FDA Approves First Therapy for Rare Joint Disease

On August 2, 2019, the FDA announced the approval of Tokyo-based Daiichi Sankyo’s “Turalio (pexidartinib) capsules for the treatment of adult patients with symptomatic tenosynovial giant cell tumor (TGCT),” a cancer of the joint synovium, “associated with severe morbidity or functional limitations and not responsive to improvement with surgery.”

“Today’s approval is the first FDA-approved therapy to treat this rare disease,” stated the agency announcement.

William Tap, M.D., chief of the Sarcoma Medical Oncology Service at Memorial Sloan Kettering Cancer Center, New York, and lead investigator for a pivotal phase 3 ENLIVEN study, said the approval “represents a paradigm shift in the treatment of carefully selected TGCT patients who face significant disease morbidity and for whom surgery is not an option. We now have a new oral treatment option that can have a meaningful clinical benefit in select patients, including a reduction in tumor size.”

Tenosynovial Giant Cell Tumor

According to the agency, TGCT is a “rare tumor that affects the synovium (thin layer of tissue that covers the surfaces of the joint spaces) and tendon sheaths (layer of membrane that covers tendons, which are fibrous tissue that connect muscle to bone). The tumor is rarely malignant but causes the synovium and tendon sheaths to thicken and overgrow, causing damage to surrounding tissue.”

ENLIVEN Study

The company said approval was based on the results of the pivotal phase 3 ENLIVEN study, the first placebo-controlled study of a systemic therapy in patients with TGCT.

“Study results showed the primary endpoint of tumor response rate by Response Evaluation Criteria v1.1 in Solid Tumors (RECIST) was 38% (95% CI: 27%, 50%) in TURALIO-treated patients and zero percent (95% CI: 0%, 6%) for placebo-treated patients at Week 25 (TURALIO N=61, placebo N=59; p<0.0001).

“In addition, overall response rate by tumor volume score (TVS) was 56% (95% CI: 43%, 67%) in patients randomized to the TURALIO arm and zero percent in patients randomized to the placebo arm at Week 25 (TURALIO N=61, placebo N=59; p<0.0001).

“Furthermore, the analysis of mean change from baseline in range of motion at Week 25 (TURALIO N=45, placebo N=43) demonstrated a statistically significant improvement in patients treated with TURALIO, compared to placebo.”

Warning and Side Effects

There is a Boxed Warning advising health care professionals and patients about the risk of serious and potentially fatal liver injury. “Health care professionals should monitor liver tests prior to beginning treatment and at specified intervals during treatment.”

“Women who are pregnant or breastfeeding should not take Turalio because it may cause harm to a developing fetus or newborn baby.”

The following common side effects were reported:

• “increased lactate dehydrogenase (proteins that helps produce energy in the body),
• increased aspartate aminotransferase (enzymes that are mostly in the liver but also in muscles),
• loss of hair color,
• increased alanine aminotransferase (enzymes that are primarily in the liver and kidney)
• and increased cholesterol.”

“Additional side effects included:

• neutropenia (low level of white blood cells that help the immune system defend against disease and infection),
• increased alkaline phosphatase (enzymes that are mostly in the cells of bone and the liver),
• decreased lymphocytes (white blood cells that help the immune system defend against disease and infection),
• eye edema (swelling around the eyes),
• decreased hemoglobin (protein in red blood cells that carry oxygen),
• rash,
• dysgeusia (altered sense of taste) and
• decreased phosphate (electrolytes that help with energy).”

The FDA granted the application Breakthrough Therapy designation and Priority Review designation. Turalio also received Orphan Drug designation.