The Phase 3 SOLSTICE trial

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)

SOLSTICE trial chart

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.

EXAMINE EFFICACY RESULTS

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 rate >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
400 mg twice daily
N=235
% (n)

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.

EXAMINE EFFICACY RESULTS

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*

Rate of all-cause mortality was similar in both treatment arms (LIVTENCITY, 11% [27/235] vs IAT, 11% [13/117]).1

*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) 

  • 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
  • LIVTENCITY showed a statistically significant difference vs IAT1

Post-treatment virologic relapse†: 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 in the follow-up period.1

*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).

Treatment effects observed through end of study1,3,4

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

  • Other secondary endpoints: 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
  • Most of the post-treatment relapses (89% [58/65] in LIVTENCITY group and 100% [11/11] in IAT group) occurred within 4 weeks after study discontinuation1
    • 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

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

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)

SCROLL FOR MORE

*LIVTENCITY was less effective against subjects with increased CMV DNA levels (≥ 50,000 IU/mL) and subjects with absence of genotypic resistance.

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Resistance and cross resistance1,2

LIVTENCITY IN PEDIATRIC POPULATION

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

Tolerability is an important part of your patients' treatment experience.

SEE THE SAFETY PROFILE

1. Livtencity (maribavir) Prescribing Information. Lexington, MA: Takeda Pharmaceuticals U.S.A., Inc. 2. Data on file. Takeda Pharmaceuticals U.S.A., Inc. 3. Avery RK, Alain S, Alexander BD, et al. Clin Infect Dis. 2021;ciab988. 4. Avery RK, Alain S, Alexander BD, et al. Clin Infect Dis. Supplement. 2021. doi.org/10.1093/cid/ciab988. 5. Shannon-Lowe CD, Emery VC. Herpesviridae. 2010;1(4):1-13. 6. Steingruber M, Marschall M. Microorganisms. 2020;8(4):515. 7. Biron KK, Harvey RJ, Chamberlain SC, et al. Antimicrob Agents Chemother 2002;46:2365-2372. 8. Wolf DG, Courcelle CT, Prichard MN, Mocarski ES. Proc Natl Acad Sci U S A. 2001;98(4):1895-1900. 9. Krosky PM, Baek MC, Coen DM. J Virol. 2003;77:905-914. 10. Bigley TM, Reitsma JM, Mirza SP, Terhune SS. J Virol. 2013;87(13):7393-7408.

Important Safety Information

Risk of Reduced Antiviral Activity When Co-administered with Ganciclovir and Valganciclovir

LIVTENCITY may antagonize the antiviral activity of ganciclovir and valganciclovir by inhibiting human CMV pUL97 kinase, which is required for activation/phosphorylation of ganciclovir and valganciclovir. Coadministration of LIVTENCITY with ganciclovir or valganciclovir is not recommended.

Virologic Failure During Treatment and Relapse Post-Treatment

Virologic failure due to resistance can occur during and after treatment with LIVTENCITY. Virologic relapse during the posttreatment period usually occurred within 4-8 weeks after treatment discontinuation. Some maribavir pUL97 resistance-associated substitutions confer cross-resistance to ganciclovir and valganciclovir. Monitor CMV DNA levels and check for maribavir resistance if the patient is not responding to treatment or relapses.

Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions

The concomitant use of LIVTENCITY and certain drugs may result in potentially significant drug interactions, some of which may lead to reduced therapeutic effect of LIVTENCITY or adverse reactions of concomitant drugs.  Consider the potential for drug interactions prior to and during LIVTENCITY therapy; review concomitant medications during LIVTENCITY therapy and monitor for adverse reactions. Refer to the full prescribing information of LIVTENCITY for important drug interactions.

Maribavir is primarily metabolized by CYP3A4. Drugs that are strong inducers of CYP3A4 are expected to decrease maribavir plasma concentrations and may result in reduced virologic response; therefore, coadministration of LIVTENCITY with these drugs is not recommended, except for selected anticonvulsants.  

Use with Immunosuppressant Drugs

LIVTENCITY has the potential to increase the drug concentrations of immunosuppressant drugs that are CYP3A and/or P-gp substrates where minimal concentration changes may lead to serious adverse events (including tacrolimus, cyclosporine, sirolimus and everolimus). Frequently monitor immunosuppressant drug levels throughout treatment with LIVTENCITY, especially following initiation and after discontinuation of LIVTENCITY and adjust immunosuppressant dose, as needed.

Adverse Reactions

The most common adverse events (all grades,> 10%) in subjects treated with LIVTENCITY were taste disturbance, nausea, diarrhea, vomiting, and fatigue.

INDICATION

LIVTENCITY is indicated for the treatment of adults and pediatric patients (12 years of age and older and weighing at least 35 kg) with post-transplant cytomegalovirus (CMV) infection/disease that is refractory to treatment (with or without genotypic resistance) with  ganciclovir, valganciclovir, cidofovir or foscarnet.

Please click for Full Prescribing Information.

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1-877-TAKEDA-7 (1-877-825-3327).

US-MAR-0102v1.0 03/22