EMA Validates Daiichi Sankyo's Marketing Authorization Application for Pexidartinib for Treatment of Patients with TGCT, a Rare, Debilitating, Non-Malignant Tumor

- Application based on results of phase 3 ENLIVEN study, the first placebo-controlled study of a systemic investigational therapy in patients with tenosynovial giant cell tumor (TGCT)

- An unmet medical need exists in Europe for TGCT, a potentially debilitating condition with no approved systemic therapies and which sometimes is not amenable to improvement with surgery

- EU Marketing Authorization Application (MAA) follows recent filing of the pexidartinib New Drug Application by the U.S. FDA with Priority Review

- TGCT is also referred to as pigmented villonodular synovitis (PVNS) or giant cell tumor of the tendon sheath (GCT-TS)

TOKYO, MUNICH and BASKING RIDGE, New Jersey, April 3, 2019 /PRNewswire/ -- Daiichi Sankyo Company, Limited (hereafter, Daiichi Sankyo) announced that the European Medicines Agency (EMA) validated the Marketing Authorization Application (MAA) for pexidartinib for the treatment of adult patients with symptomatic tenosynovial giant cell tumor (TGCT), which is associated with severe morbidity or functional limitations, and which is not amenable to improvement with surgery. TGCT is also referred to as pigmented villonodular synovitis (PVNS) or giant cell tumor of the tendon sheath (GCT-TS).

Validation confirms that the application is complete and commences the scientific review process by the EMA's Committee for Medicinal Products for Human Use (CHMP). The EU MAA is based on results of the pivotal phase 3 ENLIVEN study of oral pexidartinib, the first placebo-controlled study of a systemic investigational therapy in patients with TGCT, which met its primary endpoint of overall response rate.  Results of the phase 3 ENLIVEN study were presented during an oral presentation at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting.

"We are pleased that review of our submission for pexidartinib in Europe is now underway, and we look forward to working with the EMA to potentially offer the first approved systemic therapy to carefully-selected patients with TGCT," said Dale Shuster, Ph.D., Executive Director, Global Oncology R&D, Daiichi Sankyo.

"We are excited about the first-in-class potential of pexidartinib, another targeted therapy discovered by Plexxikon," said Gideon Bollag, Ph.D., Chief Executive Officer of Plexxikon Inc., Daiichi Sankyo's small molecule structure-guided R&D center in Berkeley, CA and a member of the Daiichi Sankyo Group. "Our drug discovery process uses structural data and a specialized scaffold-like screening library to identify and optimize novel drug candidates."

The New Drug Application (NDA) for pexidartinib is currently under Priority Review in the U.S., and the FDA is expected to make a decision on approval by August 3, 2019.

ENLIVEN is a pivotal, double-blind, randomized, global multi-center phase 3 study that evaluated pexidartinib in patients with symptomatic advanced TGCT for whom surgical removal of the tumor would be associated with potentially worsening functional limitation or severe morbidity. The first part of the study, the double-blind phase, enrolled 120 patients who were randomized (1:1) to receive either pexidartinib or placebo at 1000 mg/day for 2 weeks followed by 800 mg/day for 22 weeks in order to evaluate the efficacy and safety of pexidartinib versus placebo. The primary endpoint of the study was the percentage of patients achieving a complete or partial response after 24 weeks of treatment (Week 25), as assessed with centrally-read MRI scans using RECIST 1.1 criteria. Key secondary endpoints included range of motion, response by tumor volume score, PROMIS physical function, stiffness and measures of pain reduction.

The ENLIVEN study met its primary endpoint of overall response rate. In the ENLIVEN study, hepatic toxicities were more frequent with pexidartinib versus placebo (AST or ALT ≥3X ULN: 33 percent, total bilirubin ≥2X ULN: 5 percent, N=61). Eight patients discontinued pexidartinib due to hepatic adverse events (AEs); four were serious nonfatal AEs with increased bilirubin, one lasting ~7 months. In non-TGCT development studies using pexidartinib, two severe liver toxicity cases (one required liver transplant, one was associated with death) were observed.

About TGCT (PVNS/GCT-TS) 
Tenosynovial giant cell tumor (TGCT), also referred to as pigmented villonodular synovitis (PVNS) or giant cell tumor of the tendon sheath (GCT-TS), is a rare, non-malignant tumor that can be locally aggressive. TGCT affects the synovium-lined joints, bursae, and tendon sheaths, resulting in swelling, pain, stiffness and reduced mobility in the affected joint or limb.^{1, 2, 3}

While the exact incidence of TGCT is not known, it is estimated that the incidence of TGCT is 11 to 50 cases per million person-years, based on studies from three countries. ^4,5,6 TGCT is subcategorized into two types: localized, which is more common and accounts for 90 percent of cases, and diffuse, which accounts for 10 percent of cases.^5,6 Primary treatment of TGCT includes surgery to remove the tumor. However, in patients with a recurrent, difficult to treat, or diffuse form where the tumor can wrap around bone, tendons, ligaments and other parts of the joint, it is more difficult to remove or might not be amenable to improvement with surgery. Additional surgeries for more severe cases can lead to significant joint damage, debilitating functional impairments, and reduced quality of life and amputation may be considered.^7,8,9

Recurrence rates for localized TGCT are estimated to be up to 15 percent following complete resection.^2,10,11,12 Diffuse TGCT recurrence rates are estimated to be about 20 percent to 50 percent following complete resection.^3,10,13 TGCT affects all age groups; the diffuse type on average occurs most often in people below the age of 40 and the localized type typically occurs in people between 30 and 50 years old.^1,4,5,6 

About Pexidartinib
Pexidartinib is an investigational, novel, oral small molecule that potently inhibits CSF1R (colony stimulating factor-1 receptor), which is a primary growth driver of abnormal cells in the synovium that cause TGCT. Pexidartinib also inhibits c-kit and FLT3-ITD. Pexidartinib was discovered by Plexxikon Inc., the small molecule structure-guided R&D center of Daiichi Sankyo.

Pexidartinib has been granted Priority Review for the treatment of adult patients with symptomatic tenosynovial giant cell tumor (TGCT), which is associated with severe morbidity or functional limitations, and which is not amenable to improvement with surgery, Breakthrough Therapy designation for the treatment of patients with pigmented villonodular synovitis (PVNS) or giant cell tumor of tendon sheath (GCT-TS), where surgical resection may result in potentially worsening functional limitation or severe morbidity, and Orphan Drug designation for the treatment of PVNS/GCT-TS by the U.S. Food and Drug Administration (FDA). Pexidartinib also has received Orphan Drug designation from the European Commission for the treatment of TGCT.

On January 31, 2019, the American Society of Clinical Oncology (ASCO) recognized "Progress in Treating Rare Cancers" as the "Advance of the Year," and selected pexidartinib as one of five significant advancements in rare disease treatment, calling it the first promising investigational therapy for TGCT. 

Pexidartinib is an investigational compound that has not been approved for any indication in any country. Safety and efficacy have not been established.

About Daiichi Sankyo Cancer Enterprise
The mission of Daiichi Sankyo Cancer Enterprise is to leverage our world-class, innovative science and push beyond traditional thinking to create meaningful treatments for patients with cancer. We are dedicated to transforming science into value for patients, and this sense of obligation informs everything we do. Anchored by three pillars including our investigational Antibody Drug Conjugate Franchise, Acute Myeloid Leukemia Franchise and Breakthrough Science, we aim to deliver seven distinct new molecular entities over eight years during 2018 to 2025. Our powerful research engines include two laboratories for biologic/immuno-oncology and small molecules in Japan, and Plexxikon Inc., our small molecule structure-guided R&D center in Berkeley, CA. Compounds in pivotal stage development include: [fam-] trastuzumab deruxtecan, an antibody drug conjugate (ADC) for HER2 expressing breast, gastric and other cancers; quizartinib, an oral selective FLT3 inhibitor, for newly-diagnosed and relapsed/refractory FLT3-ITD acute myeloid leukemia (AML); and pexidartinib, an oral CSF1R inhibitor, for tenosynovial giant cell tumor (TGCT). For more information, please visit: www.DSCancerEnterprise.com.

About Daiichi Sankyo
Daiichi Sankyo Group is dedicated to the creation and supply of innovative pharmaceutical products to address diversified, unmet medical needs of patients in both mature and emerging markets. With over 100 years of scientific expertise and a presence in more than 20 countries, Daiichi Sankyo and its 15,000 employees around the world draw upon a rich legacy of innovation and a robust pipeline of promising new medicines to help people. In addition to a strong portfolio of medicines for hypertension and thrombotic disorders, under the Group's 2025 Vision to become a "Global Pharma Innovator with Competitive Advantage in Oncology," Daiichi Sankyo research and development is primarily focused on bringing forth novel therapies in oncology, including immuno-oncology, with additional focus on new horizon areas, such as pain management, neurodegenerative diseases, heart and kidney diseases, and other rare diseases. For more information, please visit: www.daiichisankyo.com. Daiichi Sankyo, Inc., headquartered in Basking Ridge, New Jersey, is a member of the Daiichi Sankyo Group. For more information on Daiichi Sankyo, Inc., please visit: www.dsi.com.

Contact

Lydia Worms
Daiichi Sankyo Europe
lydia.worm@daiichi-sankyo.eu
+49 89 7808751 (office)
+49 176 11780861 (mobile)

Kimberly Wix
Daiichi Sankyo, Inc. (US)
kwix@dsi.com
+1 908 992 6633 (office)
+1 908 656 5447 (mobile)

Koji Ogiwara
Daiichi Sankyo, Co., Ltd
ogiwara.koji.ay@daiichisankyo.co.jp
+81 3 6225 1126

References:

¹ de Saint Aubain, et al. WHO. 2013;100-103.
² Rao AS, et al. J Bone Joint Surg AM. 1984;66(1):76-94.
³ Ravi V, et al. Curr Opin Oncol. 2011;23:361-366.
⁴ Myers BW, et al. Medicine (Baltimore). 1980;59(3):223-238.
⁵ Mastboom MJL., et al. Acta Orthopaedica. 2017;88(6):688-694.
⁶ Ehrenstein V, et al. J Rheumatol. 2017; 44(10):1476-1483.
⁷ Verspoor FGM, et al. Future Oncol. 2013;10:1515-1531.
⁸ Verspoor FGM, et al. Rheumatol. 2014;53(11):2063-2070. 
⁹ Brahmi M, et al. Curr Treat Options Oncol. 2016;17(2):10.
¹⁰ Gouin F, Noailles T. Orthop Traumatol Surg Res. 2017;103(1S):S91-S97. 
¹¹ Palmerini E, Staals EL, Maki RG, et al. Eur J Cancer. 2015;51(2):210-217. 
¹² Dines JS, et al. Arthroscopy. 2007;23(9):930-937.
¹³ Xie G-P, et al. PLOS One. 2015;10(3):e0121451. 

ONP/19/0001