, 58% in urine, 58% in stool by qualitative PCR; 42% (11/26) had prior IV CDV exposure. Median BCV treatment duration 54 days (range: 1 to 108). Suppression of plasma AdV VL to < LOD by quantitative PCR was 61% (14/23) at any time on-treatment and 52% (12/23) at last on-treatment value. Median change in plasma AdV VL from BL to nadir was -1.4 log10 c/mL (range: -8.0 to 0.6), with 65% (15/23) achieving ≥ 3 log10 decrease to nadir (or to < LOD). Individual plots of plasma AdV VL over time are shown in the figure. In subjects with positive qualitative AdV PCR at BL, 42% (5/12) cleared AdV in respiratory secretions, 33% (5/15) in urine and 27% (4/15) in stool. Six of the 11 subjects with prior IV CDV achieved AdV VL < LOD and one had > 2 log10 decline at last on-treatment value. Treatment-related AEs requiring premature BCV discontinuation were limited to severe diarrhea (in two subjects). Among the 48 subjects enrolled through 19SEP2014, there were 17 deaths, including two of seven subjects with asymptomatic disease (29%), in 11 of 29 allo HCT subjects with disseminated AdV (38%) and four of 12 subjects with non-allo HCT disseminated AdV (33%), representing an overall mortality rate to-date of 35% (17/48), with a median duration of observation of 57 days for living pts. Safety and efficacy data from newly enrolled subjects will be included in the presentation. These preliminary results from 26 subjects enrolled in the pilot portion of AdVise show mortality rates of < 40% across subjects with limited and disseminated AdV and across populations with varying identified risk factors (HCT, SOT, other); these are lower mortality rates than those in the literature for disseminated disease. AdV viremia was suppressed to undetectable in over half of enrolled subjects. No new safety concerns were identified in this complex patient population. These data support progression to definitive Phase 3 BCV study for AdV.

Polyomavirus-associated nephropathy (PVAN) is common in patients who have undergone kidney transplantation and has been reported in hematopoietic stem cell (HSC) transplant recipients. Aside from reduction of immunosuppression, few therapeutic options exist for treatment of PVAN. We report a case of PVAN in a severely immunocompromised allogeneic HSC transplant recipient that was treated with brincidofovir without reduction of immunosuppression. We review our institutional experience of PVAN in HSC transplantation and discuss the potential use of brincidofovir for treatment.

Background: Infectious complications remain an important cause of morbidity/mortality following SOT. Brincidofovir (BCV), a nucleotide analog active in vitro against all major human pathogenic dsDNA viruses, is in Phase 3 development for CMV prevention in HCT. Over 400 patients (pts) have received BCV for serious or life-threatening infections with dsDNA viruses under compassionate use (Study CMX001-350, clinicaltrials.gov ID: NCT01143181 or under emergency INDs).

Background: Infectious complications remain an important cause of morbidity/mortality following SOT. Brincidofovir (BCV), a nucleotide analog active in vitro against all major human pathogenic dsDNA viruses, is in Phase 3 development for CMV prevention in HCT. Over 400 patients (pts) have received BCV for serious or life-threatening infections with dsDNA viruses under compassionate use (Study CMX001-350, clinicaltrials.gov ID: NCT01143181 or under emergency INDs). Methods: Ten multiorgan transplant pts (liver ± kidney/pancreas/small bowel) were treated for serious or life-threatening AdV, BKV, CMV, EBV or VZV infections after failing existing antiviral therapies. BCV was given orally at 2-4 mg/kg or 100-200 mg twice-weekly. Results: Pt demography and virologic responses [viral load (VL) at baseline (BL) and maximal (Max) and through end-of-treatment (EOT) decreases]/infection outcomes are summarized in the table:Table: No Caption available.ND=no data; NV=no viremia; R=infection resolved; VR=virologic response; *=undetectable (<100 c/mL) Two pts died on treatment (#7 intracranial haemorrhage, #10 hepatic failure secondary to aortic thrombus, both unrelated to BCV); 2 pts died >30 days posttreatment (#1 PTLD/Pseudomonas pneumonia, #3 septic shock). No adverse events (AEs) required BCV treatment discontinuation and there were no serious drug-related hepatic AEs. Conclusions: These data support the continued study of BCV in the treatment of dsDNA virus infections in SOT and other immunocompromised pts. There were no treatment-limiting AEs and some evidence of improved outcomes, although conclusions are limited by the small sample size and uncontrolled data collection. DISCLOSURES:Florescu, D.: Grant/Research Support, Chimerix, Inc., Other, Chimerix, Inc., Former/current investigator for CMX001 trial. Grimley, M.: Other, Chimerix, Inc., Former/current investigator for CMX001 trials. Nemecek, E.: Other, Chimerix, Inc., Former/current investigator for CMX001 trials. Chittick, G.: Employee, Chimerix, Inc., Stockholder, Chimerix, Inc. Brundage, T.: Employee, Chimerix, Inc., Stockholder, Chimerix, Inc. Mommeja-Marin, H.: Employee, Chimerix, Inc., Stockholder, Chimerix, Inc.

This variant was also detected by UDPS in another woman (3.2%).The rtM204V/I variant was detected in HBV from two women at EOT by UDPS only (rtM204V 8.5%, rtM204I 2.6%).In the control mothers, the LMV resistant variants rtA181T (detected in two women) and rtM204V (detected in one woman) were only detected by UDPS at frequencies of 2.6, 3.7 and 1.8%, respectively.Conclusions: LMV given in the last trimester achieved an overall HBV DNA load reduction of almost 3 log 10 IU/ml, however, for 6/25 (24%) of the women, the viral load remained high.Despite the short treatment period, LMV resistance emerged in HBV from one woman.The more sensitive UDPS revealed the presence of emerging as well as pre-existing genotypic resistant variants present at frequencies below the level of population based sequencing.