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TransDerm Hopes RNAi-Based Rx for Rare Skin Disorder Will Enter Clinic by End '07

TransDerm, a start-up created to develop an siRNA-based treatment for the rare skin disorder pachyonychia congenita, has recently requested a pre-investigational new drug application meeting with US regulators and is aiming to begin human testing of a lead drug candidate as early as the end of the year, RNAi News has learned.
TransDerm founder and CEO Roger Kasper told RNAi News this week that the company hopes to meet with the US Food and Drug Administration about the IND “within a couple of months.”
“If everything goes well, hopefully we’ll be treating patients by the end of the year,” he said. “We’ve been trying to cross all the ‘Ts’ and dot all the ‘Is,’ but you never know [what the agency will require] until you’re there.” As such, the drug’s clinical development timeline could change.
At the same time as it moves forward on PC, which is estimated to affect only about 500 people worldwide, TransDerm is also considering its future and indications with bigger market potential.
“We don’t expect to ever make any money” from a treatment for PC, Kasper noted. Rather, the therapy would be a proof of concept for TransDerm’s topical delivery technology, he said. “Once we’re able to [treat] PC, then we’ll expand to other [dermatological] disorders that have larger markets.”
Skin Deep
PC is an autosomal skin disorder characterized by hypertrophic nail dystrophy and focal palmoplantar keraderma with blisters. Given the extremely small population of people with the disease, treatments for the condition have not been forthcoming.
However, in late 2004, TransDerm was founded with the financial help of an undisclosed group interested in seeing a treatment for PC brought to the market. With this funding, and a network of academic and industry collaborations, the company has made significant progress towards developing a therapy for the skin disease.
In 2005, at the first meeting of the Oligonucleotide Therapeutics Society, TransDerm presented in vitro data showing that its siRNAs could specifically target certain of the mutant genes responsible for PC — in this case, keratin 6a and keratin 16 (see RNAi News, 9/30/2005).
Contributing to the data were researchers from Ninewells Medical School in the UK, Rockefeller University, and Johannes Gutenberg-Universitat in Germany. Kasper noted this week that TransDerm has also been collaborating with Dharmacon, which has been helping with siRNA development and optimization.
TransDerm and its collaborators have also conducted in vivo work in mice in which they used a plasmid vector to co-deliver mutant genes responsible for PC and siRNAs targeting those genes, Kasper said.
Thus far, the researchers have been able to show that “the siRNA inhibitors will specifically down-regulate plasmid-based expression in the mice,” he noted. “But that’s not exactly where we want to be ultimately. It’s sort of a stepping stone to get to the [PC] mouse model” that TransDerm has been developing.

That model involves grafting skin equivalents from PC patients onto mice, which retain some of the disease characteristics of PC, Kasper explained. However, the models are still under development and have not been treated with siRNAs.
“That’s something we’re hoping to get to in the coming months,” he said.
In parallel with its mouse model efforts, TransDerm is also refining a novel, lipid-based delivery technology called gene cream in collaboration with Stanford School of Medicine researcher Chris Contag.
Although gene cream has not yet been tested for its ability to deliver siRNAs, it has been successfully used to deliver expression plasmids into mice after being applied to the animals’ shaved backs.
“We can get nucleic acid delivery into keratinocytes,” Kasper said. “We don’t get as much delivery as we’d like, so it’s not ready for prime time yet, but we’re getting there.”
Once it meets with the FDA and has collected some additional in vivo data, TransDerm hopes to be able to launch a small phase I trial to evaluate the safety of its PC treatment in healthy volunteers. “Assuming that the safety study looks good … we’d [then] treat the patients that have the mutation,” Kasper added.
However, the initiation of a clinical trial would essentially mark the end of TransDerm’s role in developing the RNAi-based PC drug.

“We don’t expect to ever make any money off of” a PC treatment. We view this as proof-of-concept [for TransDerm’s topical delivery technology]. Once we’re able to [treat] PC, then we’ll expand to other [dermatological] disorders that have larger markets.”

According to Kasper, the company is partnered with the Pachyonychia Congenita Project, a charity that will assume clinical development and commercialization responsibilities for TransDerm’s PC drug once it passed the IND stage. 
As such, the company is considering other indications to which it might apply its gene cream technology.
One indication “we’re putting some attention on right now is a skin disorder called keratosis pilaris,” Kasper said.
Keratosis pilaris is a common skin condition characterized by rough bumps, similar to goose bumps, usually on the backs of the arms and thighs.
“For a lot of people it’s just an annoyance, but for other people it can be quite traumatic,” Kasper said. “This affects, in one form or another, about 40 percent of the population, [and] there really is no good treatment for it [although] we think we’ve identified genes that are involved in it.”
Though harmless, he said that in certain cases keratosis pilaris can be disfiguring.
“It’s sort of like acne,” Kasper said. “It doesn’t kill anybody but it sure causes a lot of misery — to a lot of teenagers especially.”
TransDerm is also looking to another condition similar to PC called epidermolysis bullosa simplex.
“The targets [for EBS and PC] are not the same,” Kasper said, “but they’re really quite similar, so if we can solve the delivery aspects for PC, we can then make inhibitors for EBS. If we find something for PC, we can readily generalize it for other disorders, and EBS is the most logical because it’s so similar.”
Although Kasper said TransDerm is sufficiently funded for the time being and is not actively seeking additional capital, the company may find itself on the receiving end of a cash infusion some time in the near future — a development that would facilitate the company’s expansion beyond PC.
According to Kasper, the company has received inquiries about possible licenses and collaborations. “My guess is that our financial base will broaden over the next year or two … [probably] by licensing some of our technologies like gene cream,” he said.

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