FDA Grants Orphan Drug Designation to LMP744 for Glioma

Randall B. Riggs, MBA

The FDA has granted orphan drug designation to the small molecule, indenoisoquinoline-based topoisomerase I inhibitor LMP744 for the treatment of patients with gliomas.¹

The agent has demonstrated the ability to cross the blood-brain barrier (BBB) at concentrations 10 times higher than required to kill cancer cells, and these levels are maintained for at least 24 hours per dose. Both LMP744 and another topoisomerase inhibitor, LMP400 (Indotecan), selectively target the topoisomerase I and cMyc oncogenes through binding to the G4 quadruplex of cMyc, thereby regulating 2 key drivers of cancer.

The discovery agent’s unique mechanism of action better positions LMP744 and LMP400 for further evaluation among patients displaying these cancer targets who have high unmet need. According to Gisbon Oncology, the drug’s developer, a phase 2 trial is planned in collaboration with the National Institutes of Health to evaluate both agents in patients with recurrent gliomas.

“For decades, [patients with] glioblastoma have not seen appreciable increases in overall survival rates with [temozolomide (Temodar)], the current standard-of-care treatment,” Randall Riggs, president and chief executive officer of Gibson Oncology, stated in a news release. “Our goal is to advance both LMP400 and LMP744 to market via the shortest and quickest path, thus benefiting [patients with] cancer in need.”

Notably, LMP400 received orphan drug designation from the FDA for use in malignant gliomas in October 2023.

“This crucial [orphan drug] designation [for LMP744] could not come at a more critical time for the families who are fighting this disease,” Kush Dhody, MBBS, president of Amarex, added. “Reaching this milestone sets the company up for future success and, most importantly, poises Gibson Oncology to continue its path to commercialization of this life-saving treatment.”

LMP744 is currently being evaluated in a multicenter phase 1 study (NCT03030417) in adult patients with metastatic solid tumors whose disease has progressed after 1 line of therapy, or those with lymphoma who experienced disease progression after initial therapy and are ineligible for or declined potential curative-intent treatment.^2,3

Patients enrolled onto the study received intravenous LMP744 daily on days 1 to 5 of 28-day cycles, starting at 6 mg/m2.³

The study’s primary objective was to establish the safety, tolerability and maximum tolerated dose (MTD) of LMP744. Pharmacokinetic characterization served as a secondary objective. Exploratory objectives included the assessment of preliminary antitumor activity as well as the effect of LMP744 on DNA damage markers and epithelial-mesenchymal transition in circulating tumor cells, based on pre- and post-treatment tumor biopsies in patients at the expansion cohort.²

At the 2023 ASCO Annual Meeting, investigators shared that the MTD of LMP744 was determined to be 190 mg/m2 daily on days 1 to 5 of each 28-day cycle.3 Notably, the study reverted to a 3+3 design after a dose-limiting toxicity of grade 3 hypokalemia was observed in 1 patient during cycle 1 at the MTD.

The agent displayed limited activity as monotherapy in a heavily pretreated patient population. Among 23 response-evaluable patients, 1 patient with small cell lung cancer achieved a partial response (PR) and completed 7 cycles of treatment. Stable disease (SD) was achieved by 16 patients, 1 of whom had an unconfirmed PR, and 6 patients experienced progressive disease. The median duration of response for patients who achieved SD was 4.5 cycles (range, 1-28), and most patients (72%) had prior exposure to a TOP1 inhibitor.

A total of 5 patients with SD remained on the study for at least 6 cycles. This included 3 patients with colorectal cancer, who experienced prolonged disease stabilization with LMP744 following prior disease progression on irinotecan, 1 patient with mesothelioma, and 1 patient with low-grade appendiceal mucinous neoplasm. Analysis of secondary and exploratory correlatives is ongoing.

References

1. Amarex achieves orphan drug designation for Gibson Oncology’s novel LMP744 cancer treatment. News Release. Amarex. September 24, 2024. Accessed October 9, 2024. https://www.amarexcro.com/news/amarex-achieves-orphan-drug-designation-gibson-oncologys-novel-lmp744-cancer-treatment
2. Indenoisoquinoline LMP744 in Adults With Relapsed Solid Tumors and Lymphomas. ClinicalTrials.gov. Updated October 19, 2023. Accessed October 9, 2024. https://clinicaltrials.gov/study/NCT03030417
3. Ko B, Chen AP, Kummar S, et al. Phase 1 study of indenoisoquinoline LMP744 in adults with relapsed solid tumors and lymphomas. J Clin Oncol. 2024;41(suppl 16):3022. doi:10.1200/JCO.2024.41.16_suppl.3022