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G1, Out to Shield Body From Chemo, Heads to First Clinical Test

Xconomy Raleigh-Durham — 

Chemotherapy is like nuking the body with chemicals. It kills good and bad cells alike, which is why cancer patients undergoing treatment get fatigued and suffer through a whole host of side effects. A little startup built around research at the University of North Carolina called G1 Therapeutics thinks it’s got an answer to some of those ailments—a molecular shield, of sorts, that could help protect the body from the damage. Now it just has to amass the clinical data to prove it.

Sometime within the next few months, Chapel Hill, NC-based G1 will begin its first clinical trial for what’s called G1T28-1, a compound meant to help thwart some of the toxic effects of chemotherapy, like depletion of healthy red or white blood cells. It’ll mark the first clinical step in an ambitious journey for G1, a tiny, 10-person startup trying to make its drug candidate a mainstay in a slew of chemotherapy regimens. If G1 has its way, it’ll unseat big-selling biologic drugs like Amgen’s (NASDAQ: AMGN) darbepoetin alfa (Aranesp), which, despite safety issues that have reduced their use, are still administered to patients with chemotherapy-induced anemia.

Mark Velleca, CEO of G1 Therapeutics

Mark Velleca, CEO of G1 Therapeutics

“We would posit that this could potentially be standard of care for any patient getting chemo,” says CEO Mark Velleca, who began running G1 in May.

Of course, there’s a long road ahead before G1 can claim that’s a real possibility—G1T28-1 has got to deliver the goods in the clinic, beginning with that first study later this year.

G1 was formed around the work of Norman Sharpless, the associate director for translational research at UNC’s Lineberger Comprehensive Cancer Center; and Kwok-Kin Wong, an oncologist and researcher at Dana-Farber and Harvard. The two worked for years researching the steps cancer cells take to grow and divide, before homing in on two particular enzymes, cyclin-dependent kinases 4 and 6 (CDK4/6), that they thought to be important players in the process—particularly when it comes to cells in the bone marrow.

CDK4/6 are well-known targets. One of New York-based Pfizer’s (NYSE: PFE) most highly touted cancer drug prospects, palbociclib, binds to them, as do compounds from Eli Lilly (abemaciclib) and Novartis (LEE011). The enzymes have become hot targets for cancer drugs because, in some cases—like in estrogen-receptor positive breast cancer, for example—tumors depend on them to grow. Blocking the kinases, the reasoning goes, helps shrink such tumors.

Sharpless and Wong, however, thought to use CDK4/6 in a completely different way—to protect healthy cells from the toxic effects of chemotherapy and radiation. Chemo drugs and radiation work by killing cells that are in the process of dividing. Since cancer cells tend to divide more rapidly than healthy cells, they are preferentially affected by the treatments, but there is always some collateral damage to the normally dividing cells in the bone marrow, gut, and elsewhere. Sharpless and Wong theorized that if a drug could pause cell division in those healthy cells during cancer treatment, it would shield them—and therefore spare the patient from a host of side effects.

To do this, their idea was to administer a drug that could bind to CDK4/6—which turn out to be critical switches that allow cell division to proceed in bone marrow cells—just before chemotherapy or radiation is administered, to pause the normal cells’ division briefly. G1T28-1, for instance is designed to stick around “as long as the chemo is on board,” then “wash out,” Velleca says. In theory, this would prevent damage to the bone marrow during treatment and allow the body to resume production of healthy cells more quickly after a chemotherapy blast than it otherwise would.

The two scientists formed G1 (named after the phase of the cell cycle in which they’re aiming to pause healthy cells) in late 2012, and advanced the company with the help of around $5 million in government funding from various local sources like the Small Business Innovation Research program, UNC’s University Cancer Research Fund, the Carolina Kickstart Program, and the North Carolina Biotechnology Center. The company then got its big funding break in October, when MedImmune Ventures, the VC arm of AstraZeneca, led a $12.5 million round Series A round, with help from Hatteras Venture Partners and Mountain Group Capital. G1 has since hired a full management team, led by Velleca, and including chief medical officer Raj Malik (formerly of Agennix), chief business officer Greg Mossinghoff (a veteran of Inspire Pharmaceuticals), and chief scientific officer Jay Strum (an ex-GlaxoSmithKline executive).

The big hook here is that by taking G1T28-1 with chemo, cancer patients could theoretically avoid the side effects that come from damage to the bone marrow. These include anemia, neutropenia, and thrombocytopenia—dangerous reductions in red blood cells, white blood cells, and platelets, respectively, that leave patients weak and vulnerable to infection and bleeding. Chemo-induced anemia can be treated with recombinant forms of erythropoietin, which signals to the bone marrow to make more blood cells, but it’s not used nearly as much as it used to be because of safety hazards. So-called granulocyte colony-stimulating factors like Amgen’s Neupogen and Neulasta are widely used to treat neutropenia, but Velleca contends that those types of treatments become less and less effective after the bone marrow gets exhausted by multiple rounds of chemo. Velleca contends, meanwhile, that G1’s drug has the potential to eliminate the need for such drugs.

“That is clearly the market we’re going after,” he says.

Velleca says that potential market could be big, and would include patients taking chemotherapy for tumors like small cell lung cancer or triple-negative breast cancer that don’t need CDK4/6 to grow. G1’s approach wouldn’t be appropriate for cancers that depend on CDK4/6, of course, because then it would shield the tumor cells along with the healthy ones, but Velleca says that the majority of cancers do not rely on CDK4/6.

Still, this is all early, speculative talk so far. G1 is only has animal data to support its claims right now, and so really doesn’t know what type of effects, good or bad, G1T28-1 is going to cause when it’s put in humans. As Velleca concedes, there’s always a risk when a new drug candidate is administered to people for the first time.

G1 will get a glimpse of the drug’s prospects when it begins its first trial in healthy volunteers during the third quarter. Velleca expects the company to announce its first data early next year. But it’ll see what G1T28-1 is really made of afterwards—likely in the second quarter of 2015—when the company expects to begin testing the drug in real cancer patients. Meanwhile, if all goes well, G1 hopes to close a Series B round next year, according to Velleca.

“I think we’ll know very quickly when we’re in cancer patients next year whether the drug is doing what it’s supposed to do, as far as protecting the marrow,” he says.