Clinical Trials
Voclosporin
Psoriasis Clinical Trials
Phase 3 Combined European/Canadian (ESSENCE) Trial
The ESSENCE study was a randomized, double-blind, placebo and cyclosporine (CsA) controlled parallel group study which commenced on December 3, 2006. The study was designed to investigate voclosporin in patients suffering from moderate to severe psoriasis over a period of 60 weeks with a 12 week follow-up period. 642 plaque psoriasis patients with ≥ 10% body surface area involvement and an Static Physician Global Assessment (SPGA) of ≥ 3 were randomized to voclosporin (0.4 mg/kg twice daily), CsA (1.5 mg/kg twice daily) or placebo with a switch to 0.4 mg/kg twice daily at week 12.
The primary endpoint was "clear" or "almost clear" in the SPGA at 12 weeks of voclosporin compared to placebo. Secondary endpoints of the study included non-inferiority of voclosporin compared to cyclosporine, superiority in de novo hypertriglyceridemia and superiority in de novo hypertension.
Isotechnika announced final safety and efficacy data on April 28, 2009. In the voclosporin arm, 35% of patients achieved a "clear" or "almost clear" SPGA score at 12 weeks compared to 6% of patients receiving placebo (p≤0.001). Another widely used measure of efficacy for psoriasis treatments is the reduction in the Psoriasis Area and Severity Index (PASI). In the voclosporin arm, 43% of patients at weeks 12 and 26% of patients at 60 weeks achieved a 75% reduction in PASI (PASI-75)and 67% of patients at 12 weeks and 68% of patients at 60 weeks achieved a 50% reduction in PASI (PASI-50).
In addition to the placebo control, the study also included an active comparator arm, cyclosporine. The secondary endpoint of non-inferiority to cyclosporin, which had a score of "clear" or "almost clear" in SPGA in 53% of patients, was not met.
Voclosporin demonstrated positive outcomes on other pre-specified secondary endpoints at 24 weeks reported in a descriptive manner. In each of these safety parameters, the advantages observed in the voclosporin arm at week 24 versus the cyclosporine arm were maintained through the week 60 of the study. In particular, the cardiorenal risk associated with vocloosporin appears to be reduced as the incidence of triglyceride elevation, hypertension and voclosporin showed clear improved safety over cyclosporine with regards to headache, paraesthesia, and hirsutism.
The table below summarizes the most important adverse events over 60 weeks:
| Adverse Event | Voclosporin | Cyclosporine |
| Hypertension | 9.4% | 14.7% |
| Headache | 7.3% | 12.4% |
| Paraesthesia | 0.8% | 7.0% |
| Nausea | 3.4% | 6.2% |
| Nasopharyngitis | 2.9% | 6.2% |
| Blood Creatinine Increased | 2.3% | 5.4% |
| Fatigue | 2.6% | 5.4% |
| Hair Growth Abnormal | 0.3% | 3.9% |
| Blood Urea Increased | 0.3% | 3.1% |
| Muscle Spasm | 0.8% | 3.1% |
| Diarrhea | 4.4% | 2.3% |
Patients have now completed 60 weeks of treatment and a "clear" or "almost clear" score was noted in 6.4%, 34.8%, and 51.9% of patients in the placebo, voclosporin, and CsA treatment groups, respectively. In general, results for the ESSENCE study were consistent with the Canadian Phase 3 study and showed that 0.4 mg/kg twice daily was generally safe and well tolerated over 60 weeks of treatment.
This is the first direct comparison study versus cyclosporin (current European standard of care) in moderate to severe psoriasis.
Phase 3 Canadian Trial
The Canadian Phase 3 study, which commenced on December 2, 2004, was designed to investigate voclosporin in patients suffering from moderate to severe psoriasis over a 24-week period. A total of 451 patients were enrolled and equal numbers of patients were randomized to one of the four treatment groups. This couble blind trial examined the efficacy of 3 dosing groups of voclosporin (0.2 mg/kg, 0.3 mg/kg and 0.4 mg/kg twice daily) over a 24-week period compared to placebo. Subsequent to their furst 12 weekds, those patients who received placebo were administered the mid-dose of 0.3 mg/kg twice daily for the remaining 12 weeks of the study. Patients who received active treatment with voclosporin remained in their respective dosing groups for the final 12 weeks of the trial.
The primary endpoint was the number of patients achieving a 75% decrease in the PASI score at 12 weeks. Secondary endpoints of the trial included maintenance of stable kidney function and assessment of quality of life.
The Company announced final safety and efficacy data October 5, 2006. After 24-weeks of treatment, patients exhibited a 60% mean improvement in 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.
Phase 2b North American Kidney Transplantation (PROMISE) Trial
The Company announced successful completion of the PROMISE study on May 27, 2008. Subsequently a 6 month extension, and a long term extension (for patients randomized to voclosporin) were added to the study.
A total of 334 de novo (newly transplanted) kidney transplant patients were enrolled in this study. Patients were placed into one of four separate treatment groups; three different dose groups of voclosporin (0.4 mg/kg, 0.6 mg/kg, and 0.8 mg/kg twice daily) compared with the fourth group, a tacrolimus control arm. Patients in all four treatment groups had their doses adjusted in order to achieve pre-defined blood levels of either voclosporin or tacrolimus. In addition, patients received other standard immunosuppressive therapies used in transplantation.
The primary endpoint of the study was defined as non-inferiority in biopsy proven acute rejection (BPAR) episodes in patients receiving voclosporin for six months as compared to the tacrolimus control. Additionally, kidney function and other laboratory parameters such as hypertension, hyperlipidemia and new onset diabetes mellitus will be monitored for the duration of the trial. The overall goal of the trial is to find the most appropriate dose that will result in efficacy (lack of rejection) with minimal side effects.
The Company announced 12 month safety and efficacy data April 21, 2009. The primary endpoint demonstrating non-inferiority in BPAR episodes as compared to tacrolimus control in all three dose groups at six months was met. The extended data demonstrates that voclosporin maintained efficacy at 12 months. Voclosporin also demonstrated an improved safety profile versus tacrolimus. This trial was designed to determine the most appropriate dosing strategy for the Phase 3 development programs of voclosporin in kidney transplantation. The extension study provides sufficient data to implement a dosing strategy for Phase 3 designed to provide a better safety profile than tacrolimus while maintaining efficacy at 12 months.
The long term extension portion was terminated by Isotechnika in May 2009. All sites had the option of applying for a Special Access Program in Canada and a Treatment IND in the US, which allows their patients to continue voclosporin treatment until commercially available. 2 sites are currently continuing with the Special Access Program and 1 site is currently continuing with the Treatment IND.
Uveitis Clinical Trials
Isotechnika's partner, Lux Biosciences, initiated pivotal trials of voclosporin in uveitis in February, 2007. The LUMINATE program consisted of three controlled, double masked Phase 2/Phase 3 trials investigating the use of voclosporin (referred to as LX211 by Lux) in different forms of active uveitis in addition to maintenance of quiescent disease. The program enrolled 558 patients in 7 countries (United States, Canada, United Kingdom, France, Germany, Austria and India). Uveitis is a leading cause of vision loss and long-term disability in the developed world, accounting for 10% to 20% of cases of legal blindness
Lux has been granted orphan drug designation from the FDA for voclosporin for the treatment of non-infectious posterior, intermediate, and panuveitis. This designation qualifies Lux for exclusive marketing rights in the United States for seven years if the company is the first to receive marketing approval. Furthermore, the European Agency for the Evaluation of Medicinal Products (EMEA) committee for Orphan Medicinal Products has adopted a positive opinion on orphan medicinal product designation for voclosporin for the treatment of chronic, non-infectious uveitis.
On August 7, 2007, Lux and Isotechnika announced that the FDA granted Fast-Track designation for voclosporin for the treatment of uveitis.
The key results in the LUMINATE trials were reported on March 26, 2009. Overall, of the 3 doses studied, the 0.4 mg/kg BID dose had the most acceptable safety profile relative to effect on the disease. The results of the individual studies are as follows:
· Study LX211-01 enrolled 218 patients with active non-infectious uveitis with posterior manifestation of the disease. The 0.4 mg/kg BID met the primary endpoint of superiority to placebo at both weeks 16 (p=0.008) and week 24 (p=0.04) for mean change from baseline in vitreous haze, a validated measure of inflammation of the posterior segment of the eye. The magnitude of the effect was > 1 step change, demonstrating a clinically relevant benefit.
· Study LX211-02 enrolled 232 patients with clinically quiescent disease. The 0.4 mg/kg BID dose showed a reduction by 50% vs. placebo in rate of recurrence of inflammation at 6 months. The study did not meet the primary analysis endpoint of all-cause therapeutic failure at 6 months as the drug effect on inflammation was diluted by discontinuations that were unrelated to inflammation. This was due to a pre-specified analysis that accounted for data censoring due to non-efficacy-related discontinuations. However, the reduction in inflammation vs.placebo by 50% was statistically significant (p=0.046), thus confirming the positive results from LX211-01.
· Study LX211-03 enrolled a narrow sub-set of 109 patients with active uveitis with anterior manifestation of the disease. The efficacy of the voclosporin dose groups and placebo did not separate during the steroid taper; all showed an improvement by > 1 step mean reduction from baseline in anterior chamber cells, a validated measure of inflammation in the anterior segment of the eye. This study, which is not critical for approval and was added to encompass a sub-set of patients affected by anterior chamber disease, turned out to be underpowered owing to greater than expected variability.
The integrated safety profile of 0.4 mg/kg BID voclosporin suggests that it would be suitable for chronic use in this high medical need indication. Of particular interest were the relatively small effects of voclosporin 0.4 mg/kg BID on renal function. Patients experienced a mean increase in systolic blood pressure by study-end over baseline of 6 mmHg. However, most of these patients were successfully controlled with medication and only 1.3% discontinued therapy due to hypertension. Other adverse events typical of the calcineurin inhibitor class, in particular diabetes, elevation of lipids, hypomagnesemia, and tremor, were not observed.