The promise of gene therapies and gene-editing drugs is a long-lasting treatment that’s potentially a cure. But making permanent genetic changes means any accompanying problems could be long-lasting as well, says Omega Therapeutics CEO Mahesh Karande.
Omega is developing technology that takes a more nuanced approach to genomic medicine. Instead of fixing or replacing faulty genes, the company aims to harness the biological system that regulates them. If a gene is not properly translating DNA instructions into a needed protein, Omega can tune the gene expression up, Karande says. If gene expression is too high, the company’s technology dials it down.
“We have basically tapped into the control room of biology,” says Karande, a former executive at Macrolide Pharmaceuticals and Novartis (NYSE: NVS). “Our therapeutics are allowing genes to express at their native, correct level of expression. We tap into that biology.”
Now the Cambridge, MA-based biotech has tapped into something more: $85 million in financing. Karande says the cash will support multiple programs, the first of which is expected to reach clinical testing in 2021.
The system that regulates genes is called the epigenome. The targets of Omega’s drugs are insulated genomic domains (IGDs), three-dimensional structures that rise up from the folds of DNA. IGDs regulate the activity of a gene, similar to the way a thermostat regulates the temperature of a room, the company says. Omega has developed technology that identifies IDGs and their biological functions in states of both health and disease.
Omega’s drugs are fusion proteins made up of a delivery system that takes the therapy to specific cell types, a targeting domain that binds to a specific site on the IGD, and a functional domain engineered to tweak the activity level of the IGD as needed. A single Omega drug can control the gene expression of a single gene or multiple genes, Karande says. The company can also control the length of time that a drug works, making it last days, weeks, or longer. That makes the treatment applicable for acute conditions of short duration. And unlike the permanent change made by genomic medicines, if an epigenomic Omega therapy is no longer needed, it can be turned off.
Most gene therapies and gene-editing drugs are delivered by engineered viruses. In addition to hitting the intended genetic target, these viruses can also hit other places, causing side effects, says Tom McCauley, Omega’s chief scientific officer. Also, gene-editing drugs use cutting enzymes that can snip unintended spots along the genome, sparking off-target effects. By contrast, Omega’s targeted approach gives its drugs the potential to more safely treat genomic disorders with a degree of control not offered by gene therapies or gene-editing drugs, McCauley says.
There are other epigenetic medicines companies. Cambridge, MA-based Epizyme (NASDAQ: EPZM) is developing drugs addressing the genetic causes of disease. In January, the FDA approved the company’s small molecule drug tazemetostat (Tazverik) as a treatment for the rare cancer epithelioid sarcoma. In June, it won an an additional nod for follicular lymphoma. The most advanced drug candidate, developed by another Cambridge-based epigenetics biotech, Constellation Pharmaceuticals (NASDAQ: CNST), is a small molecule in mid-stage testing in myelofibrosis, a rare blood cancer.
There’s a reason that most of the epigenetic medicines currently available and in drug pipelines are small molecules addressing some form of cancer, McCauley says. Those drugs do hit their cancer targets but they also go elsewhere in the body, sparking side effects, he says. That risk is acceptable in rare cancers, but untenable for other diseases. Cancer is one of Omega’s disease targets, but McCauley says that Omega’s capability to modulate the epigenome could more safely and effectively address other diseases as well.
The IDG science that is the basis for Omega’s epigenomic approach stems from the research of Richard Young and Rudolf Jaenisch, MIT biology professors and members of the Whitehead Institute for Biomedical Research. In 2016, their research was published in the journal Cell. They are both scientific advisors to Omega, which was founded in 2017 by venture capital firm Flagship Pioneering, the company’s only disclosed financial backer. The firm has a track record of starting companies, incubating them, and then spinning them out to advance their research.
Omega emerged from stealth last September. Karande would not say much about the company’s disease targets then, and he’s saying only a little more now. Without naming specific conditions, Karande says his startup aims to treat inflammatory and immunological disorders, metabolic conditions, and rare diseases where a targeted approach to modulating the epigenome enables the company to hit disease targets previously considered “undruggable.” The company currently has five programs. Karande says the new financing is enough to support all five, though he leaves open the possibility that some of them could be advanced in partnership with a large pharmaceutical company.
“We’re on a journey right now to get five programs, in a staggered fashion, into the clinic,” he says. “As we make milestones in the next few months, we will be talking about them.”
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