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Asrar A. Alahmadi, MBBS, is heading a first-in-human, open-label, phase 1 clinical trial (NCT06801002) investigating JBZ-001, an orally bioavailable small-molecule inhibitor of dihydroorotate dehydrogenase (DHODH) for the treatment of patients with advanced solid tumors and non-Hodgkin lymphoma.
Developed by Jabez Biosciences, JBZ-001 targets the de novo pyrimidine biosynthesis pathway by inhibiting DHODH, the rate-limiting enzyme in this pathway. Preclinical studies demonstrated JBZ-001’s broad antitumor activity across a range of cell lines and patient-derived xenograft models, particularly in aggressive cancers such as lymphoma, leukemia, and small cell lung cancer. The drug showed higher potency and lower toxicity compared with other agents in its class, suggesting its potential as both monotherapy and in combination with chemotherapy.
The phase 1 study now follows a standard 3+3 dose escalation design to determine the optimal biological dose (OBD), rather than the maximum tolerated dose. Pharmacokinetic and pharmacodynamic assessments include a novel blood-based biomarker to monitor DHODH activity in real time. Once OBD is reached, expansion cohorts will explore efficacy signals in specific tumor types.
The trial is currently enrolling patients, with future plans for combination studies and phase 2 trials in promising indications such as small cell lung cancer and hematologic malignancies, according to Alahmadi, assistant professor at The Ohio State University and lead principal investigator at The Ohio State University Comprehensive Cancer Center-James Cancer Hospital & Solove Research Institute.
In an interview with Targeted OncologyTM, Alahmadi discussed the trial in progress and key goals of the study.
Targeted OncologyTM: Can you discuss the mechanism of action of JBZ-001?
Alahmadi: The drug is a small molecule that inhibits a very critical enzyme involved in DNA and RNA synthesis, which is essential in rapidly dividing cells. That’s essentially what cancer is—unchecked, rapid cell proliferation. The molecule blocks DHODH, which is part of the pyrimidine biosynthesis pathway. This pathway is vital for cell survival during rapid division. The inhibition shows promising results against aggressive cancers like lymphoma and leukemia, and we’ve also seen potential in some relapsed solid malignancies like small cell lung cancer.
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What preclinical data supported the initiation of this phase 1 study?
We observed efficacy in cell lines, patient-derived xenograft models, and through large-scale screening across multiple malignancies. We demonstrated broad activity, which we believe is due to the drug’s mechanism. It targets cancer cell metabolism, giving it a wide scope of action.
What is the study design, including the planned dose-escalation scheme and patient eligibility?
This is a first-in-human study. We’re testing the drug as a monotherapy using a standard 3+3 dose-escalation design. We’re collecting pharmacokinetic and pharmacodynamic data, including a blood-based marker—DHO/DHODH level—which correlates with enzyme activity. Our aim is to identify the optimal biological dose, rather than just the maximum tolerated dose. Once we reach OBD, we will proceed with expansion cohorts, especially in areas where we observe potential efficacy.
What are the key goals of the study? What are you hoping to learn about the tolerability of the drug?
We want to assess safety and tolerability, of course. Preclinical data suggest this agent may be more potent and less toxic than other DHODH inhibitors. We’re hoping this translates into the clinic—more efficacy with lower toxicity. Looking ahead, we aim to test it in combination with chemotherapy to enhance treatment outcomes in solid tumors. We also want to determine the optimal biological dose that balances efficacy and safety, which aligns with the FDA’s Project Optimus initiative.
Assuming the safety and preliminary efficacy are favorable, what are the potential next steps in the clinical development of this agent?
The next step would be testing in combination with chemotherapy. Also, if we observe efficacy signals in specific cancer types, we’ll open expansion cohorts and move into phase 2 trials. For example, we’re already seeing encouraging signs in small cell lung cancer. There’s evidence from other groups, including large CRISPR-based screens, suggesting that small cell lung cancer heavily depends on the pyrimidine biosynthesis pathway—making this an attractive target.
What are the key takeaways about this study and what should oncologists know about recruitment or the drug itself?
So far, our preclinical data suggest this drug may be more potent than other DHODH inhibitors. We’re currently enrolling patients in the dose expansion phase. I think that’s a key point.
I think we can always do better in our fight against cancer. Over the years, clinical trials have brought promising new treatments to market—treatments that genuinely improve patients’ lives, like targeted therapies and immunotherapies. With this development, we hope not only to show this drug is effective, but also to identify biomarkers of response. That way, we can deliver the right drug to the right patient at the right time.