Takeda�s Phase 3 AURORA Study Provides Evidence of Maribavir�s Clinically Meaningful and Durable Effect in Cytomegalovirus (CMV) Infection in Hematopoietic Stem Cell Transplant Patients, Despite Missing Primary Endpoint

At Week 8, 69.6% of Patients Treated With Maribavir Achieved CMV Clearance vs. 77.4% for Valganciclovir, but Did Not Demonstrate Non-inferiority Based on Prespecified Margin of 7%¹
At Week 16, 52.7% of Patients Treated With Maribavir Achieved Maintenance Effect of Viremia Clearance and Symptom Control From Week 8 vs. 48.5% for Valganciclovir¹
Sustained Maintenance Effect Observed With Maribavir During Post-Treatment Evaluations at Week 12 (Maribavir 59.3%, Valganciclovir 57.3%) and Week 20 (Maribavir 43.2%, Valganciclovir 42.3%)¹
Study Reaffirmed Maribavir�s Favorable Safety Profile, Given Valganciclovirs Higher Incidence of Treatment-Emergent Neutropenia (63.5% vs. 21.2% for Maribavir) and Higher Rate of Premature Discontinuation of Therapy Due to Neutropenia (17.5% vs. 4% for Maribavir)¹
Takeda Remains Committed to the Transplant Community and Is Engaging With Regulatory Authorities to Discuss AURORA Study Outcomes

OSAKA, Japan & CAMBRIDGE, Mass.–(BUSINESS WIRE)–Takeda (TSE:4502/NYSE:TAK) today announced that in the AURORA trial, a Phase 3, multicenter, randomized, double-blind, double-dummy, active-controlled study to assess the efficacy and safety of maribavir compared to valganciclovir for the treatment of CMV infection in hematopoietic stem cell transplant (HSCT) recipients, maribavir demonstrated clinically meaningful efficacy in confirmed CMV viremia clearance^*, but did not meet its primary endpoint of non-inferiority vs. valganciclovir (maribavir 69.6% [190/273] vs. valganciclovir 77.4% [212/274]; adjusted difference, -7.7%; 95% CI: -14.98, -0.36), based on the prespecified non-inferiority margin of 7%. The primary endpoint was defined as the proportion of patients who achieved confirmed CMV viremia clearance (plasma CMV DNA <LLOQ; i.e., <137 IU/mL) after exclusively maribavir compared to valganciclovir at end of treatment phase (Week 8).¹

At Week 16, the key secondary endpoint, 8 weeks after end of treatment, a numerically higher proportion of patients treated with maribavir (52.7% [144/273]) maintained CMV viremia clearance and symptom control achieved at Week 8 compared to valganciclovir (48.5% [133/274]; adjusted difference, 4.4%; 95% CI: -3.91, 12.76). This comparable maintenance of effect with maribavir was consistent at all post-treatment evaluations at Study Week 12 (maribavir 59.3% [162/273] vs. valganciclovir 57.3% [157/274]) and Study Week 20 (maribavir 43.2% [118/273] vs. valganciclovir 42.3% [116/274]).¹

Analysis of safety data from the AURORA study reaffirmed maribavirs favorable safety profile compared to valganciclovir, which was associated with treatment-emergent neutropenia occurring in 63.5% [174/274] vs. 21.2% [58/273] with maribavir and led to premature discontinuation of therapy in 17.5% [48/274] with valganciclovir vs. 4% [11/273] with maribavir. Nausea (27.5%) and dysgeusia (25.6%) were the most common adverse events reported with maribavir.¹

Patients who suffer from a CMV infection after a stem cell transplant need a more tolerable treatment option than conventional anti-CMV medicines commonly used today, which are associated with neutropenia and renal toxicity, said Rafael F. Duarte, MD, PhD, FRCP, Principal Investigator of the AURORA Study and a Leading Hematologist with Expertise in Bone Marrow Transplants. Were thrilled that the AURORA study showed maribavir’s potential to provide clinically meaningful and durable CMV viremia clearance in HSCT patients. On behalf of the AURORA clinical trial team, Id like to express our deepest gratitude to all of the patients, caregivers and donors for their noble commitment to helping others, which made this study possible.

AURORA was the largest Phase 3, randomized, controlled clinical study for maribavir as a treatment for post-transplant CMV following the SOLSTICE pivotal study, a global, multicenter, randomized, open-label, active-controlled superiority study to assess the efficacy and safety of treatment with either maribavir or conventional antiviral therapy in 352 HSCT and solid organ transplant (SOT) recipients with CMV infection refractory, with or without resistance, to one or a combination of the conventional antiviral therapies: ganciclovir, valganciclovir, foscarnet, or cidofovir.²

Takeda is sharing the AURORA study results with relevant regulatory agencies and will continue to engage with them on a potential path forward for maribavir in asymptomatic first-episode post-transplant CMV infection.

Full data results from the AURORA study will also be submitted for publication in a peer-reviewed journal.

About CMV

CMV is a beta herpesvirus that commonly infects humans; serologic evidence of prior infection can be found in 40-100% of various adult populations.³ 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 HSCT or SOT.⁴ 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 30-80% in HSCT recipients.^4,5

In transplant recipients, reactivation of CMV can lead to serious consequences, including loss of the transplanted organ and, in extreme cases, can be fatal.^6,7 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.⁸Additionally, existing therapies may require or prolong hospitalization due to administration.^8,9

About LIVTENCITY (Maribavir)

LIVTENCITY, an orally bioavailable anti-CMV compound, is the first and only antiviral agent that targets and inhibits the UL97 protein kinase and its natural substrates.² It is approved by the U.S. Food and Drug Administration for the treatment of adults and pediatric patients (12 years of age or older and weighing at least 35 kg) with post-transplant CMV infection/disease that is refractory to treatment (with or without genotypic resistance) with ganciclovir, valganciclovir, cidofovir, or foscarnet.¹⁰ It is approved by the European Commission and Medicines and Healthcare products Regulatory Agency for the treatment of CMV infection and/or disease that are refractory (with or without resistance) to one or more prior therapies, including ganciclovir, valganciclovir, cidofovir or foscarnet, in adult patients who have undergone a HSCT or SOT.¹¹ It is also approved by Health Canada for the treatment of adults with post-transplant CMV infection/disease who are refractory (with or without genotypic resistance) to one or more prior antiviral therapies.¹² LIVTENCITY is also approved in Australia for the treatment of adults with post-transplant CMV infection and disease resistant, refractory, or intolerant to one or more prior therapies.¹³

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.

For the U.S., please click for Full Prescribing Information.

For Europe, please use the embedded link to access the LIVTENCITY Summary Product Characteristics.

Please consult with your local regulatory agency for approved labeling in your country.

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 peoples 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

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^*CMV viremia clearance is defined as confirmed CMV DNA level below lower limit of quantification (LLOQ), [i.e. <137 IU/mL] in 2 consecutive samples separated by at least 5 days, as assessed by COBAS^® AmpliPrep/COBAS^® TaqMan^® CMV test at the end of Week 8).

References

VV-SUP-123715. Takeda DOF. TAK-620-302 Topline Report. November 2022.
Avery R, Alain S, Alexander B, et al. Maribavir for refractory cytomegalovirus infections with or without resistance post-transplant: results from a phase 3 randomized clinical trial. Clin Infect Dis. 2022; 75(4):690-701.
de la Hoz R. Diagnosis and treatment approaches to CMV infections in adult patients. J Clin Virol. 2002;25(Suppl 1):S1-S12. doi:10.1016/s1386-6532(02)00091-4.
Azevedo L, Pierrotti L, Abdala E, et al. Cytomegalovirus infection in transplant recipients. Clinics (Sao Paolo). 2015;70(7):515-523. doi:10.6061/clinics/2015(07)09.
Styczynski J. Who is the patient at risk of CMV recurrence: a review of the current scientific evidence with a focus on hematopoietic cell transplantation. Infect Dis Ther. 2018;7:1-16. doi:10.1007/s40121-017-0180-z.
Ramanan P, Razonable RR. Cytomegalovirus infections in solid organ transplantation: a review. Infect Chemother. 2013;45(3):260. doi:10.3947/ic.2013.45.3.260.
Camargo JF, Komanduri KV. Emerging concepts in cytomegalovirus infection following hematopoietic stem cell transplantation. Hematol Oncol Stem Cell Ther. 2017;10(4):233-238. doi:10.1016/j.hemonc.2017.05.001.
Chemaly RF, Chou S, Einsele H, et al. Definitions of resistant and refractory cytomegalovirus infection and disease in transplant recipients for use in clinical trials. Clin Infect Dis. 2019;68(8):1420-1426. doi:10.1093/cid/ciy696.
Martín-Gandul C, Pérez-Romero P, González-Roncero FM, et al. Clinical impact of neutropenia related with the preemptive therapy of CMV infection in solid organ transplant recipients. J Infect. 2014;69(5):500-506. doi:10.1016/j.jinf.2014.07.001.
Takeda. Takedas LIVTENCITY (maribavir) approved by U.S. FDA as the first and only treatment for people ages 12 and older with post-transplant cytomegalovirus (CMV), refractory (with or without genotypic resistance) to conventional antiviral therapies. Published November 23, 2021. https://www.takeda.com/newsroom/newsreleases/2021/takeda-livtencity-maribavir-approved-by-us-fda/.
Takeda. European Commission (EC) approves LIVTENCITY? (maribavir) for the treatment of adults with post-transplant cytomegalovirus (CMV) infection and/or disease that are refractory (with or without resistance) to one or more prior therapies. Published November 11, 2022. Accessed December 8, 2022. https://www.takeda.com/newsroom/newsreleases/2022/european-commission-ec-approves-livtencitytm-maribavir/.
Takeda. Health Canada approves Takedas LIVTENCITY (maribavir) the first and only treatment for adults with post-transplant cytomegalovirus (CMV) infection. Published September 20, 2022. https://www.takeda.com/en-ca/newsroom/news-releases/2022/health-canada-approves-takedas-livtencity-maribavir-the-first-and-only-treatment-for-adults-with-post-transplant-cytomegalovirus-cmv-infection/.
Therapeutic Goods Administration (TGA). LIVTENCITY maribavir 200 mg film coated tablet bottle (380132) [Australian product information]. Therapeutic Goods Administration (TGA). Published October 8, 2022. Accessed October 17, 2022. https://www.tga.gov.au/resources/artg/380132.