February 16, 2016
Jazz Pharmaceuticals reported results
of a phase III study of defibrotide for use
in patients with hepatic veno-occlusive
(VOD), also known as sinusoidal obstruction
syndrome (SOS), with multi-organ
failure (MOF) post-hematopoietic stem-cell
transplantation (HSCT). The phase III study
investigated the safety and efficacy of
defibrotide in adult and pediatric patients
with established hepatic VOD/SOS with
MOF. Patients (n=102) given 25mg/kg/
day defibrotide were compared with 32
historical controls identified from review
of medical charts of HSCT patients by an
independent medical review committee,
blinded to outcome. Baseline characteristics
between groups were well-balanced. The
historical-control methodology offers a novel
approach for phase III evaluation of orphan
diseases associated with high mortality,
where a placebo control would be unethical.
Defibrotide was associated with a statistically
significant improvement in Day +100
post-HSCT survival, the primary endpoint,
compared to the historical controls. The
estimated between-group difference in Day
+100 survival was 23.0% (95.1% confidence
interval (CI): 5.2%-40.8%; P=0.0109), using a
propensity-adjusted analysis. The difference
of complete response (CR) rates by Day +100
post-HSCT, a secondary endpoint, resulted
in an estimated between-group difference
adjusted for propensity score of 19% (95.1%
CI: 3.5 34.6; P=0.0160). Median duration of
treatment with defibrotide was 21.5 days.
Hypotension was the most common adverse
event in both groups (39.2% with defibrotide
and 50% for historical controls). Related
adverse events included hemorrhage and
hypotension. There was no difference in the
incidence of common hemorrhagic events
between defibrotide and the historical controls.
Defibrotide was granted Orphan Drug
designation by the FDA in May 2003 and has
Fast Track designation. An NDA is under review
by the FDA. Defibrotide is being made
available as an IND free of charge through an
expanded access Treatment Protocol.
August 20, 2012
The American Journal of Transplantation published a phase III study of RAD001 (everolimus) with reduced tacrolimus for the treatment of liver transplant. This randomized, open-label, multi-center study enrolled 719 de novo liver transplant patients. Following liver transplantation and a 30-day run-in period with tacrolimus and corticosteroids (with or without mycophenolate mofetil), subjects were randomized into one of three groups: RAD001 (C0 3-8ng/mL) plus reduced-exposure tacrolimus (C0 3-5ng/mL); RAD001 (C0 6-10ng/mL)with tacrolimus withdrawal at four months; or standard-exposure tacrolimus (C0 6-10ng/mL) only. All arms included corticosteroids for at least six months post-transplant. The study met the amended primary endpoint: the composite efficacy failure rate of tBPAR, graft loss or death. The composite efficacy failure rate in the RAD001 plus reduced-exposure tacrolimus group was lower compared to the control group at month 12 (6.7% versus 9.7%, respectively). Data showed non-inferiority (against the non-inferiority margin of 12%) with -3.0% [97.5 CI (-8.7%, 2.6%)] in favor of the RAD001 plus reduced-exposure tacrolimus group (p<0.001 for non-inferiority). RAD001 plus reduced-exposure tacrolimus also demonstrated fewer episodes of tBPAR between day 30 and month 12. The FDA has accepted the filing for RAD001 for the prevention of organ rejection in adult liver transplant patients, and a decision is expected by Q4 2012.
June 9, 2008
Isotechnika reported positive top-line results from a phase IIb trial of voclosporin for the prevention and treatment of kidney transplant rejection. This randomized, multicenter, open-label, concentration controlled, dose ranging study, dubbed PROMISE, enrolled 334 subjects who had recently undergone kidney transplant surgery in the US and Canada. The subjects received three different doses of voclosporin (0.4 mg/kg, 0.6 mg/kg, and 0.8 mg/kg twice daily) or tacrolimus control (0.05 mg/kg twice daily). Voclosporin and tacrolimus were administered over a six month period along with other standard immunosuppressive therapies used following transplantation. The primary endpoint was defined as non-inferiority in biopsy proven acute rejection (BPAR) episodes between the treatment arms. This endpoint was met in all three voclosporin dose groups, showing voclosporin is as efficacious as tacrolimus. In the low dose voclosporin arm, 11% of subjects had BPAR, in the mid-dose arm, 9% had BPAR and in the high dose group 2% had BPAR, compared to 6% of the subjects in the tacrolimus arm. Secondary endpoints, including incidence of new onset diabetes mellitus (NODM), kidney function, electrolytes and neurological effects, were reached as well. A statistically significant lower incidence of NODM was seen in the low dose voclosporin group (1.6%), compared to tacrolimus (16.4%), translating into a 90% reduced risk of developing NODM (p less than 0.05). Although not statistically significant, the mid dose group had a clinically meaningful lower incidence of NODM; the high dose group was not clinically different than tacrolimus. Kidney function was well preserved in each of the three dose levels of voclosporin relative to tacrolimus and no significant differences were noted between the treatment arms. The low dose voclosporin group showed a statistically significant reduction in the number of incidences of elevated triglycerides compared to tacrolimus with a 55% risk reduction (p less than 0.05). The mid and high dose groups showed a 24% to 30% reduced risk of elevated triglycerides. Voclosporin also showed trends to a reduced incidence of insomnia and tremors at the six month time point as compared to tacrolimus. Based on the results Isotechnika plans to move forward with phase III trials.
September 8, 2003
Cordis reported positive final results from a medical device trial investigating the CYPHER Sirolimus-eluting coronary stent for the treatment of arterial blockage. Results demonstrated sustained improvement in vessel re-narrowing at 12-month follow-up compared to a conventional bare metal stent. Data also showed a trend towards lower re-blockage rates in subjects treated with the CYPHER Stent without pre-dilation. Earlier results showed that 43.6% of subjects who received the standard metal stent exhibited reblockage compared with 5.8% of subjects treated with the CYPHER. The study, called E-SIRIUS enrolled 352 subjects at 35 sites in Europe. Results were presented at the 2003 European Society of Cardiology Congress in Vienna.
King Pharmaceuticals and Wyeth reported positive results from a post-marketing trial investigating Altace (ramipril), an ACE inhibitor for the prevention of cardiovascular disease. Results showed a sustained effect of ramipril on the prevention of cardiovascular disease and no preventive effects of vitamin E. The study was conducted by the Population Health Research Institute at McMaster University and Hamilton Health Sciences in Hamilton, Ontario, Canada. Results were presented at the European Society of Cardiology Meeting in Vienna, Austria. The HOPE-TOO (HOPE-The Ongoing Outcomes) study began in November 1999 and examined the benefits seen with 4.5 years of treatment with ramipril were sustained and whether longer-term treatment with vitamin E protected against the development of cancer and cardiovascular disease.
Novartis reported positive results from a clinical trial investigating everolimus, an immunosuppressant drug for the treatment of complications from heart transplants. Results showed that everolimus was significantly more effective in reducing the severity and incidence of serious transplant complications than current therapy. Data also showed that everolimus significantly reduced the incidence of cytomegalovirus infection. The two-year international study was conducted at 52 medical centers in four countries and enrolled 634 subjects with heart transplants who were given the standard regimen of cyclosporine and steroids in addition to treatment medication. The study was designed to target acute rejection and cardiac allograft vasculopathy. Results were presented in the Aug. 28th issue of The New England Journal of Medicine.
February 4, 2002
An application for a new indication of Wyeth-Ayerst's Rapamune (sirolimus) was not recommended for approval by the Immunosuppressive Drugs Subcommittee of the FDA Antiviral Drugs Advisory Committee. The immunosuppressant agent is already approved for the prophylaxis of organ rejection in patients receiving kidney transplants. It is currently recommended that Rapamune be used in a regimen concomitantly with cyclosporine and corticosteroids. The committee's decision pertained to a new Rapamune maintenance regimen that would allow physicians to eliminate cyclosporine two to four months after transplantation. The company plans to meet with the FDA to discuss the review.