Takeda Pharmaceutical Company Limited (TSE:4502/NYSE:TAK) (“Takeda”) today announced the United States commercial availability of LIVTENCITY™ (maribavir), the first and only treatment for 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.¹ LIVTENCITY, an orally bioavailable anti-CMV compound, became available for prescription on December 2, 2021, just over a week after the U.S. Food and Drug Administration (FDA) approval which took place on November 23, 2021.

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“Those undergoing a life-saving transplant often have an incredibly complex medical journey to overcome, so when faced with the subsequent impact of a difficult-to-manage infection/disease such as CMV, it was a priority for our teams to expedite access to this additional treatment option,” said Cheryl Schwartz, Senior Vice President and U.S. Business Unit Lead, Rare Diseases, Takeda.

LIVTENCITY is now available to healthcare providers through a network of specialty pharmacies and distributors. For appropriate patients, physicians can submit a prescription and initiate access to treatment through a specialty pharmacy by visiting www.takedapatientsupport.com or by calling Takeda Patient Support at 1-855-268-1825. Requests for acquisition through a distributor for inpatient administration can be fulfilled by emailing customerservice@takeda.com.

“Treatment of post-transplant CMV has historically been a challenge for clinicians, given that conventional antivirals have been the only treatment option,” said Emily Blumberg Director, Transplant Infectious Diseases, Penn Medicine. “The availability of LIVTENCITY, the first and only FDA-approved oral treatment for post-transplant resistant/refractory CMV, represents a significant step forward for the transplant community in addressing this difficult to treat infection/disease.”

LIVTENCITY is a new molecular entity which targets CMV at UL97, resulting in inhibition of viral DNA replication, encapsidation, and nuclear egress.^1,2,3,4,5,6 Though a rare disease overall, CMV is one of the most common infections experienced by transplant recipients, with an estimated incidence rate of around 16%–56% in solid organ transplant (SOT) recipients⁷ and 30%–70% in hematopoietic stem cell (HSCT) transplant recipients.⁸ CMV can be acquired or reactivated following transplant leading to serious consequences—including loss of the transplanted organ and failure of the graft—or loss of life. In patients with compromised immunity, CMV causes clinically challenging complications that can be fatal.^9,10,11

Takeda Patient Support for LIVTENCITY

Takeda Patient Support is available to help patients prescribed LIVTENCITY gain access to their medication, find educational resources, and understand financial assistance options. A team of experts is available Monday through Friday, 8:00am to 8:00pm ET. For additional information visit www.takedapatientsupport.com or call 1-855-268-1825.

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.¹² 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).^8,13 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.^6,7,8,14

In transplant recipients, reactivation of CMV can lead to serious consequences including loss of the transplanted organ and, in extreme cases, can be fatal.^12,15 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.^{10,11,13,16,17} Additionally, existing therapies may require or prolong hospitalization due to administration.¹²

About LIVTENCITY

LIVTENCITY (maribavir), an orally bioavailable anti-CMV compound, is the first and only antiviral agent that targets and inhibits the pUL97 protein kinase and its natural substrates.¹ 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.¹

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.¹

IMPORTANT SAFETY INFORMATION¹

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.

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About Takeda Pharmaceutical Company Limited

Takeda Pharmaceutical Company Limited (TSE:4502/NYSE:TAK) 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. For more information, visit https://www.takeda.com.

Important Notice

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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.

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¹ USPI. Takeda Internal Communication (TAK620-INT) Manufacturing Information. November 2021. 2021 Takeda Pharmaceuticals USA Inc. All rights reserved.

² Wolf et al. Distinct and separate roles for herpesvirus-conserved UL97 kinase in cytomegalovirus DNA synthesis and encapsidation. Proc Natl Acad Sci USA Feb 2001;98(4):1895-900.

³ Biron et al. Potent and Selective Inhibition of Human Cytomegalovirus Replication by 1263W94, a Benzimidazole L-Riboside with a Unique Mode of Action. Antimicrobial agents and chemotherapy. Aug 2002, 46(8) 2365–2372.

⁴ Krosky et al. The Human Cytomegalovirus UL97 Protein Kinase, an Antiviral Drug Target, Is Required at the Stage of Nuclear Egress. J of Vir. Jan 2003, 77 (2). 905-914.

⁵ Chou & Marousek. Accelerated Evolution of Maribavir Resistance in a Cytomegalovirus Exonuclease Domain II Mutant. J of Vir, Jan 2008, 82 (1) 246-253.

⁶ Shannon-Lowe & Emery. The effects of maribavir on the autophosphorylation of ganciclovir resistant mutants of the cytomegalovirus UL97 protein. Herpesviridae 2010, 1:4.

⁷ 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 Ther. 2018;7:1-16.

⁸ Azevedo L, Pierrotti L, Abdala E, et al. Cytomegalovirus infection in transplant recipients. Clinics. 2015;70(7):515-523. doi:10.6061/clinics/2015(07)09.

⁹ Cho S-Y, Lee D-G, Kim H-J. Cytomegalovirus Infections after Hematopoietic Stem Cell Transplantation: Current Status and Future Immunotherapy. Int J Mol Sci. 2019;20(2666):1-17.

¹⁰ El Chaer et al. How I treat resistant cytomegalovirus infection in hematopoietic cell transplantation recipients. Blood, 2016

¹¹ 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.

¹² de la Hoz R. Diagnosis and treatment approaches to CMV infections in adult patients. J Clin Virol. 2002;25:S1-S12.

¹³ Razonable RR, Eid AJ. A Viral infections in transplant recipients. Minerva Med. 2009;100(6):23.

¹⁴ World Health Organization. Haematopoietic Stem Cell Transplantation HSCtx. Accessed December 2, 2020. https://www.who.int/transplantation/hsctx/en/.

¹⁵ Kenyon M, Babic A, eds. The European Blood and Marrow Transplantation Textbook for Nurses. Springer International Publishing; 2018. doi:10.1007/978-3-319-50026-3.

¹⁶ Ljungman et al. Guidelines for the management of cytomegalovirus infection in patients with haematological malignancies and after stem cell transplantation from the 2017 European Conference on Infections in Leukaemia (ECIL7).Lancet Vol.19, Aug 2019.

¹⁷ Razonable & Humar. Cytomegalovirus in solid organ transplant recipients— Guidelines of the American Society of Transplantation Infectious Diseases Community of Practice. Clinical Transplantation, Feb 2019.

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