After becoming the first company to get an RNAi-based drug into the clinic, Acuity Pharmaceuticals said this week that it has initiated a phase II trial of Cand5, its siRNA therapy for age-related macular degeneration.
According to Acuity President and CEO Dale Pfost, the drug could enable "substantially" less-frequent administration with "substantially longer" duration of action, which could be significant: Long-term effect is widely seen as a key to giving any new AMD treatment an edge over other therapies given the stiff competition in the field and the unpleasantness associated with ocular injections.
The phase II study "is well underway," Pfost told RNAi News this week. "We initiated the phase II a few weeks back, and the enrollment is going very well."
The trial is enrolling AMD patients at 30 sites nationwide. Pfost declined to comment on the specific number of patients that are expected to be treated in the study, but said that "it's a normally sized phase II, and reflective of the number of sites we've got." According to the US Food and Drug Administration, phase II trials typically include several hundred patients.
The phase II study is primarily designed to measure the effect of Cand5 on visual acuity, Pfost said, "but the full basket of metrics we're looking for include all the things you'd expect in this indication, which is the size … and thickness of the [ocular] lesion." Lesion measurements, he noted, will be evaluated using fluorescein angiography and optical coherence tomography.
"If [the development and marketing of Cand5] is going to be pursued more … on our own, then we would be pursing financings to fund the phase III and the market launch. In … other case[s], we would be interacting exclusively with a single partner or even [become] part of another company."
Patients will receive one of three doses of Cand5, the highest being 3 mg, once every six weeks via intravitreal injection. "That will give us a baseline," Pfost said. "We actually believe that in a clinical setting our frequency of administration would be substantially less frequent … but that the duration of action would be substantially longer than that. The clinical trial design attempts to extract some of that duration of effect information."
The two existing FDA-approved AMD drugs - Novartis' and QLT Phototherapeutics' Visudyne, which is administered intravenously and then activated with a light on the eyes, and Pfizer and Eyetech's Macugen, which is injected directly into the eye - are dosed as often as once every three months and once every six weeks, respectively. Neither drug has been shown to improve vision.
Lucentis, a phase III AMD drug administered via intraocular injection that is being developed by Genentech and Novartis, has shown the ability to improve vision in clinical trials when dosed monthly.
Although Acuity's phase II trial is set to run two years "by mandate of the FDA … the portion where we're gaining the most information will extend over a period of three or four months following initial treatment of the patient," Pfost said. He added that Acuity expects to have the trial "fully enrolled such that we'd have data to present … by the middle part of '06."
Pfost said that Acuity is not planning additional phase II trials of Cand5 as an intravitreal injection for AMD, and that phase III work is expected to start in late 2006 or early 2007.
He noted, however, that Acuity does expect Cand5 to be back in early-stage clinical testing as early as the first part of next year when the company launches a phase I/II study in diabetic macular edema. "That's a trial we're very excited about because it is thought that VEGF, [which is targeted by Cand5,] plays a central role in the progression of the disease in [diabetes] patients," Pfost said.
Additionally, Acuity is planning on developing a topical formulation of Cand5 using technology licensed from Intradigm (see RNAi News, 6/10/2005), although the company has not provided a timeline on this program.
Acuity also this week released data from its phase I trial of Cand5. Data were presented at this year's American Academy of Ophthalmology meeting in Chicago.
According to the company, data from the 15-patient, open-label trial indicate that Cand5 is safe and well-tolerated when administered once every six weeks via intravitreal injection at doses up to 3 mg. The most commonly reported adverse events were procedure-related and included subconjunctival hemorrhage, ocular pain, and vitreous floaters, the company said.
No patients withdrew from the study due to adverse events, and pharmacokinetic analyses indicated that the drug was not present in the plasma of any of the patients at any dose tested, Acuity added.
In terms of efficacy, Pfost stressed that the phase I "trial was designed to gain an understanding of the tolerance of the drug," and that none of the Cand5 presentations included statements regarding the efficacy of the drug.
"We wanted to very much have our phase I clinical trial [provide] an understanding of the safety profile [of Cand5], and then move into phase II where … it's been designed to see a biological effect of importance," he said. "With that in mind, we decided both intellectually and emotionally over a year ago … that we wouldn't be drawn on that subject - and our clinical investigators, I might add, are completely supportive of that and believe that it's probably ill-advised to try reading the tea leaves where [they're] not intended to be read."
Acuity's attitude on this subject stands in sharp contrast to that of its AMD rival Sirna Therapeutics, which moved its RNAi-based AMD drug, Sirna-027, into phase I testing shortly after Acuity.
Since presenting initial phase I data on Sirna-027 at the Association for Research in Vision and Ophthalmology annual meeting earlier this year (see RNAi News, 5/6/2005), the company has continuously made mention that its drug appears to have a positive effect on visual acuity.
At the ARVO meeting, Sirna President and CEO Howard Robin commented to RNAi News that while the phase I data was preliminary, the drug's apparent effect on vision was encouraging.
Then, earlier this month at the UBS Global Life Sciences conference in New York, Robin directly compared the phase I efficacy data on Sirna-027 to comparable data for Lucentis, stating that 100 percent of the patients in the phase I study of Sirna-027 experienced a stabilization of improvement in visual acuity versus the 89 percent improvement seen with patients receiving Lucentis in phase I trials (see RNAi News, 10/7/2005).
This week, Sirna also announced that it presented additional phase I data at the AAO meeting showing that its drug "continues to demonstrate … [that it is] safe and well-tolerated with 100 percent of patients showing visual acuity stabilization and 23 percent of those patients experiencing clinically significant improvement in visual acuity after eight weeks from a single injection. A reduction in central foveal thickness was observed by OCT in the majority of patients," Sirna added.
Pfost said that although visual acuity data on Cand5 was presented at the AAO meeting, it was done so to demonstrate that it is "consistent with a safe drug.
"The only way to really understand [how] effective a drug is is with a clinical trial designed to" determine that, he added. "It's almost intellectually, and from a technical viewpoint inappropriate, to try to do more than that."
With the phase I data under its belt and the phase II trial underway, Acuity is now actively initiating partnership discussions with "a variety of potential partners," including pharmaceutical companies with ophthalmic programs, Pfost said.
The company is, however, still considering the possibility of taking Cand5 all the way through clinical development and commercialization on its own, he added.
"We are very flexible, and over the course of the next several months would be expecting to be exploring all [the] options," Pfost said. "If [the drug's development and marketing] is going to be pursued more … on our own, then we would be pursing financings to fund the phase III and the market launch. In … other case[s], we would be interacting exclusively with a single partner or even [become] part of another company."
Pfost said that he anticipates Acuity will have settled on a development and marketing strategy by the end of 2006.
— Doug Macron ([email protected])