Omega CEO Mahesh Karande

Most biology students are taught the central dogma: DNA makes RNA that makes proteins. Molecular medicine, however, has primarily been approached from the reverse direction. Proteins were the first to be tackled, with small molecules and biologics, followed by RNA therapeutics and genetic engineering and reprogramming. Yet, sitting “above” this all, per definition, is the epigenome.

Omega Therapeutics (Nasdaq: OMGA) is a development-stage biotechnology company pioneering a new class of epigenome modulators to transform human medicine. The OMEGA Epigenomic Programming™ platform harnesses the power of epigenetics to rationally design biologically engineered, modular, and programmable mRNA-encoded epigenetic drugs that target the fundamental structural and functional units of gene control.

Headquartered in Cambridge, Massachusetts, Omega Therapeutics was founded by Flagship Pioneering in 2017 and is currently advancing a broad pipeline of programs that span regenerative medicine, multigenic diseases including immunology, oncology, and select monogenic diseases. With the guidance of founding scientific advisors Rudolf Jaenisch, PhD, and Richard Young, PhD, from MIT and the Whitehead Institute, Omega’s mission is to transform medicine in areas of high unmet need with well-defined and circumscribed patient populations.

In August 2021, Omega completed an initial public offering (IPO) that raised $131.238 million in net proceeds through the sale of 8,300,976 shares of common stock at $17 a share—including 900,976 shares pursuant to a partial exercise of the underwriters’ option to purchase 1.11 million additional shares.

GEN Edge met with President/CEO Mahesh Karande, joined by chief financial officer Roger Sawhney, MD, to discuss how Omega intends to focus internal development and commercialization efforts to leverage their epigenomic platform to develop a new class of DNA-sequence-targeting, mRNA-encoded programmable epigenetic medicines.

GEN Edge: Why does Omega Therapeutics focus on epigenomic modulation as therapeutics?

Karande: If you think about drug development over the past 100 years and the central dogma of biology, drug development has actually occurred in the reverse order. First, it was Johnson & Johnson and Pfizer with small molecules, followed by Genentech’s monoclonal antibodies and biologics, targeting proteins. In the early part of this century, companies like Moderna and Alnylam were created to treat diseases by moving up the central dogma with mRNA. Although these companies have seen tremendous success, there are limitations. None of the noncoding RNA companies can go after oncology because many oncogenes autoregulate.

More recently, people started going straight to DNA, first with gene editing and then gene therapy. Yet, both have limitations because they mostly work in monogenic settings. Now, some companies aim at epigenetics, yet most of them use small molecules. We are going to the root cause of the disease, which is the dysregulation of gene expression. That’s why we are such a broad company. Omega fits on the page with iconic companies because we work through the central dogma to save lives and create collateral and financial value.

Flagship Labs founded Omega to look at epigenetics and figure out whether there is a way we can understand what nature does very systematically to control cellular processes and gene expression. We replicate the way nature controls gene expression to correct gene expression programs and resolve disease.

Omega’s science is based on the fact that genes are organized in these three-dimensional loops of DNA called insulated genomic domains (IGDs) that contain single or multiple genes. They act as the fundamental regulators of the genome and are the control units of gene expression. Approximately 15,000 IGDs define the entire genome, and they are ubiquitous in every cell of our body. But genes get expressed differently throughout the body. There are unique regulatory sequences within the 15,000 IGDs, which are the addresses that we can target with our epigenome controllers and fine-tune gene expression.

We are a programmable medicine platform company. We have created a platform that has allowed us to translate the science into a drug development technology with epigenetic controllers. We are very broad in terms of disease areas. We can go into any disease area because all diseases are caused by dysregulation of gene expression, and we can correct that gene question. We married all the different ways that we could explore the platform with certain areas that we found to be tremendously underserved where patients have pretty limited options.

Sawhney: Our platform lends us to areas that are very upstream in the control of cellular biology by controlling the rates of transcription of particular genes, turning them on or off. Oncology is a very attractive area for us because it is an area where epigenetics and the dysregulation of the epigenetic marks are rampant and a significant cause of the disease.

Omega CFO Roger Sawhney MD

Many of the targets are highly autoregulated genes; that is to say, if you try to tap them down or address them at the protein or RNA level, you end up over-revving the production of that gene. What we do is we go upstream to reduce the production of the gene itself.

Another area where we have a particular advantage is in multigenic diseases. Many diseases involve multiple genes. When they work together or in concert, many of those genes sit within the same domain, which is the unit of operation for gene control that we address. With our controllers, we can modulate those multiple genes within a single domain. In traditional drug development, if you wanted to target four or five different gene products, whether it’s proteins or the RNA that codes for those proteins, you would need four or five small molecules or biologics to do that. We can do that with a single controller; you can get a handle on multiple interrelated genes that may be contributing to the disease process with a single controller.

GEN Edge: How is Omega organized?

Karande: Omega can be broken down into four pillars. First, we have delineated all of these targets, which we call epigenetic zipcodes (epi-zips). We have created a proprietary database and system that allows us to target any of these epi-zips for disease control. Our platform is based on these epi-zips, which are internal proprietary targets across the entire genome with high specificity.

Second, we target epi-zips with our engineered mRNA therapeutics that we call Omega Epigenomic Controllers (OECs). They have a DNA-binding domain that targets epi-zips, an effector domain that makes the epigenetic mark, and a property that allows us to control how much we want to tune a gene for the duration of the disease and the conditions we are tackling.

Third, we have engineered targeted delivery. We are delivery agnostic, but we are going with lipid nanoparticles pioneered by our older sibling Moderna. Fourth, we have a computational engine that allows us to do this all very quickly. Also, as we study this, we are creating a repository of knowledge and collecting information that we can go back to and use for the next disease condition.

We conceptualize, create, and manufacture the OECs; we fully own them. For delivery, we have a two-pronged strategy: we have our own formulations that we are developing in-house are and are also making sure that we are using the best industry standards available. We don’t want to hold up getting these drugs into patients eventually because we are a smaller company. We will ultimately have a footprint that will give us control of our value chain through the phases of clinical development and then figure out whether we should scale up or use world-class vendors for commercialization.

GEN Edge: How does Omega approach strategic partnerships?

Sawhney: We have capabilities in certain areas, like creating our controllers. However, accessing new attractive areas of biology and impacting families of or particular diseases is accelerated by finding partners. For example, in October, we announced a strategic research collaboration with researchers at the Stanford University School of Medicine to explore the therapeutic potential of OECs to control ocular disease genes associated with inflammation or degeneration of ocular tissues. The eye is a localized compartment from a delivery perspective as well. Stanford has a fantastic ophthalmology research team and group, so we felt that it could turbo-charge our ability to impact corneal regeneration and certain rental diseases. We will be opportunistic in finding other partners, whether academic or corporate, to bring particular capabilities to complement and help accelerate our ability to get into novel disease segments where we think our technology could be very valid.

From a broader partnership perspective, we can’t prosecute everything that we can do. Modulating gene expression with our controllers applies to almost every disease. In fact, we can impact roughly 95% of diseases, except for some monogenic diseases. But we can’t possibly work on all of those! So, we are starting to engage with large pharma and biotech partners who could license our technology or products to help bolster their pipelines, help us bring in non-dilutive capital, and expand the potential of what we’re doing. We’re starting to explore as well now.

Karande: Being a smaller biotech company with a platform that has immense breadth, we would be remiss if we did not explore partnerships to go into all of the disease areas in which other partners have a tremendous amount of expertise. The important thing is to develop these therapies that are potentially much safer than anything else in the genomic medicine world because you’re not changing the underlying nucleic acid sequence. The other thing is that we have a very expandable pipeline; it can scale up very quickly, but we don’t have to go and create expertise in every disease area as a small biotech company.

GEN Edge: What is the significance of going public for Omega, and how does it affect the company?

Sawhney: Going public is a milestone and a critical financing event; it’s a way to help fund the company and the important work we do. But the lion’s share of the work still has to be done. There’s more scrutiny on everything we do, and we welcome that. We’re frankly excited about that because it allows us to get more people to understand our message, what we’re doing, and be enthusiastic about our science and what we’re capable of doing. We now have a few operational commitments, timelines, and things that we need to manage towards and target. The process we’ve laid out is ambitious regarding the stuff we want to deliver within a timeframe.

I think that’s part and parcel of going public and having public market investors. We are excited about our investors; we’ve got some terrific long-term investors who supported us when we were private and continue to do so through the IPO.

Karande: We were a very solid operationally focused company before going public because we have achieved delivering in vivo proof of principles in animal data in four completely uncorrelated disease areas. We tackled new science as a company in a matter of four and a half years. That gives us confidence that this is a very operationally solid company. That doesn’t change as a public company; rather, that is our strength as a public company. From that standpoint, other than a general increase in scrutiny, nothing has changed by going public. We’re moving ahead precisely as we had planned.

GEN Edge: What is Omega’s projected trajectory?

Karande: Our ethos is ambitious, yet humble. We are on a pioneering journey, and we know we can’t do this alone. There is a risk that exists in biopharma development. We have to earn the right to put these medicines into patients eventually.

In the short term, we have commitments to our stakeholders and shareholders to get more drug development candidates into IND for one, two, or more of our products. In five years, if everything is going well, we would expect to become a commercial-stage company with a pipeline with a breadth beyond what we have today. In ten years, we want to be building an iconic integrated biopharmaceutical company as this all moves forward.

To quote David Berry, a co-founder of Omega and General Partner for Flagship Pioneering, Omega is controlling the control room of biology. That’s precisely why he also named the company Omega, which is essentially the last level of the Greek alphabet, the end-all. If it works, you can be in control of any disease.

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