FDA Grants Orphan Drug Designation to NXP800 for ARID1a-Deficient Ovarian Cancers

US FDA

The novel GCN2 kinase activator NXP800 received orphan drug designation from the FDA for the treatment of AT-rich interactive domain-containing protein 1a (ARID1a) ARID1a-deficient ovarian, fallopian tube, and primary peritoneal cancers, according to a news release from Nuvectis Pharma, Inc.¹

“We are very pleased to have received this designation from the FDA for NXP800. The prevalence of ovarian cancer, which is comprised of ovarian, fallopian tube and primary peritoneal cancers, exceeds the 200,000-patient threshold below which drugs may be eligible to receive orphan drug designation in the United States,” Ron Bentsur, MBA, chairman and CEO of Nuvectis, stated in the news release.

The oral small-molecule inhibitor targets the HSF1 pathway, and it has shown strong anti-tumor effects in xenograft models of ARID1a-mutated ovarian carcinoma, as well as in other disease models.²

Notably, the FDA granted fast track designation to NXP800 for patients with platinum-resistant, ARID1a-mutated ovarian carcinoma in December 2022, which was then followed by the initiation of the phase 1b clinical trial (NCT05226507) of NXP800 in platinum-resistant, ARID1a-mutated ovarian cancers in April 2023.^2,3

“In ovarian cancer it has been uncommon to receive this designation for the treatment of a subset of the disease. We therefore believe that this orphan drug designation granted by the FDA for NXP800 for the treatment of a subset of ovarian cancer, specifically for patients with an ARID1a deficiency, provides further validation for NXP800's mechanism of action and the target patient population in our ongoing phase 1b clinical trial in patients with platinum-resistant, ARID1a-mutated ovarian cancer,” Bentsur added in the news release.¹

At the 2024 SGO Annual Meeting on Women’s Cancer, investigators shared an overview of the ongoing study.⁴

The ongoing phase 1b trial is enrolling patients with platinum-resistant ovarian cancer harboring ARID1A mutations, which is typically a tumor type that is mostly comprised of ovarian clear-cell carcinoma and ovarian endometrioid carcinoma.^2,5 To be eligible for enrollment, patients must be 18 years of age or older, have measurable disease according to RECIST 1.1 criteria, have experienced disease progression within 6 months from completion of platinum-based therapy, and must have received between 1 and 5 prior lines of systemic therapy, including at least 1 regimen containing bevacizumab (Avastin). Additionally, all patients must have an ECOG performance status of 0 or 1, and participants with a BRCA mutation must have received prior treatment with a PARP inhibitor.

Patients who did not respond to, or progressed during, or within 4 weeks of the last dose of first-line platinum-containing chemotherapy were excluded. Treatment with radiotherapy (except for palliative reasons), endocrine therapy, chemotherapy, or an investigational agent within 28 days of the first dose of NXP800 was also not permitted, nor were active brain metastases.

The phase 1b portion of the trial is currently open for enrollment in both the United Kingdom and the United States.²

Regarding the phase 1a portion of the study, which was the first-in-human clinical trial of NXP800, as of April 2023, a total of 18 patients have received at least one dose of NXP800, with the longest treatment duration reaching 10 months, and treatment is still ongoing for some participants. The investigation evaluated 2 different dosing schedules of the agent, including once daily (with total daily doses ranging from 50 mg to 150 mg) and twice daily (with total daily doses of 100 mg and 150 mg).

Furthermore, the most common treatment-emergent adverse effects reported were vomiting, nausea, diarrhea, fatigue, decreased appetite, and weight loss.

For the phase 1b study, doses of 50 mg and 75 mg per day were selected and were chosen based on preliminary population pharmacokinetics and pharmacodynamic analyses, which indicated that once-daily oral administration of NXP800 at these levels achieved biologically active exposure while maintaining an acceptable safety and tolerability profile.

“We expect to provide a data update from this study this coming fall,” Bentsur concluded.¹

References

1. Nuvectis Pharma announces orphan drug designation granted by the FDA for NXP800 for the treatment of ARID1A-deficient ovarian, fallopian tube, and primary peritoneal cancers. News release. Nuvectis Pharma. August 29, 2024. Accessed August 29, 2024. https://nuvectis.com/press-release-view/?i=137348
2. Nuvectis Pharma announces initiation of the phase 1b study for NXP800 in platinum-resistant, ARID1A-mutated ovarian carcinoma. News release. Nuvectis Pharma. April 10, 2023. Accessed August 29, 2024. https://s3.amazonaws.com/b2icontent.irpass.cc/2609/rl117355.pdf
3. FDA grants fast track designation to Nuvectis Pharma's NXP800 for the treatment of platinum-resistant, ARID1A-mutated ovarian carcinoma. News release. Nuvectis Pharma. December 1, 2022. Accessed August 29, 2024. https://nuvectis.com/press-release-view/?i=114174
4. Banerjee SN, Eskander RN, Roxburgh P, et al. A phase 1b multicenter, open-label, 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) (trial in progress). Presented at: 2024 SGO Annual Meeting on Women’s Cancer; March 16-18, 2024; San Diego, CA.
5. A phase 1 clinical study of NXP800 in subjects with advanced cancers and expansion in subjects with ovarian cancer. ClinicalTrials.gov. Updated June 12, 2024. Accessed August 29, 2024. https://clinicaltrials.gov/study/NCT05226507?term=NCT05226507&rank=1