Fast Track Designation for CD28 Antagonist VEL-101/FR104
The FDA granted fast track designation for VEL-101/FR104, a novel investigational maintenance immunosuppressive agent being developed for prophylaxis of renal allograft rejection in recipients of kidney transplants. VEL-101 is a pegylated monoclonal antibody fragment that binds to and blocks CD28-mediated effector T-cell costimulation without blocking CTLA-4, an important protein found on T cells that acts as natural brakes on the body's immune responses. VEL-101 is, therefore, expected to impact immune function both directly by blocking CD28-mediated T-cell activation, and indirectly through preservation of CTLA-4-mediated immunoregulatory function.
VEL-101 has been evaluated in a first-in-human study to assess the safety, pharmacokinetics, pharmacodynamics, and potency of IV administrations in healthy subjects. VEL-101, a pegylated monoclonal antibody fragment CD28 antagonist, selectively blunts CD28 co-stimulation while sparing the CTLA-4 co-inhibitory signal. The net effect of CD28 antagonism is downregulating effector T cells while potentially promoting regulatory T-cell (Treg) activity.
IO-202 for R/R Acute Myeloid Leukemia
The FDA has granted fast track designation for IO-202, a first-in-class myeloid checkpoint inhibitor targeting leukocyte immunoglobulin-like receptor B4 (LILRB4, also known as ILT3) for the treatment of patients with relapsed or refractory acute myeloid leukemia (AML).
LILRB4 is an immune inhibitory transmembrane protein found on monocytic myeloid cells, including dendritic cells. It inhibits antigen-presenting cell activation, resulting in immune tolerance. LILRB4 is also expressed on certain hematologic cancer cells and monocytic myeloid cells in the solid tumor microenvironment. Researchers published pioneering research in Nature illuminating the role of LILRB4 in immune suppression and tumor infiltration in AML (2018; https://doi.org/10.1038/s41586-018-0615-z) and presented the rationale for targeting LILRB4 in solid tumors at the 2021 AACR Annual Meeting.
IO-202 is a first-in-class LILRB4 antagonist antibody with broad potential as an immunotherapy in both blood cancers and solid tumors. In hematologic malignancies, preclinical studies showed that IO-202 converts a "don't kill me" to a "kill me" signal by activating T-cell killing and converts a "don't find me" to a "find me" signal by inhibiting infiltration of blood cancer cells. In solid tumors, preclinical data showed that IO-202 enhances dendritic cell function and T-cell activation in vitro and inhibits tumor growth in a solid tumor model in vivo.
NK Cell Therapy CYNK-101 for Gastric & Gastroesophageal Junction Cancers
The FDA has granted orphan drug designation for an investigational natural killer (NK) cell therapy, CYNK-101, for the treatment of gastric/gastroesophageal junction cancer. It is being developed as a first-line treatment in combination with standard chemotherapy, trastuzumab, and pembrolizumab in patients with locally advanced unresectable or metastatic HER2/neu-positive gastric or gastroesophageal junction adenocarcinoma. CYNK-101 is an investigational, genetically modified NK cell therapy designed to synergize with approved antibody therapeutics through enhanced antibody-dependent cellular cytotoxicity.
CYNK-101 is an allogeneic, off-the-shelf human placental CD34+ derived NK cell product genetically modified to express high-affinity and cleavage-resistant CD16 (FCGRIIIA) variant to drive antibody-dependent cell-mediated cytotoxicity. Currently, CYNK-101 is being developed as a treatment in combination with standard chemotherapy, trastuzumab, and pembrolizumab for HER2-positive overexpressing gastric or gastroesophageal junction adenocarcinoma. The safety and efficacy of CYNK-101 have not been established, and CYNK-101 has not been approved for any use.
Breakthrough Device Designation for ctDNA Monitoring Assay
The FDA has granted a Breakthrough Device designation for the circulating tumor DNA (ctDNA) detection and molecular monitoring assay, FoundationOne Tracker. This technology uses optimized algorithms for identifying patient-specific variants and a personalized assay design that allows for the detection of ctDNA in plasma. The designation was granted for the assay's use in the detection of molecular residual disease (MRD) in early-stage cancer after curative therapy. This molecular detection can help guide further therapy decisions depending on MRD status and an individual's risk of relapse.
In addition to the indications granted through the Breakthrough Device designation, the molecular monitoring assay's personalized technology aims to address ctDNA detection and molecular monitoring in patients with both early- and advanced-stage cancers, including assessment of a patient's response to therapy, as well as MRD detection, surveillance, and detection of molecular residual relapse following curative intent therapy.
Fast Track Designation of Golidocitinib for Peripheral T-Cell Lymphoma
The FDA granted fast track designation of golidocitinib for the treatment of patients with refractory or relapsed peripheral T-cell lymphoma (R/R PTCL). Golidocitinib is an orally available, potent, and JAK1-specific inhibitor. The preliminary data from an ongoing Phase I/II study in R/R PTCL shows that 21 (42.9%) out of the 49 patients have achieved tumor response.
Preliminary findings from the Phase I/II JACKPOT8 clinical trial showed tumor responses to 150 mg or 250 mg of golidocitinib in 14 patients, achieving an objective response rate of 51.9 percent. Of the responses observed, complete responses were seen in 22.2 percent of patients. The median duration of response was not reached at the time of the analysis, but the longest DOR was greater than 12 months.
Safety was assessed in all patients, and 87.2 percent of the patients experienced treatment-emergent adverse events (TEAEs). Grade 3 or greater TEAEs occurred in 51.1 percent of patients. Thirty-four percent of the high-grade TEAEs were possibly related to golidocitinib, according to the study investigators. The most common Grade 3 or higher TEAEs observed during the study were thrombocytopenia (23.4%), neutropenia (17.0%), and pneumonia (12.8%). The majority of the events appeared to be manageable or reversible, and dose modifications were not needed. Based on these early findings, investigators predict that golidocitinib may be safe with anti-tumor efficacy in relapsed/refractory PTCL with the potential to fill an unmet medical need for a new therapeutic option.
The analysis was conducted in 47 patients with relapsed/refractory PTCL who had a median age of 62 years (range, 29-79) and received a median of two prior lines of therapy (range, 1-8). Six patients from the cohort had undergone hematopoietic stem cell transplant and 16 had bone marrow involvement at baseline. The patient population also had diverse histologic subtypes.
To be included in JACKPOT8, patients must have histologically confirmed disease, have measurable disease according to Lugano criteria, be transplant-ineligible, and have adequate bone marrow and organ system functions. Patients may not enroll in the study if they have any unresolved toxicity from prior anti-cancer therapy, active infection, decreased lung function, history of heart failure, central nervous system involvement, history of treatment with a JAK inhibitor, or have undergone allogeneic stem cell transplant.
JACKPOT8 is ongoing and actively recruiting patients at 51 locations in the U.S., Australia, China, and the Republic of Korea. The study is evaluating objective response rate as its primary outcome, as well as the secondary endpoints of incidence of adverse events, peak plasma concentration, and area under the plasma concentration versus time curve of golidocitinib.