voclosporin
Phase 2b Kidney Transplantation (PROMISE) Trial
The Company announced successful completion of the PROMISE trial on May 27, 2008. An extension to the six month trial is ongoing at forty-two centers 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 | |||
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.
Phase 2b (PROMISE) Trial Design
A total of 334 de novo (newly transplanted) kidney transplant patients were enrolled in this trial. 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 (0.05 mg/kg twice daily) 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. All patients received oral treatment of the drug (voclosporin or tacrolimus) over a six month period, along with other standard immunosuppressive therapies used following transplantation.
On June 7, 2007, and August 2, 2007, the Company announced that it had received permission from Health Canada and the Food and Drug Administration (USA), respectively, to allow patients to remain on voclosporin until the drug is commercially available.