Quark Pharmaceuticals this week announced that it has begun dosing patients in a phase I trial of AKLi-5, an siRNA-based treatment for acute renal failure, marking what the company said is the first time a systemic RNAi-based drug has been administered to humans (see sidebar below).
The move “signifies a very important step in Quark's clinical program and marks an important milestone in the RNAi industry,” Quark CEO Daniel Zurr said in a statement. “While the science of RNAi has been well-established, a key step in the acceptance of the technology as a promising therapeutic is the ability to deliver RNAi-based compounds systemically.
“We look forward to leading this important advance for the industry,” he added.
The initiation of the phase I study also marks a key milestone in Quark’s plan to go public after withdrawing an earlier initial public offering bid amid difficult market conditions (see RNAi News, 8/2/2007).
Although Zurr had told RNAi News this summer that Quark intended to re-file an IPO prospectus with the US Securities and Exchange Commission as early as the first half of 2008, the company has pushed the timing of the offering back indefinitely as it awaits an improvement in the financial markets and positive data from two of its clinical drug candidates.
“We are keeping an open mind about the timing of the next filing because the market is so choppy and unpredictable right now,” Gavin Samuels, Quark’s senior vice president of business development, told RNAi News this week.
Further, since Quark has already begun clinical testing of both AKLi-5 and the wet age-related macular degeneration drug RTP801i-14, which was licensed to Pfizer last year (see RNAi News, 9/28/2006), the company feels that it may be better off waiting to re-approach the public market until it has “solid clinical data,” he added.
“We haven’t made any definite decision” on the timing of a new IPO bid, Samuels said. “We’re in the process of raising a [$30 million] round of financing right now that will give us the luxury of a year to make that decision.”
In the end, “market [conditions], together with the [clinical] data that’s evolving, will ultimately determine the optimal time to go back to the public market.”
AKIi-5, which Quark licensed from Silence Therapeutics, is designed to temporarily inhibit the expression of the transcription factor human p53, which is associated with DNA repair and apoptosis. According to Quark, this strategy in acute settings such as acute kidney injury is expected to delay apoptosis and thereby allow “natural repair mechanisms to restore normal DNA and cellular integrity.”
The phase I trial is a multi-center, placebo-controlled study evaluating single intravenous doses of AKIi-5 ranging from .5 mg/kg to 10 mg/kg in patients undergoing major cardiovascular surgery.
Although the study is expected to evaluate 16 patients, up to 32 patients may be enrolled should any safety or efficacy issues require further examination, Samuels noted.
“We haven’t made any definite decision [on the timing of a new IPO bid]. We’re in the process of raising a [$30 million] round of financing right now that will give us the luxury of a year to make that decision.”
As with all phase I studies, the AKIi-5 trial is primarily looking at the drug’s safety. However, preclinical data suggests that some efficacy may be observed, although the likelihood of achieving this is low.
“The problem is that we’re not looking at very high-risk patients in the phase I trial, so their risk for developing acute kidney injury is not very high anyway,” Samuels explained. “And, with only 16 patients … it would be tough to show an efficacy result. We may get a trend, but [the study] is not powered for it.”
The phase I trial is expected to conclude as early next year since it only requires post-operative follow-up for 30 days.
“If you haven’t developed kidney injury by then, you’re not going to,” Samuels said. “So we expect to complete the trial by the end of the first quarter and initiate a phase II … at the beginning of the third quarter or the end of the second quarter.”
The phase II study will evaluate AKIi-5’s efficacy in around 200 patients at high risk for acute kidney injury following cardiac surgery, he said.
Around the same time, Quark expects to be ready to begin clinical testing of AHLi-11, an siRNA drug being developed for acute hearing loss associated with acoustic trauma or ototoxic drugs such as aminoglycoside antibiotics.
“We’re finishing off the last two experiments needed to finalize the [investigational new drug application] package [for AHLi-11 and] hope to get that in [to the US Food and Drug Administration] in the first quarter,” Samuels said.
‘Natural Delivery’ Enables Quark to Win Systemic RNAi Race to the Clinic
The race to be the first to test a systemic RNAi drug in humans had been a close one. Although Quark hit the milestone first, hot on its heels is Nucleonics with its expressed RNAi treatment for hepatitis B.
Although Nucleonics began enrolling patients for a phase I study of its drug, called NucB 1000, around the same time as Quark began recruiting patients for its AKIi-5 trial, as of this week the expressed RNAi company has not yet dosed any patients, Nucleonics President and CEO Robert Towarnicki confirmed.
He told RNAi News that the company is in the process of screening five would-be trial participants, but has not yet administered NucB 1000 to any of them.
In the end, the basic technology behind the two drugs may have been the deciding factor.
According to Gavin Samuels, Quark’s senior vice president of business development, AKIi-5 does not use any specific delivery technology since the drug is naturally carried to its target — the kidneys — by the body.
“We don’t need any special formulation or delivery device,” he said. “We rely on the siRNA moving through the bloodstream, [being] rapidly cleared through the kidneys, and being taken up in the proximal tubular cells. All that’s required is modification of the [oligo’s] backbone to protect the siRNA in the plasma.”
NucB 1000, on the other hand, is plasmid DNA encoding four short hairpin RNA molecules, each under the control of an RNA polymerase III promoter that targets a different portion of the hepatitis B genome.
As reported by RNAi News, Nucleonics had experienced some difficulty early on with optimizing the drug’s formulation for intravenous delivery, which derailed the company’s plans to get NucB 1000 into phase I by the end of 2005 (see RNAi News, 11/30/2006).