Design and Rationale of a Randomized, Double-Blind, Placebo-Controlled, Phase 2/3 Study Evaluating Dociparstat in Acute Lung Injury Associated with Severe COVID-19.

INTRODUCTION: The COVID-19 global pandemic caused by the novel coronavirus, SARS-CoV-2, and the consequent morbidity and mortality attributable to progressive hypoxemia and subsequent respiratory failure threaten to overrun hospital critical care units globally. New agents that address the hyperinflammatory "cytokine storm" and hypercoagulable pathology seen in these patients may be a promising approach to treat patients, minimize hospital stays, and ensure hospital wards and critical care units are able to operate effectively. Dociparstat sodium (DSTAT) is a glycosaminoglycan derivative of heparin with robust anti-inflammatory properties, with the potential to address underlying causes of coagulation disorders with substantially reduced risk of bleeding compared to commercially available heparin. METHODS: This study is a randomized, double-blind, placebo-controlled, phase 2/3 trial to determine the safety and efficacy of DSTAT added to standard of care in hospitalized adults with COVID-19 who require supplemental oxygen. Phase 2 will enroll 12 participants in each of two dose-escalating cohorts to confirm the safety of DSTAT in this population. Following review of the data, an additional 50 participants will be enrolled. Contingent upon positive results, phase 3 will enroll approximately 450 participants randomized to DSTAT or placebo. The primary endpoint is the proportion of participants who survive and do not require mechanical ventilation through day 28. DISCUSSION: Advances in standard of care, recent emergency use authorizations, and positive data with dexamethasone have likely contributed to an increasing proportion of patients who are surviving without the need for mechanical ventilation. Therefore, examining the time to improvement in the NIAID score will be essential to provide a measure of drug effect on recovery. Analysis of additional endpoints, including supportive biomarkers (e.g., IL-6, HMGB1, soluble-RAGE, D-dimer), will be performed to further define the effect of DSTAT in patients with COVID-19 infection. TRIAL REGISTRATION: ClinicalTrials.gov identifier; NCT04389840, Registered 13 May 2020.

A Randomized, Double-Blind, Placebo-Controlled Phase 3 Trial of Oral Brincidofovir for Cytomegalovirus Prophylaxis in Allogeneic Hematopoietic Cell Transplantation.

Cytomegalovirus (CMV) infection is a common complication of allogeneic hematopoietic cell transplantation (HCT). In this trial, we randomized adult CMV-seropositive HCT recipients without CMV viremia at screening 2:1 to receive brincidofovir or placebo until week 14 post-HCT. Randomization was stratified by center and risk of CMV infection. Patients were assessed weekly through week 15 and every third week thereafter through week 24 post-HCT. Patients who developed clinically significant CMV infection (CS-CMVi; CMV viremia requiring preemptive therapy or CMV disease) discontinued the study drug and began anti-CMV treatment. The primary endpoint was the proportion of patients with CS-CMVi through week 24 post-HCT; patients who discontinued the trial or with missing data were imputed as primary endpoint events. Between August 2013 and June 2015, 452 patients were randomized at a median of 15 days after HCT and received study drug. The proportion of patients who developed CS-CMVi or were imputed as having a primary endpoint event through week 24 was similar between brincidofovir-treated patients and placebo recipients (155 of 303 [51.2%] versus 78 of 149 [52.3%]; odds ratio, .95 [95% confidence interval, .64 to 1.41]; P = .805); fewer brincidofovir recipients developed CMV viremia through week 14 compared with placebo recipients (41.6%; P < .001). Serious adverse events were more frequent among brincidofovir recipients (57.1% versus 37.6%), driven by acute graft-versus-host disease (32.3% versus 6.0%) and diarrhea (6.9% versus 2.7%). Week 24 all-cause mortality was 15.5% among brincidofovir recipients and 10.1% among placebo recipients. Brincidofovir did not reduce CS-CMVi by week 24 post-HCT and was associated with gastrointestinal toxicity.

Brincidofovir for Asymptomatic Adenovirus Viremia in Pediatric and Adult Allogeneic Hematopoietic Cell Transplant Recipients: A Randomized Placebo-Controlled Phase II Trial.

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/mm3 versus ≥300 cells/mm3). 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 log10 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 ≥1000 copies/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.

Brincidofovir Is Not a Substrate for the Human Organic Anion Transporter 1: A Mechanistic Explanation for the Lack of Nephrotoxicity Observed in Clinical Studies.

BACKGROUND: Brincidofovir (BCV) is an orally bioavailable lipid conjugate of cidofovir (CDV) with increased in vitro potency relative to CDV against all 5 families of double-stranded DNA viruses that cause human disease. After intravenous (IV) administration of CDV, the organic anion transporter 1 (OAT1) transports CDV from the blood into the renal proximal tubule epithelial cells with resulting dose-limiting nephrotoxicity. OBJECTIVE: To study whether OAT1 transports BCV and to evaluate the pharmacokinetic and renal safety profile of oral BCV compared with IV CDV. METHODS: The cellular uptake of BCV and its major metabolites was assessed in vitro. Renal function at baseline and during and after treatment in subjects in BCV clinical studies was examined. RESULTS: In OAT1-expressing cells, uptake of BCV and its 2 major metabolites (CMX103 and CMX064) was the same as in mock-transfected control cells and was not inhibited by the OAT inhibitor probenecid. In human pharmacokinetic studies, BCV administration at therapeutic doses resulted in detection of CDV as a circulating metabolite; peak CDV plasma concentrations after oral BCV administration in humans were <1% of those observed after IV CDV administration at therapeutic doses. Analysis of renal function and adverse events from 3 BCV clinical studies in immunocompromised adult and pediatric subjects indicated little to no evidence of associated nephrotoxicity. Over 80% of subjects who switched from CDV or foscarnet to BCV experienced an improvement in renal function as measured by maximum on-treatment estimated glomerular filtration rate. CONCLUSIONS: The lack of BCV uptake through OAT1, together with lower CDV concentrations after oral BCV compared with IV CDV administration, likely explains the superior renal safety profile observed in immunocompromised subjects receiving BCV compared with CDV.