# Arylsulfonamides for the Treatment of Primary and Metastatic Uveal Melanoma

> **NIH NIH R44** · ONCOSPHERIX, INC. · 2023 · $1,024,999

## Abstract

Summary:
 The goal of this Phase II SBIR is to advance OncoSpherix’s HIF-1 inhibitor, 64B, as part of combination
therapy for metastatic and high-risk uveal melanoma (UM), the most prevalent primary eye cancer in adults. 64B
is a small molecule therapeutic that inhibits HIF function by disrupting the recruitment of the transcriptional co-
factor, p300/CBP, while leaving intact p300/CBP’s ability to function with multiple other transcription factors. As
a consequence, 64B is well-tolerated for prolonged periods in tumor bearing mice, both alone and in combination
with multiple other cancer therapeutics.
 We’ve published studies where several UM cell lines were orthotopically implanted within the uveal of
the eye, showing that 64B inhibits primary tumor growth and metastases in mice while also prolonging survival.
Results from our Phase I SBIR studies built on this prior work and strongly support the continued development
of 64B as an important, novel and innovative cancer therapeutic. 64B demonstrated superior therapeutic efficacy
when compared to two tyrosine kinase inhibitors (TKIs, sunitinib and selumetinib) that are in phase 2 or 3 clinical
testing for UM. 64B was better tolerated that the TKIs. When tumors were much larger when treatment was
started, 64B showed therapeutic synergy when combined with sorafenib, another TKI in clinical testing for UM.
 Our Phase I SBIR studies led to significant progress in the chemistry needed to advance 64B into clinical
testing. A 5-step synthesis was selected that eliminated the use of microwave reactors, chromatographic
purifications and use of palladium catalysts. The overall production yield was improved from about 2 % to >22%,
or about 75% yield per stage across the five stages. Through refinement of the process, 700 g of 64B were
produced with >98 % purity, providing sufficient 64B for proposed SBIR phase 2 studies. We tested amorphous
solid dispersion (ASD) as an enhanced formulation method that improved 64B’s solubility more than 40-fold.
Metabolic and PK studies provided evidence the plasma levels of orally delivered 64B were insufficient to fully
block HIF, most likely due to first pass effects in the liver, and thus we will focus on parenteral delivery for
preclinical and clinical studies.
 Phase II SBIR studies will identify the best 64B-TKI class combination to advance for clinical testing using
UM cells directly implanted in the uvea of the eye. Studies on responsiveness to 64B using several UM cell lines
with targeted deletion of HIF-1a, HIF-2a or both will add additional mechanistic insights. Other objectives are
focused on converting to IV dosing for both efficacy and non-GLP toxicology studies, including determining the
maximum tolerated dose of 64B and repeat dosing toxicity in two species. We anticipate successful completion
of all specific aims within 2 years and securing the additional funds needed for completing IND-enabling studies,
filing an IND, and launching clinical testing using ...

## Key facts

- **NIH application ID:** 10698765
- **Project number:** 2R44CA254756-02A1
- **Recipient organization:** ONCOSPHERIX, INC.
- **Principal Investigator:** Margaret Kenny Offermann
- **Activity code:** R44 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $1,024,999
- **Award type:** 2
- **Project period:** 2020-09-17 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10698765

## Citation

> US National Institutes of Health, RePORTER application 10698765, Arylsulfonamides for the Treatment of Primary and Metastatic Uveal Melanoma (2R44CA254756-02A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10698765. Licensed CC0.

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