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Gradalis Moves shRNA Drug into Clinic, Plans Follow-on Trial for Later in the Year

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By Doug Macron

Gradalis has joined the ranks of clinical-stage RNAi drug developers after recently initiating a phase I study of a cancer therapy that combines its bi-functional shRNA technology with an immune system stimulator, RNAi News has learned.

According to John Nemunaitis, Gradalis co-founder and executive director of the Mary Crowley Medical Research Center, the trial is expected to help lay the groundwork for a follow-on cancer therapy that will also incorporate the RNAi approach, and is expected to enter phase I testing around the third quarter.

Gradalis' bi-functional technology involves an shRNA capable of triggering both cleavage-dependent and cleavage-independent RISC-mediated inhibition of target mRNA.

Early last year, Nemunaitis told RNAi News that the company expected to begin testing in humans a drug that combines a bi-functional shRNA against stathmin-1, a protein linked to abnormal cell proliferation when mutated that is over-expressed in about 65 percent of all cancers, with an expression plasmid and a liposomal delivery vehicle (see RNAi News, 2/19/2009).

However, the company decided to hold off on that trial in order to test the bi-functional shRNA technology using a different delivery approach and a different target.

In December, Gradalis launched a phase I study examining an autologous vaccine that expresses the immunostimulator recombinant human granulocyte-macrophage colony-stimulating factor and a bi-functional shRNA against furin, an enzyme Nemunaitis said is responsible for lysing the components of the protein TGF-beta, which is involved in cellular proliferation and differentiation.

"The separate components of TGF-beta, the isomers … are important inhibitors of the immune system that the cancer cells produce to prevent the immune system from identifying and attacking" them, Nemunaitis explained.

Using a proprietary electroporation technique, autologous tumor cells are transfected with the bi-functional shRNAs, are irradiated, and then injected intradermally back into the cancer patient.

"That, in essence, sets up an immune response against that local site," he said. "In time, you generate an activated T cell population against the specific tumor antigens that were contained in the vaccine … [resulting in] a systemic response."

Thus far in that trial, which is not limited to any particular cancer type, Gradalis has harvested tumor cells from 18 patients and treated four with multiple doses, Nemunaitis said. "We're seeing very encouraging responses."

The study is expected to conclude in December.

At the same time, Gradalis is preparing to move ahead with its stathmin-1-targeting drug, having completed experiments examining the non-RNAi components in humans. The liposomal delivery agent, Nemunaitis noted, has "been successfully used in several studies," including a one-patient study evaluating a gene-replacement therapy for inclusion body myositis, a rare hereditary inflammatory muscle disease.

The expression plasmid, meanwhile, was shown in a phase I trial to safely express a GMCSF gene.

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With these data in hand, Gradalis has filed an investigational new drug application with US regulators for examining the stathmin-1 drug in melanoma patients. Nemunaitis said that the initial phase I trial, expected to begin within six months, will involve intratumoral delivery using the company's standard DOTAP-cholesterol liposome.

A second phase I is expected to follow, which will test whether the drug can be administered intravenously. After that, Gradalis expects to evaluate masking modifications it has developed for the liposomal vehicle that appear to keep it from being picked up by the liver, lungs, and heart, he noted. Gradalis is also working on targeting modifications that it expects will help carry the drug to the tumor.

"These are a series of … small studies to prove principle and safety, and to demonstrate the potency with respect to mechanism and level of knockdown," Nemunaitis said.

On Its Own

Since it was founded, Gradalis has intentionally kept a low profile, funding itself through private investments and, unlike virtually every other company in the RNAi space, choosing to avoid partnerships in favor of keeping things in-house.

Nemunaitis said this week that this strategy has not changed, and that it still does not need investments from big pharma or biotech allies.

In 2007, the company closed a $10 million Series A financing round. Nemunaitis said that that it is now poised to close an undisclosed Series B round.

As such "we've chosen to keep this technology our own; we're not seeking any partnerships," he added.

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