By Doug Macron
TransDerm, which is developing an siRNA-based treatment for a rare skin disorder, has begun evaluating a variety of different drug-delivery technologies that it hopes will improve the performance of the drug that was observed in a recent phase Ib study.
This week, the company announced that it has formed a research alliance with RXi Pharmaceuticals to evaluate RXi's proprietary RNAi compounds, including its so-called self-delivering rxRNAs, in dermatology models.
TransDerm also received this month a one-year grant from the National Institute of Arthritis and Musculoskeletal and Skin Diseases to test other siRNA-delivery vehicles, including Traversa Therapeutics' PTD-DRBD technology and Thermo Fisher Scientific's Accell reagents, in a human skin system.
TransDerm was founded in late 2004 to develop a therapy for pachyonychia congenita, a rare autosomal skin disorder caused by a mutation in any one of the dozens of genes encoding keratins (RNAi News 9/30/2005). It is characterized by hypertrophic nail dystrophy and focal palmoplantar keraderma with blisters, and affects roughly 600 patients worldwide. There currently are no treatments available for PC.
By early 2008, TransDerm had begun testing a naked, unmodified siRNA targeting a particular mutation associated with the disease in a one-patient study (RNAi News 1/17/2008). Although the company has been working on a topical delivery system for the drug, it was not quite ready in time for the trial and the patient received treatment via intradermal injections.
As reported by RNAi News last April, the study suggested that the drug, TD101, was safe and potentially effective (RNAi News 4/23/2009). However, the injections proved too painful and TransDerm CEO Roger Kaspar said that the company expected later trials to use a lipid-based topical delivery vehicle, dubbed Gene Cream, under development with Stanford School of Medicine researcher Chris Contag.
But it appears that TransDerm isn't banking entirely on Gene Cream. The company said this week that it will be working with RXi "to explore the use of both existing and proprietary delivery approaches for dermatological applications," in addition to seeing how RXi's RNAi molecules work in dermatology models.
Under the deal, each firm will contribute "technology and resources … to evaluate and develop novel transdermal RNAi delivery," they said. Additional terms were not disclosed.
"The RXi technology has significant delivery advantages over the siRNA used in our initial phase 1b clinical trial and we are keen to return to the clinic as soon as possible," Kaspar said in a statement.
For its part, RXi is likely to benefit from TransDerm's experience in developing dermal RNAi delivery technologies as it continues early-stage work on compromised skin conditions.
Last month, RXi's Vice President of Pharmaceuticals Development Pamela Pavco presented data showing that the company's sd-rxRNAs could knock down a target gene in skin cells when delivered via intradermal injection.
With an eye toward wound-healing applications, RXi is planning in vivo dose-response and extended duration studies with RNAi molecules against therapeutically relevant target genes, according to Pavco's presentation.
"We have made excellent progress in the delivery of our novel rxRNA compounds in a variety of systemic and local applications, including intradermal delivery," RXi President and CEO Noah Beerman said in a statement. "As we refine the therapeutic focus for our unique technology … we will continue to collaborate on complementary delivery systems to ensure the rapid progression of our compounds into clinical development."
Meanwhile, TransDerm recently secured $340,859 in grant funding from the NIAMS to look at a variety of other companies' delivery technologies.
According to the grant's abstract, TransDerm will use the money to develop a human epidermal equivalent system in which "pre-existing gene expression … can be monitored," including the expression of mutant keratin 6a, which is responsible for PC.
"This model system will be used to evaluate and optimize Traversa's PTD-DRBD siRNA delivery technology … as well as other commercially available delivery uptake technologies including [Life Technologies'] Invivofectamine [and] Accell," the abstract adds. "The most promising of these will be used in combination with our stratum corneum delivery technologies," such as Gene Cream and micro-needle arrays.
In the next phase of the grant project, TransDerm will test the best delivery technologies it identifies in mouse models, including immunocompromised animals harboring human skin grafts, the abstract states. "The most effective combinations of these technologies will then be subjected to toxicology and pharmacokinetics studies in preparation for evaluation in the clinic."
Officials from TransDerm did not return a request for comment.