Overview of OT-101

OT-101 (Trabedersen) is a novel phosphorothioate antisense oligodeoxynucleotide targeting TGF-β2 mRNA. TGF-β2 plays a crucial role in tumor immune evasion and progression. OT-101 has shown promising efficacy in early-phase clinical trials and is currently being evaluated in Phase 3 trials for multiple indications.

OT-101 in Glioblastoma

High expression of TGF-β2 is associated with poor survival in adult gliomas and pediatric diffuse midline gliomas. OT-101 delivered via intracranial microperfusion showed durable responses in the G004 Phase IIb trial, with confirmed complete and partial responses correlating with long overall survival (CR: >66 months; PR: 36.9 months).

• Evaluated across five glioma trials (G001-G005)
• Orphan drug and rare pediatric disease designations

OT-101 in Pancreatic Cancer

In PDAC, high TGF-β2 correlates with worse prognosis. In the P001 Phase I/II study, OT-101 showed favorable safety and long-term disease control in over half of the treated patients. A follow-up Phase 2b/3 trial (STOP-PC, NCT06079346) is ongoing, combining OT-101 with mFOLFIRINOX, where synergy has been observed with irinotecan-based regimens.

• More than double OS benefit observed in patients with high AUC exposure (9.6 vs. 2.4 months)
• OT-101 selectively synergizes with irinotecan, not gemcitabine/paclitaxel
• CROMOS is the CRO partner for the ongoing STOP-PC study — learn more on Cromos Pharma's website

OT-101 in Colorectal Cancer

In colorectal cancer, OT-101 demonstrated activity in a mesenchymal-specific subset. Bioinformatics data show that TGFB2 and TGM6 together strongly predict poor prognosis. OT-101 may benefit CRC patients within the CMS4 mesenchymal subtype, where TGF-β2 signaling drives tumor aggressiveness.

OT-101 and IL-2 Combination Therapy

OT-101 synergizes with high IL-2 levels to enhance anti-tumor immunity, particularly when used with PD-1 checkpoint inhibitors. In a completed Phase I trial (NCT04862767), OT-101 in combination with recombinant IL-2 showed tolerability and encouraging objective responses, supporting advancement to Phase II.

Mechanism of Action

OT-101 inhibits TGF-β2 at the mRNA level, reprogramming the tumor microenvironment. It converts immunosuppressive M2 macrophages into pro-inflammatory M1 macrophages, enhances anti-tumor immunity, and may synergize with PD-1 inhibitors such as pembrolizumab.

OT 101 + Pembrolizumab in NSCLC (NEBRASKA MEDICINE ONC740 24)

NEBRASKA MEDICINE is currently recruiting for a Phase I/II trial (ONC740 24) investigating OT 101 in combination with pembrolizumab as first-line therapy in patients with newly diagnosed, PD L1 positive advanced non small cell lung cancer.

• Phase I: Establish safety, dose limiting toxicities (DLTs), and maximum tolerated dose (MTD)
• Phase II: Evaluate progression free survival (PFS) as the primary endpoint, with secondary endpoints including overall response rate (ORR), disease control rate (DCR), and duration of response (DOR)
• PI: Dr. Omar Abughanimeh; contact: Kimberly Shields (kimberly.shields@unmc.edu)