Deciphera Pharmaceuticals Inc. CEO Steven Hoerter told BioWorld Asia the FDA approval of Turalio (pexidartinib) from Daiichi Sankyo Co. Ltd. last week "leaves a lot of headroom for efficacy," given the response rate of about 40%. "One of the most significant concerns that the FDA had was hepatotoxicity, which is an off-target effect," he added, so the approval came with "some fairly onerous monitoring requirements." His firm's phase I prospect, a colony stimulating factor receptor 1 (CSF1R) inhibitor like Turalio, may help in that regard, too.

Turalio won the green light as the first treatment for adults with symptomatic tenosynovial giant cell tumor (TGCT) associated with severe morbidity or functional limitations and not responsive to improvement with surgery. TGCT is a rare tumor that affects the synovium and tendon sheaths. Though seldom malignant, it causes the synovium and tendon sheaths to thicken and overgrow, leading to damage to surrounding tissue, which can severely disable those afflicted. Surgery has been the primary option until now – Turalio is the first approved drug for the indication – but some patients are not eligible for surgery, and tumors may recur after the operation. In a 2017 pivotal phase III study called Enliven, the drug later to be branded Turalio met its primary endpoint of tumor response, measured by size reduction, in patients with symptomatic TGCT. (See BioWorld, Nov. 2, 2017, and Aug. 5, 2019.)

The win with Turalio, which was discovered by Plexxikon Inc. (bought by Daiichi in 2011) and inhibits KIT plus FLT3-ITD as well as CSF1R, must have seemed especially sweet to Tokyo-based Daiichi after the setback in May at the hands of the FDA's Oncologic Drugs Advisory Committee regarding quizartinib tablets for adults with relapsed or refractory acute myeloid leukemia (AML) that is FLT3-ITD-positive. On the voting question, "Do the results of Study AC220-007 demonstrate that treatment with quizartinib provides for a benefit that outweighs the safety risks for patients with relapsed or refractory FLT3-ITD-positive AML?" panelists voted eight no, three yes. Daiichi gained that drug in the buyout of Ambit Biosciences Inc., of San Diego, paying $315 million up front and up to $95 million in contingent value rights. (See BioWorld, Oct. 1, 2015, and May 15, 2019.)

Deciphera, of Waltham, Mass., in a recent SEC filing listed others known to have CSF1R interest, including Array Biopharma Inc., Amgen Inc., Eli Lilly and Co., Bristol-Myers Squibb Co. (BMS), Five Prime Therapeutics Inc., Roche Holding AG, Novartis AG and Syndax Pharmaceuticals Inc. "It's been explored quite broadly in immuno-oncology," Hoerter said, but clinicaltrials.gov shows his firm as running the only active clinical trial in TGCT. The cancer "to my knowledge is the only disease that is truly driven exclusively" by CSF1R, which makes DCC-3014 an "exquisite monotherapy approach," with potential value in combination with PD-1 inhibitors, he said. "It's an area we may choose to explore" after the next milestone is reached: phase I data from a "handful" of patients to be unveiled at a scientific meeting in the second half of this year.

Deciphera investors are more focused at the moment on the top-line data from the phase III Invictus trial evaluating ripretinib, a broad-spectrum inhibitor of KIT and PDGFRA mutants, vs. placebo in fourth-line and beyond gastrointestinal stromal tumors (GIST). The company recently said those results are expected this month, a narrowing of prior guidance from mid-2019. "We see potential upside of 50% in a best-case scenario and 60% downside in a worst-case scenario," SVB Leerink analyst Andrew Berens wrote in a report yesterday. "Importantly, we believe investors are most interested in the data as a potential read-through to the ongoing phase III Intrigue trial in second-line GIST, which represents a larger commercial opportunity, as well as a potentially riskier clinical trial vs. active comparator in Sutent (sunitinib malate, Pfizer Inc.)."

In CSF1R, New York-based BMS entered a major deal with Five Prime, of South San Francisco, about four years ago centered on the antibody FPA-008. BMS exercised its option to exclusively license the drug and other candidates in the CSF1R program, thereby positioning Five Prime to earn up to $1.74 billion, inclusive of a $350 million up-front payment. Five Prime could collect up to $1.05 billion in development and regulatory milestone payments per anti-CSF1R product for oncology indications, including combinations with BMS's PD-1 immune checkpoint inhibitor, Opdivo (nivolumab), and any other agent. (See BioWorld, Oct. 16, 2015.)

In the CSF1R ballpark is San Diego-based Turning Point Therapeutics Inc., which last week launched a phase I study with MET inhibitor TPX-0022. Undergoing tests in patients with solid tumors that harbor alterations in MET, the drug has been designed with what Turning Point called a unique, compact macrocyclic structure to not only target MET, but also modulate the tumor microenvironment by inhibiting CSF1R and Src oncogenic signaling.

CSF1R has been implicated in more than cancer. Two studies published earlier this year in the American Journal of Human Genetics described nine people with mutations in both copies of the gene, which is crucial for immune response-mediating microglia, and some subjects turned up missing their corpus callosum, which joins the two brain hemispheres. Bone abnormalities were found, too. People with one nonfunctional copy of CSF1R eventually manifest a neurodegenerative disease called adult-onset leukoencephalopathy with axonal spheroids and pigmented glia.

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