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GenSpera enrolls brain cancer mid-stage trial with 'grenade' delivery
March 19, 2014

The weed Thapsia garganica, which provides the active ingredient thapsigargin for G-202--Courtesy of GenSpera.

By Michael Gibney, Fierce Drug Delivery

Texas cancer drug delivery specialist GenSpera is enrolling a new study for its molecular "grenade" candidate G-202. This time it's a Phase II for the treatment of the notoriously aggressive brain cancer glioblastoma.

The G-202 candidate in question is the same as one that garnered GenSpera positive results in a Phase I study ending in October last year. That trial aimed at solid tumors with a subset of patients with hepatocellular carcinoma, a type of liver cancer.

Along with a research team at the University of California in San Diego, GenSpera will conduct the new study in two stages in up to 34 patients with recurrent forms of glioblastoma who have already undergone at least one major treatment--surgery or radiation. The drug is designed to be delivered via intravenous infusion for about an hour over the course of three days.

As an endpoint, GenSpera is looking for patients to be progression-free at 6 months. Historically, GenSpera CEO Craig Dionne told FierceDrugDelivery, about 15% of glioblastoma patients are progression-free by this point, and GenSpera is aiming to boost that number to 30%.

G-202 has shown to be effective before. But there are many delivery challenges that come with getting drugs past the blood-brain barrier, and here's where GenSpera's drug could have an edge: it doesn't need to cross the barrier and its drugs work from within the blood vessels in the tumor.

Since G-202 is designed to act on the blood vessels inside a tumor, constricting them so as to starve the tumor, Dionne said, it doesn't come up against the same challenges as other drugs that need to cross the endothelial cells to get into the tumor's mainframe.

"Our approach to the blood-brain barrier," Dionne said, "is we don't need to worry about it."

Dionne compares G-202's release mechanism to a "grenade" complete with a "pin" that's pulled at a specific site in a tumor's blood vessel. G-202 is the first to take advantage of the enzymatic action of the prostate-specific membrane antigen, PSMA, that exists in abundance at tumors such as glioblastoma. The PSMA enzyme pulls off a peptide cap on the drug that delivers a hefty dose of the specifically deadly toxin 12ADT.

"If you look at glioblastoma, it is highly vascularized and makes a lot of PSMA, which is perfect for us," Dionne said. "The toxin is targeted with the antibody drug conjugate and, taking advantage of the enzymatic action, it delivers thousands of active molecules. The amplification is a huge part."

The toxin 12ADT is the final component of the uniquely designed drug. Its active ingredient, thapsigargin, is derived from a Mediterranean wild weed called Thapsia garganica, Dionne said, which works by disrupting a pump that regulates calcium levels in the blood vessel cells. The toxin is extremely potent, more so even than common cancer drugs such as doxorubicin, and kills independently of cell division rate, which means it can affect slow-growing tumors or even cancer stem cells that can linger after a tumor is mostly eradicated. According to Dionne, once the toxin is released, it is highly lipophilic and stays there in the tumor.

GenSpera's other Phase II trial for G-202 in hepatocellular carcinoma is also currently being enrolled, Dionne said, with 16 patients on board.

 

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