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Resolve Partners Preclinical Lupus Therapy in Takeda Deal


By Catherine Shaffer
Staff Writer

A new deal with Takeda Pharmaceutical Co. Ltd. will help Resolve Therapeutics LLC, of Seattle, forge ahead through clinical proof of concept with its investigational systemic lupus erythematosus therapy, RSLV-132.

Jim Posada, Resolve's CEO, attributed Takeda's interest to a "pretty robust preclinical data package" that Resolve presented. The compound showed activity in animal models and performed well in pharmacodynamic models. "I think that was what convinced Takeda and other companies," Posada told BioWorld Today.

Under the agreement, Resolve will be responsible for development work through completion of a Phase Ib/IIa trial in lupus patients. At that point, Takeda has an exclusive option to license that compound, and all other compounds from the Resolve platform.

Takeda is forking over $8 million for the option. Upon exercise, it would pay an additional option exercise fee, plus potential development milestone payments totaling up to $247 million.

Although Resolve had discussions with other companies, Takeda was the ultimate winner. "We just liked working with folks there," Posada said. "It just felt like a good fit."

As well, there were no competing compounds in Takeda's pipeline to complicate things later on. "That's always an issue in licensing deals," Posada said.

RSLV-132 is a mono-specific nuclease Fc-fusion protein that is designed to target and destroy immune complexes associated with lupus, preventing the activation of interferon, and ameliorating kidney damage, according to Resolve.

The company's preclinical compounds are part of the deal as well. Posada explained that the lead compound is an Rnase nuclease fused to Fc, and as such it digests RNA.

The other compounds, Posada said, are RNase fused to DNase, and they target both the RNA and DNA of the immune complexes.

"Those are earlier in development," Posada said, "But they show promise."

Currently, Benlysta (belimumab), marketed by GlaxoSmithKline plc, is the newest drug on the market for lupus, an autoimmune disease that can strike anywhere in the body, attacking its own cells, causing inflammation and damage to tissues. The heart, joints, skin, lungs, blood vessels, liver, kidneys and nervous system are common targets of the disease, whose course can be very unpredictable, featuring periods of flare and remission.

Prior to Benlysta, typical treatments were steroids, anti-inflammatory drugs and immune suppressants.

Those treatments are very potent, with toxic side effects. "It's the sledgehammer pproach to shutting down the immune system," Posada said.

Benlysta targets BlyS, in a strategy to shut down the antibodies that form the immune complexes.

"That drug hasn't shown to be as efficacious as we had hoped," Posada explained. "There's a huge amount of unmet need in lupus."

A crowd of other compounds are following Benlysta into the lupus space, following a variety of mechanistic approaches to tackle the disease.

Compounds such as Roche AG unit Genentech Inc.'s rontalizumab target interferon-alpha to modulate the immune response. Cephalon Inc.'s forigerimod has a novel mechanism of action. It is designed to modify the B-cell response to an antigen so that the body no longer recognizes it as foreign.

And Anthera Pharmaceuticals Inc.'s A-623 (blisibimod) also targets Blys, but it's a peptibody, allowing more protein to be delivered with less volume. If successful, A-623 could be delivered through subcutaneous injection.

That drug missed its endpoints in a Phase IIb trial, but Anthera is pressing ahead with Phase III testing after convincing the FDA that the failure was due to weak results in the two lower-dose groups in the study. (See BioWorld Today, Jan. 28, 2013.)

In November, Resolve raised $5.8 million in a Series B equity financing led by a previous investor, New Science Ventures, with participation of its new investor WRF Capital, the venture investment arm of the Washington Research Foundation, and previous investor Easton Capital. It funneled those funds toward advancing RSLV-132 to clinical trials.

The first part of the trial will "be done toward the end of this year," Posada said, and will enroll healthy volunteers to establish safety and pharmacokinetics.

The company expects to begin the second part of the trial, a multidose study, in lupus patients near the beginning of 2014.

Posada said the company would be looking at various biomarkers of inflammatory gene expression, as well as the ability of the drug to remove immune complexes from the patients' circulation.