Prelude Therapeutics

While several epigenetic-focused biotechs have zeroed in on lysine and its effects on DNA regulation, Prelude Therapeutics is taking a different tack by aiming at the methylation of arginine. (Prelude Therapeutics)

Chasing a lesser-known epigenetic target to overcome cancer drug resistance.

CEO: Kris Vaddi, Ph.D.
Founded: 2016
Based: Wilmington, Delaware
Clinical focus: Targeting PRMT5, an enzyme related to treatment resistance and oncogenesis in both solid and hematological cancers.

The scoop: While several epigenetic-focused biotechs have zeroed in on lysine and its effects on DNA regulation, Prelude Therapeutics is taking a different tack by aiming at the methylation of arginine—specifically, the enzyme PRMT5 and its effects on the cell cycle, RNA splicing and signaling.

By blocking it, Prelude hopes to starve treatment-resistant cancers of the splicing and proliferative mechanics necessary for tumor growth and survival.

PRMT5 is overexpressed in several types of cancer, including solid and blood-based disease. Those with sensitive pathways include bladder cancer and triple-negative breast cancer, as well as lymphoma and myeloid malignancies.

Prelude’s lead inhibitor, PRT543, is in a phase 1 dose-escalation study enrolling patients with relapsed or refractory disease among multiple parallel arms. The company plans to expand its cohorts early next year after establishing safe dosing. 

What makes Prelude fierce: The company’s target is also connected to the oncogene MYC, a well-studied driver of drug resistance, says Prelude CEO Kris Vaddi, Ph.D.

“And it appears that MYC-driven splicing operations are fundamental in a number of cancers that are mediated through this particular enzyme, PRMT5,” Vaddi said. “So because those cancers are proliferating, you need to be able to make the protein very rapidly to support that growth. So if you inhibit it, you could impair your intake-dependent cancers that have that proliferative drive.”

PRMT5 also helps regulate JAK3, a tyrosine kinase enzyme in the same family as those targeted by Incyte’s $1 billion drug Jakafi (ruxolitinib)—an inhibitor Vaddi helped discover, develop and push to approval during his 12-year career with that company, culminating as group vice president, while the company grew from a few handfuls of employees to about 800. 

Now, he’s looking to do the same with Prelude, right down the street from Incyte’s home in Wilmington, Delaware.

RELATED: Prelude Therapeutics nabs $60M series B, gains biopharma veteran as CMO

“The vision of Prelude is not to bring up one or two compounds and license them out, or sell the company,” Vaddi says. “The vision of Prelude is to build a strong pipeline—molecules with a very high probability of success, that we design and create—and, based on our experience, advance them and ultimately commercialize them. I think Prelude is unique in the sense that our whole focus and expertise is about coming up with a solid molecule internally, where we actually have a significant number of our team members focused on internal discovery.”

And with the company’s $60 million series B round this past June, Prelude has plans to continue the growth it's seen over the past year, from about one dozen, to two dozen, to its current headcount of about 35.

That includes the company’s new chief medical officer, David Mauro, M.D., Ph.D., formerly of Bristol-Myers Squibb, Merck and Advaxis, who joins from the same role at Checkmate Pharmaceuticals.

“We certainly have plans to grow significantly over the course of the next 12 to 18 months, as our molecules enter the clinic and hopefully move to later stages of development,” Vaddi says.

Investors: OrbiMed Advisors

Prelude Therapeutics