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Gradalis Pushes Back shRNA Rx Trial to Evaluate Delivery, Expression Tech

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Although it had expected to begin phase I testing of its lead expressed RNAi cancer drug last month, Gradalis pushed back the clinical trial in order to test the non-RNAi components of the therapy separately in humans first, a company official told RNAi News this week.

Gradalis now plans to file an investigational new drug application for the treatment later this year, and expects the added work that delayed the phase I trial will have laid the groundwork for more rapidly moving follow-on drugs into clinical studies.

Gradalis' RNAi drug comprises three components: a novel bi-functional shRNA that triggers both cleavage-dependent and cleavage-independent RISC-mediated inhibition of target mRNA, an expression plasmid, and a liposomal delivery vehicle.

While the drug was on track to enter phase I testing earlier this year, the company decided to first put together a data package "that gives confidence in [the safety of the] components of the overall product," John Nemunaitis, co-founder of Dallas-based Gradalis and executive director of the Mary Crowley Medical Research Center, said.

To do so, the company began a clinical trial of a gene-based cancer vaccine that uses the same expression vector as the RNAi therapy. Thus far in this program, which is being conducted in collaboration with Champions Biotechnology (see RNAi News, 2/5/2009), 15 patients have been treated and have exhibited no adverse events, Nemunaitis said.

"With that [drug] in the clinic and … showing safety, we've been able to generate [data indicating] that the vector delivering those genes is safe," he said. "The next thing we did is move forward in the clinic to validate the delivery vehicle."

That vehicle, a DOTAP-cholesterol liposome developed at the National Institutes of Health, was used with a gene-replacement therapy for hereditary inclusion body myositis, a rare inflammatory muscle disease, in a one-patient study, Nemunaitis said.

"That patient successfully has improved muscle function in the muscle into which we've injected," he noted. Now, with encouraging safety data for the plasmid and delivery vehicle, "two components of the [therapy] are now in place."

The last piece is the bi-functional shRNA, which is designed to inhibit expression of Stathmin-1, a protein involved in microtubule formation that has been linked to abnormal cell proliferation when mutated and is over-expressed in about 65 percent of all cancers.

Gradalis' primary focus is to develop personalized cancer treatments by analyzing tumor samples from individual cancer patients for cancer-relevant molecular targets. In mid-2007, Nemunaitis and colleagues published a paper describing their target-identification process.

Last year, at the American Society for Gene Therapy's annual meeting, Nemunaitis presented data showing how his team from Mary Crowley used tissue samples from about 150 patients with various solid tumors to identify Stathmin-1 as a promising therapeutic target (see RNAi News, 6/12/2008).

During that presentation, he said that in vitro testing showed the shRNA construct was able to knock down Stathmin-1 levels by 90 percent to 98 percent in a variety of tumor cells. This week, he said that Gradalis has since "been able to generate [in animal models] the knockdown effect of Stathmin-1 mRNA and show the mature shRNA that is produced" from the plasmid, with or without the liposomal delivery vehicle.

Gradalis is preparing the data for peer review and plans to present them at the annual ASGT meeting in late May, he added.

Having generated promising animal data on the shRNA construct, Gradalis is now preparing to move the Stathmin-1-targeting drug into formal animal toxicology studies, which will likely take "several months," Nemunaitis said. An investigational new drug application is expected to be filed with the US Food and Drug Administration in the second half of the year.

He noted that although Gradalis plans to test it as an intratumoral injection in the initial phase I trial, the firm envisions that the final version of the drug will be systemically delivered.

'Gain Confidence'

Even though the studies involving the expression plasmid and delivery vehicle put Gradalis behind schedule with its RNAi drug, Nemunaitis said that he expects the added effort to pay off later when the company seeks regulatory clearance to test follow-on therapies.

Having identified three other cancer targets, "our strategy is to gain confidence with the vector and delivery vehicle so that if the initial prototype product is safe … the FDA could potentially consider rapid movement forward with [other bi-functional shRNA drugs] to targets that are relevant to specific patients," he explained.

And Gradalis, it appears, is financially positioned to take its time with its drug-development efforts. In 2007, the company raised $10 million in a Series A round of financing and has since raised additional undisclosed cash, giving it enough cash reserves to continue operations for three years, according to Nemunaitis.

As a result, "we're well-positioned to move [the expressed RNAi therapy] to phase I without any partnership," he added.

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