sabizabulin (VERU-111)

TNBC therapy includes a combination of cytotoxic chemotherapies, including microtubule-targeting agents (MTAs) like paclitaxel (taxane class) or eribulin (vinca class); however, there are currently no FDA-approved MTAs that bind to the colchicine-binding site. In contrast, VERU-111 preferentially inhibited liver metastases and lung metastasis repression was similar. Together, these results position 60c as an additional promising CBSI for TNBC therapy, particularly for patients with TxR disease.

We previously tested the combination regimen of tubulin inhibitor VERU-111 with vem, as well as USP14 selective inhibitor b-AP15 in combination with vem, both of which have showed profound therapeutic effects in overcoming vem resistance in vitro and in vivo. Interestingly, overexpression of USP14 antagonized all the ferroptosis cascade events induced by MitoCur-1, therefore, we conclude that MitoCur-1 induces ferroptosis through inhibition of USP14. We believe that by inhibition of USP14, vem resistance can be reversed and will finally benefit melanoma patients in future.

P3, N=105, Terminated, Veru Inc. | N=245 --> 105 | Trial completion date: Sep 2024 --> May 2023 | Active, not recruiting --> Terminated | Trial primary completion date: May 2024 --> May 2023; Administrative reasons

P1b/2, N=80, Terminated, Veru Inc. | N=58 --> 80 | Completed --> Terminated; Administrative decision

P1b/2, N=58, Completed, Veru Inc. | Active, not recruiting --> Completed | N=41 --> 58

P2, N=0, Withdrawn, Veru Inc. | N=200 --> 0 | Not yet recruiting --> Withdrawn

P3, N=245, Active, not recruiting, Veru Inc. | Recruiting --> Active, not recruiting

Preferred frontline treatment relies on anti-HER2 therapies, such as trastuzumab and pertuzumab, combined with microtubule inhibitors, such as taxanes. While sabizabulin shows promising results for treatment in HER2+ breast cancer, we further optimized the structure of sabizabulin to create a new class of anti-cancer molecules: 40a, CH-2-77, and 60c. Based on in vitro data, 60c showed higher potency in HER2+ breast cancer cell lines and was chosen as the lead compound to further study in a paclitaxel-resistant triple negative breast cancer in vivo study where it was able to effectively inhibit primary tumor growth compared to the vehicle group.

This clinical trial demonstrated that chronic oral daily dosing of sabizabulin has a favorable safety profile with significant preliminary cytotoxic and cytostatic antitumor activity. These data support the ongoing Phase 3 VERACITY trial of sabizabulin in men with mCRPC who have progressed on an androgen receptor targeting agent.

P2, N=200, Not yet recruiting, Veru Inc. | Trial completion date: Feb 2024 --> May 2024 | Trial primary completion date: Dec 2023 --> Mar 2024

P1b/2, N=41, Active, not recruiting, Veru Inc. | Trial completion date: Nov 2022 --> Apr 2023 | Trial primary completion date: Sep 2022 --> Feb 2023

Current frontline therapy for HER2+ metastatic breast cancer relies on targeted antibodies, trastuzumab and pertuzumab, combined with microtubule inhibitors in the taxane class (paclitaxel or docetaxel). In vivo, sabizabulin inhibits breast tumor growth in the BT474 (ER+/PR+/HER2+) xenograft model and a HER2+ (ER-/PR-) metastatic patient-derived xenograft (PDX) model, HCI-12. We demonstrate that sabizabulin is a promising alternative agent to target tubulin in HER2+ breast cancer with similar anti-metastatic efficacy to paclitaxel, but with the advantage of oral bioavailability and lower toxicity than taxanes.