Phase 3 Clinical Trial Subgroup Analysis Across Solid Organ Transplant (SOT) Types Supports Efficacy of Maribavir Over Conventional Therapies in Post-Transplant Recipients With Cytomegalovirus (CMV) Infection (Refractory, With or Without Resistance)

• Building Upon Previous Data Showing More Than Twice as Many SOT Recipients Receiving Maribavir Achieved CMV Viremia Clearance Compared to Conventional Antiviral Therapies, Subgroup Analysis Showed Consistent Efficacy in SOT Recipients Receiving Investigational Drug Maribavir In Heart, Lung and Kidney Transplants¹
• With the U.S. Food and Drug Administration’s (FDA) Recent Granting of Priority Review for Maribavir, Takeda Takes Another Step Towards Addressing Unmet Treatment Needs for Post-Transplant Recipients With CMV Infection

Takeda Pharmaceutical Company Limited (TSE:4502/NYSE:TAK) (“Takeda”) today at the American Transplant Congress (ATC) 2021 Virtual Connect presented results from a new subgroup analysis of SOT recipients in the Phase 3 TAK-620-303 (SOLSTICE) trial, for the investigational drug TAK-620 (maribavir). More than twice (55.6%, 79/142) as many SOT recipients with R/R 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 (26.1%, 18/69) (investigator assigned treatment; IAT consists of one or a combination of ganciclovir, valganciclovir, foscarnet or cidofovir) (adjusted difference [95% CI]: 30.5% [17.3, 43.6]).¹ The results presented showed consistent efficacy in SOT recipients receiving maribavir in heart, lung and kidney transplants.

Key findings by transplant type included:¹

• More than 3 times as many lung transplant recipients with R/R CMV infection treated with maribavir achieved confirmed CMV viremia clearance as compared to those on conventional therapies (47.5% [19/40] vs 13.6% [3/22]; adjusted difference [95% CI]: 38.2% [16.89, 59.53]).
• More than 1.5 times as many kidney transplant recipients with R/R CMV infection treated with maribavir achieved confirmed CMV viremia clearance as compared to those on conventional therapies (59.5% [44/74] vs 34.4% [11/32]; adjusted difference [95% CI]: 26.7% [7.48, 45.85]).
• 42.9% (6/14) of heart transplant recipients with R/R CMV infection treated with maribavir achieved confirmed CMV viremia clearance as compared to 11.1% (1/9) of those on conventional therapies (adjusted difference [95% CI]: 30.7% [-1.72, 63.15]).

“CMV infections are a common yet unpredictable threat for transplant teams, with an estimated incidence rate between 16-56% in solid organ transplant recipients,” said Obi Umeh, MD, Vice President and Maribavir Global Program Leader, Takeda. “These results build on previously presented data on the potential of maribavir to treat CMV infection in some of these challenging patient populations.”

These findings reinforce the results from the overall trial population which 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 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 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

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. Most recently, the FDA has granted priority review of maribavir for the treatment of post-transplant recipients with CMV infection in those R/R to prior anti-CMV treatment. These designations and NDA acceptance 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 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.

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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

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