With an investigational new drug application ready for submission to US regulators, Australian firm Benitec Biopharma anticipates launching a phase I/IIa study of its hepatitis C treatment TT-034 before the end of the year, the company's chief executive said this week.
Meanwhile, Benitec is also laying the groundwork for a follow-on phase IIb trial of the drug and preparing for the possibility that it will run the trial on its own by drumming up interest in the company among those in the investment community, CEO Peter French told Gene Silencing News.
TT-034 expresses shRNAs targeting three portions of the HCV genome. It was originally developed by Benitec, but financial problems led the company to license the agent to startup Tacere Therapeutics in 2006.
Tacere later encountered difficulties of its own, most notably the loss of Pfizer in 2011 as a partner on TT-034, and a revitalized Benitec bought the company and its HCV program late last year for about $1.5 million in stock.
Having received the green light for TT-034 from the National Institutes of Health’s Recombinant DNA Advisory Committee this summer, Benitec is now poised to launch its first clinical trial. But the company must clear one more hurdle before doing so — a 30-day waiting period following the submission of an IND during which time the US Food and Drug Administration may raise questions about a drug candidate.
According to French, Benitec took great care to ensure that its IND is robust, but since its planned clinical trial would represent the first time its expressed RNAi technology has been used systemically in humans, he believes that the FDA may ask for additional safety information.
As an expressed RNAi compound, once TT-034 is administered, it lasts for the lifetime of the liver cell to which it is delivered. "That's both its strength and its potential weakness," French said.
As such, safety is "the main issue we anticipate the FDA to be looking at," he noted. And while Benitec has provided "extensive documentation" on this issue in its IND, "I would be surprised, with a 15,000-page document, if the FDA didn't come back with some clarification questions."
Even with requests for added comment from the FDA, Benitec has "a high level of confidence" that its submission will be approved based on the two pre-IND meetings it had with the regulatory agency and the unanimous vote of the NIH's RAC, Benitec Chairman Peter Francis said in a letter to shareholders last week.
"We expect that the process of addressing the FDA's questions will likely mean that the trial will be able to start early in the New Year," Francis added.
The phase I/IIa trial, which is being run at two sites in the US by a contract research organization, is designed to enroll 14 HCV patients who have failed the current standard of care.
The first patient will receive a subtherapeutic intravenous dose of TT-034 and be followed for six weeks. Should they experience no adverse effects, a second patient will undertake a similar treatment and monitoring regimen. Three additional cohorts of three patients each will then receive increasingly higher doses of the drug after safety has been established in the previous cohort.
In addition to safety, the study will also evaluate TT-034's effect on viral load, the presence of viral escape mutations, as well as vector DNA and shRNA levels in the liver and blood. French said that safety data should start coming out around three months after the trial starts, with efficacy readouts available by mid-2014.
Should those initial data prove positive, he said, Benitec would then begin ramping up for a phase IIb study in earnest. And while it would consider partnering TT-034 prior to beginning that larger trial, French said that the company is making sure that it is equipped to doing so without an ally.
"We have to be in a position to move quickly into a phase IIb trial in [hepatitis] C," which would require, among other things, scaled-up manufacturing for TT-034 to have enough drug for testing, he said.
To make sure the company has access to the money needed for this effort, French has been in the US for the past few weeks, pitching Benitec and its technology to potential investors and financial analysts.
The exact amount of funding the company will seek has yet to be determined. However, French noted that the phase I/IIa trial will cost roughly $6 million, and it's likely that a larger phase IIb study would require more than this to run.
Also requiring funding is Benitec's second pipeline program in non-small cell lung cancer, which recently yielded data showing that the company’s expressed RNAi constructs targeting the beta III tubulin gene could boost survival in an orthotopic mouse model of the disease.
French said that the company has reached out to the FDA about designing toxicology studies for its lung cancer drug candidate, dubbed Tribetarna, and that it is waiting to hear back. He noted that although this compound uses a non-viral vector that has already been tested in a clinical trial with an unrelated therapeutic, it has never been used in man to delivery an shRNA against an endogenous human gene.
"Once we've gotten guidance from the FDA, we'll go to a CRO with the appropriate model … and we will commence those studies," French said. "I'm hoping we could … have an IND put together by late-2014."