New England Journal of Medicine Publishes Results of a Phase 2 Trial Evaluating Takeda’s TAK-620 (Maribavir) as a Potential Treatment of Cytomegalovirus (CMV) Infection

– From the results of a Phase 2 study, maribavir, an investigational agent that targets a specific CMV protein, may result in the clearance of CMV infections, a condition with potentially fatal complications in transplant patients

– Two global Phase 3 trials for maribavir are currently enrolling patients

OSAKA, Japan–(BUSINESS WIRE)–Takeda Pharmaceutical Company Limited (TSE:4502/NYSE:TAK) (“Takeda”) today announced that the New England Journal of Medicine has published results of a Phase 2, randomised, 12-week, open-label study of TAK-620 (maribavir), an investigational, orally bioavailable antiviral compound being evaluated in patients with cytomegalovirus (CMV) infection after undergoing hematopoietic cell transplant or solid organ transplant. CMV is a beta herpes virus that, in patients with compromised immunity, including organ or stem cell transplant recipients, causes clinically challenging complications that can be fatal.¹

Maribavir is designed to target a specific CMV protein, which may lead to inhibition of CMV DNA replication and encapsidation, and the prevention of the escape of viral capsids from the nucleus of infected cells. By inhibiting the CMV UL97 protein kinase, maribavir may potentially affect several processes in CMV replication including viral DNA synthesis, viral gene expression, encapsidation and egress of mature capsids from the nucleus.²

The Phase 2 study sought to assess the safety and tolerability of maribavir versus valganciclovir. It was a randomised, 12-week, open-label study of 159 adults (≥18 years of age) undergoing hematopoietic stem cell transplant or solid organ transplant with cytomegalovirus reactivation – evaluated maribavir at 400 mg (n=40), 800 mg (n=40) or 1200 mg (n=39) twice daily against valganciclovir at 900 mg twice daily for weeks 1-3, 900 mg once daily after week 3 (n=40).

The primary efficacy endpoint was the proportion of responsive patients with central laboratory-confirmed undetectable plasma CMV DNA. Sixty-two percent of patients treated with any dose of maribavir showed a treatment effect within three weeks of treatment versus 56% with valganciclovir (risk ratio 1.12; 95% CI, 0.84-1.49). At six weeks, response rates were 79% and 67% with maribavir and valganciclovir, respectively (risk ratio 1.20; 95% CI, 0.95-1.51).

The Phase 2 study showed that maribavir has demonstrated antiviral activity as a potential treatment of CMV infection and demonstrated a reduction of actively multiplying CMV in the blood, following hematopoietic cell transplant or solid organ transplant.

Safety and tolerability reported in the Phase 2 study found 67% percent of patients treated with any evaluated dose of maribavir experienced at least one treatment emergent adverse event (TEAE) that was considered by the investigators to be related to treatment versus 22% of those treated with valganciclovir. In the study, most TEAEs with maribavir (58%) were considered mild to moderate in severity versus 42.5% for valganciclovir. The most common TEAE with maribavir was dysgeusia, or altered taste, (40% vs 2% in the valganciclovir group). In line with earlier reported results, maribavir was associated with an increased incidence of gastrointestinal adverse events compared with valganciclovir (20-23% vs. 10-15%). The most frequently reported treatment emergent serious adverse events (SAE) for those treated with maribavir were acute graft versus host disease, diarrhea, renal failure and urinary tract infection with each reported by 3% of treated patients, versus bacterial sepsis, which was reported in 8% of patients treated with valganciclovir. Treatment-related SAEs occurred in 10% of patients treated with maribavir versus 2% of those treated with valganciclovir.

Treatment emergent neutropenia was identified in 4% of patients administered maribavir versus 15% of valganciclovir patients through week six of treatment and through week 12 neutropenia was seen in 5% of maribavir-treated patients versus 18% of valganciclovir-treated patients. Neutropenia occurs when a patient has too few neutrophils, a type of white blood cell, and is a complication experienced by transplant patients after their procedure, which can increase the risk of serious post-transplant complications, including life-threatening bacterial and fungal infections and, in solid organ transplant patients, is associated with organ rejection.³ No patients in the maribavir arm discontinued treatment due to myelosuppression or renal impairment.

“There is a significant unmet need for an additional treatment for post-transplant patients with CMV infection especially those with a CMV infection that is resistant to currently available antiviral therapies,” said Johan Maertens, M.D., Ph.D. of Universitaire Ziekenhuizen Leuven in Leuven, Belgium, and the trial’s principal investigator and lead author. “These results are encouraging and warrant further investigation of maribavir as a potentially effective and tolerated treatment for CMV in transplant patients.”

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 U.S. Food and Drug Administration (FDA) for treatment of clinically significant cytomegalovirus 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 cytomegalovirus 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. Breakthrough Therapy designation does not guarantee that FDA will approve maribavir for the treatment of CMV infections in transplant patients, and the timing of any such approval is uncertain.

“Based on these results, we are evaluating maribavir for the treatment of post-transplant CMV infection in two global Phase 3 trials,” said Daniel Curran, M.D., Head of the Rare Diseases Therapeutic Area Unit, at Takeda. “The continued development of maribavir reflects the progress of our late-stage rare disease pipeline and our commitment to delivering innovative medicines for patients who have diseases like CMV where there are significant unmet needs.”

The two randomised Phase 3 trials evaluating maribavir for the treatment of CMV infection in transplant patients are currently enrolling patients. The first is an open-label superiority study of maribavir 400 mg twice daily for eight weeks compared to investigator-assigned treatment, including ganciclovir, valganciclovir, foscarnet or cidofovir, in hematopoietic cell transplant or solid organ transplant patients with resistant or refractory CMV infection or disease. The second is a double-blind non-inferiority study of maribavir 400 mg twice daily for eight weeks in hematopoietic cell transplant patients experiencing a first episode of CMV infection.

About the Phase 2 Study

Within three weeks, 62% of patients treated with maribavir, regardless of study dose, saw an effect as result of treatment (400 mg [67%], 800 mg [58%] and 1200 mg [61%]) compared to 56% of those treated with valganciclovir. Treatment effect within six weeks increased to 79% on the maribavir arm (400 mg [79%], 800 mg [83%] and 1200 mg [74%]) versus 67% on the valganciclovir arm.

The most common TEAE on the maribavir arm was dysgeusia, or an altered state of taste, which was reported by 40% of those patients compared to 2% of valganciclovir patients. The most frequently reported treatment-emergent SAEs were acute graft versus host disease, diarrhea, renal failure and urinary tract infection, each reported by 3% of maribavir-treated patients. For those treated with valganciclovir, SAEs of bacterial sepsis were reported by 8% of patients. Adverse events led to some study drug discontinuation, with maribavir discontinued in 23% of patients and 12% of valganciclovir patients. The most frequent reason for discontinuation of maribavir was CMV infection (5%), but there were no discontinuations due to renal impairment or myelosuppression. The most frequent cause of discontinuation on the valganciclovir arm was leukopenia (5%). Dose adjustments due to adverse events occurred in 8% of maribavir compared to 48% of valganciclovir patients.

Results of the Phase 2 study were first presented at Infectious Disease Week (ID Week) 2016.⁴

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 bringing Better Health and a Brighter Future to patients by translating science into highly-innovative medicines. Takeda focuses its R&D efforts on four therapeutic areas: Oncology, Gastroenterology (GI), Rare Diseases and Neuroscience. 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 and regions.

For more information, visit https://www.takeda.com

Forward-Looking Statements

This press release and any materials distributed in connection with this press release may contain forward-looking statements, beliefs or opinions regarding Takeda’s future business, future position and results of operations, including estimates, forecasts, targets and plans for Takeda. In particular, this press release contains forecasts and management estimates related to the financial and operational performance of Takeda, including statements regarding forecasts for Revenue, Operating profit, Adjusted EBITDA, Profit before income taxes, Net profit attributable to owners of Takeda, Basic earnings per share, Amortization and impairment and other income/expense, Underlying Revenue, Underlying Core Earnings margin, Underlying Core EPS and Net Debt. Without limitation, forward looking statements often include the words such as “targets”, “plans”, “believes”, “hopes”, “continues”, “expects”, “aims”, “intends”, “will”, “may”, “should”, “would”, “could” “anticipates”, “estimates”, “projects” or words or terms of similar substance or the negative thereof. Any forward-looking statements in this document are based on the current assumptions and beliefs of Takeda in light of the information currently available to it. Such forward-looking statements do not represent any guarantee by Takeda or its management of future performance and involve known and unknown risks, uncertainties and other factors, including but not limited to: the economic circumstances surrounding Takeda’s business, including general economic conditions in Japan, the United States and worldwide; competitive pressures and developments; applicable laws and regulations; the success of or failure of product development programs; decisions of regulatory authorities and the timing thereof; changes in exchange rates; claims or concerns regarding the safety or efficacy of marketed products or products candidates; and post-merger integration with acquired companies, any of which may cause Takeda’s actual results, performance, achievements or financial position to be materially different from any future results, performance, achievements or financial position expressed or implied by such forward-looking statements. For more information on these and other factors which may affect Takeda’s results, performance, achievements, or financial position, see “Item 3. Key Information—D. Risk Factors” in Takeda’s Registration Statement on Form 20-F filed with the U.S. Securities and Exchange Commission, available on Takeda’s website at: https://www.takeda.com/investors/reports/sec-filings/ or at www.sec.gov. Neither Takeda nor its management gives any assurances that the expectations expressed in these forward-looking statements will turn out to be correct, and actual results, performance or achievements could materially differ from expectations. Persons receiving this press release should not place undue reliance on forward looking statements. Takeda undertakes no obligation to update any of the forward-looking statements contained in this press release or any other forward-looking statements it may make. Past performance is not an indicator of future results and the results of Takeda in this press release may not be indicative of, and are not an estimate, forecast or projection of Takeda’s future results.

¹ Maertens J, Cordonnier C, Jaksch P, et.al. Maribavir for Preemptive Treatment of Cytomegalovirus Reactivation. N Engl J Med 2019;381:1136-47. DOI: 10.1056/NEJMoa1714656.

² Prichard MN. Function of human cytomegalovirus UL97 kinase in viral infection and its inhibition by maribavir. Rev Med Virol. 2009;19(4):215–229. doi:10.1002/rmv.615

³ Zafrani L, Truffaut L, Kreis H, et.al. Incidence, Risk Factors and Clinical Consequences of Neutropenia Following Kidney Transplantation: A Retrospective Study. Am J Transplant. 2009 Aug;9(8): 1816-25. DOI: 10.1111j. 1600-6143.2009.02699.x. Epub 2009 Jun 16.

⁴ Maertens J, Cordonnier C, Jaksch P, et.al. Maribavir Versus Valganciclovir for Preemptive Treatment of Cytomegalovirus (CMV) Viremia: A Randomized, Dose-Ranging, Phase 2 Study Among Hematopoietic Stem Cell Transplant (SCT) and Solid Organ Transplant (SOT) Recipients. Infectious Disease Week 2016. Abstract #2287.

Contacts

Japanese Media

Kazumi Kobayashi

[email protected]
+81 (0) 3-3278-2095

Media outside Japan

Linda Calandra

[email protected]
+1 (617) 301-2092