Benitec May Change HCV Paradigm Again With Single-Dose, DNA-Directed RNAi

The Australian biotech recently got FDA authorization to move its first (dd)RNA candidate, TT-034, into clinical development for hepatitis C. Dosing in a 14-patient, five-cohort, Phase I/IIa study will begin in mid-March and produce final data in about 18 months.

Both hepatitis C treatment and RNA-interference therapeutic development have claimed a lot of headlines in recent months, but in neither case has the story been completed. Australia’s Benitec Biopharma Ltd. believes it will have much to say in both of those areas as it moves its DNA-directed RNAi technology into its first clinical trial for HCV this month at Duke University and University of California, San Diego.

Although (dd)RNAi is different from the modalities being pursued by RNAi companies such as Alnylam Pharmaceuticals Inc. and Arrowhead Pharmaceuticals Inc., the approach is not especially new, dating back to research findings presented in 1997, explained Benitec Senior VP of Research and Development David Suhy in an interview.

The Phase I/IIa study of Benitec’s gene therapy approach in HCV will inform the progress of its preclinical (dd)RNA programs in hepatitis B and drug-resistant lung cancer.

It uses DNA plasmids to deliver long-lasting therapies inside a patient’s cells. In fact, what Suhy calls Benitec’s short hairpin RNA or shRNA therapeutics potentially could offer a single-dose cure for hepatitis C. Benitec’s technology links those DNA plasmids with viral vectors or other types of vectors, delivering a gene-therapy molecule to the patient’s cells that creates long-lasting production of a therapeutic within those cells.

“Once we get inside cells and the plasmid is there, typically with many vectors, especially the viral vectors, [our candidates] effectively can yield months if not years of production of shRNA,” Suhy said. “One typical example is TT-034, our lead compound which will be going into clinical development. We know from preclinical studies that a one-time injection in [test] animals resulted in at least six months of therapeutic expression of shRNA molecules, which essentially was the length of the experiment.”

So, even though Benitec is just entering the clinic with ‘034 while the next wave of HCV therapies offering better cure rates and safety profiles and reduced durations of therapy has arrived or will reach market shortly, Benitec still thinks plenty of opportunity exists for its candidate. The issue of patient compliance ensures that clinical trial response rates usually don’t get reproduced in real-world use, Suhy explained, meaning a single-administration cure could be of great interest not only to patients and clinicians, but to payers as well.

Benitec also hopes to bring (dd)RNA candidates for hepatitis B and drug-resistant lung cancer into the clinic in short order, and the study of ‘034 will provide a lot of useful guidance for advancing those two programs, Suhy said.

“The hepatitis B compound that we’re working on is essentially an identical delivery mechanism and vector [compared with ‘034],” he noted. “The only thing we’re switching out is the shRNA sequences.”

Niche Anticipated For Single-Dose HCV Therapy

Regarding the HCV program, Suhy added, “from a patient perspective and a payer perspective, $84,000 [the 12-week cost for Gilead Sciences Inc.’s recently approved Sovaldi] is a significant chunk of change. At the end of the day, it still will be an interferon-containing regimen for those who cannot afford it or whose insurance will not cover that benefit.”

While the previous game-changers in HCV, Vertex Pharmaceuticals Inc.’s Incivek (telaprevir) and Merck & Co. Inc.’s Victrelis (boceprevir), produced cure rates of roughly 75% in clinical trials, he added, a recent presentation at the 2013 American Association for the Study of Liver Disease meeting showed that the drugs produced cure rates closer to 60% in real-world practice.

“Those therapies are still dependent on patient compliance. Even with the treatment duration as short as eight or 12 weeks, you’ll still have patients who go on a drug holiday because they don’t feel well or go on vacation,” Suhy asserted. “We believe that by taking patient compliance out of the picture altogether, that’s a significant step forward, in addition to giving patients a more friendly therapeutic regimen of a one-shot infusion.”

While Benitec pioneered (dd)RNA, it actually in-licensed ‘034 from Tacere Therapeutics Inc. after that company’s previous partnership with Pfizer Inc. crumbled following the 2009 Pfizer/Wyeth merger [See Deal].

Pfizer had partnered with Tacere in 2008 and brought ‘034 into its portfolio in 2009, but after the Wyeth merger a portfolio review reduced the pharma’s focus on infectious disease [See Deal]. The review also resulted in the shuttering of an R&D facility that housed about 90% of Tacere’s personnel, Suhy said. “The program wasn’t returned to us for a lack of scientific merit, it just didn’t fit their portfolio at that point,” he said.

But because ‘034 started out at Pfizer, it benefits now from a wealth of preclinical development, done on big pharma scale, Suhy noted, rather than small biotech scale. The IND package submitted to FDA last December was approved in roughly one month, and the approval is for a Phase I/IIa protocol under which ‘034 will be investigated for both safety and efficacy.

Benitec has begun patient screening for a trial that will test ‘034 in 14 genotype 1, treatment-failure HCV patients, with six-month follow-up after dosing. As a biologic, there’s little point dosing ‘034 in healthy volunteers, which is why FDA approved a Phase I/IIa structure for the study. Suhy said the first two cohorts will produce safety data, after which the remaining cohorts will be studied for efficacy as well as safety.

“By cohort three, we anticipate that we should be in the sweet spot of therapeutic efficacy for this compound, so cohorts three, four and five are really aimed at looking not only at the safety of the concentrations of TT-034 administered but also of potential efficacy,” he explained. “So we will be looking at things like viral load. We will be taking a liver biopsy at day 21 to assess how well the drug has gotten into the liver hepatocytes as well as how shRNA is being expressed.”

Benitec used the FDA approval of its IND as a financing hook, announcing on Feb. 24 a $31.5 million private placement involving U.S. institutional investors RA Capital Management, Perceptive Advisors, Special Situations Funds and Sabby Management. The offering placed 29.4 million ordinary shares at AUD $1.07 per share. Benitec trades publicly on the Australian stock exchange but operates offices both at home and in the U.S.

“Up until recently we’ve been owned by retail and high-net-worth individuals in Australia,” Suhy said. “But the reason for the listing, in addition to raising capital to support the programs, was to get the U.S. institutional investors on board, which we feel is major validation not only for the technology but the company as a whole in terms of how we’ve been performing.”

“RNAi has come back into favor,” he added. “We saw Alnylam release clinical data recently and go from under $1 billion in market cap to over $5.2 billion,” he noted (Also see "Alnylam Validates Subcutaneous Delivery Technology With Strong Phase I Results" - Pink Sheet, 11 Jul, 2013.). “You see the IPO for Dicerna Pharmaceuticals Inc., you see Arrowhead now valued at $893 million and it’s all on the back of the clinical data. I think that the key driver for this stock and the key interest in the money raising … has really been the green light by FDA.”