TransDerm became the latest RNAi drug developer to move a product into the clinic this week when its investigational pachyonychia congenita therapy, called TD101, was administered to the lone patient enrolled in a phase Ib trial.
Although the company is developing a topical delivery system for the drug termed gene cream, TransDerm Founder and CEO Roger Kaspar told RNAi News this week that the study will evaluate the safety of the siRNA-based treatment when delivered through intradermal injections.
However, he noted that the company has developed an assay to measure how well TD101 is knocking down its target, which should give some indication of the drug’s efficacy. If that can be demonstrated, “then we’ll focus our attention on trying to get more patient-friendly [delivery approaches] going.”
For TD101, he said, “there are two issues: one is if the siRNAs are going to work, and the other is if the gene cream is going to work. We decided to look at the efficacy of the siRNAs first … [and] if that works, we have a lot of incentive to push the gene cream forward.”
PC is a rare autosomal skin disorder caused by a mutation in any one of the dozens of genes encoding keratins. It is characterized by hypertrophic nail dystrophy and focal palmoplantar keraderma with blisters, and affects an estimated 550 patients worldwide. There currently are no treatments available for PC.
In the clinical trial, TD101 will be injected into a defined intradermal region on the bottom of the foot of the only adult in the US known to have the particular mutation that the drug targets.
Although the trial is primarily designed to evaluate TD101’s safety, “we have assays set up to see how well we’re inhibiting the mutant” gene, Kaspar noted. “So really, this is a safety trial that we hope to get a little bit of efficacy data out of.”
The patient will receive TD101 twice a week for 14 weeks.
If data from the phase Ib trial is positive, TD101 will be tested in additional PC patients in Ireland, according to Mary Schwartz, director of PC Project, the non-profit organization funding the drug’s clinical development.
Given the limited market for a PC treatment, it remains unclear how TD101 will be marketed should it ultimately receive regulatory approval.
“It could be that this is never commercialized in the traditional sense of the word,” Kaspar said, adding that a more likely scenario would see PC Project and its network of collaborators handling distribution of the drug to patients.
“That’s part of the remarkable story we have going on here,” he said. “We’re developing these drugs for people who haven’t had any hope in the past, and now we’re finding a way to make them in a relatively low-cost way.”
Despite not testing gene cream in the PC trial, Kaspar hopes that the technology will eventually be used with TD101 and other siRNA-based medicines the company plans to develop.
“One of the issues with pachyonychia is that you get this very thickened skin, [and] with the gene cream we have to penetrate quite thick skin to get it where we need it to be,” he explained. “So there are some additional hurdles that we have with pachyonychia that we don’t have with other skin disorders.
“We decided to look at the efficacy of the siRNAs first … [and] if that works, we have a lot of incentive to push the [topical delivery method] forward.”
“The bottom line is that the intradermal injections have worked better for us so far” in preclinical testing, he added. “We’ve tested [the gene cream] in a number of mouse models and some look better than others, [but] we need to push it to the next level.”
Once TransDerm knows that TD101 is effective in humans, “we’ll have a lot of incentive to make the jump from animals to humans,” he said.
Still, there are other diseases for which gene cream “might be ready for prime time,” he said. Among them is keratosis pilaris, a common skin condition characterized by rough bumps, similar to goose bumps, usually on the backs of the arms and thighs. Though this condition is harmless, in certain cases it can be disfiguring.
TransDerm is also considering developing an siRNA therapy for a condition similar to PC called epidermolysis bullosa simplex.
However, as a small company with just three full-time staffers, TransDerm is keeping its near-term focus on TD101 and making advances with its delivery technologies. In addition to gene cream, the company is developing a delivery technology based on dissolvable, hollow, micro-needle arrays, Kaspar said.
“We can make these arrays and load them with whatever we want — of course, of interest to us is loading them with siRNAs,” he said.
“We might have the needles spaced a millimeter apart and have a 10-by-10 array, so we’d have 100 needles, each one of which could be loaded” with a drug, he added. “Theoretically, we can then deliver equal amounts in the same area and get fairly uniform delivery.”
Because the indications TransDerm is currently chasing target a very small patient population, financial success for the company may rest on its delivery technologies.
Kaspar said that while TransDerm isn’t actively pursuing commercial funding opportunities, the company has had discussions with possible industry collaborators interested in its delivery technologies. He declined to elaborate, citing confidentiality agreements.