JBI802 a Highly Potent Corest Inhibitor Demonstrated Anti-Tumor Activity at Low Dose, Thrombocytopenia at Higher Dose NOW Leading to an Opportunity to Treat ET Myeloproliferative Neoplasms (MPN) /Essential Thrombocythemia [ET]) and Myelodysplastic/Myeloproliferative Neoplasms (MDS/MPN) with Thrombocytosis
Authors: Dolan Melda , Rajagopal Sridharan , G Chandru , Mittal Deepak , Zainuddin Mohd. , Sadhu Naveen , Baruah Abhijit 
Published: December 2024

Background and Significance: Epigenetic alterations have emerged as hallmarks of cancer. Post-translational modifications (PTM) of histones have been implicated in several diseases including cancer. JBI-802 is a highly potent LSD1/HDAC6 selective CoREST inhibitor with superior anti-tumor activity in several pre-clinical models compared to LSD1 or HDAC6 inhibitors.
JBI-802 in its first-in-human study in patients with solid tumors showed a dose dependent, reversible decrease in platelets which at the highest dose resulted in thrombocytopenia but did not show any other toxicities, particularly a lack of effect on haemoglobin. Based on these data, there is a strong scientific rationale to test the activity of JBI-802 in diseases such MPN and MDS/MPN with thrombocytosis where platelet reduction without anemia induction would represent an advantage over currently available therapies.
Two treatment resistant lung cancer patients displayed improvement in tumor-related symptoms with confirmed and durable partial response (PR) in one patient, and significant improvement in cancer related pain and symptoms. Overall, JBI-802 was well tolerated with good safety profile, with grade 3/4 thrombocytopenia as the only adverse event observed at the highest dose. Dose-dependent decrease in platelets as a part of MOA of LSD1 inhibition demonstrated that JBI-802 is pharmacologically active and provided an opportunity to treat patients with hematological malignancies like essential thrombocythemia (ET) and other myeloproliferative neoplasms (MPN) and Myelodysplastic/Myeloproliferative Neoplasms (MDS/MPN) characterized by thrombocytosis.
Study Design and Methods: Herein we are initiating a phase 1/2 clinical trial to assess the safety and preliminary efficacy of orally administered JBI-802 in ET, PV and MDS/MPN patients with thrombocytosis (Trial ID: ACTRN12624000478516) with two phases:
Part 1: Dose Escalation Phase with objectives of both determining the recommended phase 2 dose (RP2D) of JBI-802 in subjects with ET, MPN and MDS/MPN neoplasms with thrombocytosis in all patients and evaluating the overall safety and tolerability of JBI-802 as a single agent.
Part 2: Dose Expansion Phase with primary objective of obtaining preliminary evidence of efficacy
at the RP2D in subjects with ET, MPN and MDS/MPN.
Conclusion: JBI-802 in its first-in-human study in patients with solid tumors demonstrated a dose dependent, reversible decrease in platelets which at the highest dose resulted in thrombocytopenia but did not show any other toxicities. Based on these data, there is a strong scientific rationale to test the activity of JBI-802 in diseases such MPN and MDS/MPN with thrombocytosis representing an advantage over currently available therapies. As the study progress, interim data from the phase 1/2 clinical trial of ET and MPN patients will be presented.