RNA therapeutics veteran Art Krieg is back. A year after he was abruptly let go by Sarepta Therapeutics (NASDAQ: SRPT) amidst a reported boardroom scuffle, Krieg has resurfaced as the CEO of a Cambridge, MA-based startup called Checkmate Pharmaceuticals. The firm is emerging from stealth today with a $20 million round of financing.
Checkmate isn’t starting from scratch. It has grabbed part of a failed Swiss firm, Cytos Technology, to jumpstart development of drugs that stimulate a cancer patient’s immune system to fight the disease. The plan is to apply Krieg’s expertise with oligonucleotide drugs, which can interrupt cellular mechanisms involved in gene expression, to the hot and crowded field of cancer immunotherapy.
Specifically, Checkmate has taken rights to Cytos’s “virus-like particles,” which look like viruses and are supposed to trick the immune system into responding. Checkmate will pair these particles with oligonucleotide drugs as a one-two punch to rev up the immune system, according to Krieg (pictured above).
Why Cytos? It turns out that one of Checkmate’s two main investors was also a lead investor in Cytos. In 2012, venBio led an attempt to recapitalize and turn around the fortunes of then-struggling Cytos. It did not go well. After a key trial failure in asthma in 2014, Cytos decided to wind down operations.
Sofinnova Ventures is joining venBio in Checkmate’s Series A round.
Checkmate will redevelop Cytos’s asthma drug, CYT-003, as a cancer treatment. Cytos tested CYT-003 in hundreds of asthma patients, and though it failed to effectively treat the disease, it appeared safe and can quickly move into clinical trials for cancer patients, Krieg says.
So what makes Checkmate believe that a drug that once failed a trial can not only become a valuable cancer immunotherapy tool, but stand out in a competitive field?
Krieg contends that the drug stimulates a target—known as toll-like receptor 9 (TLR9)— that drives “a stronger killer T cell response” than many of the other companies in the cancer immunotherapy scrum.
Here’s the rationale: Antibody drugs called “checkpoint inhibitors,” which remove a brake that stops T cells from destroying tumors, have shown remarkable results treating patients with skin, lung, and recently other cancers. But they work for only a fraction of patients; Krieg estimates between 15 to 20 percent. That limited effectiveness has led to a rush of companies scouring for drugs to pair with checkpoint inhibitors and boost their power.
Some companies have tried drugs that target parts of the innate immune system—the body’s first line of defense—as opposed to the adaptive immune system, which churns out antibodies like T cells that can remember foreign invaders and destroy them. TLR9 is part of a class of molecules in the innate immune system that, when amped up, can recruit T cells to attack a pathogen.
By combining a TLR9 stimulator with a checkpoint inhibitor, the idea is that T cells would be unleashed when they wouldn’t have been otherwise.
Others are already trying this approach. Dynavax Technologies (NASDAQ: DVAX) and Idera Pharmaceuticals (NASDAQ: IDRA) both have TLR9-activating drugs. Dyanavax is combining its candidate with a checkpoint inhibitor from Merck, and Idera has teamed up with The University of Texas MD Anderson Cancer Center.
Krieg says that CYT-003 is structurally different and as a result does a better job of stimulating a signaling protein called interferon alpha, “a critical signal to get the strongest T cell responses.”
“That makes us believe that we should have stronger responses in the clinic,” he says.
Checkmate could begin its first trial this year, in skin cancer patients who are candidates for checkpoint inhibitors. It also has the cash to run two additional studies in different cancer types, Krieg says.
Krieg co-founded oligonucleotide drug developer Coley Pharmaceutical Group in 1997, which was bought by Pfizer in 2008. He then became CSO of Pfizer’s oliogonucleotide therapeutics unit for the next three years, working under Corey Goodman, now a venBio partner and a member of Checkmate’s board of directors.
He then served as the CEO of another Cambridge RNA drug startup, RaNA Therapeutics, from 2011 to 2013 before taking over as the CSO of Sarepta in January 2014. Krieg was abruptly fired six months later. Though Sarepta never explained the reasons for the decision, several reports indicated he clashed with then-Sarepta CEO Chris Garabedian about the direction of the company. (Garabedian resigned 10 months later.)
Krieg wouldn’t speak to the reports of his dismissal directly. “I really have decided I’m just going to look forward,” he says. After everything went down, he went backpacking in the Appalachian Trail and later Wyoming to clear his head and decide what to do next, and he says he’s visited friends and colleagues at Sarepta several times over the past few months.
“I really have very positive feelings for a great majority of the people there,” Krieg says.