OSAKA, Japan--(뉴스와이어)--Takeda Pharmaceutical Company Limited (TSE:4502/NYSE:TAK) (“Takeda”) today during the Presidential Symposium at the 47th Annual Meeting of the European Society for Blood and Marrow Transplantation (EBMT) announced the results from a subgroup analysis of the Phase 3 TAK-620-303 (SOLSTICE) trial, for the investigational drug TAK-620 (maribavir), which supported the efficacy results from the overall randomized population. More than three times as many (62.8%; 76/121) transplant recipients with confirmed genotypic resistant CMV infection at baseline treated with maribavir achieved confirmed CMV viremia clearance at Study Week 8 (end of treatment phase) compared to those treated with conventional antiviral therapies (20.3%, 14/69) (investigator assigned treatment; IAT consists of one or a combination of ganciclovir, valganciclovir, foscarnet or cidofovir) (adjusted difference [95% CI]: 44.1% [31.3, 56.9]).[1]

Findings from the overall trial population showed the study met its primary endpoint, demonstrating that maribavir was superior to conventional antiviral therapies in CMV viremia clearance at Study Week 8. Specifically, 55.7% (131/235) of transplant recipients with refractory, with or without resistance (R/R), CMV infection/disease treated with maribavir achieved confirmed CMV viremia clearance as compared to 23.9% (28/117) of those on conventional antiviral therapies (adjusted difference [95% CI]: 32.8%, [22.8, 42.7]; p<0.001).[1]*†‡

“Transplant recipients with CMV infections resistant to conventional antiviral therapies are some of the hardest to treat. Current treatment options are limited, and hematologist-oncologists have to engage in a careful balance of viral clearance and side effect management,” said Dr. Rafael Duarte, Hospital Universitario Puerta de Hierro, Madrid. “We believe these data are important as they build on previously presented results supporting the potential of maribavir, which, if approved, could transform the management of CMV in these patients.”

Transplant recipients receiving maribavir exhibited lower incidence of treatment-related toxicities common with conventional antiviral therapies. Those receiving maribavir experienced lower rates of treatment-related neutropenia vs. valganciclovir/ganciclovir (1.7% [4/234] vs. 25% [14/56]) and acute kidney injury vs. foscarnet (1.7% [4/234] vs. 19.1% [9/47]). Incidence of any treatment-emergent adverse events (TEAEs) was 97.4% (228/234) for maribavir and 91.4% (106/116) for the conventional therapy group.[1] The most common TEAEs in the maribavir group were dysgeusia (35.9%, 84/234), nausea (8.5%, 20/234) and vomiting (7.7%, 18/234).[2] Incidence of TEAEs leading to study drug discontinuation was 13.2% (31/234) in the maribavir group and 31.9% (37/116) in the conventional therapy group.[1] Two treatment-related serious TEAEs led to death (1 patient per treatment group).[1]

“Current CMV management is associated with difficult tradeoffs, including management of toxicities and viremia clearance,” said Obi Umeh, MD, Vice President and Maribavir Global Program Leader, Takeda. “As we continue our research of maribavir, an oral antiviral compound, across patient populations, we are committed to addressing this unmet need so physicians potentially have an additional treatment option.”

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 hematopoietic cell transplant (HCT) or solid organ transplant (SOT).[4,5] Out of the estimated 200,000 adult transplants per year, 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 HCT recipients.[5-10]

In transplant recipients, reactivation of CMV can lead to serious consequences including loss of the transplanted organ and, in extreme cases, can be fatal.[11,12] Existing therapies to treat posttransplant CMV infections may demonstrate toxicities that require dose adjustments or may fail to adequately suppress viral replication.[13-15] Additionally, existing therapies may require or prolong hospitalization due to administration.[13-14]

About Maribavir

Maribavir, an orally bioavailable anti-CMV compound, is the only antiviral agent presently in Phase 3 development for the treatment of post-transplant patients with CMV in SOT or HCT. Maribavir is an investigational treatment that has not been approved for use by the U.S. Food and Drug Administration (FDA), European Medicines Agency (EMA) or any other regulatory authorities. Maribavir is the only CMV antiviral drug that targets and inhibits the UL97 protein kinase and its natural substrates.[16-19]

Maribavir has been granted Orphan Drug Designation by the European Commission as a treatment of CMV disease in patients with impaired cell mediated immunity and by the FDA for treatment of clinically significant CMV viremia and disease in at-risk patients. Orphan status is granted to certain investigational medicines intended for the treatment or prevention of a rare, life-threatening disease. The FDA has also granted maribavir Breakthrough Therapy Designation as a treatment for CMV infection and disease in transplant patients resistant or refractory to prior therapy. Breakthrough Therapy Designation expedites the development and review of investigational treatments for serious conditions with preliminary clinical evidence indicating that the drug may demonstrate substantial improvement over available therapy. These designations do not guarantee that the EMA or FDA will approve maribavir for the treatment of CMV infections in transplant patients, and the timing of any such approval is uncertain.

About Takeda’s SOLSTICE Trial

The TAK-620-303 (SOLSTICE) trial (NCT02931539) is a multicenter, randomized, open-label, active-controlled trial comparing treatment with either maribavir or investigator assigned treatment, IAT, (conventional antiviral therapy) in 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. Patients underwent a 2-week screening period, followed by randomization 2:1 to maribavir (n=235) (400 mg) or IAT (n=117) for an 8-week treatment period, plus 12 weeks of follow-up.

The trial’s primary endpoint was defined as the proportion of patients who achieved confirmed CMV viremia clearance (plasma CMV DNA <137 IU/mL in two consecutive tests ≥5 days apart at central laboratory) compared to IAT at the end of Study Week 8. The key secondary endpoint was defined as achievement of CMV viremia clearance and symptom control at end of Study Week 8, maintained through Study Week 16.

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 Genetic 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.

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*The difference in proportion of responders between treatment groups was obtained using Cochran-Mantel-Haenszel (CMH) weighted average across all strata and tested using stratum-adjusted CMH method, with transplant type and baseline plasma CMV DNA concentration as two stratification factors

† 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] Duarte R. Maribavir Versus Investigator-Assigned Therapy for the Treatment of Transplant Recipients with Refractory/Resistant Cytomegalovirus Infection: Efficacy Data From a Randomized Phase 3 Open-Label Study. In: 47th Annual Meeting of the European Society for Blood and Marrow Transplantation (EBMT), 2021. Abstract.

[2] Duarte R. Maribavir Versus Investigator-Assigned Therapy for the Treatment of Transplant Recipients with Refractory/Resistant Cytomegalovirus Infection: Efficacy Data From a Randomized Phase 3 Open-Label Study. In: 47th Annual Meeting of the European Society for Blood and Marrow Transplantation (EBMT), 2021. Oral Presentation.

[3] Krech U. Complement-fixing antibodies against cytomegalovirus in different parts of the world. Bull WHO. 1973;49:103-106.

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

[5] 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.

[6] World Health Organization. International Report on Organ Donation and Transplantation Activities- Executive Summary 2018.; 2020. Accessed December 2, 2020. http://www.transplant-observatory.org/wp-content/uploads/2020/10/glorep2018-2.pdf.

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

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

[9] 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.

[10] 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.

[11] Fishman JA. Infection in Organ Transplantation. Am J Transplant. 2017;17:856-879.

[12] 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.

[13] 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.

[14] 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.

[15] Beyer K. Outpatient Foscarnet Administration Incorporating Home Infusions Is Feasible Greatly Enhancing the Care of Hematopoietic Stem Cell Transplant Recipients. Biol Blood Marrow Transpl. 2017;23:S18-S391.

[16] Abdel-Magid AF. New Inhibitors of Cytomegalovirus DNA Polymerase. ACS Med Chem Lett. 2013;4(12):1129-1130. doi:10.1021/ml4004099.

[17] Hamirally S, Kamil JP, Ndassa-Colday YM, et al. Viral Mimicry of Cdc2/Cyclin-Dependent Kinase 1 Mediates Disruption of Nuclear Lamina during Human Cytomegalovirus Nuclear Egress. Nelson JA, ed. PLoS Pathog. 2009;5(1):e1000275. doi:10.1371/journal.ppat.1000275.

[18] Kotton CN, Kumar D, Caliendo AM, et al. The Third International Consensus Guidelines on the Management of Cytomegalovirus in Solid-organ Transplantation: Transplantation. 2018;102(6):900-931. doi:10.1097/TP.0000000000002191.

[19] Krosky PM, Baek M-C, Coen DM. The Human Cytomegalovirus UL97 Protein Kinase, an Antiviral Drug Target, Is Required at the Stage of Nuclear Egress. JVI. 2003;77(2):905-914. doi:10.1128/JVI.77.2.905-914.2003.

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