Now that licensing partner Lux Biosciences Inc. has lifted the lid on short-of-the-mark Phase III results from another try with voclosporin for uveitis, Isotechnika Pharma Inc. is turning its attention fully to nephrology – especially kidney transplants, the indication for which the calcineurin inhibitor originally was designed.

"We just need to stick to our knitting," said Robert Foster, founder of Isotechnika, who has been an officer and director at the Edmonton, Alberta-based firm since 1993.

Lux, of Jersey City, N.J., has informed Isotechnika that the latest Phase III experiment, mandated by the FDA two years ago, failed to meet its endpoint of change from baseline in vitreous haze at 12 weeks or at the time of treatment failure, if earlier.

In the summer of 2010, the FDA's complete response letter (CRL) appeared to deem acceptable the data from just one of two previous pivotal trials testing voclosporin, branded Luveniq, for the inflamed-eye indication. Lux had filed for approval in the U.S. and Europe, based on outcomes from its LUMINATE program. (See BioWorld Today, Feb. 5, 2010, and Aug. 5, 2010.)

Results from the study called LX211-01 in uncontrolled uveitis gained a 50 percent reduction in mean vitreous haze vs. 29 percent in the placebo arm. But the second trial, LX211-02 in patients with clinically quiescent disease, missed the primary analysis endpoint of all-cause therapeutic failure at six months.

For Isotechnika, the CRL meant skipping a $7. 1 million milestone from Lux, which licensed the compound in ophthalmic indications; for Lux, the CRL meant doing another Phase III trial. With the blowup of the latest study, Lux does not expect to move forward with its campaign to get Luveniq approved in the U.S. and overseas.

Isotechnika continues, though, to investigate voclosporin in such areas as kidney transplant rejection. A 334-patient Phase IIb trial called PROMISE met its primary endpoint of non-inferiority when compared to market-leading calcineurin inhibitor tacrolimus (Prograf, Astellas Pharma Inc.) in biopsy-proven acute rejection episodes – a much more solid endpoint than vitreous haze, Foster noted. Twelve-month safety and efficacy data were disclosed in April 2009.

The science behind voclosporin is fairly straightforward. Isotechnika adds one carbon molecule at the amino acid-1 residue of cyclosporine to strengthen the binding of the voclosporin/cyclophilin complex to calcineurin and make the major metabolites of voclosporin eliminate faster, so the potency should be higher and the metabolite load lower than cyclosporine.

Metabolites "distort the [pharmacodynamics] picture, because you have almost interference or noise," Foster said. "They also contribute to the overall toxicity of cyclosporine." Changing its molecular structure lets Isotechnika use "probably about a quarter or a third as much drug, relative to cyclosporine," which leads to fewer off-target toxicities. Isotechnika hopes voclosporin also will reduce cases of new-onset diabetes in transplant patients, too.

Testing the Mood of Potential Phase III Backers

Voclosporin has found its way into about 2,000 patients over the years, "so we know it works," Foster said. The problem is getting the cash to prove as much at the Phase III level.

In June, Isotechnika said 3SBio Inc., of Shenyang, China, received approval from the State Food and Drug Administration there to conduct a multicenter Phase III trial in kidney transplants, which was due to begin in the third quarter of this year. Isotechnika granted 3SBio exclusive rights to all transplant and autoimmune indications of voclosporin in China, including Hong Kong and Taiwan, excluding ophthalmic indications and medical devices, in 2010.

"We're ready to go over here, too," Foster said. "We're just looking to get our finances in order." A special protocol assessment agreement has been granted by the FDA, and an equivalent plan has won the nod from European regulators.

A snag in the advancement of voclosporin involves Isotechnika's agreement with Iljin Life Sciences Co. Ltd., of Seoul, South Korea. Earlier this month, Isotechnika said a partial award has been issued in arbitration regarding the dispute between the pair. Iljin is obligated to purchase 39.6 million shares of Isotechnika at a price of about $0.215 per share, for aggregate gross proceeds of $8.5 million, and must pay $500,000 as a final license fee upon the joint steering committee determining that Isotechnika satisfactorily advanced the Phase III kidney transplant trial for voclosporin in accordance with the development plan.

"They're supposed to infuse another $9 million into our company, and we're talking to them about the timing of the $9 million, or [whether they will allow] us to seek other partners, depending on what they want to do," Foster told BioWorld Today.

Meanwhile, at the JPMorgan Healthcare Conference in San Francisco next month, Isotechnika will prowl for funders. "We're testing the mood," he said. "If the appetite is good, we'll hopefully be doing this [Phase III program] sooner rather than later."

The uveitis setback is a comparatively small bump in the road. Calcineurin inhibitors such as tacrolimus mostly sell for solid-organ transplants; this is where the $2 billion worth of revenues for the Astellas drug comes from, Foster said.

Were such compounds "panacea drug[s] for ophthalmology, they would be all over the place" in eye disease, he said, and it's not so. "[Astellas] must have known something we didn't know," Foster added.

"As a small company, if somebody comes along who's got deeper pockets than we have, and says, 'We want to try to get this drug into the marketplace quickly,' well, you're hoping you can get cash flow," he said. "That's what it's all about."

Shares of Isotechnika (TSX:ISA) dipped 16.7 percent Thursday, to close at C$0.05 (US$0.05).