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With a Phase I Trial in Asthma Nearing, ZaBeCor Drops Veil of Secrecy as It Looks for Partners


While most RNAi drug developers have strived to make their names well-known, ZaBeCor has taken the opposite approach and maintained a low profile.

That, however, is starting to change as ZaBeCor moves its lead compound, an siRNA-based drug called Excellair, toward a phase I study for asthma -- set to begin possibly as early as this year -- and begins the search for development partners in other indications.

ZaBeCor was founded in 2002 by University of Pennsylvania researcher Alan Schreiber to develop and commercialize discoveries related to inflammation made in his lab over the past two decades.

"We've been studying the basic mechanisms that are involved in inflammation and made a significant observation, which has a potential impact on a whole range of disorders," Schreiber, who also serves as chairman of ZaBeCor's scientific advisory board, told RNAi News this week. "The initiation of many inflammatory responses, based on immune reactions, [begin with] an initial step involving an intracellular kinase called Syk.

"Through our work, we have shown there is no bypass around the Syk kinase molecule, which is unusual because in most plasma protein systems and cellular systems there are mechanisms that bypass the inhibition of a particular molecule," he said. "If you inhibit Syk kinase, as we have done [with Excellair], you can inhibit the release of a wide range of inflammatory mediators whether they be cytokines, histamines, et cetera."

"We've been in contact with the FDA, [and] human testing [in asthma] is going to begin shortly. It will probably begin if not late this year then early next year."

Based on this and other data, ZaBeCor hired contract research and consulting firm SRS International to begin testing Excellair in animal models as a treatment for asthma.

"We've been in contact with the [US Food and Drug Administration, and] human testing [in asthma] is going to begin shortly," Schreiber said. "It will probably begin if not late this year then early next year." After that, the company plans to begin evaluating the drug as a treatment for allergic rhinitis, he added.

Currently, ZaBeCor is what Schreiber termed a "virtual company" with no formal headquarters or laboratory space of its own. All research and development work is conducted by SRS, while day-to-day management duties are handled by CEO Dan Matthias, who Schreiber noted is compensated entirely with company equity.

This business structure has allowed ZaBeCor, which is privately funded by "friends and family," to maintain a burn rate low enough that the company expects its cash reserves will be sufficient to fund phase II studies of Excellair for asthma, Schreiber said.

"We've kept a low profile, we're below the radar screen," he said. "We haven't advertised, and [the company] is a privately funded enterprise. For the near term, through phase II, we are content with our private [status and] it's not necessary to go to … big pharma" for a partnership.

Schreiber noted that UPenn holds an undisclosed equity stake in ZaBeCor.

As part of its low-key nature, ZaBeCor has not published any data related to Excellair, although it is currently preparing a manuscript for submission to a peer-reviewed journal. Schreiber declined to comment in any detail on the composition of Excellair, such as whether it incorporates a modified or unmodified siRNA, but said that preclinical testing has revealed "no toxicity that we can see and it's very potent."

When asked about Excellair's duration of effect, he said that "we don't need a long-term [one] in most treatments. Rather, to administer it every couple of days or until the inflammation has receded" would be appropriate for the indications the company is pursuing.

Aside from asthma and allergic rhinitis, ZaBeCor sees potential for Excellair as a treatment for inflammatory conditions such as atherosclerosis, rheumatoid arthritis, acute respiratory distress syndrome, and cystitis.

"Bird flu causes death from inflammation in the lung from the release of a wide range of inflammatory mediators that cause lung damage. Although we haven't directly studied bird flu, we have studied lung inflammation and we think our work … is likely applicable to bird flu."

Schreiber also sees potential for the drug for treating avian flu, an indication currently being explored by Alnylam Pharmaceuticals and RNAi newcomer Nastech Pharmaceuticals. Both of these companies are developing RNAi-based flu drugs and have made it a point to state that while their drugs aren't under development for avian flu per se, they are expected to be effective against all strains of the virus -- including H5N1 (see RNAi News, 3/16/2006 and 5/25/2006).

"Bird flu causes death from inflammation in the lung from the release of a wide range of inflammatory mediators that cause lung damage," Schreiber said. "Although we haven't directly studied bird flu, we have studied lung inflammation and we think our work … is likely applicable to bird flu."

He noted that ZaBeCor has been in contact with the US Centers for Disease Control and Prevention regarding the use of Excellair for avian flu, suggesting that his company may have joined the line of drug developers looking to grab a share of government funding. Late last year, Alnylam announced it had received $240,000 from the US Department of Defense's Defense Advanced Research Projects Agency to fund its flu research (see RNAi News, 12/16/2005), while Nastech has said that it plans to "work closely" with the CDC to accelerate development of its flu drug (see RNAi News, 2/23/2006).

Schreiber said that Excellair is administered directly, so in the case of asthma it would likely be formulated for inhalation, although the company has tested intranasal delivery in animals. For arthritis, he added, "you would deliver it to the joint by injection."

For atherosclerosis, a condition in which the build-up of fatty plaque on the walls of arteries is preceded by inflammation, "you would deliver it to the heart by catheterization. Similarly, for the treatment of cystitis in the bladder, which is a major problem in urology because there isn't an effective treatment, you would administer it directly to the bladder," he said.

Although Schreiber said that ZaBeCor intends to keep its asthma and allergic rhinitis programs in house, at least for the time being, the company has just begun putting out feelers for Excellair partnerships in other indications, namely acute respiratory distress syndrome, arthritis, cardiovascular disorders, and cystitis.

These indications, he said, are simply too costly for the company to handle on its own. For example, with acute respiratory distress syndrome, a lung injury characterized by severe inflammation and associated with a variety of diseases, "most of the patients are in the hospital in the intensive care unit. To carry out studies in the intensive care unit is expensive."

Schreiber expects that deals in the various indications ZaBeCor is looking to partner out will resemble its recent alliance with Acuity Pharmaceuticals. Under that arrangement, Acuity picked up the rights to Excellair and related intellectual property for ophthalmic indications such as uveitis and ocular allergies (see RNAi News, 5/4/2006).

Specific terms of the deal were not disclosed, but Schreiber said that ZaBeCor would be working closely with Acuity in its efforts to develop Excellair.

"We would foresee similar types of partnerships in regard to arthritis, acute respiratory distress syndrome, bird flu, cardiovascular disease, and cystitis of the bladder," he noted.

-- Doug Macron ([email protected])

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