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Carrick Therapeutics Advances Second CDK Inhibitor Into Clinic, Explores Biomarker Approaches

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NEW YORK – When Carrick Therapeutics treated the first patient in a Phase I/II clinical trial of CT7439 last month, it touted that it is the first company to move a CDK12/13 inhibitor into the clinic. Now, the firm is ironing out its precision development strategy for the drug. 

"Carrick really buys into the idea of directing therapies to patients who are most likely to experience benefit from them," said Carrick Chief Medical Officer Stuart McIntosh. "And [with CT7439], we think we're targeting something that's clearly highly relevant to patients." 

Carrick's CT7439 is a cyclin dependent kinase 12/13 inhibitor and cyclin-K glue degrader in one. In the recently launched first-in-human trial for the agent, Carrick plans to enroll 50 patients with any type of advanced or metastatic solid tumor, and for now at least, it isn't limiting enrollment based on biomarkers. But the trial does have a modular design and allows for protocol amendments that will enable researchers to evaluate CT7439 in specific patient populations. 

Carrick is interested initially in establishing the safety and dose of CT7439 in the Phase I portion of the study, McIntosh said, before taking it into the Phase II portion. The firm is also tracking the drug's impact on secondary outcome measures, including anti-tumor activity according to imaging and whole-blood RNA tests, as well as patients' progression-free survival rates and duration of response.

With the whole-blood RNA assay, McIntosh said the firm will be able to look for knockdown of specific homologous recombination repair genes. Right now, Carrick is using the assay to gauge early pharmacodynamic markers of activity. "But depending on what we see in the pattern of the genes that are affected, that may give us some clues as to where we should move forward with the therapy," he said.

Carrick, which launched in Dublin in 2016 but has since moved its headquarters to Boston, is also planning to perform circulating tumor DNA analyses on patients both at baseline and throughout treatment. 

"What we see at baseline, and the changes we may see as treatment progresses, will be really significant for how we shape the program toward the tumor types or mutations [that] become of most interest to us." 

Carrick hasn't yet decided on the specific tumor types for which it will develop CT7493, but McIntosh said the drug's mechanism of action seems to support advancing it in tumors driven by homologous recombination repair deficiency. In preclinical studies, CT7439 knocked down several homologous recombination repair deficiency genes, including RCC4, RAD51, and POLQ. 

"It may be that we have a mechanism for treating PARP resistance with upregulation of those pathways, or it may be that we have a way for broadening PARP indications outside the classical BRCA1/2 mutation phenotype," he said. "The known mechanism of action on homologous recombination repair does push us to tumors where the PARP inhibitors have shown good activity." These tumor types could include ovarian and breast cancers as well as Ewing sarcoma. 

Looking ahead, the firm may also pair CT7439 with other drugs. And while a PARP inhibitor does seem like the obvious partner of choice, it's not the only possibility. 

McIntosh said Carrick may explore combination approaches with treatments implicated in DNA damage, potentially including platinum-based chemotherapy and irinotecan topoisomerase I inhibitors. There's also the possibility that CT7439 could drive some neoantigen expression and immunogenic cell death, which could open up the possibility of combining it with immunotherapy, McIntosh said. 

The firm is hoping to share early data from the new trial during the second half of 2025. Those data, McIntosh said, should inform Carrick's future development decisions for CT7439. 

While CT7439 may be the first CDK12/13 inhibitor to enter the clinic, it isn't Carrick's first CDK inhibitor to enter human trials. The firm is also studying the CDK7 inhibitor samuraciclib in hormone receptor-positive, HER2-negative advanced breast cancer. 

"We were able to build on that [samuraciclib] expertise, and our in-house chemistry, to develop our CDK12 inhibitor," McIntosh said. 

In that Phase II trial of samuraciclib, Carrick is evaluating it with or without fulvestrant. The firm has also inked deals with Roche, Menarini Group, and Arvinas and Pfizer to study samuraciclib combined with selective endocrine receptor degraders (SERDs). 

For instance, Carrick and Menarini Group are studying samuraciclib plus Menarini's Orserdu (elacestrant) in HR-positive, HER2-negative metastatic breast cancer patients whose tumors have developed resistance to CDK4/6 inhibitors. Carrick is also studying samuraciclib combined with Roche's investigational SERD gerdestrant and Arvinas and Pfizer's investigational estrogen receptor protein degrader vepdegestrant

"We have a compelling hypothesis [with samuraciclib] that has generated interest from major pharma, and now we need to generate the Phase III data," McIntosh said. 

Depending on the outcomes of these studies, Carrick could be making Phase III development decisions for samuraciclib "in the not too distant future," according to McIntosh. 

In the samuraciclib development program, Carrick is considering selecting patients based on TP53 mutation status. "The CDK7 inhibitor has a couple of very interesting signals, including the TP53 status of the patient, which could be very relevant to how that therapy performs," he said. 

The firm is hoping to make these decisions sometime in 2025 and potentially start Phase III development for samuraciclib in 2026. 

And while Carrick is currently refining the strategies for its two lead CDK inhibitors, McIntosh said the firm "would like to continue its drug hunting and find other pathways of interest to [develop] useful options for patients."