North American Kidney Transplantation (PROMISE) Study Meets Primary Endpoint

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 (low, mid and high dose) 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 6 month study was defined as non-inferiority in biopsy proven acute rejection (BPAR) episodes in patients receiving voclosporin compared to tacrolimus, which is a market leader. Additionally, new onset diabetes after transplantataion (NODAT), kidney function and other laboratory parameters such as blood pressure and lipids were monitored for the duration of the trial. The overall goal of the trial was to find the most appropriate dose that will result in efficacy (lack of rejection) with minimal side effects.

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.   The results of this study demonstrated:

• The incidence of NODAT for VCS was 1.6%, 5.7% and 17.7% versus 16.4% in TAC (low-dose VCS, p = 0.03).
• Nankivell estimated glomerular filtration rate was 71, 72, 68 and 69mL/min (statistically lower in the high-dose group, p = 0.049).
• The incidence of hypertension and adverse events was not different between the VCS groups and TAC.
• VCS demonstrated an excellent correlation between trough and area under the curve (r2 = 0.97) and no difference in mycophenolic acid exposure compared to TAC.

This 6-month study showed VCS to be as efficacious as TAC in preventing acute rejection with similar renal function in the low and medium-exposure groups, and potentially associated with a reduced incidence of NODAT.

The Company announced 12 month safety and efficacy data April 21, 2009.  The objective of this extension was to obtain additional efficacy and safety information (BPAR and renal function) in those subjects who consented to continue in the study beyond Month 6.  The results of this study clearly provided the information needed to define the therapeutic concentration range of VCS necessary to achieve a non-inferior BPAR and superior NODAT rate.  This can be accomplished by targeting trough concentrations below 60 ng/mL while minimizing the incidence of BPAR with trough concentrations above 35 ng/mL. 

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.