Shots:

• Mahesh talked about the data presented on its lead candidate in hepatocellular carcinoma at the AACR 2022
• Mahesh also spoke about Omega’s drug-development platform that identifies and targets specific and unique DNA sequences of regulatory elements 
• The interview gives a profound grip on Omega’s development strategies to use mRNA therapeutics as a new class of epigenetic medicines

Smriti:  Let’s start by discussing the details of OTX-2002 (MOA, ROA, formulations, etc.)

Mahesh: OTX-2002 is our lead Omega Epigenomic Controller™ (OEC) candidate designed to downregulate the expression of c-Myc (MYC), a key gene involved in cellular growth commonly overexpressed in cancer cells. OECs are programmable mRNA medicines that encode a two-part protein: a DNA binding domain that specifies the target location on the DNA, which we call EpiZips™, and an effector domain that makes precise and durable epigenetic marks to alter gene expression. OECs are translated into proteins by the cell’s ribosomal machinery, then travel to the nucleus to lay epigenetic marks at the programmed specific genomic address.

While OTX-2002 is delivered as mRNA via lipid nanoparticles, our platform enables a delivery agnostic approach, creating the opportunity for a range of delivery options that can be tailored to the characteristics of a disease.

Smriti: What were the key findings of the preclinical study of OTX-2002?

Mahesh: We recently presented preclinical data at AACR 2022 on OTX-2002 as a potential treatment for hepatocellular carcinoma (HCC), a disease where MYC overexpression is a common driver of pathology. Despite being dysregulated in > 70% of HCC cases, MYC has remained an undruggable target to date. In in vitro studies, OTX-2002 durably reduced MYC mRNA expression as well as MYC protein levels for two weeks. In HCC cell lines, downregulation of MYC by OTX-2002 caused a significant, targeted reduction in viability of these cancer cells while primary healthy hepatic cells were not impacted. In addition, in xenograft mouse models of HCC, OTX-2002 significantly reduced tumor growth and was well tolerated. Cumulatively, these data support the potential of our epigenomic programming approach to precisely control gene expression and demonstrate a path forward for OTX-2002 as a potential new approach to treat HCC.

Smriti: You have mentioned the OMEGA Epigenomic Programming platform, what exactly is this platform and how will this platform tackle previously intractable diseases?

Mahesh: Our OMEGA Epigenomic Programming platform is a deterministic drug-development platform that allows us to prospectively engineer programmable epigenetic mRNA therapeutics, OECs, to control cellular programming and restore gene expression to homeostasis. We leverage our deep and continually improving understanding of genomic architecture and our computational expertise in machine learning and artificial intelligence to rationally and rapidly design OECs. 

The OMEGA platform has a computational engine that allows us to identify and target specific and unique DNA sequences of regulatory elements. These epigenomic “zip codes,” or EpiZips, are located within discrete chromatin looping regions called insulated genomic domains (IGDs), which house one or more genes and their regulatory elements. We then prospectively design and optimize OECs that lay epigenetic marks at these EpiZips to durably tune the expression of the target gene(s) in the appropriate cells and tissues. We have mapped and validated thousands of EpiZips across IGDs, which allows the rapid design of OECs for the disease/condition under consideration. 

Our mRNA medicines, OECs, act pre-transcriptionally, and our work with MYC gives us the confidence that our approach overcomes autoregulation that is typically seen with oncogenes. We can also regulate multiple genes with a single therapeutic, which allows us to tackle complex diseases in an unprecedented way. Controlling the epigenetic state of cells also opens the door to achieving cellular regeneration. Our pipeline indications reflect many previously intractable conditions that our platform is uniquely positioned to address.

Our computational approach allows us to develop candidates rapidly, potentially going from target identification, and optimizing clinical candidate OECs, to clinical trials within 24-36 months. We believe that this timeline will become shorter as we continue to optimize our platform through iterative learning.  

Smriti: Is the company planning to use any other drug under the epigenomic programming platform for other indications?

Mahesh: Our pipeline and target indications were purposefully selected to demonstrate the broad potential applications of our OMEGA Epigenomic Programming platform. In addition to oncology, where we have a program in non-small cell lung cancer (NSCLC) as well as in HCC, we are also developing epigenomic controllers for tissue regeneration, multigenic diseases, including immunological disorders, and select monogenic diseases like alopecia.

Smriti: How does the company plan to use mRNA therapeutics as a new class of programmable epigenetic medicines?

Mahesh: Epigenomic programming represents a new frontier in genetic medicine for precision genomic control. Historically, generic medicines have a binary impact on gene expression, either turning genes off entirely or expressing them in an unregulated manner. Our approach, which leverages nature’s fundamental epigenetic mechanism of gene regulation to tune gene expression to the desired levels, creates a potentially safer opportunity to treat a broader range of diseases than previously possible.

Smriti: As you have already mentioned, MYC has remained undruggable, how will the company overcome limitations faced by previous technologies and develop a treatment against MYC?

Mahesh: MYC is a key driver in more than 50% of all cancers. However, attempts to drug MYC in the past have failed to yield benefits to patients for two primary reasons. First, the MYC protein is complex and lacks a specific binding pocket suitable for targeting small molecules. Second, MYC levels are tightly autoregulated by cellular feedback mechanisms, which can counteract approaches to regulate its expression.  

Epigenomic programming enables finetuning of MYC expression, as opposed to turning it on/off like other gene editing approaches, which we believe will be able to overcome the feedback mechanisms that keep MYC levels high in cancer.

Smriti: Please tell us about Omega Therapeutics’ plans to proceed with OTX-2002 into clinical trials and IND applications.

Mahesh: Omega plans to file an Investigational New Drug application (IND) in the first half of 2022 to further develop this asset with the hope of bringing novel mRNA therapeutics to patients in need with hepatocellular carcinoma (HCC). 

Source: Canva

About the Author: 

Mahesh Karande is the President and CEO at Omega Therapeutics. He has rich experience in running biopharma businesses across discovery, preclinical development, clinical development, commercialization and product life cycle management stages. Mr. Karande holds a M.B.A. degree from the Wharton School, University of Pennsylvania. He completed his MS in engineering from the Georgia Institute of Technology and undergraduate studies from the University of Bombay. 

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