# Maribavir for refractory cytomegalovirus infection (with or without resistance) in solid organ transplant recipients: Subgroup analysis of the phase 3 randomized SOLSTICE study

Emily A Blumberg, Oliver Witzke, Mark Harber, Michael G Ison, Faouzi Saliba, Nassim Kamar, Aimee K Sundberg, Joan Gu, Deepali Kumar, Ricardo M La Hoz

► To cite this version:

Emily A Blumberg, Oliver Witzke, Mark Harber, Michael G Ison, Faouzi Saliba, et al. Maribavir for refractory cytomegalovirus infection (with or without resistance) in solid organ transplant recipients: Subgroup analysis of the phase 3 randomized SOLSTICE study. The Journal of Heart and Lung Transplantation, 2025, 44 (6), pp.986 - 994. 10.1016/j.healun.2024.11.026. hal-05523683

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ELSEVIER

ISHLT MEETING

# Maribavir for refractory cytomegalovirus infection (with or without resistance) in solid organ transplant recipients: Subgroup analysis of the phase 3 randomized SOLSTICE study

<figure><img src="image_3.png" /></figure>

CrossMark

Emily A. Blumberg, MD,ª Oliver Witzke, MD,ᵇ Mark Harber, MBBS, PhD,ᶜ

Michael G. Ison, MD, MS,ᵈ Faouzi Saliba, MD,ᵉ,>f Nassim Kamar, MD, PhD, g

Aimee K. Sundberg, PharmD, h Joan Gu, PhD, i Deepali Kumar, MD, FRCPC, MSc, j
and Ricardo M. La Hoz, MD k

From the ᵃDepartment of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104; ᵇDepartment of Infectious Diseases, West German Centre of Infectious Diseases, University Medicine Essen, University Duisburg-Essen, Essen 45141, Germany; ᶜDepartment of Renal Medicine, University College London. Royal Free London NHS Foundation Trust, London NW3 2QG, UK; ᵈBethesda, MD 20852; ᵉUniversity Paris-Saclay, INSERM Unit 1193, France; ṼAP-HP Hôpital Paul Brousse, Hepato-Biliary Centre, 94800 Villejuif, France; ᶜDepartment of Nephrology and Organ Transplantation, Toulouse Rangueil University Hospital, INFINITY-Inserm U1291-CNRS U5051, University Paul Sabatier, Toulouse 31062, France; ᵇClinical Sciences, Takeda Development Center Americas, Inc., Lexington, MA 02421; ᵈBiostatistics, Takeda Development Center Americas, Inc., Lexington, MA 02421; ᵈAjmera Transplant Centre, University Health Network, Toronto, ON M5G 2N2, Canada; and the ᶜDivision of Infectious Diseases and Geographic Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390.

**KEYWORDS:**
Clinical research;
Solid organ
transplantation;
Infection and infectious
agents - viral:
cytomegalovirus
(CMV);
Complication:
infectious

**BACKGROUND:** In the phase 3 SOLSTICE study (NCT02931539), maribavir was superior to investigator-assigned therapy (IAT) for confirmed cytomegalovirus viremia clearance at study week 8 in hematopoietic cell/solid organ transplant (HCT/SOT) recipients. We report additional efficacy and safety analyses from the SOT subgroup.

**METHODS:** Eligible SOT recipients (n=211) received maribavir 400 mg twice daily (n=142) or IAT (n=69) for 8 weeks (12 weeks' follow-up). Cytomegalovirus viremia clearance at week 8 (primary endpoint) and cytomegalovirus viremia clearance plus symptom control at the end of week 8 maintained through week 16 (key secondary endpoint) were assessed. Graft outcomes and treatment-emergent adverse events were analyzed.

**RESULTS:** A higher proportion of maribavir-treated patients achieved the primary endpoint than with IAT across transplant organ types, including kidney (maribavir: 59.5%, IAT: 34.4%), lung (47.5%, 13.6%), and heart (42.9%, 11.1%). Similar proportions of patients achieved the key secondary endpoint in both arms (13.4% versus 11.6%; adjusted difference: 2.4%; 95% CI: -7.05, 11.83%; p=0.620). Rates of treatment-emergent adverse events were: maribavir (96.5%), IAT (88.4%). Maribavir (3.5%)

**Abbreviations:** BID, twice daily; CI, confidence interval; CMV, cytomegalovirus; EAC, endpoint adjudication committee; HCT, hematopoietic cell transplant; HR, hazard ratio; IAT, investigator-assigned therapy; IV, intravenous; N/A, not applicable; R/R, resistant/refractory; SOT, solid organ transplant; TEAE, treatment-emergent adverse event; ULN, upper limit of normal

Corresponding author: Emily Blumberg, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
Telephone: (215) 316-5151.

E-mail address: eblumber@pennmedicine.upenn.edu.
had fewer treatment discontinuations due to treatment-emergent adverse events than IAT (23.2%). There were no graft losses; patients in both arms experienced acute rejection (maribavir: 9 [6.3%]; IAT: 4 [5.8%]). Treatment-emergent maribavir mutations occurred in 28.2% of patients; 19/33 patients achieved viremia clearance with subsequent alternative treatment.

**CONCLUSIONS:** Consistent with findings in the overall SOLSTICE population, this subgroup analysis of SOT recipients demonstrated greater effectiveness of maribavir for cytomegalovirus viremia clearance and fewer discontinuations due to treatment-emergent adverse events than IAT.

**CLINICAL TRIAL REGISTRATION NUMBER:** ClinicalTrials.gov; NCT02931539

J Heart Lung Transplant 2025;44:986-994

© 2025 The Authors. Published by Elsevier Inc. on behalf of International Society for Heart and Lung Transplantation. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

## Introduction

Despite antiviral prophylaxis or pre-emptive therapy, cytomegalovirus (CMV) infection following solid organ transplantation (SOT) remains a common and severe complication that increases the risk of graft dysfunction, rejection, and mortality.<sup>1-4</sup> Prophylaxis relies primarily on conventional antiviral drugs such as intravenous (IV) ganciclovir and oral valganciclovir, which are associated with toxicities, notably cytopenias, that limit their use.<sup>5-7</sup> While letermovir prophylaxis in SOT recipients has been investigated in a few studies,<sup>8-10</sup> there is limited evidence regarding its use in clinical practice. Moreover, these drugs are associated with high economic burden.<sup>11</sup> Inadequate response to conventional anti-CMV therapies can include those with refractory CMV with or without genotypic resistance (resistant/refractory [R/R] CMV) and its incidence is up to 18% among SOT recipients.<sup>12</sup> Conventional treatment options for R/R CMV are often suboptimal<sup>1</sup> and are associated with toxicities.<sup>13,14</sup>

Maribavir is an orally bioavailable antiviral drug that inhibits UL97 kinase and viral DNA synthesis.<sup>15-17</sup> Based on the findings from the phase 3 SOLSTICE study (NCT02931539), maribavir was approved by the FDA in 2021.<sup>18</sup> The results demonstrated that maribavir was superior to investigator-assigned therapy (IAT; ganciclovir/valganciclovir, foscarnet, or cidofovir) for the primary endpoint of CMV viremia clearance at week 8 (55.7% versus 23.9%; adjusted difference: 32.8%; 95% confidence interval [CI]: 22.80, 42.74%; *p* < 0.001) in hematopoietic cell transplant (HCT)/SOT recipients with R/R CMV.<sup>19</sup> A consistent benefit of maribavir versus IAT for the primary endpoint was observed for SOT recipients (55.6% versus 26.1% [adjusted difference: 30.5%; 95% CI: 17.31, 43.61%]). Furthermore, maribavir was associated with fewer treatment discontinuations due to treatment-emergent adverse events (TEAEs) than IAT in the overall population.<sup>19</sup> The current article presents additional efficacy and safety data from the SOT subgroup from the SOLSTICE study.

## Materials and methods

### Study design

The SOLSTICE study, reported previously, was a phase 3, global, randomized, open-label, multicenter, active-controlled

study of maribavir compared with IAT in HCT and SOT recipients with CMV infections refractory to treatment with ganciclovir/valganciclovir, foscarnet, and/or cidofovir, with or without genotypic resistance.<sup>19</sup> It was conducted in accordance with the International Conference on Harmonization Good Clinical Practice guidelines and the principles of the Declaration of Helsinki. Ethics approval was obtained from the institutional review boards/independent ethics committees of each participating institution. Written informed consent was obtained from all patients/legal guardians. The study complies with the International Society of Heart and Lung Transplantation ethics statement.

### Patients

Key eligibility criteria for study enrollment included being an HCT or SOT recipient of ≥12 years of age and weighing ≥35 kg, with a life expectancy of ≥8 weeks; documented CMV infection in whole blood or plasma, with a screening value ≥2730 IU/mL in whole blood or ≥910 IU/mL in plasma in two consecutive assessments, separated by ≥1 day; current CMV infection refractory to the most recently administered of the 4 anti-CMV treatment agents – ganciclovir/valganciclovir, foscarnet, or cidofovir; documentation of ≥1 CMV genetic mutation associated with resistance to ganciclovir/valganciclovir, foscarnet, and/or cidofovir must have also met the definition of refractory CMV infection.<sup>20</sup> Key exclusion criteria were resistant or refractory CMV infection due to inadequate adherence to prior anti-CMV treatment; CMV disease with central nervous system involvement or retinitis; concomitant need for leflunomide, letermovir, or artesunate; aspartate transferase > 5.0 × upper limit of normal (ULN), or alanine aminotransferase > 5.0 × ULN, or total bilirubin ≥3.0 × ULN at screening (except for documented Gilbert's syndrome). For this analysis, only patients from the study who received an SOT were included.

### Treatment

Enrolled patients were randomly assigned in a 2:1 ratio to receive either maribavir 400 mg twice daily (BID) or IAT (ganciclovir/valganciclovir, foscarnet, cidofovir) for 8 weeks followed by a 12-week follow-up phase. IAT type was chosen at the investigators' discretion and could
include mono- or combination therapy (≤2 drugs) with IV ganciclovir, oral valganciclovir, IV foscarnet, or IV cidofovir. Switching between ganciclovir and valganciclovir was permitted. After a minimum of 3 weeks of treatment, patients in the IAT arm with worsening or lack of improvement of CMV infection or failure to achieve viremia clearance plus IAT intolerance could enter a maribavir rescue arm (8-week treatment, 12-week follow-up).

## Study endpoints

The primary endpoint of the study was confirmed CMV clearance (plasma CMV DNA <137 IU/mL in 2 consecutive tests ≥5 days apart) at end of study week 8. Non-responders comprised patients who failed to achieve confirmed CMV viremia clearance at week 8, including patients with missing virologic data, as well as those who received maribavir rescue or alternative anti-CMV treatment before the end of week 8. The key secondary endpoint was the composite of confirmed CMV viremia clearance in conjunction with CMV infection symptom control at the end of week 8 and maintained through study week 16. Non-responders included those who achieved CMV clearance and symptom control at the end of week 8 but in whom these effects were not maintained through week 16 (including missing virologic data), and those who received alternative anti-CMV therapy prior to week 16. Pre-specified safety analyses for SOT recipients included assessment of graft outcomes, TEAEs), and treatment-related TEAEs. The proportion of patients with resistance mutations and who achieved CMV viremia clearance at week 8 was also determined.

## Statistical analysis

The difference in the proportion of patients achieving the primary endpoint or key secondary endpoint between treatment arms was obtained using Cochran–Mantel–Haenszel weighted average across strata of baseline central laboratory CMV viral load. Safety data were analyzed descriptively in all patients who received a dose of study drug.

## Results

### Patient disposition and baseline characteristics

Of the 352 patients enrolled in the SOLSTICE study, 211 were SOT recipients (maribavir arm: *n* = 142; IAT arm: *n* = 69). In the IAT arm, 14 patients received rescue medication and thus were considered non-responders in the primary efficacy analysis; reasons for not achieving the primary endpoint are provided in Figure S1. The baseline characteristics were balanced between the two arms in the SOT subgroup (Table 1). The majority of the SOT recipients were male. Kidney transplant was the most common transplant type in both arms. All patients had a functioning graft at baseline.

## Efficacy

As previously reported, a benefit of maribavir compared with IAT in reaching the primary endpoint (confirmed viremia clearance at week 8) was observed for SOT recipients (Figure 1A).²⁰ This benefit was observed across all SOT types and was statistically significant for kidney and lung transplant recipients. (Figure 1B). A statistically significant benefit for maribavir versus foscarnet/cidofovir was also observed in SOT recipients and in those receiving a kidney transplant (Figure 2). In the maribavir arm, of the 103 SOT recipients who had resistance to ganciclovir, foscarnet and/or cidofovir at baseline, 63 (61%) achieved confirmed CMV viremia clearance at study week 8.

For the key secondary endpoint, the proportion of patients with CMV viremia clearance and symptom control at the end of week 8 and maintained through week 16 was similar in the maribavir arm and IAT arm (13.4% versus 11.6%; adjusted difference: 2.4%; 95% CI: -7.05, 11.83%; *p* = 0.620) in the overall SOT subgroup.

Median time to first confirmed CMV viremia clearance within study week 8 was shorter for maribavir (25.0 days [95% CI: 22.0, 29.0]) than IAT (30.0 days [95% CI: 25.0, 48.0]; *p* = 0.0724). Figure 3 presents data on time to first viremia clearance within week 8 in the SOT subgroup. The proportion of SOT recipients with first viremia clearance within study week 8 was greater for maribavir (73.2%) than IAT (46.4%). Few SOT recipients experienced acute rejection in both the maribavir (6.3%) and IAT (5.8%) arms, while none experienced new chronic rejection or graft loss in either arm during the study period.

During the treatment phase, changes to immunosuppression regimens occurred in a similar number of SOT recipients in each arm: deintensification 19.0% and 20.3%, intensification 15.5% and 11.6%, and no change 65.5% and 68.1% in the maribavir and IAT arms, respectively. Confirmed CMV viremia clearance response at study week 8 in the maribavir arm was similar irrespective of immunosuppressive regimen changes (13/27 [48.1%] deintensification, 11/22 [50.0%] intensification, and 55/93 [59.1%] no change), whereas the proportion of patients in the IAT arm with confirmed CMV viremia clearance at study week 8 was 7/14 (50.0%) with deintensification, 0/8 (0%) with intensification, and 11/47 (23.4%) with no change in immunosuppression regimen.

## Safety

In the SOT subgroup of the SOLSTICE study, median duration of exposure was higher in the maribavir (57 days) than in the IAT arm (43 days). TEAEs occurring in ≥10% of patients in either treatment arm or for the individual IAT safety population (ganciclovir/valganciclovir or foscarnet) are listed in Table 2. Treatment with maribavir was associated with a lower incidence of neutropenia compared with ganciclovir/valganciclovir and acute kidney injury compared with foscarnet. At least 1 TEAE was reported in 96.5% and 88.4% of patients in the maribavir and IAT
<table><caption>**Table 1** Baseline Characteristics of Patients in the SOT Subgroup of the SOLSTICE Study</caption><thead><tr><th>Characteristics</th><th>Maribavir<br>(n = 142)</th><th>IAT<br>(n = 69)</th></tr></thead><tbody><tr><td>Age, years</td><td></td><td></td></tr><tr><td>Median</td><td>56.0</td><td>55.0</td></tr><tr><td>Range</td><td>20-79</td><td>19-77</td></tr><tr><td>Sex, n (%)</td><td></td><td></td></tr><tr><td>Male</td><td>100 (70.4)</td><td>45 (65.2)</td></tr><tr><td>Female</td><td>42 (29.6)</td><td>24 (34.8)</td></tr><tr><td>SOT type, <sup>a</sup> n (%)</td><td></td><td></td></tr><tr><td>Kidney transplant</td><td>74 (52.1)</td><td>32 (46.4)</td></tr><tr><td>Lung transplant</td><td>40 (28.2)</td><td>22 (31.9)</td></tr><tr><td>Heart transplant</td><td>14 (9.9)</td><td>9 (13.0)</td></tr><tr><td>Liver transplant</td><td>6 (4.2)</td><td>1 (1.4)</td></tr><tr><td>Pancreas transplant</td><td>2 (1.4)</td><td>0</td></tr><tr><td>Intestine transplant</td><td>1 (0.7)</td><td>0</td></tr><tr><td>Multi-organ transplant<sup>b</sup></td><td>5 (3.5)</td><td>5 (7.2)</td></tr><tr><td>History of transplant(s) prior<br>to current transplant, n (%)</td><td></td><td></td></tr><tr><td>No</td><td>126 (88.7)</td><td>58 (84.1)</td></tr><tr><td>Yes</td><td>16 (11.3)</td><td>11 (15.9)</td></tr><tr><td>Median days from current<br>transplant date to treatment<br>start date, (range)<sup>c</sup></td><td>268.5<br>(54-8218)</td><td>250.0<br>(85-2568)</td></tr><tr><td>CMV serostatus, n (%)</td><td></td><td></td></tr><tr><td>Donor +/recipient +</td><td>11 (7.7)</td><td>8 (11.6)</td></tr><tr><td>Donor -/recipient +</td><td>3 (2.1)</td><td>1 (1.4)</td></tr><tr><td>Donor +/recipient -</td><td>120 (84.5)</td><td>56 (81.2)</td></tr><tr><td>Donor -/recipient -</td><td>7 (4.9)</td><td>3 (4.3)</td></tr><tr><td>Missing</td><td>1 (0.7)</td><td>1 (1.4)</td></tr><tr><td>Baseline CMV DNA levels</td><td></td><td></td></tr><tr><td>Low</td><td>84 (59.2)</td><td>47 (68.1)</td></tr><tr><td>Intermediate</td><td>46 (32.4)</td><td>15 (21.7)</td></tr><tr><td>High</td><td>12 (8.5)</td><td>7 (10.1)</td></tr><tr><td>CMV infection based on EAC<br>assessment</td><td></td><td></td></tr><tr><td>CMV syndrome</td><td>10 (7.0)</td><td>7 (10.1)</td></tr><tr><td>CMV tissue-invasive disease</td><td>5 (3.5)</td><td>0</td></tr><tr><td>Asymptomatic CMV<br>infection</td><td>128 (90.1)</td><td>62 (89.9)</td></tr><tr><td>Presence of CMV mutation<br>resistant to either<br>ganciclovir/foscarnet/<br>cidofovir per central<br>laboratory results</td><td></td><td></td></tr><tr><td>No</td><td>33 (23.2)</td><td>9 (13.0)</td></tr><tr><td>Yes</td><td>103 (72.5)</td><td>56 (81.2)</td></tr><tr><td>Missing</td><td>6 (4.2)</td><td>4 (5.8)</td></tr><tr><td>Current graft status</td><td></td><td></td></tr><tr><td>Functioning</td><td>127 (89.4)</td><td>61 (88.4)</td></tr><tr><td>Functioning with<br>complications</td><td>12 (8.5)</td><td>8 (11.6)</td></tr><tr><td>Other</td><td>3 (2.1)</td><td>0</td></tr><tr><td>Anti-lymphocyte use</td><td></td><td></td></tr><tr><td>No</td><td>98 (69.0)</td><td>46 (66.7)</td></tr><tr><td>Yes</td><td>44 (31.0)</td><td>23 (33.3)</td></tr></tbody></table>

<table><caption>**Table 1** (Continued)</caption><thead><tr><th rowspan="2">Characteristics</th><th>Maribavir</th><th>IAT</th></tr><tr><th>(n = 142)</th><th>(n = 69)</th></tr></thead><tbody><tr><td>Baseline immunosuppression<sup>d</sup></td><td></td><td></td></tr><tr><td>Corticosteroids for<br>systemic use</td><td>118 (83.1)</td><td>61 (88.4)</td></tr><tr><td>Prednisone</td><td>95 (66.9)</td><td>48 (69.6)</td></tr><tr><td>Prednisolone</td><td>16 (11.3)</td><td>11 (15.9)</td></tr><tr><td>Methylprednisolone</td><td>9 (6.3)</td><td>2 (2.9)</td></tr><tr><td>Hydrocortisone</td><td>2 (1.4)</td><td>1 (1.4)</td></tr><tr><td>Dexamethasone</td><td>0</td><td>1 (1.4)</td></tr><tr><td>Immunosuppressants</td><td>139 (97.9)</td><td>66 (95.7)</td></tr><tr><td>Tacrolimus</td><td>128 (90.1)</td><td>59 (85.5)</td></tr><tr><td>Mycophenolate mofetil</td><td>68 (47.8)</td><td>34 (49.3)</td></tr><tr><td>Azathioprine</td><td>8 (5.6)</td><td>3 (4.3)</td></tr><tr><td>Everolimus</td><td>8 (5.6)</td><td>5 (7.2)</td></tr><tr><td>Cyclosporin</td><td>6 (4.2)</td><td>4 (5.8)</td></tr><tr><td>Sirolimus</td><td>6 (4.2)</td><td>5 (7.2)</td></tr><tr><td>Belatacept</td><td>4 (2.8)</td><td>1 (1.4)</td></tr><tr><td>Net immunosuppression use<br>changed prior to the study<br>treatment initiation<sup>e</sup></td><td></td><td></td></tr><tr><td>No</td><td>98 (69.0)</td><td>38 (55.1)</td></tr><tr><td>Yes</td><td>44 (31.0)</td><td>31 (44.9)</td></tr><tr><td>Missing</td><td>0</td><td>0</td></tr></tbody></table>

Abbreviations: CMV, cytomegalovirus; EAC, Endpoint Adjudication Committee; IAT, investigator-assigned therapy; SOT, solid organ transplant.

<sup>a</sup>Organ types are based on most recent transplant type. Those classed as "multi-organ" had >1 organ transplanted at once.

<sup>b</sup>Multi-organ transplant included 2 intestine/liver/pancreas transplants, 1 kidney/liver transplant, and 7 kidney/pancreas transplants.

<sup>c</sup>Duration (days) from current transplant to study treatment start date is calculated as: date of first exposure of the study drug administered - current transplant date +1.

<sup>d</sup>As reported during the 3 months prior to study enrollment.

<sup>e</sup>Per investigator reporting based on review of immunosuppression regimen changes due to CMV infection prior to enrollment.

arms, respectively, during the on-treatment period (Table 2). The percentages of any treatment-related TEAE occurring in the maribavir and IAT arms were 66.9% and 46.4% (Table 3). The most frequently reported treatment-related TEAE was dysgeusia, occurring in 43.7% patients who received maribavir. Dysgeusia resolved either during treatment with maribavir or shortly after discontinuation of treatment. In the IAT arm, neutropenia was the most common treatment-related TEAE (maribavir: 0; IAT: 14.5%), followed by acute kidney injury (maribavir: 2.8%; IAT: 13.0%). Fewer patients discontinued study treatment due to TEAEs in the maribavir arm (3.5%) than in the IAT arm (23.2%) (Table 4).

## Treatment-emergent mutations

Of the 142 SOT recipients in the maribavir arm, 40 (28.2%) had maribavir treatment-emergent mutations. Of these 40
<figure><img src="image_4.png" /><figcaption>**Figure 1** Confirmed CMV viremia clearance at week 8 in the SOT subgroup of the SOLSTICE study (A) and by transplant type (B).<sup>a,b</sup> CI, confidence interval; CMV, cytomegalovirus; IAT, investigator-assigned therapy; N/A, not applicable; SOT, solid organ transplant. <sup>a</sup>Cochran–Mantel–Haenszel weighted average approach was used for the adjusted difference in proportion (maribavir–IAT), the corresponding 95% CI, and the *p* value after adjusting for the baseline plasma CMV DNA concentration if homogeneity was met. The minimum risk weight method was used if the homogeneity was not met. <sup>b</sup>Reasons for non-response are provided in Figure S1.</figcaption></figure>

<figure><img src="image_5.png" /><figcaption>**Figure 2** Confirmed CMV viremia clearance at week 8 in the SOT subgroup of the SOLSTICE study for maribavir versus foscarnet/ cidofovir and by transplant type. <sup>a</sup>CI, confidence interval; CMV, cytomegalovirus; IAT, investigator-assigned therapy; N/A, not applicable; SOT, solid organ transplant. <sup>a</sup>Cochran–Mantel–Haenszel weighted average approach was used for the adjusted difference in proportion (maribavir–IAT), the corresponding 95% CI, and the *p* value after adjusting for the baseline plasma CMV DNA concentration if homogeneity was met. The minimum risk weight method was used if the homogeneity was not met.</figcaption></figure>
<figure><img src="image_6.png" /><figcaption>**Figure 3** Time to first viremia clearance within week 8 in the SOT subgroup of the SOLSTICE study. CMV, cytomegalovirus; IAT, investigator-assigned therapy; SOT, solid organ transplant.</figcaption></figure>

<table><caption>**Table 2** TEAEs Occurring in ≥10% of Patients in Either Treatment Arm or for Individual IAT (safety set) in the SOT Subgroup of the SOLSTICE Study</caption><thead><tr><th rowspan="2">Preferred Term</th><th colspan="4">By IAT Type<sup>a</sup></th></tr><tr><th>Maribavir<br>(n = 142),<br>n (%)</th><th>IAT<br>(n = 69),<br>n (%)</th><th>Ganciclovir/Valganciclovir<br>(n = 36),<br>n (%)</th><th>Foscarnet<br>(n = 29),<br>n (%)</th></tr></thead><tbody><tr><td>Any TEAE</td><td>137 (96.5)</td><td>61 (88.4)</td><td>32 (88.9)</td><td>26 (89.7)</td></tr><tr><td>Dysgeusia<sup>b</sup></td><td>62 (43.7)</td><td>1 (1.4)</td><td>1 (2.8)</td><td>0</td></tr><tr><td>Nausea</td><td>24 (16.9)</td><td>10 (14.5)</td><td>3 (8.3)</td><td>6 (20.7)</td></tr><tr><td>Diarrhea</td><td>23 (16.2)</td><td>14 (20.3)</td><td>8 (22.2)</td><td>6 (20.7)</td></tr><tr><td>CMV DNAemia</td><td>23 (16.2)</td><td>4 (5.8)</td><td>4 (11.1)</td><td>0</td></tr><tr><td>Immunosuppressant drug level<br>increased</td><td>18 (12.7)</td><td>1 (1.4)</td><td>1 (2.8)</td><td>0</td></tr><tr><td>Taste disorder<sup>b</sup></td><td>18 (12.7)</td><td>0</td><td>0</td><td>0</td></tr><tr><td>Fatigue</td><td>16 (11.3)</td><td>8 (11.6)</td><td>5 (13.9)</td><td>3 (10.3)</td></tr><tr><td>Anemia</td><td>14 (9.9)</td><td>7 (10.1)</td><td>0</td><td>6 (20.7)</td></tr><tr><td>Vomiting</td><td>13 (9.2)</td><td>5 (7.2)</td><td>2 (5.6)</td><td>3 (10.3)</td></tr><tr><td>Acute kidney injury</td><td>12 (8.5)</td><td>10 (14.5)</td><td>1 (2.8)</td><td>9 (31.0)</td></tr><tr><td>Headache</td><td>11 (7.7)</td><td>6 (8.7)</td><td>1 (2.8)</td><td>5 (17.2)</td></tr><tr><td>Pyrexia</td><td>6 (4.2)</td><td>8 (11.6)</td><td>4 (11.1)</td><td>4 (13.8)</td></tr><tr><td>Neutropenia</td><td>6 (4.2)</td><td>13 (18.8)</td><td>10 (27.8)</td><td>3 (10.3)</td></tr><tr><td>Hypomagnesemia</td><td>5 (3.5)</td><td>7 (10.1)</td><td>2 (5.6)</td><td>5 (17.2)</td></tr><tr><td>Hypocalcemia</td><td>0</td><td>5 (7.2)</td><td>1 (2.8)</td><td>4 (13.8)</td></tr></tbody></table>

Abbreviations: CMV, cytomegalovirus; IAT, investigator-assigned therapy; SOT, solid organ transplant; TEAE, treatment-emergent adverse event.

patients, 33 went on to take alternative anti-CMV drugs (7 of 40 did not). Out of the 33 who went on to take alternative anti-CMV medication, 19/33 (58%) achieved viremia clearance, 13/33 (39%) did not achieve clearance, and 1/33 (3%) patients did not have follow up data to verify clearance.

## Discussion

Efficacy results from this subgroup analysis of SOT recipients with refractory CMV infection showed that maribavir demonstrated greater effectiveness than IAT in

<footnote><sup>a</sup>Data on cidofovir and > 1 IAT were excluded due to low patient numbers (n = 1 and n = 3, respectively).</footnote>

<footnote><sup>b</sup>Dysgeusia and taste disorder were reported as separate terms by the investigator.</footnote>
<table><caption>**Table 3** Treatment-related TEAEs Occurring in ≥5% of Patients in Either Treatment Arm or For Individual IAT (safety set) in the SOT Subgroup of the SOLSTICE Study</caption><thead><tr><th rowspan="2">Preferred Term</th><th rowspan="2">Maribavir<br>(n = 142),<br>n (%)</th><th rowspan="2">IAT<br>(n = 69),<br>n (%)</th><th colspan="2">By IAT type<sup>a</sup></th></tr><tr><th>Ganciclovir/Valganciclovir<br>(n = 36),<br>n (%)</th><th>Foscarnet<br>(n = 29),<br>n (%)</th></tr></thead><tbody><tr><td>Any treatment-related TEAE</td><td>95 (66.9)</td><td>32 (46.4)</td><td>12 (33.3)</td><td>18 (62.1)</td></tr><tr><td>Dysgeusia</td><td>61 (43.7)</td><td>0</td><td>0</td><td>0</td></tr><tr><td>Taste disorder</td><td>17 (12.0)</td><td>0</td><td>0</td><td>0</td></tr><tr><td>Immunosuppressant drug level<br>increased</td><td>12 (8.5)</td><td>0</td><td>0</td><td>0</td></tr><tr><td>Nausea</td><td>9 (6.3)</td><td>4 (5.8)</td><td>0</td><td>4 (13.8)</td></tr><tr><td>CMV DNAemia</td><td>9 (6.3)</td><td>1 (1.4)</td><td>1 (2.8)</td><td>0</td></tr><tr><td>Vomiting</td><td>8 (5.6)</td><td>2 (2.9)</td><td>0</td><td>2 (6.9)</td></tr><tr><td>Diarrhea</td><td>4 (2.8)</td><td>4 (5.8)</td><td>1 (2.8)</td><td>3 (10.3)</td></tr><tr><td>Acute kidney injury</td><td>4 (2.8)</td><td>9 (13.0)</td><td>0</td><td>9 (31.0)</td></tr><tr><td>Headache</td><td>2 (1.4)</td><td>3 (4.3)</td><td>0</td><td>3 (10.3)</td></tr><tr><td>Anemia</td><td>0</td><td>5 (7.2)</td><td>0</td><td>5 (17.2)</td></tr><tr><td>Febrile neutropenia</td><td>0</td><td>2 (2.9)</td><td>2 (5.6)</td><td>0</td></tr><tr><td>Leukopenia</td><td>0</td><td>3 (4.3)</td><td>2 (5.6)</td><td>1 (3.4)</td></tr><tr><td>Neutropenia</td><td>0</td><td>10 (14.5)</td><td>8 (22.2)</td><td>2 (6.9)</td></tr><tr><td>Edema peripheral</td><td>0</td><td>2 (2.9)</td><td>0</td><td>2 (6.9)</td></tr><tr><td>Hypomagnesemia</td><td>0</td><td>5 (7.2)</td><td>1 (2.8)</td><td>4 (13.8)</td></tr><tr><td>Hypocalcemia</td><td>0</td><td>5 (7.2)</td><td>1 (2.8)</td><td>4 (13.8)</td></tr><tr><td>Hypokalemia</td><td>0</td><td>3 (4.3)</td><td>0</td><td>3 (10.3)</td></tr><tr><td>Hypophosphatemia</td><td>0</td><td>2 (2.9)</td><td>0</td><td>2 (6.9)</td></tr><tr><td>Peripheral edema</td><td>0</td><td>2 (2.9)</td><td>0</td><td>2 (6.9)</td></tr><tr><td>Muscle spasms</td><td>0</td><td>2 (2.9)</td><td>0</td><td>2 (6.9)</td></tr></tbody></table>

Abbreviations: CMV, cytomegalovirus; IAT, investigator-assigned therapy; TEAE, treatment-emergent adverse event.

<table><caption>**Table 4** Treatment-related TEAEs Leading to Study Treatment Discontinuation in Either Treatment Arm or Individual IAT (safety set) in the SOT Subgroup of the SOLSTICE Study</caption><thead><tr><th rowspan="2">Preferred Term</th><th rowspan="2">Maribavir<br>(n = 142),<br>n (%)</th><th rowspan="2">IAT<br>(n = 69),<br>n (%)</th><th colspan="2">By IAT type<sup>a</sup></th></tr><tr><th>Ganciclovir/Valganciclovir<br>(n = 36),<br>n (%)</th><th>Foscarnet<br>(n = 29),<br>n (%)</th></tr></thead><tbody><tr><td>Any related TEAE leading to study<br>treatment discontinuation</td><td>5 (3.5)</td><td>16 (23.2)</td><td>8 (22.2)</td><td>8 (27.6)</td></tr><tr><td>Diarrhea</td><td>1 (0.7)</td><td>1 (1.4)</td><td>1 (2.8)</td><td>0</td></tr><tr><td>Pyrexia</td><td>1 (0.7)</td><td>0</td><td>0</td><td>0</td></tr><tr><td>CMV infection</td><td>1 (0.7)</td><td>0</td><td>0</td><td>0</td></tr><tr><td>CMV syndrome</td><td>1 (0.7)</td><td>0</td><td>0</td><td>0</td></tr><tr><td>CMV DNAemia</td><td>1 (0.7)</td><td>1 (1.4)</td><td>1 (2.8)</td><td>0</td></tr><tr><td>Hepatic enzyme increased</td><td>1 (0.7)</td><td>0</td><td>0</td><td>0</td></tr><tr><td>Headache</td><td>1 (0.7)</td><td>0</td><td>0</td><td>0</td></tr><tr><td>Leukopenia</td><td>0</td><td>1 (1.4)</td><td>1 (2.8)</td><td>0</td></tr><tr><td>Neutropenia</td><td>0</td><td>7 (10.1)</td><td>7 (19.4)</td><td>0</td></tr><tr><td>Nausea</td><td>0</td><td>1 (1.4)</td><td>0</td><td>1 (3.4)</td></tr><tr><td>Edema peripheral</td><td>0</td><td>1 (1.4)</td><td>0</td><td>1 (3.4)</td></tr><tr><td>Acute kidney injury</td><td>0</td><td>6 (8.7)</td><td>0</td><td>6 (20.7)</td></tr></tbody></table>

Abbreviations: CMV, cytomegalovirus; IAT, investigator-assigned therapy; TEAE, treatment-emergent adverse event.

achieving confirmed CMV clearance at end of week 8 (the primary endpoint used in the SOLSTICE study). These findings are consistent with those in the overall population in

the phase 3 SOLSTICE study.¹⁹ In this subgroup analysis, a higher proportion of patients treated with maribavir achieved CMV viremia clearance compared with that in the IAT arm,

<footnote><sup>a</sup>Data on cidofovir and >1 IAT were excluded due to low patient numbers (n = 1 and n = 3, respectively).</footnote>

<footnote><sup>a</sup>Data on cidofovir and >1 IAT were excluded due to low patient numbers (n = 1 and n = 3, respectively).</footnote>
across all SOT types evaluated; these specific results should
be interpreted with caution as there was no multiplicity
control. The incidence of treatment-emergent resistance to
maribavir in the maribavir arm of the SOT subgroup (28%)
was consistent with that observed in the maribavir arm of the
overall study population in the SOLSTICE study (26%).²¹

Safety results in this current analysis should be interpreted
in the context of a longer median duration of exposure in the
maribavir arm (57 days) than in the IAT arm (43 days). This
longer median duration is likely due to fewer treatment
discontinuations. Safety outcomes in the SOT subgroup were
consistent with the previously reported observations in the
overall population of the SOLSTICE study.¹⁹ The higher
incidence of treatment-related TEAEs in the maribavir arm
compared with that in the IAT arm in the SOT subgroup was
due to a higher incidence of dysgeusia. Although there were
a large number of treatment-related TEAEs of dysgeusia in
the maribavir arm, none led to study drug discontinuation. In
addition, patients in the maribavir arm had a higher incidence
of immunosuppressant (tacrolimus, sirolimus) level increases
than those in the IAT arm. Previous studies have shown that
maribavir treatment is associated with increased im-
munosuppressant levels, especially at higher dose [1200 mg
BID]).²²,²³ This may be because maribavir inhibits P-gly-
coprotein, a transporter involved in distribution and dis-
position of standard immunosuppression medications.²⁴ As
such, additional monitoring might need to be considered for
patients receiving calcineurin inhibitors or mTOR inhibitors
during treatment with maribavir.

There are a few limitations of this study and the analyses
reported here. The first limitation concerns the open-label
study design, which might have introduced bias. Second,
the results of this subgroup analysis are from a randomized
clinical study data and so may not reflect real-world clinical
practice. For example, in real-world practice, anti-CMV
treatment is typically continued until viremia clearance is
achieved, whereas in this study, CMV treatment was
stopped at week 8 per protocol. In addition, there was
variation in the immunosuppression regimen and manage-
ment across different study centers, which in turn may have
an effect on the findings. Lastly, the small sample size for
individual transplant types, eg, heart (n = 23), liver (n = 7),
and pancreas (n = 2) made it difficult to draw conclusions
from any of the differences between the maribavir and IAT
treatment arms for these groups.

Taken together, the efficacy and safety results from
this subgroup analysis in SOT recipients were consistent
with those of the overall population in the SOLSTICE
study. The results demonstrated an efficacy and safety
benefit of maribavir in treating refractory CMV after
common SOTs, such as kidney and lung transplants. In
particular, the lower incidence of TEAEs in the maribavir
arm, including neutropenia when compared with ganci-
clovir/valganciclovir and acute kidney injury when com-
pared with foscarnet is of significance for SOT recipients.
Additional studies investigating strategies for combined and
long-term antiviral treatment with maribavir may further
enhance therapy options and reduce disease burden in this
patient population.

**Financial Disclosure Statement**

EAB reports research support from Merck, Scynexis, and
Takeda/Shire; royalties from UpToDate; consulting fees from
Aerium and University of Toronto; honoraria from University
of Manitoba; participation on a data safety monitoring board or
advisory board for Amplyx, NIH Trialnet; and a leadership role
with the American Society of Transplantation.

OW has received research grants for clinical studies,
speaker's fees, honoraria and travel expenses from Amgen,
Alexion, Astellas, AstraZeneca, Basilea, Biotest, Bristol Myers
Squibb, Correvio, Chiesi, Gilead, GSK, Hexal, Janssen, Dr. F.
Köhler Chemie, Moderna, MSD, Novartis, Roche, Pfizer,
Sanofi, Shionogi, Takeda, TEVA, Tillotts and UCB.

OW is supported by an unrestricted grant of the Rudolf-
Ackermann-Stiftung (Stiftung für Klinische Infektiologie).

MH reports honoraria from Takeda.

MGI reports research support from GlaxoSmithKline paid to Northwestern University; consulting fees from Adagio, ADMA Biologics, Adamis, AlloVir, Atea, Cidara, Genentech, Janssen, Roche, Shionogi, Takeda, Telaris, and Viracor Eurofins; All of these conflicts ended December 2022; royalties from UpToDate and a leadership role with ISIRV AVG and *Transplant Infectious Disease* journal, which are ongoing.

FS reports speaker's honoraria and/or research grants and/or
travel from Novartis, Astellas, Chiesi, Gilead, Merck Sharp &
Dohme, Pfizer, Biotest, Neovii, Takeda, Mundipharma and
Baxter.

NK reports royalties from UpToDate; consulting fees
from Astellas, Biotest, Chiesi, ExeViR, Hansa, Merck
Sharp and Dohme, and Takeda; honoraria from Astellas,
AstraZeneca, Biotest, CSL Behring, Chiesi, ExeViR,
Hansa, Merck Sharp and Dohme, GSK, Novartis Pharma,
Sanofi, Sandoz, and Takeda; travel support from Astellas,
AstraZeneca, Biotest, CSL Behring, Chiesi, Hansa, Merck
Sharp and Dohme, GSK, Novartis Pharma, Sanofi, Sandoz,
and Takeda.

AKS and JG report employment with and stock or stock
options from Takeda Pharmaceuticals.

DK reports research funding from GSK, Roche, and
Takeda; consulting fees from Exevir, GSK, Medscape,
Merck, Roche, and Takeda; and a leadership role with the
American Society of Transplantation.

RML reports serving on an advisory board for Takeda.

**Author Contributions**

Study conception and design: AKS and JG. Acquisition of data:
EAB, OW, MH, MI, FS, NK, JG, DK, RML. Analysis and
interpretation of data EAB, OW, MH, MGH, FS, NK, AKS,
JG, DK, RML. All authors were involved in drafting the article
and revising it critically for important intellectual content, and
all authors approved the final version to be published.

**Data availability statement**

The datasets, including the redacted study protocol, re-
dacted statistical analysis plan, and individual participants
data supporting the results reported in this article, will be
made available within three months from initial request, to
researchers who provide a methodologically sound pro-
posal. The data will be provided after its deidentification, in
compliance with applicable privacy laws, data protection
and requirements for consent and anonymization.

Acknowledgments

The authors would like to posthumously acknowledge Dr
Diana F. Florescu for her contributions to this study and the
manuscript. This study was funded by Takeda Development
Center Americas Inc., Lexington, MA, USA. Under the di-
rection of the authors, Sweta Rathore, PhD, of Caudex, a di-
vision of IPG Health Medical Communications, Toronto, ON,
Canada, provided writing assistance and Mary Casey, PhD, of
Caudex, Oxford, UK, provided editorial assistance. Caudex
was funded by Takeda Development Center Americas, Inc. for
these medical writing and editorial services.

**Appendix A. Supporting information**

Supplemental data associated with this article can be found
in the online version at doi:10.1016/j.healun.2024.11.026.

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