Isotechnika has path forward for pivotal trial

October 25, 2011 by Leonard Zehr

Isotechnika Pharma (TSX:ISA) has taken an important step toward launching final testing of a potential breakthrough drug to prevent rejection of a transplanted kidney.

“We now have a clear path forward for a proposed Phase 3 clinical trial protocol of our voclosporin drug,” CEO Dr. Robert Foster says in an exclusive interview with BioTuesdays.com.

He was referring to last week’s positive Scientific Advice from the European Medicines Agency for a pivotal clinical trial of voclosporin. This ensures that no major objections regarding the design of the study or the clinical endpoints are likely to be raised down the road during the agency’s evaluation of the company’s final marketing application.

Isotechnika also is awaiting a decision later this year from the FDA for a Special Protocol Assessment in order to finalize plans to initiate its Phase 3 program by mid-2012. The company plans to conduct two trials, with about 600 new kidney transplant patients in each study. One trial will be conducted predominatly in North America and the other, predominatly in Europe, with each study costing nearly $30 million.

“Voclosporin is the only new calcineurin inhibitor (CNi) close to commercialization,” Dr. Foster points out.

One of two CNi drugs – tacrolimus or cyclosporine, first introduced into the marketplace in 1982 – is prescribed for some 93% of patients after kidney transplant surgery in order to suppress the immune system from rejecting the donor kidney. But the use of tacrolimus or cyclosporine can lead to severe side effects.

In a large Phase 2B study, involving 334 patients, voclosporin was as effective as tacrolimus in preventing rejection of a transplanted kidney.  More importantly, volcosporin was superior to tacrolimus in several important safety areas, including the incidence of new onset of diabetes. Specifically, patients receiving voclosporin in the blood concentration ranges planned to be used in Phase 3, had, on average, a 65% reduced risk of developing diabetes, compared with tacrolimus, the current market leader.

Isotechnika's voclosporin is a potential breakthrough drug to prevent rejection of a transplanted kidney.

Patients on voclosporin in the Phase 2b study also demonstrated preservation of magnesium levels, whereas patients taking tacrolimus exhibited altered magnesium homeostasis leading to hypomagnesemia. These lower levels of magnesium with tacrolimus use can lead to cardiac arrhythmia, hypertension, muscle cramps and increased irritability of the nervous system, resulting in tremors, confusion, hallucinations and insomnia. In addition, voclosporin showed a reduced incidence of elevated triglycerides, which are a contributing factor to cardiovascular risk.

“The big win for us in Phase 3 would be to show statistically that we have better safety parameters than the gold standard tacrolimus, especially reducing the incidence of diabetes, as well as having the same efficacy as tacrolimus,” Dr. Foster says, adding “this is a story about the same efficacy and better safety than what’s out there.”

Isotechnika’s story shows a dogged determination to bounce back from a body blow in 2007 when its development partner, Roche (NASDAQ: RHHBY), made a strategic decision to end its involvement in the development of transplant rejection drugs and focus instead on treatments for oncology, immunology, virology, metabolism and central nervous system diseases.

“Roche was very thorough back then and, in some ways, the Phase 2b was a mini Phase 3 trial,” he recalls. “Clinically, we’re using the same endpoints and everything else is the same in the Phase 3 as it was in the Phase 2b, except it’s just bigger. So, we think clinically, the risk is low because the Phase 2b worked and there shouldn’t be any reason why the Phase 3 doesn’t work.”

Voclosporin is the only CNi to show a predictable concentration effect relationship

Among other things, the Phase 2b study established clarity on the ideal dosing regimen of voclosporin to be used in the Phase 3 program – at 30-to-60 nanograms/milliliter. “We started seeing rejection episodes in the Phase 2b when the concentration went below 30 ng/mL and when we pushed the concentration up above 60 ng/mL, our drug started performing more like tacrolimus – with some patients developing diabetes,” he adds.  An optimized dosing strategy “balances rejection with reduced new onset diabetes after transplant and preservation of both kidney function and electrolytes,” according to Dr. Foster.

Isotechnika also found a very strong correlation between the administered dose of voclosporin and the resulting drug blood concentration in patients.  This pharmacometric evaluation, Dr. Foster points out, not only revealed the optimal dosing regimen for Phase 3, but also indicated that voclosporin will be easy to use in practice, as patients’ blood levels need to be adjusted into a therapeutic range.

The main driver of the primary endpoint in the Phase 3 trials will be biopsy-proven acute rejection (BPAR) for both voclosporin and tacrolimus. The key reading in the secondary endpoints will be to determine the proportion of patients with new onset diabetes after one year as well as overall safety and tolerability of voclosporin relative to tacrolimus.

Last February, Isotechnika finalized a partnership accord with the Iljin Life Sciences group of South Korea to finance the first Phase 3 trial of voclosporin. Iljin has injected about $28 million into Isotechnika in return for voclosporin’s marketing rights in the United States, Central and South America and Asia (with the exception of China).

The marketing rights to mainland China, Hong Kong and Taiwan were licensed in 2010 to 3SBio (NASDAQ:SSRX), a Chinese biotech company, in return for $6 million. As part of the Phase 3 program, 3SBio will run a clinical study with a few hundred new transplant patients in its territories, which will result in cost savings to Isotechnika, according to Dr. Foster.

What’s left unpartnered is Europe and Dr. Foster says the company will be looking for another partner to finance the second Phase 3 trial. “Ideally, we’d like to run both trials at the same time so that we can aggressively recruit patients and reduce the length of the trials,” he adds.

Kidney transplants represent 62% of the transplant market in seven major markets. The annual market for CNi drugs, which represent the cornerstone of immunosuppression, was around $3 billion in 2009, with tacrolimus accounting for two-thirds of the total and cyclosporine the balance. Tacrolimus is approved for kidney, liver and heart transplants, while cyclosporine is approved for all solid organ and bone marrow transplants, as well as several autoimmune diseases.

If the pivotal trials are successful, Dr. Foster predicts voclosporin has the “potential to replace the majority of the new cyclosporine market share by demonstrating a superior overall safety/efficacy profile. We also expect to gain market share from tacrolimus based on overall safety advantages, specifically reduced incidence of new onset of diabetes and CNS effects, and from the benefit of having a drug that is clinically easy to use.”

The development of voclosporin in the mid-1990s involved “making tiny adjustments” to the chemical structure of cyclosporine, resulting in a molecule that binds to the calcineurin enzyme a “lot better than cyclosporine does,” he recalls.  He adds, “In vitro and in vivo voclosporin data demonstrate that 100% calcineurin inhibition is readily achieved.  This is not the case for cyclosporine; 100% inhibition does not occur.”

The chemical structure of voclosporin vs. cyclosporine

Voclosporin, which has been studied in more than 2,000 patients, has increased potency, enabling the use of lower doses, compared with cyclosporine; produces fewer metabolites than cyclosporine, which can lead to side effects; and demonstrates a known effect at a known concentration.

Isotechnika has 240 patents and patent applications, relating to the compound, mixtures of isomers, synthesis and formulation of voclosporin, and expiring in 2023 and 2024. “We believe that between patent-term adjustments and extensions, the various patents will extend out further.  So, if we can launch the drug in 2015 or 2016, it will give us at least 10 or 11 years of patent protection, which is a good runway in front of us,” he says.

Although there are generic versions of cyclosporine and tacrolimus available, Dr. Foster says physicians are reluctant to use them because they were developed with only bioequivalence studies, not a comprehensive Phase 3 program.

“With a hypertensive drug, if a generic misses a few millimeters of mercury on the systolic or diastolic pressure, it’s probably not a big deal for the patient,” he notes. “But in transplantation, if you miss the mark by a couple of nanograms/mL, the patient could face some serious problems with side effects that could lead to death.”

The concentrations of CNi drugs in the bloodstream “need to be carefully monitored and adjusted within a very narrow concentration range,” he points out.  Dr. Foster adds, “Additionally, the patient’s health is changing daily post-transplant, and that could make the drug levels much more variable.  Given the choice, most transplant physicians would very likely gravitate toward using a drug that is branded and accompanied by years of clinical research and not just a simple bioequivalency study of healthy human subjects.”

The bottom line: “We are undertaking a Phase 3 transplant program that has been de-risked economically, with a business relationship that utilizes leverage and clinically, with a Phase 2b clinical trial that was a mini-Phase 3,” he says.