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AstraZeneca Licenses New Class of Antidepressants Developed at Mayo Clinic, Virginia Tech

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AstraZeneca has licensed a portfolio of preclinical antidepressant compounds from the Mayo Clinic and Virginia Tech University, and will sponsor research at the institutions to discover next-generation versions of the drugs, the pharma giant said this week.

Under the terms of the agreement, AstraZeneca will receive a global license for all uses of the compounds, called triple reuptake inhibitors, as well as exclusive manufacturing and commercial rights.

In return, the Mayo Clinic and Virginia Tech, as co-owners of the intellectual property, have received an undisclosed upfront payment and will be eligible to receive additional undisclosed payments based on milestones, as well as royalties should a product based on the compounds reach the market, AstraZeneca said.

As such, the licensing seems to help validate a pair of technology-commercialization financing initiatives established in recent years by the Mayo Clinic.

The initiatives helped fund toxicology studies on the compounds, making them a more attractive licensing target for AstraZeneca by eliminating some up-front risk, according to Elliott Richelson, a professor of psychiatry and pharmacology at Mayo Clinic's Jacksonville, Fla., branch and one of the co-inventors of the compounds.

"These are very early-stage compounds, and there are certain thresholds you have to overcome to get someone to license it," Richelson told BTW this week. "There is a battery of pre-clinical toxicology tests that … to do in the fashion required by the [US Food and Drug Administration] would cost perhaps close to $1 million."

Some academic labs have the expertise to perform these tests, Richelson said, but most don't have the financial resources to do so.

"We were able to get funding from Mayo and Virginia Tech, but mostly from Mayo, to do some of the pre-clinical toxicology testing," he said. "We added value to the compounds by showing that they are not toxic."

Current commercially available antidepressants such as selective serotonin reuptake inhibitors and dual serotonin/norepinephrine inhibitors address only serotonin and norepinephrine imbalances in the brain.

So-called triple reuptake inhibitors, or TRIs, also inhibit a third major neurotransmitter, dopamine, and may prove to be more efficacious than SSRIs or SNRIs, according to the researchers.

Paul Carlier, a professor of organic and medicinal chemistry at Virginia Tech, is credited with creating a new synthesis method for the compounds and using it to create the collection of TRIs.

In the mid-1990s, Carlier contacted Richelson about testing the compounds in his lab at Mayo Clinic. "He wasn't set up to test these compounds for activity," Richelson said. "Over the years, we've probably gone through more than 100 compounds, and studied their structure, function, and activity. We came up with a compound that we've done a lot of papers on." He did not elaborate.

Mayo Clinic took the lead on filing patent applications on the compounds; and Mayo and Virginia Tech have been awarded several patents, including a composition-of-matter patent, and have several pending applications around the TRIs.

Although there are no TRIs currently on the market, other pharmaceutical companies, including GlaxoSmithKline and Sepracor, are developing similar treatments, according to Richelson.

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"What is frustrating is that even though we are probably one of the first in the world to have this kind of compound, we're not the first to have it in the clinic," he said. "Some other companies are already in humans."

However, the activity of TRIs can vary dramatically based on their rank potency and relative potency against the various neurotransmitters.

"TRIs are not all the same," Richelson said. "If we focus just on the pharmacodynamics, each drug will be different based on its rank order of potency, and will certainly be clinically different. If they're equally potent on all three transporters, you'll have equal effects. So the point is that if one company has a TRI and another has a TRI, that it's not necessarily a 'me-too' drug."

Frank Yocca, vice president and head of CNS and pain drug discovery at AstraZeneca, told BTW that the market for TRIs is highly competitive, but that AstraZeneca believes the compounds developed by Richelson and Carlier have superior qualities.

"We wanted a compound that had good properties and one that we could move into development quickly," Yocca said. "There could be situations where TRIs are not well-tolerated. We found that these candidates had a very good mixture of compounds, and seemed to have good side-effect profiles. If they really look good in terms of tolerability in animal models, these are things you can fast-track quickly."

Funding for toxicology studies on the TRIs came mostly from Mayo's innovation loan program and discovery translation fund, which the school put in place in 2005 to help its researchers perform proof-of-concept studies on commercially promising technologies (see BTW, 10/22/2008).

The ILP is funded through royalty income Mayo receives from out-licensed technologies, and provides as much as $200,000 in interest-free loans to researchers developing technologies with commercial potential. The DTF, which draws its funds from a philanthropic gift the clinic received in 2005, offers awards of between $300,000 and $500,000 as a final boost to technologies on the brink of commercialization.

As reported by BTW last October, at the time Mayo had made 25 loans or awards that resulted in eight startup companies. It is unclear whether any other previous internal financing helped attract existing companies as potential licensees, but the latest deal would seem to endorse the approach.

All told, Mayo provides some $500,000 of funding from both mechanisms to support Richelson and Carlier's work. "We get money for signing this deal, and we have to pay off the loan, and we've had to pay for patent attorneys and patent applications," Richelson said. "But I'm pleased … that this was money well-spent."

According to Mark Coburn, president of Virginia Tech Intellectual Properties, the office of the vice president of research at Virginia Tech also provided an undisclosed amount of money to fund the project.

"It was more translational in character than the typical research that goes on in a university," he told BTW. "My sense is that the case was that these compounds had to be further along the continuum for [AstraZeneca] to be interested."

He said that Virginia Tech does not have dedicated funding mechanisms akin to those at Mayo, but that the school is currently working with the state of Virginia to create a similar program at the school.

Moving forward, both Richelson’s and Carlier's labs will receive undisclosed funding from AstraZeneca to continue to refine the existing TRI compounds and to develop next-generation versions.

The research will be a division of labor, with Carlier and Virginia Tech taking the lead on chemistry; Richelson and colleagues at Mayo conducting biological testing; and AstraZeneca performing additional development steps.

"It is all going to be funneled through AstraZeneca," Richelson said. "Compounds will be made at VaTech, and AstraZeneca will file them and send them to me for in vitro tests. [AstraZeneca] has put together a super group of scientists, and we've already met a couple of times to work out the plan to design new compounds."

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