MYC, a frequently deregulated oncogene in human cancers, has been a challenging target for cancer therapy due to its intrinsically disordered nature. MYC acts as a pleiotropic transcription factor, orchestrating transcriptional programs crucial for tumor development and maintenance. Its continuous activity in cancer cells contrasts with its transient role in physiological tissue regeneration. While MYC's role in cancer makes it an attractive therapeutic target, developing effective inhibitors has been hampered by technical difficulties. OMO-103, a 91-amino acid miniprotein derived from Omomyc (a MYC dominant-negative initially developed as a research tool), represents a novel approach to MYC inhibition. Preclinical studies have demonstrated Omomyc's therapeutic potential and safety in various mouse cancer models, showing efficacy in both primary tumors and metastases, even in combination with standard-of-care chemotherapy. The discovery of Omomyc's cell-penetrating properties paved the way for its development as OMO-103, a pharmacological agent. This first-in-human phase 1 trial aimed to evaluate the safety, pharmacokinetics (PK), and preliminary antitumor activity of OMO-103 in patients with advanced solid tumors.

The literature extensively documents MYC's role as a central oncogene, highlighting its involvement in cell proliferation, growth, metabolism, apoptosis, and immune suppression. Its aberrant activity in cancer leads to hypertranscription, further emphasizing its importance as a therapeutic target. However, the development of clinically viable MYC inhibitors has been historically challenging. Previous research has explored various strategies to target MYC, but the protein's intrinsically disordered nature presented significant obstacles. The development of OMO-103 builds upon extensive preclinical research utilizing Omomyc, which demonstrated significant antitumor activity in multiple cancer models. These preclinical studies laid the groundwork for the clinical translation of this novel MYC inhibitor.

This open-label, multicenter, phase 1 dose-escalation study (MYCure, NCT04808362) enrolled 22 patients with histologically confirmed advanced solid tumors that had progressed on standard-of-care treatment. Patients received weekly intravenous infusions of OMO-103 at six dose levels (DLs) (0.48, 1.44, 2.88, 4.32, 6.48, and 9.72 mg/kg) in 21-day cycles. A 3+3 dose-escalation design was used, with safety and tolerability as primary endpoints and pharmacokinetics, recommended phase 2 dose (RP2D), and preliminary antitumor activity as secondary endpoints. Treatment continued until disease progression. Safety was assessed using the Common Terminology Criteria for Adverse Events (CTCAE) v. 5.0. Pharmacokinetic (PK) analysis involved serum and tissue biopsies. Anticancer activity was evaluated by computed tomography (CT) scans every 9 weeks using RECIST v.1.1 criteria. The Guardant360 assay was used as a complementary measure of tumor response by assessing cell-free circulating tumor DNA (ctDNA). Transcriptomic analysis using digital spatial profiling (DSP) and ultradeep protein profiling by mass spectrometry (MS) were conducted on paired pre- and on-treatment biopsies to evaluate target engagement. Blood samples were analyzed using Luminex technology to identify potential predictive and pharmacodynamic biomarkers of response.

The study demonstrated that OMO-103 was well-tolerated, with the most common adverse events being grade 1 infusion-related reactions (IRRs) in ten patients. One dose-limiting toxicity (DLT), grade 2 pancreatitis, occurred at DL5 (6.48 mg/kg). Pharmacokinetic analysis revealed nonlinearity above DL5, indicating tissue saturation. The estimated terminal half-life in serum was approximately 40 hours. Of the 19 patients evaluable for response, 12 reached the 9-week time point for antitumor activity assessment. Eight of these patients showed stable disease (SD) by CT scan, with disease stabilization lasting from 35 to 765 days. One patient showed a 49% reduction in total tumor volume. Transcriptomic analysis through DSP demonstrated target engagement by showing a shutdown of MYC transcriptional signatures in tumor biopsies, particularly prominent in patients with SD. Analysis also revealed the upregulation of immune-related gene sets, particularly those associated with T cell-mediated immunity. Furthermore, the study identified soluble factors (MIP-1β, IL-8, CD62E, and GM-CSF) that may serve as predictive biomarkers of response. Patients who achieved SD at cycle 3 showed significantly lower baseline levels of these factors compared to patients with progressive disease. A pharmacodynamic signature, characterized by a transient increase in interferon-γ (IFNY), CD62E, and IL-17A after OMO-103 infusion, was also identified and associated with SD.

This phase 1 study provides the first evidence of safety and tolerability of a direct MYC inhibitor, OMO-103, in humans. The observed safety profile, primarily consisting of manageable grade 1 IRRs, is encouraging. While RECIST did not show objective responses, the observed disease stabilization in half the patients with heavily pretreated advanced disease suggests clinical activity. This is further supported by target engagement demonstrated through transcriptomic analysis showing shutdown of MYC-driven transcriptional signatures. The identification of potential predictive and pharmacodynamic biomarkers in serum opens the door for non-invasive monitoring of response to OMO-103. The transient increase in IFNY, CD62E, and IL-17A observed in patients with SD suggests a potential antitumor immune response triggered by MYC inhibition. These findings justify further investigation of OMO-103's potential, especially in combination with other therapies.

The MYCure phase 1 trial demonstrates the safety and tolerability of OMO-103, a first-in-class MYC inhibitor, with encouraging preliminary signs of antitumor activity and identifies potential biomarkers predictive of response. Future studies should focus on confirming the clinical activity in larger cohorts and exploring the potential of combining OMO-103 with other therapies to enhance its efficacy.

The limited sample size in this phase 1 study restricts the statistical power of the analyses, especially for the biomarker studies. The heterogeneity of tumor types and prior treatments among patients also limits the generalizability of findings. The lack of objective responses as per RECIST criteria, despite disease stabilization in several patients, should be considered when interpreting the efficacy results. Further studies are needed to fully validate the identified predictive and pharmacodynamic biomarkers in larger, more homogenous patient populations.