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Safety and Preliminary Signs of Activity of OMO-103, a MYC Inhibitor, in Allcomers Solid Tumours

Findings from a dose-escalation phase I study
09 Feb 2024

In a first-in-human phase I dose-escalation study of OMO-103, a MYC inhibitor, conducted in patients with solid tumours, treatment was safe and showed preliminary clinical activity along with demonstrated target engagement and identification of potential pharmacodynamic markers.

The most deregulated oncogene in human cancers is MYC, but it has remained an elusive target in cancer biology for decades. This is the first successful phase I study validating the safety and tolerability of a first-in-modality direct MYC inhibitor according to Laura Soucek of the Vall d’Hebron Institute of Oncology (VHIO) in Barcelona, Spain, and colleagues who published the findings on 6 February 2024 in the Nature Medicine.

Many factors have pointed towards MYC as an excellent therapeutic target, but several technical difficulties, especially the intrinsically disordered nature of the protein, have so far prevented the development of a clinically viable MYC inhibitor. OMO-103 is a drug based on Omomyc, a MYC dominant negative initially designed and published in 1998 as a laboratory tool to study MYC perturbation, then later used to model MYC inhibition and its marked therapeutic potential in different mouse models of cancer, where it also showed safety and tolerability.

Omomyc was previously expressed genetically to show that it could prevent tumourigenesis and even eradicate tumours in multiple cancer models, regardless of their driving oncogene or tissue of origin. The more recent discovery of unexpected cell-penetrating properties of the purified Omomyc miniprotein led to its development as a pharmacological tool that demonstrated therapeutic efficacy both in vitro and in mouse models of non-small cell lung cancer and triple-negative breast cancer and opened the way for its clinical development.

Omomyc showed safety and efficacy both upon intranasal and intravenous administration and induced shutdown of MYC transcriptional programmes and reprogramming of the tumour microenvironment, recapitulating several key features of expression of the Omomyc transgene. Its therapeutic impact was reported in both primary tumours and metastases, alone and in combination with chemotherapy. In the preclinical models, the degree of response to Omomyc correlated only with its level of expression and not with MYC levels.

In the article published now in the Nature Medicine, the authors report the results of a first-in-human phase I study to assess the safety, pharmacokinetics, and preliminary signs of activity of OMO-103, a first-in-modality anti-MYC miniprotein in allcomers solid tumours. Primary outcomes were to examine safety and tolerability and secondary pharmacokinetics, recommended phase 2 dose and preliminary signs of activity.

A classical 3 + 3 design was used for dose escalation of weekly intravenous, single-agent OMO-103 administration in 21-day cycles, encompassing 6 dose levels. A total of 22 patients were enrolled, with treatment maintained until disease progression. The most common adverse events were grade 1 infusion-related reactions, occurring in 10 patients. One dose-limiting toxicity occurred at dose level 5.

Pharmacokinetics showed non-linearity, with tissue saturation signs at dose level 5 and a terminal half-life in serum of 40 hours. Of the 19 patients evaluable for response, 12 reached the predefined 9-week time point for assessment of drug antitumour activity, 8 of those showing stable disease by computed tomography. One patient with a stable disease defined by RECIST showed a 49% reduction in total tumour volume at best response.

Transcriptomic analysis supported target engagement in tumour biopsies. In addition, the study team identified soluble factors that are potential pharmacodynamic and predictive response markers. Based on all these data, the recommended phase 2 dose was determined as dose level 5, 6.48 mg kg−1.

The authors concluded that this study showed safety and preliminary signs of drug activity of OMO-103, supported by target engagement and immune-related biomarkers. It caused mainly grade 1 side effects and showed also suitable pharmacokinetic properties up to the recommended dose, with low or absent immunogenicity. In addition, the study indicated encouraging signs of drug activity based on both clinical response and assessment of molecular target engagement and biomarkers of response. Drug activity was also supported by target engagement as demonstrated by the shutdown of bona fide MYC-driven transcriptional signatures in patient biopsies.

The findings and the safety profile of OMO-103 encourage further investigation of its clinical activity and safety. In addition, a combination of MYC inhibition with chemotherapy, precision medicine therapeutics and immunotherapy could increase their efficacy both in contexts where MYC is not overexpressed as well as where it is amplified or overexpressed which is a common mechanism of drug resistance.

The authors commented that identification of pharmacodynamic and predictive biomarkers is based on a limited and heterogenous number of patients, with very different previous lines of treatment, as is inherent in any phase I study in oncology, and hence their validity and potential antitumourigenic role require further testing in a larger and more homogenous patient population. The identified signatures are currently being tested in a new clinical study with OMO-103 in combination with chemotherapy, where the predictive signature is being used for patient selection.

Drs. Elena Garralda and Marie-Eve Beaulieu contributed equally.

The authors from VHIO thanked the Cellex Foundation for providing research facilities and equipment, and the CERCA Programme from the Generalitat de Catalunya for their support on this research. They also acknowledged the Agencia Estatal de Investigación for financial support as Center of Excellence Severo Ochoa. They thanked the teams at Abzu and Biognosys for their service. This research has received funding from the Generalitat de Catalunya, the European Union Horizon 2020 research and innovation programme, the Ministerio de Ciencia e Innovación, the Ministerio de Ciencia, Innovación y Universidades grants and the European Union NextGenerationEU/PRTR.


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