The FDA has granted an orphan drug designation to JBI-802 for the treatment of patients with small cell lung cancer (SCLC) and acute myeloid leukemia (AML), according to an announcement from Jubilant Therapeutics, Inc.

The agent is currently under evaluation in a phase 1/2 trial (NCT05268666) in patients with advanced solid tumors.

“JBI-802 is the lead product candidate from our TIBEO [Therapeutic Index and Brain Exposure Optimization] Discovery Engine,” Syed Kazmi, chief executive officer of Jubilant Therapeutics Inc, stated in a press release. “It is our unique approach of structure-based drug design to generate novel pharmacophores with improved target product profile compared to existing agents.”

JBI-802 is a dual LSD1- and HDAC6-directed epigenetic modulator engineered in a single pharmacophore to inhibit the transcriptional regulator CoREST, which regulates the development of cellular lineages responsible for neuroendocrine tumors like SCLC and hematopoietic tumors like AML.

Previously, the LSD1-only inhibitor, bomedemstat (IMG-7289), reported positive clinical findings in patients with essential thrombocythemia, supporting the role of epigenetic modulators in hematologic malignancies.

Moreover, preclinical research has shown synergistic antitumor activity with JBI-802 compared with inhibitors directed toward either target alone. The agent has also been found to have a favorable safety profile with no significant safety concerns. As such, JBI-802 is expected to be more tolerable than first-generation, single-target epigenetic modulators.

“The orphan drug designations were supported by several relevant preclinical models. In SCLC, JBI-802 showed unique activity not just in normal neuroendocrine models but also in the ‘variant’ models driven by MYC amplification. [These] data also support the ongoing phase 1/2 clinical trial in neuroendocrine tumor patients,” Kazmi explained. “In AML, the activity was uniquely seen in models of erythroleukemia, a subset of leukemia, with a unique erythroid phenotype and a very high unmet need based on its aggressive nature and limited therapy.”

In January 2022, the FDA cleared the investigational new drug application for JBI-806 for the treatment of SCLC, treatment-induced neuroendocrine prostate cancer, and other mutation-defined neuroendocrine tumors.

In April 2022, the first patient had been dosed in the open-label, two-part dose-escalation and -expansion phase 1/2 trial.

 The study population comprised patients with locally advanced or metastatic solid tumors whose disease has progressed on prior standard therapy. Planned expansion cohorts will consist of patients with SCLC, NEPC, and other neuroendocrine-derived cancers, with a goal to expand into hematologic malignancies such as AML, essential thrombocythemia, and other myeloproliferative neoplasms (MPNs).

“This designation and emerging clinical data from the ongoing first-in-human JBI-802 study will now underpin expansion of our clinical activities in thrombocythemia, leukemia and other erythroid tumors like MPNs,” Kazmi concluded.

Jubilant Therapeutics Inc. receives orphan drug designation for JBI-802 for acute myeloid leukemia (AML) and small cell lung cancer (SCLC). News release. Jubilant Therapeutics, Inc. January 5, 2023. Accessed January 16, 2023. 

Jubilant Therapeutics announces FDA clearance of IND for JBI-802, a novel dual LSD1 and HDAC6 inhibitor, for treatment of solid tumors. News release. Jubilant Therapeutics, Inc. January 6, 2022. Accessed January 16, 2023. 

Jubilant Therapeutics Inc. doses first patient in phase I/II trial evaluating JBI-802, dual inhibitor of LSD1 and HDAC6, in patients with advanced solid tumors. News release. Jubilant Therapeutics, Inc. April 26, 2022. Accessed January 16, 2023. 

Articles

The FDA has granted an orphan drug designation to JBI-802 for the treatment of patients with small cell lung cancer and acute myeloid leukemia.

FDA Grants Orphan Drug Designation to JBI-802 for Small Cell Lung Cancer and AML

ADXS-504, an investigational off-the-shelf neoantigen therapy, has been reported to be well tolerated and safe in patients with biochemically recurrent early prostate cancer, according to an analysis performed on the first 3 patients who received treatment at the first dose level (1e7 CFU) and 3 at the second dose level (1e8 CFU) of an ongoing phase 1 trial (NCT05077098).

“We have completed evaluation of the dose-limiting-toxicity period for three patients at the second dose level for this phase 1 trial of ADXS-504. At both the first [dose level] and at this higher dose level, patients have experienced mild and short-lived flu-like symptoms after the infusion of ADXS-504,” Karie Runcie, MD, lead study author and assistant professor of medicine in the Division of Hematology/Oncology at Columbia University Vagelos College of Physicians and Surgeons in New York, New York, said in a press release. “The safety of ADX-504 and encouraging early data led to our decision to increase enrollment at the second dose level to better characterize its clinical activity.”

Approximately 20% to 30% of patients with prostate cancer develop biochemical recurrence, defined as rising prostate-specific antigen (PSA) levels after definitive therapy with radical prostatectomy or radiation therapy.2 The optimal therapy and timing of treatment for this population is unknown. For patients who are not eligible for salvage radiation, androgen deprivation therapy (ADT) is the standard first-line treatment. However, ADT is associated with many acute and long-term toxicities. As such, novel approaches to reduce ADT exposure and prolong disease control are needed.

ADXS-504 is a novel Listeria monocytogenes (

)–based immunotherapy. It is bioengineered to elicit T-cell responses against 24 tumor antigens, including 14 peptide antigens derived from hotspot mutations in patients with prostate cancer and 10 peptide antigens derived from sequence-optimized tumor-associated antigens that are differentially expressed or overexpressed in prostate cancer.

ADXS-504 is designed to express several tumor antigen targets, potentially leading to generation of a broad set of effector T cells and NK cells that may enhance tumor control. Like the company’s other 

-based immunotherapies, ADXS-504 is expected to induce an innate immune response followed by the adaptive response and modification of the immunosuppressive tumor microenvironment (TME) by reducing regulatory T cells and myeloid-derived suppressor cell frequencies in the TME.

In a preclinical murine model, a prototype 

-construct reduced the number of metastases after removal of the primary tumor by eliminating residual tumor cells. Runcie presented the design of the phase 1, open-label dose-escalation study at the 

Eligible patients must have received a diagnosis of biochemically recurrent prostate cancer with an elevated PSA in the blood of 0.3 ng/mL or greater and a PSA doubling time of at least 4 months after radical prostatectomy or radical radiotherapy without evidence of metastatic disease on traditional CT imaging and bone scans. Patients currently receiving androgen ablation therapy are excluded.

In the study, patients will receive an infusion of ADXS-504 every 4 weeks for a total of 6 doses, followed by 4 additional maintenance doses every 12 weeks. The primary end points are safety and tolerability.

The trial is currently expanding enrollment at the second dose level by up to 6 additional patients for a total of 9 patients. The study investigators will evaluate the immunogenicity data after all patients at the higher dose level have completed the study treatment.

“We are excited that our collaborators at Columbia have elected to expand the enrollment of this Phase 1 trial in ADXS-504. We are also encouraged by the safety data, and we are actively collecting long-term PSA results from all the patients in this trial. We look forward to analyzing the composite data to gain further insight into the safety and efficacy of this novel therapy,” Kenneth A. Berlin, president and chief executive officer of Advaxis, said.

Advaxis Updates on the Phase 1 Clinical Trial of ADXS-504 for the Treatment of Early Prostate Cancer. News release. Advaxis, Inc. January 12, 2023. Accessed January 12, 2023. 

A phase I study of ADXS-504, a cancer type specific immunotherapy, for patients with biochemically recurrent prostate cancer. 

. 2022;40(suppl 16):TPS5115.doi:10.1200/JCO.2022.40.16_suppl.TPS5115

ADXS-504, an investigational off-the-shelf neoantigen therapy, has been reported to be well tolerated and safe in patients with biochemically recurrent early prostate cancer.



Pipeline Report: January 2023

Articles

FDA Grants Orphan Drug Designation to JBI-802 for Small Cell Lung Cancer and AML

ADXS-504 Study Increases Enrollment After Confirming Safety in Recurrent Early Prostate Cancer