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RXi Releases Blinded Phase I Data Hinting at Efficacy of Anti-Scarring Drug, On Track for Phase II

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RXi Pharmaceuticals has completed patient dosing in the second of two phase I trials of its lead drug candidate, the anti-scarring agent RXI-109, and is on track to initiating a phase II study before the end of the year, the company's top executive said last week.

Speaking at this year's Biotechnology Industry Organization's BIO-CEO event, RXi President and CEO Geert Cauwenbergh also disclosed limited phase I data on RXI-109 that, while still blinded, offer hints of efficacy.

RXI-109 comprises siRNAs designed to inhibit connective tissue growth factor, of CTGF, a protein linked to wound healing and other fibrotic processes. It employs the company's proprietary self-delivering technology, which comprises a number of undisclosed chemical modifications that enable cellular uptake without the need for a delivery vehicle.

Last summer, RXi initiated a phase I study of single, ascending doses of the drug in patients slated to undergo elective abdominoplasty. Patients received four abdominal incisions, two of which were treated with injections of RXI-109 at the incision sites and two of which received placebo.

In December, the company began a second phase I trial in healthy volunteers, this time testing three doses of RXI-109. Patients received eight surgical incisions, half of which received the drug and half of which received placebo.

During BIO-CEO, Cauwenbergh said that the last patient in the second study was treated last week, and that unblinded data from the two trials is expected to be available in the second quarter of the year. In the interim, however, he offered a look at preliminary blinded data, which showed differences between the sets of incisions.

In a patient who received 7.5 mg doses of RXI-109 in the single-dose study, histology data revealed one set of incisions with a larger “scar tissue component” beneath the epidermis compared with the other set.

Given that each incision received only one injection, the potential effects of RXI-109 are expected to be great, Cauwenbergh noted. “Having said that, I can see a difference in the clinical pictures,” with one set of scars showing improved healing versus the other, he said.

Meanwhile, an analysis of the scar tissue from all three patients in the 7.5 mg cohort shows that “there is always one side where there is a smaller scar surface area than the other side,” he added. “You would expect that a scar surface area would be the same if there was no effect [from drug treatment], but only unblinding will help us” know.

Furthermore, an examination of CTGF protein levels in a patient from the first study also showed that the “intensity of the staining for the protein itself” is markedly reduced for one set of scars compared with the other set.

Cauwenbergh also presented photos of a patient in the multi-dose phase I study, which showed a level of hypertrophy in the scar tissue forming on one set of incisions. The data remain blinded, but “I think we may have some interesting observations in that study,” he said.

“We do see differences … [and] we can only hope that they go in the right direction” to indicate drug efficacy, he added.

In both studies, tolerability and safety were “considered excellent, both by the investigators and the subjects,” Cauwenbergh said. “We had no negative effects of [the drug] on the wound healing itself.”

Side effects were minimal, and included redness around the injection site that is potentially drug related, but not dose related, he said. Notably, the redness was only reported in the first, single-dose trial and not the multiple-dose study.

Should the final, unblinded data from the two studies prove positive, RXi is on track to beginning a phase II trial of the drug in the second half of 2013.

Cauwenbergh told Gene Silencing News this week that the phase II study would likely enroll patients with hypertrophic scars from previous procedures such as breast augmentation, hysterectomy, and thoracic surgeries, or those with keloids, and who are eligible for scar-revision surgery.

As in the phase I trials, some of the patients' scars will be treated with RXI-109 and others with placebo so that “you would be able, in the same subject and in a matter of [around] three months, see the difference” between the two, he said.

If RXI-109 proves effective in eliminating hypertrophic scars, patients would be given the opportunity to have placebo-dosed scars treated with the drug.

The exact details of the phase II program are still being worked out, but Cauwenbergh said he expects to get some guidance from Excaliard Pharmaceuticals, which had developed an antisense-based inhibitor of CTGF for scar reduction through phase II before being acquired by Pfizer in late 2011.

He added that RXi is encouraged by Excaliard's success in the clinic, which validated CTGF as a therapeutic target for scarring, and said that the market for such drugs is significant enough to support more than one compound.

Despite maintaining a tight focus on its anti-scarring program, RXi is also advancing a number of other drug compounds through its pipeline, the most advanced of which is a self-delivering RNAi agent for proliferative vitreal retinopathy, an ocular disorder caused by scar tissue buildup on the retina and a common complication of retinal detachment.

According to Cauwenbergh, preclinical data suggests that CTGF plays a key role in the condition, and the company expects that much of the anti-scarring data used with its investigational new drug application package for RXI-109 can be used with a candidate for proliferative vitreal retinopathy, speeding its way to the clinic.

He said at BIO-CEO that RXi has already generated animal data showing that its sd-rxRNAs can be delivered intravitreally, achieving dose-depending target gene silencing in retinal cells with no overt toxicities.

“We've also been able to show that after three weeks, we find a statistically significant difference versus controls in terms of silencing in the eye,” Cauwenbergh said at the time.

Earlier-stage efforts are also underway in liver fibrosis, macular degeneration, retinoblastoma, and amyotrophic lateral sclerosis.

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