Frequently Asked Questions
When was Isotechnika founded?
The Company was incorporated in 1993 and was listed on the Alberta Stock Exchange in 1996.
Where is the stock listed?
Isotechnika’s common shares are currently listed on the Toronto Stock Exchange (TSX) and trade under the symbol ISA.
What is the Company's current cash position?
At September 30, 2008, cash, cash equivalents and short-term investments totalled $28.0 million.
What is the vision for Isotechnika?
Isotechnika is focused on the discovery and development of novel therapeutic immunosuppressive drug candidates.
How many people are employed by Isotechnika?
As of February 15, 2009, the Company employs 43 people.
Voclosporin
What is voclosporin?
Voclosporin is an immunosuppressive drug in the class of calcineurin inhibitors.
What stage of clinical trials is voclosporin currently in?
Voclosporin has successfully completed a Phase 2b North American (PROMISE) trial for the prevention of kidney rejection following transplantation. An extension to the PROMISE trial, and a combined Phase 3 European/Canadian trial for the treatment of moderate to severe psoriasis, is ongoing.
Our partner, Lux Biosciences, completed three separate Phase 2/3 pivotal trials investigating voclosporin (referred to as LX211 by Lux) for the treatment of uveitis. In addition to the uveitis trials, Lux Biosciences has also commenced a Phase 1 trial using the voclosporin ophthalmic solution as a candidate for dry eye syndrome.
Voclosporin has also entered First-in-Man trials as the drug utilized in the CINATRA TM Drug Coated Coronary Stent system developed by the Company's partner, Atrium Medical Corporation.
What is the status of the combined Phase 3 European/Canadian (ESSENCE) trial?
On March 31, 2008, the Company announced that an independent data monitoring committee (DMC) met and reviewed the interim data from the ongoing blinded Phase 3 psoriasis trial. The review included 24-week data from approximately 50% of the patients enrolled in the trial. Based on their review of the safety and efficacy data, the DMC did not raise any concerns that would require a change to the original study trial.
The first patient was enrolled in the ESSENCE trial on December 3, 2006. On July 20, 2007, the Company completed patient recruitment at 642 patients. The patient population is composed of 295 patients from Germany, 116 from Poland and 231 from Canada. The trial is currently being performed at a total of 50 centers.
The ESSENCE trial is being conducted as a randomized, orally administered placebo and cyclosporine controlled study with patients receiving voclosporin (0.4mg/kg twice daily), patients receiving cyclosporine (1.5 mg/kg twice daily) and patients receiving placebo in a 3:1:1 ratio for 24 weeks. Patients enrolled in the placebo group will be converted to the voclosporin arm following the first 12 weeks of treatment.
Upon the Company receiving regulatory approval for an extension to this trial, patients who had not yet finished the 24 week portion of the trial were given the opportunity to remain on therapy for an additional 36 weeks - making the total length of treatment 60 weeks for those patients.
Successful completion of the trial will be determined by the primary endpoint of superiority in the proportion of patients achieving a score of "clear" or "almost clear" in the Static Physician's Global Assessment (SPGA) score at 12 weeks in the voclosporin treatment group compared to placebo control. Secondary endpoints include, amongst others, non-inferiority of voclosporin compared to the cyclosporine control arm in the proportion of patients achieving a score of "clear" or "almost clear" in the SPGA score at 12 weeks and a 75% reduction in the PASI score.
What were the unblinded 60 week results for the Canadian Phase 3 psoriasis trial?
On October 5, 2006, Isotechnika announced final safety and efficacy results (60 week data) from the Canadian Phase 3 psoriasis trial. Patients received continuous treatment with voclosporin for a total of 60 weeks. Over the course of the 24-week Phase 3 trial, patients exhibited a 60% mean improvement in Psoriasis Area and Severity Index (PASI) scores. After an additional 36 weeks of treatment, there was a 54% mean improvement in PASI scores indicating continued therapeutic benefit. This beneficial effect was still observed twelve weeks after discontinuing voclosporin treatment; mean PASI scores remained at 35% below pre-treatment scores.
Subsequent to 60 weeks of continuous treatment, there were no clinically significant changes in kidney function, cholesterol, triglycerides, new onset diabetes, infectious complications, or other laboratory parameters. This supports the long term safety of voclosporin.
What other studies must Isotechnika complete to commercialize voclosporin for psoriasis?
The Company, to meet FDA guidelines, was required to perform a multiple dose QTc study to confirm that there are no unanticipated, significant QTc effects associated with repeated dose treatment of voclosporin. As psoriasis is not considered a life threatening disease, safety is of paramount importance. A single dose QTc trial was successfully conducted by the Company in 2004 indicating no cardiac conduction abnormalities were detected at therapeutic doses of voclosporin. The required multiple dose QTc trial commenced in September, 2005. The trial was delayed by approximately one month when a cohort of trial subjects had to be replaced due to one of the subjects being inadvertently admitted to the trial with pre-existing tuberculosis by the CRO (SFBC Anapharm, a division of SFBC International, Inc.). The diagnosed tuberculosis, therefore, was not drug-eluted. The last patient, last visit portion of the trial was completed on January 24, 2006. The draft results from this trial, received on April 25, 2006, indicate that repeated oral dosing of voclosporin at 1.5 mg/kg bid for 13 doses is not associated with QTc elevation. This result meets the regulatory criteria for a negative QTc effect with voclosporin. The final results received by the Company in June, 2006 reflected no differences from those indicated in the draft report noted above.
For regulatory purposes, the Company is required to perform rat and mouse carcinogenicity studies where voclosporin is repeatedly administered over a period of two years. Carcinogenicity studies are required by the FDA and other regulatory authorities, and are a critical part of the package submitted for marketing approval. Carcinogenicity studies are performed by administering a range of doses of a drug, including a dose considerably higher than the anticipated clinical dose, for a period of two years. This timeframe is equivalent to administering the drug over a lifetime in humans.
The FDA approved the protocol for the two year rat study in November 2004, and the study commenced on January 25, 2005. The active dosing portion of the rat study was completed in December 2006. The CRO performing the study is in the process of analyzing the data and preparing the required study report. The Company received the final draft report in November 2007. Voclosporin did not exhibit any carcinogenicity up to the highest doses tested in male and female rats over a two year period.
Commencing in the third quarter of 2005, the Company conducted dose-range finding studies in mice to determine the appropriate dosing for the two year mouse study. The information obtained from the dose-range studies was submitted to the FDA. The Company received FDA approval for the protocol for the two year mouse study in February 2006 and the study commenced in March 2006. The active dosing portion of the study was completed in December 2007 with receipt of the final report scheduled for late 2008.
What were the results of the voclosporin Phase 2a kidney transplantation trial?
The primary endpoint of the trial was to demonstrate that stable kidney transplant patients receiving mix-voclosporin experienced no negative change in kidney function when compared to patients on cyclosporine (Neoral®). The secondary endpoint of the study was to measure the pharmacodynamics and pharmacokinetics of mix-voclosporin in renal transplant patients. All of these endpoints were achieved.
Patients receiving mix-voclosporin showed no further deterioration in kidney function when compared to those receiving cyclosporine. In this trial renal transplant patients switched from cyclosporine to mix-voclosporin in a safe and effective manner. Additionally, no rejection episodes occurred in patients receiving mix-voclosporin.
Drug concentrations of cyclosporine in blood were three times higher than that of mix-voclosporin. However, immunosuppressive activity of both drugs, as measured by calcineurin inhibition, was the same. This indicated that mix-voclosporin was at least three times more potent than cyclosporine which was consistent with all pre-clinical and Phase 1 trial results.
What is the status of voclosporin for transplantation?
The Company announced on May 27, 2008 the successful completion of the PROMISE trial. The PROMISE trial involved 334 de novo (newly transplanted) kidney patients from forty-two clinical trial sites across North America, including thirty-eight centers in the United States and four centers in Canada. Patient enrolment was completed on June 26, 2007.
Efficacy Results
In PROMISE, the primary endpoint (biopsy proven acute rejection, BPAR) was clearly met in all three voclosporin dose groups. BPAR is a measure of acute rejection in transplant. In clinical practice, patients with more episodes of BPAR, typically 10-15% at 6 months, have worse outcomes. The results show that voclosporin is as efficacious as tacrolimus, has the dose response expected in a Phase 2 trial, and provides the rationale for dose selection for the Phase 3 clinical program.
| Drug | Patients with BPAR |
| Low dose voclosporin | 11%* |
| Mid dose voclosporin | 9%* |
| High dose voclosporin | 2%* |
| Tacrolimus | 6% |
| *statistically non-inferior to tacrolimus | |
Safety Results
The three dose groups of voclosporin were shown to be safe. Voclosporin demonstrated improvements over tacrolimus in several key areas, specifically with respect to NODM, triglycerides, magnesium, insomnia and tremors.
New Onset Diabetes Mellitus (NODM)
NODM is a serious complication in transplant patients and negatively impacts patient outcomes. Published literature shows that mean graft survival of 11 years decreases to 8 years with NODM.
A statistically significant lower incidence of NODM was seen in the low dose voclosporin group, translating into a 90% reduced risk of developing NODM as compared to tacrolimus. Althought not statistically significant, the mid dose group had a clinically meaningful lower incidence of NODM with a 65% reduced risk. The high dose group had an incidence of NODM that was not clinically different than tacrolimus. This reduced burden of NODM in the low and mid dose groups represents a large benefit to patients.
Triglycerides
Trigyceride elevation is a risk factor of cardiovascular complications. The low dose voclosporin group showed a statistically significant reduction in the number of incidences of elevated trigycerides compared to tacrolimus translating into a 55% risk reduction. The mid and high dose groups showed a 24 to 30% reduced risk of elevated triglycerides.
Magnesium
Magnesium is involved in many important functions in the body, and is regulated by the kidneys. Low magnesium levels can lead to cardiac arrhythmia, hypertension, muscle cramps, and increased irritability of the nervous system, resulting in tremors, confusion, hallucinations and insomnia. Voclosporin showed significantly higher levels of magnesium than tacrolimus, improving the overall saftey profile.
| Drug | Patients with NODM | Elevated Trigycerides | Magnesium (6 months) |
| Tacrolimus | 16.4% | 39.2% | 1.77 mmol |
| Low dose voclosporin | 1.6%* | 17.5%* | 1.98 mmol** |
| Mid dose voclosporin | 5.7% | 29.7% | 1.95 mmol |
| High dose voclosporin | 17.7% | 27.5% | 1.89 mmol |
| *significantly different from tacrolimus, p<0.05 **significantly different from tacrolimus, p<0.005 | |||
Voclosporin also showed trends to a reduced incidence of insomnia and tremors at the six month time point as compare to tacrolimus. This reduced side effect burden is also clinically meaningful to patients and their physicians.
| Drug | Tremors (6 months) | Insomnia |
| Tacrolimus | 12.5% | 14.0% |
| Low dose voclosporin | 3.0% | 7.1% |
| Mid dose voclosporin | 3.1% | 10.4% |
| High dose voclosporin | 2.9% | 6.9% |
Kidney Function
In the elevation of kidney function, there were no significant differences noted between the voclosporin and tacrolimus groups. Kidney function was well preserved in each of the three dose levels of voclosporin relation to tacrolimus. Voclosporin did not meet one of the secondary objectives, a 5% improvement in kidney function as determined by iothalamate GFR.
| Drug | Iothalamate GFR (mL/min) | Nankivell GFR (mL/min) | Serum Creatinine (µmol/L) |
| Tacrolimus | 65 | 69 | 120 |
| Low dose voclosporin | 56 | 71 | 122 |
| Mid dose voclosporin | 64 | 72 | 123 |
| High dose voclosporin | 60 | 68 | 131 |
Better kidney function is indicated by a higher GFR and a lower serum creatinine.
The results indicate that the dosage can be adjusted to maximize efficacy without having deleterious effects on the kidney.
Dose response relationship
Analysis of the pharmacokinetic and pharmacodynamic data from this trial suggests that an ideal dosing strategy is readily identifiable with voclosporin. A wide therapeutic window which optimizes both efficacy and safety has now been confirmed, allowing transplant physicians and surgeons to individualize voclosporin dosing for their patients.