Daiichi Sankyo, Inc. and Plexxikon Inc., a member of the Daiichi Sankyo Group, announced that the US Food and Drug Administration (FDA) has granted Breakthrough Therapy designation to its investigational oral CSF-1R inhibitor pexidartinib (formerly PLX3397) for the treatment of tenosynovial giant cell tumour (TGCT) where surgical removal of the tumour would be associated with potentially worsening functional limitation or severe morbidity.

Breakthrough Therapy designation is designed to expedite the development and review of medicines that may demonstrate substantial benefit over currently available treatments in order to ensure that patients with serious diseases have access to new treatments as soon as possible. Currently, there is no FDA-approved systemic therapy for the treatment of TGCT.

“Surgery is the primary treatment for TGCT, but for patients with a diffuse form of the condition, the tumour is more difficult to remove and has a high rate of recurrence, resulting in multiple complicated surgeries and even amputation in some patients,” said Mahmoud Ghazzi, MD, PhD, executive vice president and global head of development for Daiichi Sankyo.

“We are pleased that the FDA recognises the unmet need for the treatment of TGCT and we look forward to working closely with the Agency on the expedited development of this potential non-surgical treatment for patients with TGCT.”

The Breakthrough Therapy designation was granted based on results from an extension cohort of a single-arm, multi-center phase 1 study that assessed the safety and efficacy of pexidartinib. Results of this study were published in the July 30, 2015 issue of The New England Journal of Medicine.

“The responses seen in our ongoing phase 1 study provided initial proof-of-concept that selective CSF-1R inhibition with pexidartinib may safely and effectively reduce tumour burden in patients with TGCT, providing the rationale to move directly into a phase 3 clinical trial,” said Gideon Bollag, PhD, chief executive officer of Plexxikon.

“This Breakthrough Therapy designation represents another significant milestone in our commitment to develop novel targeted agents that address unmet medical needs in rare conditions such as TGCT.”

A pivotal, phase 3 study of pexidartinib called ENLIVEN is currently enrolling patients with symptomatic TGCT for whom surgical removal of the tumor would be associated with potentially worsening functional limitation or severe morbidity.

The most common treatment-related adverse events seen in the ongoing phase 1 study of pexidartinib included fatigue, hair colour changes, nausea, dysgeusia (abnormal taste), and periorbital edema (swelling around the eyes), which rarely led to drug discontinuation. Treatment-related severe adverse events included fatigue, diarrhea, anemia, hyponatremia, elevated liver enzymes and neutropenia.

Tenosynovial giant cell tumour (TGCT) – a group of neoplasms including pigmented villonodular synovitis (PVNS) and giant cell tumour of the tendon sheath (GCT-TS) – is a rare, usually non-metastatic tumour that affects the synovium-lined joints, bursae, and tendon sheaths, resulting in swelling, pain, stiffness and reduced mobility in the affected joint or limb. It is estimated that TGCT has an annual incidence of 11 cases per million. Patients are commonly diagnosed in their 20s to 50s, and depending on the type of TGCT, women can be up to twice as likely to develop a tumor as men.

Primary treatment of TGCT includes surgery to remove the tumour, but in patients with a diffuse form where it can wrap around bone, tendons, ligaments and other parts of the joint, the tumor is more difficult to remove and may require multiple surgeries or joint replacement, eventually advancing to the point where surgery is no longer an option and amputation may be considered. It is estimated that the rate of recurrence in the diffuse form of the disease can be about 45 per cent or higher in some case series.

Pexidartinib is an investigational novel, oral small molecule that potently and selectively inhibits CSF-1R (colony stimulating factor-1 receptor), which is a primary growth driver of abnormal cells in the synovium that causes TGCT. Pexidartinib has not been approved by the US Food and Drug Administration (FDA) or any other regulatory authority for uses under investigation.

In addition to Breakthrough Therapy designation, pexidartinib has been granted Orphan Drug designation by the US Food and Drug Administration (FDA) for the treatment of PVNS and GCT-TS. Pexidartinib also has received Orphan designation from the European Commission for the treatment of TGCT.

Pexidartinib is being evaluated in several other potential clinical indications including glioblastoma, melanoma, ovarian and breast cancer as well as in combination with anti-PD-1 therapy, pembrolizumab, for advanced melanoma and other multiple solid tumours. Pexidartinib also is being studied in the I-SPY 2 TRIAL, a collaborative research effort studying the effects of adding specific investigational drugs to standard chemotherapy prior to surgery in women with newly diagnosed, locally advanced breast cancer.

Plexxikon, a member of the Daiichi Sankyo Group since April 2011, is a leader in the structure-guided discovery and development of novel small molecule pharmaceuticals to treat human disease. The company’s drug Zelboraf (vemurafenib/PLX4032) was approved by the FDA in 2011, and is being co-promoted in the US by Daiichi Sankyo Inc. and Genentech. Plexxikon is developing a portfolio of preclinical and clinical stage compounds to address significant unmet medical needs in oncology and other therapeutic areas. Plexxikon’s Scaffold-Based Drug Discovery platform integrates multiple state-of-the-art technologies, including structural screening as a key component that provides a significant advantage over other drug discovery approaches.