On January 11, 2021 Exicure, Inc. (NASDAQ: XCUR), a pioneer in gene regulatory and immunotherapeutic drugs utilizing spherical nucleic acid (SNA) technology, reported that the U.S. Food and Drug Administration (FDA) has granted Fast Track designations for its clinical product candidate, cavrotolimod (AST-008), for two development programs (Press release, Exicure, JAN 11, 2021, View Source [SID1234573797]):

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cavrotolimod in combination with anti-programmed death-1 (PD-1) therapy for the treatment of patients with locally advanced or metastatic Merkel cell carcinoma (MCC) refractory to prior anti-PD-1 blockade; and
cavrotolimod in combination with anti-PD-1/anti-PD-ligand 1 (anti-PD-(L)1) therapy for the treatment of patients with locally advanced or metastatic cutaneous squamous cell carcinoma (CSCC) refractory to prior anti-PD-(L)1 blockade
Fast Track is a designation granted by the FDA that is intended to facilitate development and expedite review of drugs to address an unmet medical need in the treatment of a serious life-threatening condition, and for which nonclinical or clinical data has demonstrated the potential of the drug candidate to address this medical need.

"There is an urgent need to investigate novel immunotherapeutic agents such as cavrotolimod that can be given to enhance the clinical efficacy of immunotherapy, particularly in patients with refractory solid tumors," said Dr. Adil Daud, M.D., Clinical Professor at UCSF Helen Diller Family Comprehensive Cancer Center and principal investigator in the Phase 1b/2 clinical trial of cavrotolimod.

Cavrotolimod is a spherical nucleic acid toll-like receptor 9 (TLR9) agonist designed to robustly activate the patient’s innate and adaptive immune systems in order to potentially induce potent anti-cancer immune responses. The Phase 1b dose-escalation stage of the open-label, multi-center trial was designed to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics and preliminary efficacy of intratumoral cavrotolimod injections alone and in combination with intravenous pembrolizumab in patients with advanced solid tumors. The patients from the Phase 1b stage included those with advanced or metastatic MCC, head and neck squamous cell carcinoma, CSCC, melanoma and leiomyosarcoma. A summary of the key highlights from the Phase 1b stage of the trial include:

– No observed treatment-related serious adverse events ("SAEs") or dose limiting toxicity (DLT);

– Confirmed overall response rate (ORR) in 21% of evaluable patients (4/19 patients) in the Phase 1b dose escalation stage across all doses, reflecting 1 complete response and 3 partial responses;

– Confirmed ORR in 33% of evaluate patients (2/6 patients) in the highest dose cohort (32 mg), which was selected as the Phase 2 recommended dose;

– Overall responses occurred in two patients with advanced MCC and two patients with melanoma;

– Three of four responders were progressing on anti-PD-1 therapy at the time of enrollment in the trial;

– Durable and ongoing responses, with progression-free survival exceeding six months in all four responders and 16 months in two responders;

– In addition to the four overall responses, target tumor shrinkage occurred in one CSCC patient and two melanoma patients;

– Increases in leukocytes in injected tumors after cavrotolimod (AST-008) alone and in combination with pembrolizumab versus baseline. Uninjected tumors also showed increased immune cell levels after patients received cavrotolimod (AST-008) plus pembrolizumab;

– Dose-dependent activation of key immune cells, including cytotoxic T cells and natural killer cells, as well as increases in cytokine/chemokine levels in patient blood after cavrotolimod (AST-008) treatment alone, and cavrotolimod (AST-008) plus pembrolizumab treatment;

– Systemic (abscopal) effects were observed, with regression in noninjected tumors distant from injected lesions; and

– The cavrotolimod pharmacodynamic profile corroborated the efficacy data, as increased serum cytokines/chemokines, activated immune cells, and tumor infiltration by immune cells were observed.

"I am encouraged by the Phase 1b dose-escalation results and excited about the potential of cavrotolimod to address the significant unmet need facing these patients," said Dr. Michael Wong, M.D., Ph.D., Professor at MD Anderson Cancer Center and principal investigator in the Phase 1b/2 clinical trial of cavrotolimod.

"These Fast Track designations underscore the pressing need to develop new therapies to treat refractory non-melanoma skin cancers as well as the promising preclinical and initial clinical results of cavrotolimod in patients with locally advanced or metastatic Merkel cell carcinoma and cutaneous squamous cell carcinoma," said Dr. Shailender Bhatia, M.D., Associate Professor at University of Washington/Fred Hutchinson Cancer Research Center and principal investigator in the Phase 1b/2 clinical trial of cavrotolimod.