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TransDerm Preps for New Phase I Trial with New RNAi Drug, Delivery System

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TransDerm is preparing to begin the toxicology studies needed to launch a phase I trial of an improved version of its siRNA-based treatment for pachyonychia congenita, or PC, and expects the study to begin next year, Gene Silencing News has learned.

And while its focus remains on the rare skin disorder, the company also sees its newly developed intradermal delivery technology as laying the groundwork for expansion into other, more common diseases, TransDerm CEO Roger Kaspar said this week.

“TransDerm has really turned into a delivery company, so we're really working on developing delivery technologies,” he said. “We like to think we're going to help a few people with PC, then use what we've learned along the way to help a large number of people with different disorders.”

TransDerm was founded in 2004 by Kaspar and colleagues in order to develop a treatment for PC, an autosomal disorder caused by mutations in certain keratin genes and characterized by hypertrophic nail dystrophy and focal palmoplantar keraderma with painful blisters (GSN 9/30/2005).

Given Kaspar's background as vice president of RNAi firm SomaGenics, TransDerm focused its efforts on using the gene-silencing technology to inhibit the mutant form of keratin 6. It achieved some success, demonstrating in a single-patient phase I trial that its siRNA drug TD101 was safe.

The company also found that the drug, when administered to the feet of the PC patient, could improve the lesions caused by the condition. However, the route of administration was too painful to advance into further testing.

In the phase I trial, TransDerm administered TD101 directly to the affected areas using a standard hypodermic needle, Kaspar explained. While the approach was effective, “the reason we were getting efficacy [was that] that we were setting up a high-pressure situation” that was extremely painful for the patient.

“When we went back and tried to deliver by topical creams or microneedles, we no longer had that pressure and the siRNA was no longer being taken up by the keratinocytes,” he said.

To address this problem, TransDerm developed a dissolvable microneedle array made of polyvinal alcohol that resembles a sheet of plastic with a series of small protrusions. When the sheet is applied to the skin, the protrusions penetrate only into the epidermis. After a short time, they swell and break off, remaining in the skin to release the siRNA drug until eventually dissolving away themselves.

Importantly, the epidermis is not innervated, “so theoretically you won't get any pain when you apply these,” Kaspar noted.

To ensure that the siRNAs would still penetrate affected cells, TransDerm also reworked TD101's payload to incorporate Thermo Scientific Accell technology. Unveiled for research applications in 2008, Accell siRNAs are chemically modified to enter cells without the need for a delivery vehicle.

TransDerm last month reported in Human Gene Therapy that the new drug, called sd-TD101, could inhibit a target gene in an animal model when administered using the new microneedle system.

In that study, TransDerm grafted human skin onto immunocompromised mice to create a human skin system, and developed Accell-modified siRNAs against CD44, a gene that previous studies had shown to be uniformly expressed throughout the epidermis.

“Treatment of human skin equivalents with CD44 sd-siRNA markedly decreased CD44 mRNA levels, which led to a reduction of the target protein as confirmed by immunodetection in epidermal equivalent sections with a CD44-specific antibody,” the paper's authors wrote.

Kaspar noted that while CD44 isn't related to PC, trying to knock down genes relevant to the disease in animal models isn't practical because they are involved in the wound response during stress and therefore are not normally expressed.

“The level of [PC] genes is all over the map, and … [it's] quite technically challenging ... to do a statistical analysis of the effectiveness of your inhibitor when you have such variable expression,” he said. By focusing on CD44, “we could convince ourselves that it was working and where it was working.”

With these and other data in hand, TransDerm is having sd-TD101 manufactured and is preparing to begin building additional microneedle arrays for use in the toxicology studies needed to file an investigational new drug application. Should all go well, Kaspar anticipates beginning a new phase I trial in 2013.

He said that while the exact details of the study have yet to be worked out, he expects it will be significantly bigger than the previous phase I trial, with between five and ten PC patients. He also said that with the new microneedle system, TransDerm aims to increase the number of weekly doses tested from two to three.

While all this work is going on, he said, the company continues to weigh its options for expanding into additional indications that affect more than the estimated few thousand people who have the condition.

Kaspar said that TransDerm is not currently undertaking any formal drug-development efforts in other diseases, but previously indicated that the company could begin work on conditions including psoriasis and atopic dermatitis.