NXP800 receives FDA orphan drug designation for ARID1a-deficient ovarian cancer

This article was originally published on Targeted Oncology® and has been lightly edited.

• The FDA granted NXP800 orphan drug designation (ODD) for the potential treatment of patients with AT-rich interactive domain-containing protein 1a (ARID1a)-deficient ovarian cancer, fallopian tube cancer and primary peritoneal cancer.
• NXP800 is a novel GCN2 kinase activator.
• The active ingredient is currently being evaluated in a phase 1b clinical trial (NCT05226507).

NXP800, a novel GCN2 kinase activator, received orphan drug designation from the FDA for the treatment of ovarian cancer, fallopian tube cancer, and primary peritoneal cancer deficient in AT-rich interactive domain-containing protein 1a (ARID1a).¹

The drug, an oral small molecule inhibitor, works by targeting the HSF1 signaling pathway. In xenograft models, NXP800 has demonstrated potent antitumor effects. ARID1a-mutated ovarian carcinoma and other disease models.²

Previously, in December 2022, the FDA granted NXP800 Fast Track designation for the potential treatment of patients with platinum-resistant, ARID1a-mutated ovarian cancer. Shortly thereafter, in April 2023, a Phase 1b clinical trial began to evaluate the drug NXP800 in platinum-resistant, ARID1a-mutated ovarian cancer began.³

“We are very pleased with the FDA's approval of NXP800,” said Ron Bentsur, MBA, chairman and CEO of Nuvectis, in a press release. “The prevalence of ovarian cancer, which consists of ovarian, fallopian tube and primary peritoneal cancer, exceeds the 200,000 patient threshold below which drugs can be designated as orphan drugs in the United States.” 1

“In ovarian cancer, it is unusual to receive this designation for the treatment of a subset of the disease,” continued Bentsur. “We therefore believe that this FDA-granted orphan drug designation for NXP800 for the treatment of a subset of ovarian cancer, particularly for patients with ARID1a deficiency, provides further validation of the mechanism of action of NXP800 and the target patient population in our ongoing Phase 1b clinical trial in patients with platinum-resistant, ARID1a-mutated ovarian cancer.”

In the Phase 1b study, patients aged 18 years and older with platinum-resistant ovarian cancer and ARID1a Mutations will be included. Patients must have measurable disease according to RECIST 1.1 criteria, have experienced disease progression within 6 months of completing platinum-based therapy, have an ECOG performance status of 0 or 1, and have received between 1 and 5 prior lines of systemic therapy, including at least 1 bevacizumab (Avastin; Genentech)-containing regimen.⁴ If the patient has a BRCA Mutation, they must have previously been treated with a poly(ADP-ribose) polymerase (PARP) inhibitor.

Phase 1a of the study is the first-in-human clinical trial of NXP800. As of April 2023, 18 patients have received at least one dose of NXP800. The longest treatment duration to date has been 10 months, and some participants are still on treatment. Two different dosing regimens were evaluated. In the first, NXP800 was administered once daily with a total daily dose of 50 mg to 150 mg, and in the second, twice daily with a total daily dose of 100 mg and 150 mg.⁵

The most commonly observed treatment-emergent adverse reactions (AEs) in this part of the study included vomiting, nausea, diarrhea, fatigue, decreased appetite, and weight loss.

The Phase 1b study evaluated doses of 50 mg and 75 mg per day. Preliminary population pharmacokinetics and pharmacodynamics analyses support this choice and demonstrate that once-daily oral administration of NXP800 at these doses achieved biologically active exposure while maintaining an acceptable safety and tolerability profile.

For Part A, the primary endpoint is the number of patients with treatment-emergent adverse events, clinical laboratory abnormalities, and dose-limiting toxicities. In Part B, the primary endpoints are estimates of disease response per RECIST v 1.1 and the number of patients with treatment-emergent adverse events and/or clinical laboratory abnormalities.⁴

“We expect to be able to present a data update on this study next fall,” said Bentsur.¹

References

1. Nuvectis Pharma Announces FDA Orphan Drug Designation of NXP800 for the Treatment of ARID1A-Deficient Ovarian, Fallopian Tube and Primary Peritoneal Cancers. Press Release. Nuvectis Pharma. August 29, 2024. Retrieved August 30, 2024. https://tinyurl.com/ycks8ztb
2. Nuvectis Pharma announces the initiation of Phase 1b study for NXP800 in platinum-resistant, ARID1A-mutated ovarian cancer. Press release. Nuvectis Pharma. April 10, 2023. Retrieved August 30, 2024. https://tinyurl.com/59rzkfm7
3. FDA grants Fast Track designation to Nuvectis Pharma's NXP800 for the treatment of platinum-resistant, ARID1A-mutated ovarian cancer. Press release. Nuvectis Pharma. December 1, 2022. Retrieved August 30, 2024. https://tinyurl.com/fu7bnbmh
4. A Phase 1 clinical trial of NXP800 in subjects with advanced cancer and expansion in subjects with ovarian cancer. ClinicalTrials.gov. Updated June 12, 2024. Accessed August 30, 2024. https://clinicaltrials.gov/study/NCT05226507
5. Banerjee SN, Eskander RN, Roxburgh P, et al. A multicenter, open-label, Phase 1b study of NXP800, a novel GCN2 kinase activator, in patients with platinum-resistant, ARID1a-mutated ovarian cancer (ENGOT-GYN5/NCRI/NXP800-101; GOG-3087; NCT05226507) (study ongoing). Presented at: 2024 SGO Annual Meeting on Women's Cancer; March 16-18, 2024; San Diego, CA.