Acuity Pharmaceuticals released this week the details of a study examining Cand5, its age-related macular degeneration RNAi drug, in non-human primates, a move made concurrently with the publication of the preclinical data in the journal Retina.
The release of the primate data — which follows the publication of a key US patent application earlier this month (see RNAi News, 2/6/2004) and a recent meeting with the US Food and Drug Administration — marks the achievement of the final milestone driving the company’s ongoing Series B financing round. (See RNAi News, 11/14/2003).
“The data that was announced today is really quite important because it’s not only the first demonstration of RNA interference in a large model system,” Acuity CEO Dale Pfost told RNAi News, “but it’s also … a rigorous [AMD] study with the most promising results, at a comparable [development] stage, of any compound that’s come before it.”
According to the Retina paper, eight adult cynomolgus monkeys (or long-tailed macaques, Macaca fascicularis) received laser injuries to the Bruch’s membranein their eyes to induce choroidal neovascularization. The monkeys then received via intravitreal injection either the Cand5 delivery vehicle alone or the vehicle along with one of three doses of the siRNA drug (70 micrograms, 150 micrograms, or 350 micrograms).
Cand5 is designed to stop the production of vascular endothelial growth factor, a well-established target for AMD therapies.
For the next 36 days, the monkeys’ eyes were monitored weekly by ophthalmic examination, color photography, and fluorescein angiography, the paper’s authors wrote. Electroretinograms were measured at baseline and at 5 weeks after laser treatment. CNV on fluorescein angiograms, they added, were measured for area and graded for clinically significant leakage in a randomized and double-masked fashion on days 15, 22, 29, and 36.
No inflammation, cataract formation, retinal detachment, or vitreous hemorrhage was observed in any of the animals at any point of the study, according to the paper. Additionally, there was no significant change in electroretinograms between baseline and the post-injection time point.
Efficacy analysis showed that all three doses of Cand5 inhibited growth of neovascular area versus growth in control animals. The highest dose of the drug demonstrated a greater effect on decreasing new blood vessel growth, the paper’s authors noted, but this difference was not statistically significant.
Overall, the area of CNV was reduced by more than 50 percent of the normalized control area when Cand5 was administered following laser injury. The area of neovascularization remained lower in the Cand5-treated eyes compared with control throughout the 36-day follow-up period.
Cand5 treatment also appeared to inhibit vascular leakage: An eye that received just the delivery vehicle demonstrated a large confluent bridging lesion and extensive late leakage on day 36. “By contrast, an eye treated with 350 [micrograms] of Cand5 demonstrated an imperceptible increase in size to the laser lesion and no late leakage of any of the laser spots,” according to the Retina paper.
On day 15, the authors also noted, as much as 70 percent of spots with active leakage were found in the control eyes. This compares to 27 percent, 6 percent, and 4 percent of spots in eyes treated with the lowest, middle, and highest doses of Cand5, respectively.
The paper was authored by researchers from Scheie Eye Institute at the University of Pennsylvania and Acuity. Among the UPenn researchers was Michael Tolentino, assistant professor of ophthalmology at Scheie and Acuity co-founder.
A key finding of the study, according to both Pfost and the paper’s authors, is Cand5’s duration of action.
“A single injection of our high dose suppressed leakage throughout the follow-up period, indicating that the duration of action on vascular permeability with one injection of Cand5 is five weeks, especially at our higher dose,” the authors wrote in Retina. “In contrast to protein [antagonists under clinical investigation for AMD], the prevention of VEGF production could potentially translate into a much longer interval between administrations.”
“A lot of specialists … see the need for a long-term treatment of [AMD],” Pfost said. “There’re other compounds that are in clinical testing, but when it comes to duration of effect and degrees of efficacy both in leakage and ceasing choroidal neovascularization, we think we’re the top.”
Pfost said that Acuity has met with US regulators to discuss the company’s pre-investigational new drug application activities, but declined to comment specifically on the meetings other than to state that “we are on track, and all of our interactions [with the FDA] have been very encouraging.”
He said that Acuity expects to meet its previously announced goal of filing an IND for Cand5 in the second half of this year, with a phase I trial beginning before year end. Pfost added that additional preclinical tests needed for the IND, namely ADMET (absorption, distribution, metabolism, excretion, and toxicology) experiments, are currently underway.
Pfost also said that a deal has been made with a manufacturer for Cand5, and that some product for clinical testing has already been made. He declined to break out the nature of the manufacturing arrangement, although he noted that the deal would bring Acuity through phase I studies.
Pfost also declined to name the manufacturer, beyond stating that it is a company “well-geared toward the regulatory rigor and manufacturing specification necessary to produce oligo-based drugs. We have a variety of relationships with a variety of such companies and … in fact may form one or more relationships of a long-term nature” with another company down the road, he added.
As for the financing, Pfost said that he was in New York City meeting with members of the financial community about raising money under the company’s Series B financing round. While he told RNAi News in November that Acuity might raise in excess of $10 million, he said this week that $10 million “is a good number, but it could be more than that by about $5 million or it could be less than that by $5 million.”
He said that the final result of the financing round would depend on market conditions, adding that a recent spate of IPOs indicates that conditions might be favorable for an early-stage company looking to raise capital.
“We’ve had ongoing discussions with folks, and people are very encouraged by our progress,” Pfost said. “They have now known us for, in some cases, almost a year, and seen the great progress the company has made.”
When asked if Acuity had gotten any commitments from investors, he said the company’s “getting very close.”