It's been over a year since Nastech, a company that specializes in intranasal drug-delivery technologies, announced that it was eyeing the RNAi-based therapeutics field after taking a license to the fundamental Fire-Mello patent (see RNAi News, 2/6/2004).
In that time, though, it seems the company has been hard at work. This week, at the 2005 American Society for Biochemistry and Molecular Biology annual meeting in San Diego, Nastech presented preclinical data from its program investigating the use of RNAi to treat rheumatoid arthritis.
Nastech also announced that it had established a collaboration with the Mayo Clinic to help wrap-up preclinical work on the RA drug candidate while it finalizes discussions with potential development partners from big pharma.
According to Steven Quay, chairman, president, and CEO of Nastech, the company decided to pursue RA for its lead RNAi program for a number of reasons. Firstly, the disease has a well-validated target in human tumor necrosis factor alpha, a protein over-expressed in RA, he told RNAi News this week.
Additionally, there is opportunity to compete with existing RA treatments because these "only bind up TNF-alpha," Quay said. "Therefore, they stabilize [the protein] in the bloodstream and increase its residence time, [and there] … might be up-regulation of the messenger RNA because of that activity."
Thirdly, "there's a regulatory path for approval" for TNF-alpha targeting RA treatments already established at the US Food and Drug Administration, he added. "So, for example, doing a comparative study for changing TNF-alpha levels might be a good surrogate marker [and] we may not have to do a full-blown rheumatoid arthritis study."
Finally, the market for RA treatments is quite lucrative. Existing treatments are expensive, Quay noted, "and the market is willing to pay $20,000 to $30,000 per patient per year for those therapies."
Nastech said that it has already screened 56 candidate siRNAs in human cells that secrete H-TNF-alpha, identifying a group of oligos that can reduce expression of the protein by up to 85 percent with IC50 values of less than 10 picomoles.
The most potent of these siRNAs were individually combined with Nastech's proprietary delivery peptides to create drug candidates able to knock down TNF-alpha mRNA and protein levels in activated human monocytes in vitro, the company said.
Nastech also said it has conducted in vivo tests with one especially promising siRNA-based drug, comparing it to infliximab, a TNF-alpha targeting antibody marketed as an RA treatment by Johnson & Johnson as Remicade. In these studies, transgenic mouse models of RA, which constitutively express H-TNF-alpha, were treated twice weekly with either a 2 mg/kg intravenous injection of the RNAi drug, infliximab, or saline. Treatment began when the mice were six weeks of age.
Both siRNA- and infliximab-treated animals showed RA score stabilization, as judged by paw and joint inflammation, beginning at age seven weeks, compared with controls whose condition persisted through week 10, according to Nastech.
At nine weeks of age, siRNA-treated animals showed reductions in RA score comparable to their infliximab-treated counterparts, but significantly lower plasma TNF-alpha protein levels, the company said.
"We were quite surprised [with the protein level results,] but when we talked to experts, they were not," Quay noted. "When you give Remicade, you double to triple the TNF-alpha in the bloodstream, mainly because you're stabilizing it against degradation, so it hangs around longer."
While this preclinical work was done with an intravenously delivered RNAi compound, and though Nastech is known for its intranasal delivery approaches, Quay said that the company's RA drug will, in all likelihood, ultimately be a subcutaneously administered one.
"It's a cost-of-goods issue," he said. "With the nasal drugs that we deliver for obesity or osteoporosis, we get about 50 percent bioavailability compared to subcutaneous, [and this] is really good if you have just a peptide. But the cost-of-goods on [an RNAi] drug is going to be very high, so initially at least we will want to go with a subcutaneous administration."
Quay declined to speculate on when an siRNA drug could be ready for human testing, but noted that "we'd like to be among the very first, if not the first, company to be doing systemic disease treatments with RNAi."
In order to meet that goal, Nastech has also signed on the Mayo Clinic to help it finalize the selection of a drug candidate for clinical development. The company said the collaboration will involve the measurement of a series of inflammatory cytokines, including H-TNF-alpha, in serum from RA patients receiving existing therapies. Additionally, drug candidates will be screened for their ability to knock down H-TNF-alpha in monocytes taken from the patients.
Quay said that Nastech is fairly certain that it has identified the siRNA on which it wants to focus its development efforts, "but we want to test it against a couple of the back-up" candidates. "The prejudice is that we have our candidate, and the data has to show that it's not the right one as opposed to the other way around," he added.
Financial terms of the Mayo Clinic deal were not disclosed, but Quay said that no royalties are involved. "It's just a research collaboration. It's a fairly modest financial arrangement," he noted.
Once a decision on a drug candidate is finalized, Quay said Nastech expects to stick to its previously expressed expectation that it would move forward into clinical development with the help of a partner. According to Quay, the company is already engaged in "partnership discussions [with] … large pharmaceutical companies. We would want to partner this sooner rather than later," he said.
Quay declined to offer a timeline for when a deal might be signed beyond stating that "it will be done when it's done."