Takeda’s Maribavir Phase 3 Clinical Trial Met Primary Endpoint of Superiority to Conventional Antiviral Therapy in Transplant Recipients With Refractory, With or Without Resistance, Cytomegalovirus Infection/Disease

More Than Twice As Many Transplant Recipients With Refractory, With or Without Resistance (R/R), Cytomegalovirus (CMV) Infection/Disease Treated With Maribavir, an Oral Antiviral Compound, Achieved CMV Viremia Clearance As Compared to Patients Treated With Conventional Antiviral Therapies[1]
Phase 3 Clinical Trial Also Demonstrated Fewer Treatment-limiting Adverse Events Leading to Treatment Discontinuation in Patients Treated With Maribavir Compared to Conventional Antiviral Therapies[1]
Maribavir Is Also Under Investigation for the First-line Treatment of CMV in Hematopoietic Cell Transplant Recipients in an Ongoing Phase 3 Clinical Trial
Takeda is Committed to Advancing the Care of These Vulnerable Transplant Recipients, and if Approved, Maribavir Will Be the First and Only Treatment Indicated for Post-transplant R/R CMV Infection/Disease

Feb 15, 2021 16:16 KST

OSAKA, JAPAN--(Business Wire / Korea Newswire) February 15, 2021 -- Takeda Pharmaceutical Company Limited (TSE:4502/NYSE:TAK) (“Takeda”) today at the 2021 Transplantation & Cellular Therapy (TCT) Meetings Digital Experience announced new, late-breaking Phase 3 data from the TAK-620-303 (SOLSTICE) trial, for the investigational drug TAK-620 (maribavir) which met its primary endpoint of superiority compared to conventional antiviral therapies (investigator assigned treatment, [IAT], one or a combination of ganciclovir, valganciclovir, foscarnet or cidofovir) in transplant recipients with refractory, with or without resistance (R/R), cytomegalovirus (CMV) infection/disease. Overall, more than twice as many (55.7%; n=131/235) transplant recipients with R/R CMV infection/disease treated with maribavir achieved confirmed CMV viremia clearance at Study Week 8 (end of treatment phase), the study’s primary endpoint, as compared to 23.9% (n=28/117) of those on conventional antiviral therapies (95% CI: 32.8%, 22.8-42.7; p<0.001).[1]*†‡

The study’s key secondary endpoint was met by demonstrating maribavir's improvement over conventional therapies in clearance of CMV viremia and associated symptom control maintained through Study Week 16.[1]

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]). Any treatment-emergent adverse events (TEAEs) were 97.4% (228/234) for maribavir and 91.4% (106/116) for the conventional therapy group. TEAEs leading to study drug discontinuation were 13.2% (31/234) in the maribavir group and 31.9% (37/116) in the conventional therapy group. Two treatment-related serious TEAEs led to death (1 patient per treatment group).

“We are pleased that the SOLSTICE trial, which compared maribavir to available antiviral treatments for transplant patients with refractory/resistant cytomegalovirus infections, met its primary endpoint. More than half the patients who received maribavir were able to have their CMV infections treated successfully for 8 weeks and experienced less neutropenia and acute kidney injury compared to currently available treatments valganciclovir/ganciclovir and foscarnet, respectively,” said Francisco M. Marty, MD, Associate Physician, Brigham and Women's Hospital, Associate Professor of Medicine, Harvard Medical School. “These new findings are a promising advance in the quest for potential new treatments of CMV for transplant recipients.”

Key efficacy findings presented by Dr. Marty, a SOLSTICE trial investigator, included:

Subgroup Analyses of Primary Endpoint (Confirmed CMV Clearance at Week 8 [Randomized Set])[1]

· 55.6% of solid organ transplant (SOT) recipients with R/R CMV infection/disease receiving maribavir achieved confirmed CMV viremia clearance compared to 26.1% of those on conventional therapies.
· 55.9% of hematopoietic cell transplant (HCT) recipients with R/R CMV infection/disease receiving maribavir achieved confirmed CMV viremia clearance compared to 20.8% of those on conventional therapies.
· A greater proportion of transplant recipients with R/R CMV infection/disease receiving maribavir achieved CMV clearance at week 8 regardless of baseline viral load category (62.1% and 43.9% of patients receiving maribavir vs. 24.7% and 21.9% receiving conventional therapies, in low [<9,100 IU/mL] and intermediate/high [≥9,100 IU/mL] baseline viral load respectively).

Analyses of Key Secondary Endpoint (CMV Clearance and Symptom Control Followed by Maintenance Through Study Week 16 [Randomized Set])[1]

· 18.7% (44/235) of transplant recipients treated with maribavir maintained CMV viremia clearance and symptom control through Study Week 16 compared to 10.3% (12/117) of those treated with conventional therapies (p=0.013).

“We are excited by the results of the SOLSTICE trial, which were shared in greater detail with the scientific community at the 2021 TCT Meetings. This is an important development for transplant patients who are at increased risk of CMV, which if not controlled, can pose grave challenges. Maribavir, if approved, has the potential to redefine treatment for post-transplant refractory, with or without resistance, CMV,” said Obi Umeh, MD, Vice President and Maribavir Global Program Leader, Takeda.

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.[2] However, serious disease may occur in individuals with compromised immune systems, which includes patients who received immunosuppressants associated with various types of transplants including HCT or SOT.[3] CMV typically resides latent and asymptomatic in the body but reactivates during periods of immunosuppression.[3,4] 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.[4-9]

In transplant recipients, reactivation of CMV can lead to serious consequences including loss of the transplanted organ and, in extreme cases, can be fatal.[10,11] Existing therapies to treat post-transplant CMV infections may demonstrate toxicities that require dose adjustments, need hospitalization for administration, or may fail to adequately suppress viral replication.[12-14]

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.[15-18]

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 eight weeks of 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 healthcare 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] Marty F. A Phase 3 Randomized Study of Maribavir (MBV) Versus Investigator-Assigned Antiviral Therapy (IAT) for the Treatment (Tx) of Refractory/Resistant (R/R) Cytomegalovirus (CMV) Infection in Hematopoietic Cell Transplant (HCT) or Solid Organ Transplant (SOT) Recipients. In: The 2021 TCT Meetings Digital Experience; 2021. Abstract LBA2.
[2] Krech U. Complement-fixing antibodies against cytomegalovirus in different parts of the world. Bull WHO. 1973;49:103-106.
[3] de la Hoz R. Diagnosis and treatment approaches to CMV infections in adult patients. J Clin Virol. 2002;25:S1-S12.
[4] 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.
[5] 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.
[6] World Health Organization. Haematopoietic Stem Cell Transplantation HSCtx. Accessed December 2, 2020. https://www.who.int/transplantation/hsctx/en/.
[7] Razonable RR, Eid AJ. A Viral infections in transplant recipients. Minerva Med. 2009;100(6):23.
[8] 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.
[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] Fishman JA. Infection in Organ Transplantation. Am J Transplant. 2017;17:856-879.
[11] 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.
[12] 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.
[13] 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.
[14] 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.
[15] Abdel-Magid AF. New Inhibitors of Cytomegalovirus DNA Polymerase. ACS Med Chem Lett. 2013;4(12):1129-1130. doi:10.1021/ml4004099.
[16] 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.
[17] 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.
[18] 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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