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Nastech Shows In Vivo Data on Arthritis Drug, Sees RNAi s Knock Down as Key Selling Point


RNAi newcomer Nastech released last week the first in vivo data on its experimental siRNA-based rheumatoid arthritis treatment to come out of its partnership with the Mayo Clinic.

The data, presented at the American College of Rheumatology's annual scientific meeting in San Diego, indicate that the company's RNAi drug is able to stop the production of human TNF-alpha in mouse models of the disease. TNF-alpha is a protein that is over-expressed in certain inflammatory disorders including rheumatoid arthritis.

According to Nastech President and CEO Steven Quay, this ability to shut down TNF-alpha production may help the company differentiate its RNAi-based therapy from existing treatments such as Centocor's Remicade (infliximab), which appears to cause cells to increase production of the disease-causing protein.

According to Nastech, it and Mayo Clinic researchers screened over 50 siRNA candidates targeting human TNF-alpha in LPS-activated human monocytes purified from peripheral blood mononuclear cells, of which five were found to have knockdown properties of greater than 70 percent.

"Purified monocytes and serum samples from 25 patients with active [rheumatoid arthritis] on various treatment regimens were used to characterize cytokine mRNA and protein profiles," the abstract of the Nastech presentation states. "Treatment of isolated monocytes with siRNA reduced both TNF-alpha mRNA and protein levels."

Antibody therapy "itself actually causes patients to get worse, as it were. That may be the Achilles' heel
of all antibody-based therapy, which would mean that the RNAi approach … may have
a fundamental solution
to all antibody therapy problems."

Additionally, the researchers used a Nastech peptide-based delivery system to test one siRNA candidate in two independent rheumatoid arthritis transgenic mouse models that constitutively express human TNF-alpha. "Administration of a siRNA-peptide formulation by [intravenous] injection resulted in a lowering of [human TNF-alpha] protein levels in mouse plasma compared to infliximab-treated or saline controls and reduced … paw and joint inflammation … comparable to infliximab-treated animals," the abstract states.

Quay noted that the researchers also obtained similar results through subcutaneous administration of the RNAi drug, a delivery route he expects to be used in clinical trials.

Exploiting an Achilles' Heel

Through primarily known for its intranasal drug-delivery technology, Nastech threw its hat into the RNAi therapeutics ring early last year when it took a license to the fundamental Fire-Mello patent (see RNAi News, 2/6/2004). A little more than a year later, the company said it had hired the Mayo Clinic to help screen and select a drug candidate for clinical development — a task that is now done, according to Quay.

With a clinical candidate settled upon, "the program is continuing to transition from research to development with the establishment of work on formulation, and then designing various products for the [toxicology] studies that are required to get into humans," Quay said.

He noted, however, that the siRNA candidate chosen for testing in humans might not be the same one used in upcoming preclinical studies. "For the toxicity studies in animals … the [US Food and Drug Administration] requires that you have at least some level, if not similar levels, of efficacy at the target in animals species that you have in the human," he said. "So sometimes your [siRNA] sequences are different for your tox studies."

Quay declined to provide any timeline on the toxicology studies or on when an investigational new drug application for the siRNA drug might be ready. "We haven't given guidance [on timing] because [the field] is so competitive and we want to be as aggressive as we can without tipping our hand," he said.

Quay did indicate, however, that Nastech expects it will find a development partner in a big drug maker based on an IND filing alone. "I suspect our IND package will be strong enough to … generate interest in partnering" without the company having to supply phase I data as well, he said. He declined to comment on how the partnering process is proceeding beyond stating that "there's an active interest in our program from the usual big pharma and biotech companies."

Although data usually fuel the fire of an alliance, Quay noted that RNAi's ability to shut down production of a specific disease-causing protein may help boost the interest of companies looking for opportunities in the rheumatoid arthritis space.

Among the data presented at the ACR meeting, he said, "was the finding that in patients with rheumatoid arthritis, when they were given … the kinds of treatments that tend to soak up TNF-alpha, [the protein] was increased in the bloodstream. The patients' white cells respond [to antibody treatment] by up-regulating the message and making more TNF-alpha.

"So the therapy itself actually causes patients to get worse, as it were," he said. "That may be the Achilles' heel of all antibody-based therapy, which would mean that the RNAi approach … may have a fundamental solution to all antibody therapy problems."

Quay added that the company started its RNAi program in rheumatoid arthritis "thinking that if we're as good or as safe with a different mechanism of action it would be quite interesting. But it looks like actually the existing rheumatoid arthritis therapies, which are up to $2 billion in sales every year … may have [a weakness] based on the mechanism of action."

— Doug Macron ([email protected])

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