Maribavir for Refractory Cytomegalovirus Infections With or Without Resistance Post-Transplant: Results From a Phase 3 Randomized Clinical Trial

Abstract

Background: Therapies for refractory cytomegalovirus infections (with or without resistance [R/R]) in transplant recipients are limited by toxicities. Maribavir has multimodal anti-cytomegalovirus activity through the inhibition of UL97 protein kinase.

Methods: In this phase 3, open-label study, hematopoietic-cell and solid-organ transplant recipients with R/R cytomegalovirus were randomized 2:1 to maribavir 400 mg twice daily or investigator-assigned therapy (IAT; valganciclovir/ganciclovir, foscarnet, or cidofovir) for 8 weeks, with 12 weeks of follow-up. The primary endpoint was confirmed cytomegalovirus clearance at end of week 8. The key secondary endpoint was achievement of cytomegalovirus clearance and symptom control at end of week 8, maintained through week 16.

Results: 352 patients were randomized (235 maribavir; 117 IAT). Significantly more patients in the maribavir versus IAT group achieved the primary endpoint (55.7% vs 23.9%; adjusted difference [95% confidence interval (CI)]: 32.8% [22.80-42.74]; P < .001) and key secondary endpoint (18.7% vs 10.3%; adjusted difference [95% CI]: 9.5% [2.02-16.88]; P = .01). Rates of treatment-emergent adverse events (TEAEs) were similar between groups (maribavir, 97.4%; IAT, 91.4%). Maribavir was associated with less acute kidney injury versus foscarnet (8.5% vs 21.3%) and neutropenia versus valganciclovir/ganciclovir (9.4% vs 33.9%). Fewer patients discontinued treatment due to TEAEs with maribavir (13.2%) than IAT (31.9%). One patient per group had fatal treatment-related TEAEs.

Conclusions: Maribavir was superior to IAT for cytomegalovirus viremia clearance and viremia clearance plus symptom control maintained post-therapy in transplant recipients with R/R cytomegalovirus. Maribavir had fewer treatment discontinuations due to TEAEs than IAT. Clinical Trials Registration. NCT02931539 (SOLSTICE).

Keywords: antiviral agents; cytomegalovirus; drug resistance; maribavir; transplant recipients.

Conflict of interest statement

Potential conflicts of interest. R. K. A.: study grant support: AiCuris, Astellas, Chimerix, Merck, Oxford Immunotec, Qiagen, and Takeda/Shire. S. A.: research funding as a scientific expert and site principal investigator: Altona, BioMérieux, Biotest, GlaxoSmithKline, Merck, Merck Sharp & Dohme, Qiagen, Shire, a Takeda company; honoraria for lectures paid to their institution: Biotest, Merck Sharp & Dohme, IQone; support for attending meetings: BioMérieux, Biotest, Quality Control for Molecular Diagnostics; advisory board (unpaid): Quality Control for Molecular Diagnostics. Primary investigator for this study in France. B. D. A.: research funding for work as an investigator: Scynexis, Shire, a Takeda company; research funding to institution for work as an investigator: Astellas, Cidara, F2G, Leadiant; royalties or licenses: UpToDate; consulting fees: Astellas, Scynexis; leadership or fiduciary role: Past President Infectious Diseases Society of America. E. A. B.: research support to their institution: Hologic, Merck, Takeda; scientific medical advisor (unpaid): Merck; Data and Safety Monitoring Board: Amplyx; leadership or fiduciary role: board member (including office holder) American Society of Transplantation. R. F. C.: institutional research grants: AiCuris, Ansun Biopharma, Chimerix, Janssen, Karius, Merck, Novartis, Oxford Immunotec, Pulmotect, Shire, a Takeda company, Viracor; consulting fees: ADMA Biologics, Ansun Biopharma, Janssen, Merck, Molecular Partners, Qiagen, Shire, a Takeda company; honoraria: Genentech, Merck, Oxford Immunotec, Partner Therapeutics, Pulmotect, Shire, a Takeda company; Data Safety Monitoring Board or Advisory Board: Enanta, Duke; stock or stock options: Xenex. C. C.: departmental research funding: Merck, Shire, a Takeda company; consulting fees for advisory board and speaker bureau participation: Merck, Takeda. R. F. D.: departmental research funding: Janssen, Merck, Novartis, Omeros, Roche Diagnostics; consulting fees for advisory boards and speaker bureau participation: Bristol Myers Squibb, Gilead Sciences, Incyte, Jazz Pharmaceuticals, Merck, Omeros, Pfizer, Sanofi Oncology, Sobi, Shire, a Takeda company. D. F. F.: research support for work as an investigator: Astellas, Merck, Nobelpharma, Novavax, Shire, a Takeda company; Data Safety Monitoring Board: Amplyx; advisory boards: Merck, Takeda. N. K.: advisory board and speaker’s fees: Astellas, Biotest, Chiesi, CSL Behring, Merck Sharp & Dohme, Neovii, Novartis Pharma, Sandoz, Sanofi, Shire, a Takeda company. D. K.: consultant: Roche, Sanofi, Takeda; grant/research support: Merck, Qiagen, Roche, Takeda; speaking fee: Astellas. J. M.: consulting fees from Shire/Takeda during the conduct of the study, as well as consulting fees and nonfinancial support from Amgen, Astellas Pharma, Basilea, Cidara, F2G, Schering-Plough, Scynexis; and grants, consulting fees, and nonfinancial support from Bio-Rad, Gilead Sciences, Merck, Pfizer Inc, outside the submitted work; honoraria: Astellas, F2G, Gilead, Pfizer Inc, Merck Sharp & Dohme, Mundipharma. F. M. M.: consultant: AlloVir, Amplyx, Avir, Emcure, F2G, Gilead, Janssen, Kyorin, Merck, Regeneron, ReViral, Symbio, United Medical; investigator and research funding: Ansun, Chimerix, Cidara, Scynexis, Shire, a Takeda company, WHISCON; research funding: AlloVir, Amplyx, F2G, Gilead, Merck, Regeneron. G. A. P.: consulting fees: ADMA Biologics, AlloVir, Amplyx, Astellas, Behring, Cidara, Octapharma, Partner Therapeutics, Shionogi, Shire, a Takeda company, Siemens Healthineers; investigator: Merck, Shire, a Takeda company; honoraria for speaking engagement: Basilea, Merck, Merck Sharp & Dohme Europe. F. P. S.: research support for work as an investigator: Ansun Biopharma, Gilead, Merck, Novartis, Qiagen, Shire, a Takeda company, SlieaGen, WHISCON; travel funding to meetings: Shire, a Takeda company; lecture honoraria: Janssen; consulting fees: Takeda. O. W.: research grants for clinical studies, speaker’s fees, honoraria, and travel expenses: Alexion, Amgen, Astellas, Basilea, Biotest, Bristol Myers Squibb, Chiesi, Correvio, Gilead, Hexal, Janssen, Dr. F. Köhler Chemie, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Sanofi, Takeda, Teva, UCB; unrestricted grant from the Rudolf-Ackermann-Stiftung (Stiftung für Klinische Infektiologie). J. W., A. K. S., and M. F.: employees of and holding stock/stock options in: Takeda Development Center Americas, Inc. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America.

Figures

Graphical Abstract

Figure 1.

Trial design. aVisit 2A/2A(R) was only required for patients receiving tacrolimus, cyclosporine, everolimus, or sirolimus at visit 2/2R. Abbreviations: BID, twice daily; BL, baseline; R, rescue; Rand, randomization; Wk, week.

Figure 2.

Patient disposition at enrollment, randomization, and follow-up. Percentages were calculated based on the number of patients randomized to each treatment group. Percentages may not total to 100% due to rounding. Serious AEs were recorded until the end of trial participation or resolution (whichever was later); median on-study duration was 141.0 days in each group. aPatients could have multiple reasons for not being randomized. Other reasons were: patient did not receive an HCT or SOT (n = 1); CMV infection not confirmed refractory to most recent treatment (n = 2); investigator not willing to treat the patient with ganciclovir, valganciclovir, foscarnet, or cidofovir (n = 2); platelet count <25 000/mm3 (n = 5); hemoglobin <8 g/dL (n = 1); eGFR ≤30 mL/min/1.73 m2 (n = 1); pregnancy (n = 1); patient was not willing/not able to comply fully with study procedures/restrictions (n = 3); current refractory or resistant CMV infection due to inadequate adherence to prior treatment (n = 2); serum aspartate aminotransferase >5 × ULN at screening, or serum alanine aminotransferase >5 × ULN at screening, or total bilirubin ≥3.0 × ULN at screening (n = 1); received any investigational agent with known anti-CMV activity within 30 days before initiation of study treatment or investigational CMV vaccine at any time (n = 1); and active malignancy (n = 1). bOne patient per group was randomized but did not receive trial medication. Percentage for each IAT type was calculated based on n = 116. cOther reasons for treatment discontinuation in the maribavir group included investigator decision to switch to letermovir, CMV detected in patient’s cerebrospinal fluid, nothing-by-mouth status with mental status change with risk for aspiration, and disease progression (in 1 patient each). dOther reasons for treatment discontinuation in the IAT group were: low viral load/CMV clearance (with concern of toxicity with continued administration of IAT (n = 9), patient safety (n = 3), patient/investigator request (n = 2), no efficacy and patient ineligible for rescue therapy (n = 1), and peripherally inserted central catheter issues (n = 1). eThese results are based on investigator determination for the primary reason for study discontinuation. fOther reasons for study discontinuation in maribavir or IAT group included investigator discretion to discontinue 1 patient before dosing with maribavir, and no efficacy with IAT for a patient who was not eligible for rescue therapy. gPer protocol, maribavir rescue arm treatment was discontinued in 1 patient due to CMV encephalitis. hOne patient was unable to complete follow-up visits in the study due to hospitalization in a different city and therefore did not complete the maribavir rescue study period. Abbreviations: AE, adverse event; CMV, cytomegalovirus; eGFR, estimated glomerular filtration rate; HCT, hematopoietic-cell transplant; IAT, investigator-assigned therapy; SOT, solid-organ transplant; ULN, upper limit of normal.

Figure 3.

A, CMV viremia clearance at week 8 overall (primary endpoint). B, CMV viremia clearance at week 8 in subgroups (randomized population). Between-group differences adjusted for applicable stratification factor(s) of baseline CMV DNA level (low or intermediate/high) and SOT/HCT. Six patients received cidofovir as IAT (data not shown); 1 patient did not receive a dose of IAT. Symptomatic CMV infection at baseline was determined by an independent and blinded EAC. Abbreviations: CI, confidence interval; CMV, cytomegalovirus; EAC, Endpoint Adjudication Committee; HCT, hematopoietic-cell transplant; IAT, investigator-assigned therapy; NA, not applicable as adjusted between-group differences used the full maribavir group; SOT, solid-organ transplant.

Figure 4.

Secondary endpoints: confirmed viremia clearance and symptom control at week 8 and maintained through week 12, week 16 (key secondary endpoint), and week 20 (randomized population). Symptom control was defined as resolution/improvement of CMV disease/syndrome for patients symptomatic at baseline or absence of the development of CMV disease/syndrome for patients asymptomatic at baseline. Abbreviations: CI, confidence interval; CMV, cytomegalovirus; IAT, investigator-assigned therapy.