JBI-802 Demonstrates Preliminary Activity in Advanced Solid Tumors

Treatment with JBI-802, the first-in-class CoREST (co-repressor of Repressor Element-1 Silencing Transcription) inhibitor with dual LSD1 and HDAC6 activity was shown to be safe and active, according to topline data from a phase 1 trial (NCT05268666) in patients with locally advanced or metastatic cancer.¹

A dose-proportional increase in exposure and a correlation between exposure and the on-target effects of platelet decrease were seen in the first 11 patients enrolled on the trial, demonstrating the achievement of pharmacologically relevant levels of LSD1 inhibition.

Results from the trial provide further support for expanding the development of JBI-802 in essential thrombocythemia (ET) and related myeloproliferative neoplasms (MPN) with thrombocytosis.

Regarding safety, the only adverse effect above grade 1 was platelet count decrease. No cases of anemia or dysgeusia were reported, suggesting a potentially favorable effect of HDAC6 inhibition in erythrocytes.

“The anti-tumor activity seen in these two NSCLC patients is remarkable given the poor prognosis based on their genetic and metastatic pattern. The 10 mg dose of JBI-802 was well-tolerated without any clinically significant adverse effects and the initial clinical data suggest a good therapeutic index for JBI-802,” Alexander Starodub, MD, The Christ Hospital – Cincinnati, said in a news release.

The combination of JBI-802 and immunotherapy has shown synergistic activity in preclinical xenograft models. Moreover, the CoREST inhibition from JBI-802 has been shown to resensitize immunotherapy-resistant tumors, particularly those with STK11 mutations. As such, the combination of JBI-802 and immunotherapy could provide an important treatment option to patients who otherwise would have limited therapeutic options.

On January 5, 2024, the FDA granted an orphan drug designation to the agent for the treatment of patients with small cell lung cancer (SCLC) and acute myeloid leukemia.²

The multi-center, first-in-human, open-label, 2-part trial was designed to evaluate the safety, tolerability, maximum tolerated dose, pharmacologically active dose, efficacy, and predictive and pharmacodynamic biomarkers in up to 126 participants with advanced solid tumors with no available effective treatment options. Expansion cohorts of patients treated at the recommended phase 2 dose with SCLC, neuroendocrine prostate cancer, and other neuroendocrine-derived cancers will be enrolled to collect further efficacy and safety data.3

To be eligible for enrollment patients had to have an absolute neutrophil count of at least 1500 cells/mm3, platelet count of at least 100,000 cells/mm3, total bilirubin no greater than 1.5 × the upper limit of normal (ULN), aspartate and alanine aminotransferase no greater than 2.5 × ULN, calculated creatinine clearance of at least 60 mL/min, and prothrombin time or activated partial thromboplastin time no greater than 1.5 × ULN if the patient is not anticoagulated. At least one measurable lesion on CT/MRI per RECIST v1.1 criteria and an ECOG performance status of 2 or less was also required. Notably, in part 1 patients with microsatellite stable colorectal cancer and hepatocellular carcinoma were precluded from enrollment.³

Patients received JBI-802 at a starting dose of 10 mg once daily for 4 days on and 3 days off.³

In the trial, two patients had non–small cell lung cancer that had progressed on nivolumab (Opdivo) and ipilimumab (Yervoy) in the frontline setting. Both patients derived antitumor activity with JBI-802 and both were treated at the lower dose level of 10 mg where no significant decrease in platelet counts were observed.¹

The first patient had a STK11 mutation, which is known to confer resistance to immunotherapy. Despite this, JBI-802 led to a durable confirmed partial response in this patient, with a 39% decrease in the target lung lesion, and a complete resolution of pancoast syndrome (lung lesion affecting the nerves of brachial plexus). The patient remains on therapy after 9 cycles of treatment.

The second patient had involvement of both lung lesion and liver metastasis, which are associated with poor prognosis and immunotherapy resistance. In this patient, treatment with JBI-802 led to greater than 50% shrinkage of the liver metastasis and a complete resolution of related portal hypertension, edema as well as an improvement in quality of life.

A phase 1/2 trial evaluating JBI-802 is being planned in the first quarter of 2024 for patients with MPN/ET and MPN/myelodysplastic syndrome.

References

1. JBI-802 initial phase I data suggests therapeutic potential in sensitizing immunotherapy resistant tumors and in myeloproliferative neoplasms with thrombocytosis. News release. Jubilant Therapeutics. January 8, 2024. Accessed January 15, 2024. https://www.prnewswire.com/news-releases/jbi-802-initial-phase-i-data-suggests-therapeutic-potential-in-sensitizing-immunotherapy-resistant-tumors-and-in-myeloproliferative-neoplasms-with-thrombocytosis-302028480.html
2. 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. January 5, 2024. Accessed January 15, 2024. https://www.prnewswire.com/news-releases/jubilant-therapeutics-inc-receives-orphan-drug-designation-for-jbi-802-for-acute-myeloid-leukemia-aml-and-small-cell-lung-cancer-sclc-301714552.html
3. A study or orally administered JBI-802, an LSD1/HDAC6 inhibitor, in patients with advanced solid tumors. ClinicalTrials.gov. Updated June 15, 2023. Accessed January 15, 2024. https://clinicaltrials.gov/study/NCT05268666