Washington Editor

Privately held Wellstat Therapeutics Corp. stands to gain up to $350 million, including an undisclosed up-front payment, in exchange for global rights to its Type II diabetes oral insulin sensitizer PN2034 and related compounds in a development and commercialization deal with Sanofi-Aventis Group SA, which sought the licensing agreement to beef up its diabetes platform.

In addition to the development and regulatory milestone payments, the Gaithersburg, Md.-based biotech also could bank royalties on worldwide sales from any commercialized products, said David Wohlstadter, vice president of licensing and business development at Wellstat.

PN2034, a product developed in-house by Wellstat and now in Phase II development, acts in the liver to restore its capability to respond to insulin. Wohlstadter contended that PN2034 may not have the adverse effects of other insulin sensitizers, such as weight gain and edema.

The company has completed two Phase IIa studies in the U.S. involving a total of about 180 patients, with "encouraging results," which helped seal the deal with Sanofi, Michael Bamat, Wellstat's vice president of R&D, told BioWorld Today.

Wellstat chose Sanofi for the partnership because of the Paris drugmaker's longstanding experience in the diabetes field, Wohlstadter said.

Sanofi's once-daily long-acting insulin product Lantus (insulin glargine rDNA origin), which works for 24 hours with no pronounced peak, is the world leader in insulin product sales, Wohlstadter noted.

"They have really established a commitment to the diabetes community with Lantus and with their efforts in diabetes treatment," he said. "We thought, and I think they thought, that PN2034 really fits well into that metabolic disease portfolio and is a perfect complement to their Lantus franchise."

The agreement calls for Sanofi to take over development of PN2034 and certain related products through to regulatory approval and commercialization, Wohlstadter noted.

As a first-in-class insulin sensitizer, PN2034 could be developed as a standalone therapy, but because it acts through a different mechanism than other products in the space, also could be used in combination with other diabetes drugs as an add-on treatment, Bamat explained.

"One of the great things about an insulin sensitizer is that it is really addressing the core problem in Type II diabetes, and because of that, and if the safety profile of PN2034 holds up through development, it really can be used for the earliest stages of insulin resistance through late-stage Type II diabetes, where patients are dependent on exogenous insulin," he said. "It really has the potential to address the full range as monotherapy, we believe, as well as in combination from the beginning of Type II diabetes through the last stages."

PN2034's safety profile in nonclinical and clinical testing "looked very good," Bamat said.

"We have been very encouraged by the safety profile, and we didn't see any dose-limiting toxicity at this point in the clinic," he added.

Wohlstadter said the licensing agreement with Sanofi is the first major pharmaceutical partnership for Wellstat Therapeutics, which is part of the Wellstat Group, a multiproduct company established in 1985 by Amgen Inc. co-founder Samuel Wohlstadter, who also was a co-founder of Applied Biosystems, Hyperion Catalysis International Inc. and Roche AG subsidiaries IGEN International Inc. and BioVeris Corp.

Other Wellstat divisions, however, have other ongoing partnerships, Wohlstadter said.

The biotech's pipeline also includes vistonuridine (PN401), which is under development to treat neurodegenerative and mitochondrial diseases and pancreatic and gastric cancers.

But the lead indication Wellstat is seeking for vistonuridine is as an antidote for overdose of 5-fluorouracil (5-FU), a mainstay chemotherapy drug used in regimens against several solid tumors, including colon, stomach, esophagus, head and neck and breast cancers.

Of the 275,000 patients in the U.S. who undergo 5-FU therapy annually, 1,300 die of 5-FU overexposure, which can result from either overdoses or poor drug clearance, according to the National Institutes of Health.

There currently are no FDA-approved antidotes in the U.S. for 5-FU overexposure, Bamat noted.

In the body, vistonuridine is converted to uridine, a specific pharmocologic antidote for 5-FU toxicity. Once converted, vistonuridine reduces the incorporation of 5-FU metabolites into the genetic material of noncancerous cells.

Because oral uridine has poor bioavailability and the infused product has complications, uridine alone is not a clinically viable treatment for 5-FU overexposure.

Vistonuridine delivers about eightfold more uridine into the bloodstream than oral administration of uridine, according to Wellstat.

At last spring's annual meeting of the American Society of Clinical Oncology in Orlando, Wellstat reported the outcomes of 17 cases of 5-FU overdoses for which the firm supplied vistonuridine under FDA emergency-use investigational new drug application provisions.

All 17 of the vistonuridine-treated patients recovered, even though a fatal outcome for at least 13 of the patients would have been predicted by the dose and rate of 5-FU administration, Wellstat reported.

Data from a review of 13 other cases of 5-FU in which patients did not receive vistonuridine showed that 11 resulted in deaths.

Bamat noted that his firm plans to seek approval of vistonuridine, which has received orphan drug designation as a 5-FU poisoning antidote from the FDA and the EMEA, "in the near future."

Wellstat's pipeline also includes an early stage gout drug and an adult stem cell therapy.

Published  October 22, 2009