Rare Daily Staff

The U.S. Food and Drug Administration has approved Daiichi Sankyo’s Turalio to treat TGCT a rare, non-malignant tumor that affects small and large joints, the first FDA-approved therapy to treat the condition.

The disease can cause debilitating symptoms and can be locally aggressive.

The approval of Turalio covers adults with symptomatic TGCT associated with severe morbidity or functional limitations and not amenable to improvement with surgery.

TGCT (tenosynovial giant cell tumor), also referred to as pigmented villonodular synovitis (PVNS), is a rare tumor that affects the synovium, the thin layer of tissue that covers the surfaces of the joint spaces and tendon sheaths, the layer of membrane that covers tendons. The tumor is rarely malignant but causes the synovium and tendon sheaths to thicken and overgrow, causing damage to surrounding tissue.

The current standard of care for TGCT is surgical resection. However, in patients with a recurrent, difficult-to-treat, or diffuse form of TGCT, the tumor may wrap around bone, tendons, ligaments and other parts of the joint. In these cases, the tumor may be difficult to remove and/or may not be amenable to improvement with surgery. Multiple surgeries for more severe cases can lead to significant joint damage, debilitating functional impairments and reduced quality of life, and amputation may be considered.

“TGCT can cause debilitating symptoms for patients such as pain, stiffness and limitation of movement. The tumor can significantly affect a patient’s quality of life and cause severe disability,” said Richard Pazdur, director of the FDA’s Oncology Center of Excellence. “Surgery is the primary treatment option, but some patients are not eligible for surgery, and tumors can recur, even after the procedure.”

The approval of Turalio was based on the results of a multi-center international clinical trial of 120 patients, 59 of whom received placebo. The primary efficacy endpoint was the overall response rate (ORR) analyzed after 25 weeks of treatment. The clinical trial demonstrated a statistically significant improvement in ORR in patients who received Turalio, with an ORR of 38 percent, compared to no responses in patients who received placebo.

The complete response rate was 15 percent and the partial response rate was 23 percent. A total of 22 out of 23 responders who had been followed for a minimum of six months following the initial response maintained their response for six or more months, and a total of 13 out of 13 responders who had been followed for a minimum of 12 months following the initial response maintained their response for 12 or more months.

The approval comes with a boxed warning for hepatotoxicity due to the risk of serious and potentially fatal liver injury. Across 768 patients who received Turalio in clinical trials, there were two irreversible cases of cholestatic liver injury. One patient died with advanced cancer and ongoing liver toxicity and one patient required a liver transplant.

But regulators and outside experts felt the benefits outweighed the risks. Because of the risk of hepatotoxicity, Daiichi will make Turalio available only through a REMS ( Risk Evaluation and Mitigation Strategy) program.

Turalio (pexidartinib) is an oral small molecule that inhibits CSF1R, or colony stimulating factor-1 receptor, which is a primary growth driver of abnormal cells in the synovium that cause TGCT. Turalio also inhibits KIT and FLT3-ITD. The molecule was discovered by Plexxikon, a subsidiary of Daiichi Sankyo.

Turalio was granted Priority Review, Breakthrough Therapy designation and Orphan Drug status by the FDA. Pexidartinib is currently under regulatory review for the treatment of TGCT with the European Medicines Agency and has received Orphan Drug designation.

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