MA-TAKEDA-PHARMACEUTICAL

Takeda (TSE:4502/NYSE:TAK) (“Takeda”) today announced that it will present four company-sponsored abstracts at the Tandem Transplantation & Cellular Therapy Meetings in Salt Lake City, Utah, and the 32nd European Congress of Clinical Microbiology and Infectious Diseases (ECCMID) in Lisbon, Portugal between April 23 and 26, 2022. The exploratory data presented at both meetings provide an opportunity to share important new analyses of LIVTENCITY™ (maribavir) with the transplant and infectious disease communities. These data announcements follow completion of patient enrollment in Takeda’s AURORA (TAK-620-302) study, focusing on LIVTENCITY for first-line use in hematopoietic stem cell transplant (HSCT) recipients with cytomegalovirus (CMV) infection/disease.

The abstracts include additional analyses that underscore the relevance of the multicenter, randomized, open-label Phase 3 SOLSTICE trial data, which supported the U.S. Food and Drug Administration (FDA) approval of LIVTENCITY as the first and only treatment for people ages 12 and older and weighing at least 35kg with post-transplant CMV infection/disease, refractory^† (with or without genotypic resistance^‡ ) to conventional antiviral therapies (one or a combination of ganciclovir, valganciclovir, foscarnet or cidofovir).^5,6

CMV is one of the most common and serious post-transplant infections with an estimated global incidence rate of around 16-56% in solid organ transplant (SOT) recipients and 30-70% in HSCT recipients,^7–12 and can lead to serious consequences, including loss of the transplanted organ and failure of the graft.^13,14

“When managing post-transplant CMV infections, we're always looking for additional treatment options for patients that are refractory with or without resistance,” said Barbara Alexander, MD, Professor of Medicine and Professor of Pathology at Duke University School of Medicine. “The additional LIVTENCITY data being presented at the Tandem Meetings and ECCMID, including time to confirmed CMV DNA level

Highlights of data being presented at the 2022 Tandem Meetings include:

Healthcare Resource Utilization in Transplant Recipients With Cytomegalovirus Infection Refractory/Resistant to Treatment Receiving LIVTENCITY Versus Investigator Assigned Therapy: Exploratory Analysis of a Phase 3 Trial

• Data from an exploratory analysis of the Phase 3 SOLSTICE trial evaluating the impact of treatment with LIVTENCITY compared to conventional antiviral therapies on healthcare utilization, including number of patients with ≥1 hospitalization and length of hospital stay will be presented [Poster #52].¹
• This analysis aimed to quantify the healthcare resource utilization experience of patients requiring treatment for post-transplant CMV. During the treatment phase, 31.9% of patients treated with LIVTENCITY (n=75/235) had at least one hospitalization compared to 36.8% of patients treated with conventional therapies (n=43/117). Adjusting for time on treatment, the LIVTENCITY treatment group had a 34.8% reduction compared to the conventional therapy group (p=0.021). The length of hospital stay during the treatment phase (adjusting for time on treatment) was 13.27 days/person/year in LIVTENCITY-treated patients compared to 28.73 for those conventionally treated, a 53.8% decrease (p=0.029). Reducing hospitalizations is a critical part of reducing disease burden to healthcare systems.¹

Population Pharmacokinetics and Exposure-Response Relationships of LIVTENCITY in Transplant Recipients With Cytomegalovirus Infections

• Data from population pharmacokinetic and pharmacodynamic (PK/PD) models based on Phase 1, 2 and 3 (SOLSTICE) studies, which were developed to characterize LIVTENCITY plasma concentrations and exposure-response relationships, which support dosage recommendations, will be presented [Poster #470].⁴
• PK/PD modeling results suggest that dose adjustments of LIVTENCITY will not be required in adult transplant patients for the treatment of CMV infection regardless of age, body weight, sex, race, transplant type, baseline plasma CMV DNA, or presence of CMV mutations.⁴

Assessment of Discontinuations and Anti-Cytomegalovirus Treatment Switching in Post-Transplant Refractory/Resistant Cytomegalovirus Infections: Safety and Sensitivity Analyses From a Phase 3 Randomized Trial

• Data from a safety and sensitivity analysis of the Phase 3 SOLSTICE trial, assessing the impact of discontinuations or treatment switching on achieving confirmed CMV DNA level 3

Highlights of data being presented at ECCMID include:

Kaplan-Meier Estimates of Time to First Cytomegalovirus Viremia Clearance in Transplant Recipients With Refractory Cytomegalovirus Infection With or Without Resistance Receiving LIVTENCITY Versus Investigator-Assigned Therapy: Subgroup Analyses of a Phase 3 Trial

• Data from a subgroup analysis of the Phase 3 SOLSTICE trial assessing median time to first confirmed CMV DNA level 2
• Post-hoc analyses by subgroups, including baseline resistance status and transplant type, were consistent with previously reported results, demonstrating a shorter time to confirmed CMV DNA level 2

The company-sponsored abstracts for the Tandem Meetings can be found here and for ECCMID can be found here .

About Cytomegalovirus

CMV is a beta herpesvirus that commonly infects humans; serologic evidence of prior infection can be found in 40%-100% of various adult populations.^15,16 CMV typically resides latent and asymptomatic in the body but may reactivate during periods of immunosuppression. Serious disease may occur in individuals with compromised immune systems, which includes patients who receive immunosuppressants associated with various types of transplants including hematopoietic stem cell transplant (HSCT) or solid organ transplant (SOT).^7,15,16 Out of the estimated 200,000 adult transplants per year globally, CMV is one of the most common viral infections experienced by transplant recipients, with an estimated incidence rate between 16-56% in SOT recipients and 30-70% in HSCT recipients.^7–12

In transplant recipients, reactivation of CMV can lead to serious consequences including loss of the transplanted organ and, in extreme cases, can be fatal.^13,14 Existing therapies to treat post-transplant CMV infections may demonstrate serious side effects that require dose adjustments or may fail to adequately suppress viral replication. ^17,18 Additionally, existing therapies may require or prolong hospitalization due to administration.^17,18

About LIVTENCITY^TM (Maribavir)

LIVTENCITY (maribavir), an orally bioavailable anti-CMV compound, is the first and only antiviral agent that targets and inhibits the pUL97 protein kinase.⁵ It is approved in the U.S. for the treatment of adults and pediatric patients (12 years of age or 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. For more information on LIVTENCITY, visit LIVTENCITY.com.⁵

About Takeda’s SOLSTICE Trial

The TAK-620-303 (SOLSTICE) trial (NCT02931539) was a multicenter, randomized, open-label, active-controlled superiority trial to assess the efficacy and safety comparing treatment with either LIVTENCITY (maribavir) or conventional antiviral therapy in 352 hematopoietic cell transplant and solid organ transplant recipients with CMV infection refractory, with or without resistance, to one or a combination of the conventional antiviral therapies: ganciclovir, valganciclovir, foscarnet or cidofovir. Adult patients underwent a 2-week screening period, followed by randomization 2:1 to LIVTENCITY (n=235) (400 mg, twice daily) or conventional antiviral therapies (n=117) (as dosed by the investigator) for up to 8-weeks. After completion of the treatment period, subjects entered a 12-week follow-up phase.⁶

The trial’s primary endpoint was confirmed CMV DNA level ® AmpliPrep/COBAS^® TaqMan^® CMV test at the end of Week 8). The key secondary endpoint was CMV DNA level § at the end of Study Week 8 with maintenance of this treatment effect through Study Week 16.⁶

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.⁵

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.

Please click for Full Prescribing Information .

About Takeda

Takeda is a global, values-based, R&D-driven biopharmaceutical leader headquartered in Japan, committed to discover and deliver life-transforming treatments, guided by our commitment to patients, our people and the planet. Takeda focuses its R&D efforts on four therapeutic areas: Oncology, Rare Genetics and Hematology, Neuroscience, and Gastroenterology (GI). We also make targeted R&D investments in Plasma-Derived Therapies and Vaccines. We are focusing on developing highly innovative medicines that contribute to making a difference in people’s lives by advancing the frontier of new treatment options and leveraging our enhanced collaborative R&D engine and capabilities to create a robust, modality-diverse pipeline. Our employees are committed to improving quality of life for patients and to working with our partners in health care in approximately 80 countries and regions. For more information, visit https://www.takeda.com .

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Medical information

This press release contains information about products that may not be available in all countries, or may be available under different trademarks, for different indications, in different dosages, or in different strengths. Nothing contained herein should be considered a solicitation, promotion or advertisement for any prescription drugs including the ones under development.

^{* Conventional antiviral therapies: ganciclovir, valganciclovir, cidofovir, or foscarnet}

^{§ 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}

^{† Refractory defined as documented failure to achieve >1 log10 decrease in CMV DNA level in whole blood or plasma after a 14 day or longer treatment period with IV ganciclovir/oral valganciclovir, IV foscarnet, or IV cidofovir}

^{‡ Resistant defined as refractory CMV and documentation of >1 CMV genetic mutations associated with resistance to ganciclovir, valganciclovir, foscarnet, and/or cidofovir}

1. Hirji I, et al. Healthcare resource utilization in transplant recipients with cytomegalovirus infection refractory/resistant to treatment receiving LIVTENCITY versus investigator assigned therapy: Exploratory analysis of a Phase 3 trial. In: The 2022 Tandem Transplantation & Cellular Therapy (TCT) Meetings Of ASTCT and CIBMTR . 2022. Abstract 52.
2. Alain S, et al. Time to First Cytomegalovirus Viremia Clearance in Transplant Recipients with Refractory Cytomegalovirus Infection With or Without Resistance Receiving Maribavir Versus Investigator-Assigned Therapy: Subgroup Analyses of a Phase 3 Trial. In: The 32^nd European Congress of Clinical Microbiology and Infectious Diseases . 2022. Abstract O0059.
3. Alexander B, et al. Assessment of Discontinuations and Anti-Cytomegalovirus Treatment Switching in Post-Transplant Refractory/Resistant Cytomegalovirus Infections: Safety and Sensitivity Analyses from a Phase 3 Randomized Trial. In: The 2022 Tandem Transplantation & Cellular Therapy (TCT) Meetings Of ASTCT and CIBMTR . 2022. Abstract 467.
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