- For U.S. Healthcare Professionals Only
- Important Safety Information
- Prescribing Information
The Phase 3 SOLSTICE trial
- STUDY DESIGN
- EFFICACY RESULTS
SOLSTICE trial
Designed to evaluate the efficacy and safety of LIVTENCITY vs investigator-assigned treatment (IAT)1,2
LIVTENCITY was evaluated in a Phase 3, multicenter, randomized, open-label, active-controlled superiority trial in patients who received solid organ transplant (SOT) or hematopoietic cell transplant (HCT)
Patients were stratified by:
| Transplant type: | SOT | HCT |
| Baseline viral load: | Low | Intermediate | High |
Primary Endpoint: Confirmed CMV DNA level <LLOQ (ie, <137 IU/mL in 2 consecutive samples tested ≥5 days apart) at end of Week 8
Key Secondary Endpoint: CMV DNA level <LLOQ and CMV infection symptom control at Week 8, with maintenance through Week 16
Additional prespecified evaluation timepoints at Weeks 12 and 20 were not controlled for multiplicity
LIV=LIVTENCITY; LLOQ=lower limit of quantification; IAT=investigator-assigned anti-CMV treatment with 1 or 2 of the conventional CMV antivirals: Ganciclovir, valganciclovir, foscarnet, and/or cidofovir.
*Refractory: CMV DNA levels were not decreased by >90% (>1 log10) after 2 weeks of treatment.
†Resistant: CMV DNA levels were not decreased by >90% (>1 log10) after 2 weeks of treatment. Additionally, DNA sequence analysis showed the presence of a mutation known to be associated with resistance to ganciclovir/valganciclovir, foscarnet, or cidofovir.
‡Defined as ≥2730 IU/mL in whole blood or ≥910 IU/mL in plasma in 2 consecutive assessments separated by ≥1 day.
§Investigator assigned anti-CMV treatment with 1 or 2 of the conventional CMV antivirals: Ganciclovir, valganciclovir, foscarnet, and/or cidofovir. Combination therapy with cidofovir and foscarnet was not permitted. Changes to dose or dosing schedule were permitted. Discontinuation of one of the combination agents was permitted. Only switches between ganciclovir and valganciclovir were permitted.
||Per protocol, secondary prophylaxis was not recommended but was permitted in specific situations when deemed necessary by the investigator.
LIVTENCITY in pediatric population1
Only patients ≥18 years of age were enrolled in the study. Use of LIVTENCITY in pediatric patients 12 years of age and older and weighing at least 35 kg is based on the following:
- Evidence from controlled studies of LIVTENCITY in adults
- Population pharmacokinetic modeling and simulation demonstrating that age and body weight had no clinically meaningful effect on plasma exposures of LIVTENCITY
- LIVTENCITY exposure is expected to be similar between adults and children 12 years of age and older and weighing at least 35 kg
- The course of the disease is similar between adults and pediatric patients to allow extrapolation of data in adults to pediatric patients
- The safety and effectiveness of LIVTENCITY have not been established in children younger than 12 years of age
Select Inclusion Criteria1,3,4
- SOT or HCT recipients
- Documented CMV infection (≥2730 IU/mL in whole blood or ≥910 IU/mL in plasma) in 2 consecutive assessments, separated by ≥1 day
- CMV infection refractory to treatment with ganciclovir, valganciclovir, foscarnet, or cidofovir; including CMV infections with or without confirmed resistance to ≥1 of the IATs
- Age ≥12 years old*
- Weight ≥35 kg
- Laboratory-confirmed platelet ≥25,000/mm3
- Absolute neutrophil count ≥1,000/mm3
- Hemoglobin ≥8 g/dL
- eGFR >30 mL/min/1.73m2
Select Exclusion Criteria4
- Concurrent use of other antivirals or agents with activity against CMV for other conditions
- CMV disease involving the central nervous system, including the retina
- Pregnancy, breast feeding, active malignancy, HIV+, or undergoing treatment for Hepatitis C
- AST or ALT >5x ULN or total bilirubin ≥3.0x ULN
- Those receiving leflunomide, letermovir, or artesunate when study treatment was initiated
- Current refractory or resistant infection due to inadequate adherence to prior anti-CMV treatment
ALT=alanine aminotransferase; AST=aspartate aminotransferase; eGFR=estimated glomerular filtration rate; ULN=upper limit of normal.
*Only patients ≥18 years of age were enrolled in the study.
Baseline characteristics1
| Characteristic | LIVTENCITY | IAT N=117 % (n) |
|---|---|---|
| Transplant type | ||
| SOT | 60% (142) | 59% (69) |
Kidney | 52% (74) | 46% (32) |
Lung | 28% (40) | 32% (22) |
Heart | 10% (14) | 13% (9) |
Other (multiple, liver, pancreas, intestine) | 10% (14) | 9% (6) |
| HCT | 40% (93) | 41% (48) |
| CMV DNA level category as reported by central laboratory | ||
| Low (<9,100 IU/mL) | 65% (153) | 73% (85) |
| Intermediate (≥9,100 to <91,000 IU/mL) | 29% (68) | 21% (25) |
| High (≥91,000 IU/mL) | 6% (14) | 6% (7) |
| Confirmed symptomatic CMV infection at baseline | ||
| No | 91% (214) | 93% (109) |
| Yes* | 9% (21) | 7% (8) |
CMV syndrome (SOT only) | 43% (9) | 88% (7) |
Tissue Invasive disease | 57% (12)* | 13% (1) |
*One patient had both CMV syndrome and disease but was counted for CMV disease only.
See the results from the Phase 3 SOLSTICE trial.
Primary Endpoint:
LIVTENCITY was statistically superior to IAT1
More than twice the proportion of patients achieved CMV DNA level <LLOQ vs IAT1
56%
131/235
24%
28/117
33%
Adjusted difference
95% CI [23, 43]
P<0.001
Confirmed CMV DNA level <LLOQ at Week 8 vs IAT
(% of patient responders)
Primary Endpoint in post-transplant adult patients with refractory or resistant CMV:
- CMV DNA level <LLOQ (<137 IU/mL) at the end of Week 8 confirmed by central laboratory in 2 consecutive samples separated by ≥5 days1*
*As assessed by COBAS® AmpliPrep/COBAS® TaqMan® CMV test.
Cochran-Mantel-Haenszel weighted average approach was used for the adjusted difference in proportion of responders (MBV-IAT), 95% CI, and p-value, after adjusting for transplant type and baseline plasma CMV DNA level concentration. Computation included only those with both stratification factors.1
Key Secondary Endpoint:
With LIVTENCITY, a significantly higher proportion of patients with CMV DNA level <LLOQ and symptom control at Week 8 maintained efficacy through Week 161
Key Secondary Endpoint:
19%
44/235
10%
12/117
9%
Adjusted difference
95% CI [2, 17]
P=0.013
Post-treatment follow up at Week 16
(% of patient responders)
*CMV infection symptom control was defined as resolution or improvement of tissue-invasive disease or CMV syndrome for symptomatic patients at baseline, or no new symptoms for patients who were asymptomatic at baseline.
†Virologic relapse, also known as recurrence, was defined as plasma CMV DNA concentrations ≥LLOQ, when assessed in 2 consecutive samples separated by at least 5 days after achieving confirmed CMV DNA <LLOQ (<137 IU/mL).
- Composite endpoint in post-transplant adult patients with refractory or resistant CMV: Achievement of CMV DNA level <LLOQ and CMV infection symptom control* at Week 8, with maintenance through Week 161
- For the composite Key Secondary Endpoint, a fixed sequence testing procedure was used to control for multiplicity3
- For the composite Key Secondary Endpoint, a fixed sequence testing procedure was used to control for multiplicity3
- LIVTENCITY showed a statistically significant difference vs IAT1
- In both treatment arms, the percentage of patients achieving this composite endpoint was lower than the primary endpoint3
- Due in part to virologic relapse†
- Reflects the latent nature of CMV infection in which the virus may reactivate during periods of immunosuppression
*CMV infection symptom control was defined as resolution or improvement of tissue-invasive disease or CMV syndrome for symptomatic patients at baseline, or no new symptoms for patients who were asymptomatic at baseline.
†Virologic relapse, also known as recurrence, was defined as plasma CMV DNA concentrations ≥LLOQ, when assessed in 2 consecutive samples separated by at least 5 days after achieving confirmed CMV DNA <LLOQ (<137 IU/mL).
Other secondary endpoints in post-transplant adult patients with refractory or resistant CMV1,3,4
23%
10%
14%
Adjusted difference
95% Cl [6, 21]
19%
10%
9%
Adjusted difference
95% Cl [2, 17]
18%
9%
10%
Adjusted difference
95% Cl [3, 17]
53/235
12/117
44/235
12/117
43/235
11/117
Week 12
Week 16
Week 20 (End of study)
Prespecified Evaluation Timepoint
Key Secondary Endpoint
Prespecified Evaluation Timepoint
- Treatment effects observed through end of study: More patients receiving LIVTENCITY vs IAT maintained CMV DNA level <LLOQ and CMV symptom control at Weeks 12, 16, and 203,4
- Additional prespecified evaluation timepoints at Weeks 12 and 20 were not controlled for multiplicity
- All-cause mortality for the entire study period was an additional secondary endpoint:
- Rate of all-cause mortality was similar in both treatment arms (LIVTENCITY 11% [27/235]; IAT 11% [13/117])1
Key Secondary Endpoint: CMV DNA level <LLOQ and CMV symptom control at the end of Week 8, followed by maintenance of treatment effect for an additional 8 weeks post-treatment (follow-up Week 16).1
Other secondary endpoints: Maintenance of CMV DNA level <LLOQ and CMV infection symptom control achieved at the end of Week 8 through Weeks 12 and 20.4
Risk of virologic relapse1
- Virologic relapse, also known as recurrence, during the post-treatment period usually occurred within 4-8 weeks after treatment discontinuation
- After the end of treatment phase, among patients who achieved CMV DNA level <LLOQ at Week 8, 50% (65/131) in the LIVTENCITY group and 39% (11/28) in the IAT group experienced virologic relapse
- Most of the relapses [58/65 (89%) in LIVTENCITY group and 11/11 (100%) in IAT group] occurred within 4 weeks after study drug discontinuation; and the median time to relapse after CMV DNA level <LLOQ was 15 days (range 7-71) in the LIVTENCITY group and 15 days (range 7-29) in the IAT group
- Virologic failure due to resistance can occur during and after treatment with LIVTENCITY
In post-transplant adult patients with refractory or resistant CMV
Treatment effect of LIVTENCITY was consistent across key subpopulations1
Responders by subgroup at Week 8 (%)
SOT
56%
(79/142)
26%
(18/69)
HCT
56%
(52/93)
21%
(10/48)
Low <9,100 IU/mL
62%
(95/153)
25%
(21/85)
Intermediate ≥9,100 and <91,000 IU/mL
47%
(32/68)
20%
(5/25)
High ≥91,000 IU/mL
29%
(4/14)
29%
(2/7)
Yes
63%
(76/121)
20%
(14/69)
No
44%
(42/96)
32%
(11/34)
Yes
48%
(10/21)
13%
(1/8)
No
57%
(121/214)
25%
(27/109)
18 to 44
51%
(28/55)
25%
(8/32)
45 to 64
56%
(71/126)
28%
(19/69)
≥65
59%
(32/54)
6%
(1/6)
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*LIVTENCITY was less effective against subjects with increased CMV DNA levels (≥ 50,000 IU/mL) and subjects with absence of genotypic resistance.
Resistance and cross resistance1,2
In the Phase 3 trial, mean treatment duration for LIVTENCITY was 48.6 days (SD =13.8) and 31.2 days (SD=16.9) for IAT.1
- The UL97, UL27, and UL54 CMV genes were sequenced in baseline and postbaseline samples that met the criteria for genotyping in the randomized, safety population (n=116 IAT and n=234 MBV)2
- Specifically, genotypic analysis was performed on patient samples >500 copies/mL, (455 IU/mL), known to be associated with resistance to IATs or MBV, i.e. identified known baseline Resistance-Associated amino acid Substitutions (RAS)2
- In patients with phenotypic resistance to valganciclovir/ganciclovir, DNA sequence analysis of the entire coding regions of pUL97 and pUL27 was performed on 134 paired sequences from maribavir-treated patients. Treatment-emergent pUL97 substitutions were detected in 58 patients (47 subjects were on-treatment failures and 11 subjects were relapsers)1
- Cross-resistance has been observed between maribavir and valganciclovir/ganciclovir in cell culture and in clinical studies:
- Specific pUL97 valganciclovir/ganciclovir resistance-associated substitutions reduce susceptibility to maribavir >4.5-fold1
- pUL54 DNA polymerase substitutions conferring resistance to valganciclovir/ganciclovir, cidofovir, or foscarnet remained susceptible to maribavir1
- There are no reports of pUL97 RAS substitutions being evaluated for valganciclovir/ganciclovir, foscarnet or cidofovir cross-resistance. Given the lack of RAS for drugs mapping to pUL27, cross-resistance is not expected for pUL27 maribavir substitutions1
- Maribavir-resistant virus (RAS F342Y and C480F) remained susceptible to cidofovir and foscarnet1
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