KSQ Therapeutics Inc.’s chief scientific officer, Frank Stegmeier, said that the CRISPRomics technology that drew Takeda Pharmaceutical Co. Ltd. to the table allows, “for the first time, genome-scale functional screening [in vivo as well as in vitro] across multiple disease settings. It really takes the guessing game out of your drug target selection.” Working with “an encyclopedia of gene function,” he said, KSQ aims to identify prospects that can have monotherapy activity in PD-1-refractory solid tumors.

John Trzupek, chief business officer at the Cambridge, Mass.-based firm, noted that the tie-up with Takeda, of Tokyo, is the “first strategic collaboration utilizing the platform for discovery in this manner,” though KSQ has a cross-license arrangement with CRISPR Therapeutics AG, of Zug, Switzerland, disclosed in October 2019. “It was a priority for us to identify an oncology partner in 2020,” he said, and the firm “went through an extensive process” during which Takeda surfaced as the best option, he told BioWorld.

The arrangement includes two T-cell targets previously identified and validated by KSQ, with the potential to introduce two more. Also, the companies will collaborate to discover and develop therapeutics that modulate natural killer (NK) cell targets. Up-front and potential preclinical milestone payments could exceed $100 million. KSQ will be eligible for option money along with development and commercialization milestone rewards. Such payments can reach up to more than $400 million per program.

John Trzupek, chief business officer, KSQ

“There are multiple different types of products in the deal,” Trzupek said. “Depending on which stream we’re working from, you can have different values.” KSQ stands to collect tiered royalties on net sales of each drug approved. The pair will work together on IND-enabling activities, with clinical development led by Takeda – which will fund all development and commercialization efforts – to explore multiple modalities. KSQ owns the option to participate in cost/profit-sharing in the U.S. on one of the two products based on T-cell targets that KSQ came up with, and would retain royalties on all ex-U.S. sales for that product.

Frank Stegmeier, chief scientific officer, KSQ

Stegmeier cited “great chemistry” from the outset as the reason for choosing Takeda, plus the pharma outfit’s “appreciation of the complementarity of scientific talents at the companies. While Takeda will do more of the heavy lifting at the end, there will be continuous involvement” by both parties, he said. NK cell therapy is not an area where KSQ had been active, he said, but Takeda – partnered with MD Anderson Cancer Center – leads there, and will make good use of his firm’s expertise. Trzupek said KSQ “field[s] interest in areas that we have enabled as well as in areas outside” them. He said the company “will have a blend of partnership[s] and wholly owned” programs. “I wouldn’t say we would be overly proscriptive,” though the firm will probably sign at least one more collaboration.

Regarding its internal pipeline, KSQ last October rolled out the first preclinical data for its lead push with KSQ-4279, a ubiquitin specific peptidase 1 (USP1) inhibitor being evaluated in targeted oncology. It’s described as a potential first-in-class inhibitor of USP1, a gene target identified and validated using CRISPRomics. Findings were presented in a poster at the EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics and highlighted the potential of KSQ-4279 for the treatment of ovarian and triple-negative breast cancers. The compound, due to enter the clinic this year, showed dose-dependent tumor growth inhibition as a single agent as well as in combination with a PARP inhibitor in BRCA-deficient models.

KSQ also has KSQ-001, part of its engineered tumor-infiltrating lymphocyte (TIL) adoptive cell therapy program, which will be developed for the treatment of PD-1-refractory solid tumors. A top player in the TIL space is San Carlos, Calif.-based Iovance Biotherapeutics Inc., which last November offered interim data from the phase II trial called IOV-COM-202, testing LN-145 in combination with Keytruda (pembrolizumab, Merck & Co. Inc.) in advanced, recurrent, or metastatic head and neck squamous cell carcinoma patients who are immune checkpoint inhibitor-naive at the annual meeting of the Society for Immunotherapy of Cancer. The compound yielded a 44.4% overall response rate, and the median duration of response had not been reached at 8.6 months of follow-up.

CRISPR players to gain attention recently include Editas Medicine Inc., of Cambridge, Mass., which at the J.P. Morgan Healthcare Conference updated investors, disclosing plans to accelerate enrollment in the phase I/II Brilliance trial with EDIT-101 for the treatment of Leber congenital amaurosis 10 with a revised protocol, and to dose first patient in the adult mid-dose cohort in the first quarter of this year. J.P. Morgan’s Cory Kasimov said in a report that “overall, we continue to think that Editas is well positioned to ultimately capitalize on the enormous potential of CRISPR, though we look to positive data from EDIT-101 – or other earlier-stage programs – to support clinical proof-of-concept for the platform.”



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