Isotechnika announces positive 12 month data from PROMISE trial
EDMONTON, April 21 /CNW/ - Isotechnika Inc. (TSX:ISA) today announced positive 12 month follow up data from the Phase 2b PROMISE trial evaluating its lead drug, voclosporin, a next generation calcineurin inhibitor, in de novo kidney transplant patients. As a dose ranging study, the Phase 2b trial was successful in meeting the primary endpoint demonstrating non-inferiority in biopsy proven acute rejection (BPAR) episodes as compared to tacrolimus control in all three dose groups at six months. 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.
Isotechnika is in ongoing discussions with regulatory agencies and potential partners with regards to the planning and implementation of a Phase 3 pivotal trial for voclosporin in kidney transplantation. Physician prescribing practices for transplant patients continue to be heavily influenced by side effect profiles and market research indicates that three significant side effect considerations are renal function, new onset diabetes mellitus after transplant (NODAT) and neurological symptoms. Voclosporin in its anticipated therapeutic range demonstrated less NODAT and neurological symptoms with equivalent renal function. In addition, the pharmacokinetic and pharmacodynamic analysis confirms a strong concentration-effect relationship for voclosporin. Based on these results, the ideal dose for a Phase 3 trial will encompass the concentration range obtained in the low to mid dose treatment groups.
"The results from this study are promising and demonstrate the potential to decrease cases of new onset diabetes," stated Dr. Herwig-Ulf Meier-Kriesche, Professor of Medicine, Medical Director Kidney Pancreas Transplant Program, Central Florida Kidney Center Endowed Chair in Medicine, University of Florida. "New onset of diabetes is really the Achilles heal of most currently used immunosuppressive regimens for transplantation. A calcineurin inhibitor which has the potential to achieve the same excellent rejection prophylaxis and renal function preservation as tacrolimus with a significant reduction in diabetogenicity while maintaining the impressive safety profile of the calcineurin inhibitor family would mean significant progress for our field."
"I'm very pleased that our PROMISE study further demonstrated that the efficacy of voclosporin is competitive with the market leader tacrolimus, with the bonus of a favorable safety profile," stated Dr. Robert Foster, Isotechnika's President & CEO. "This data combined with the previously announced positive trial results in uveitis from our partner, Lux Biosciences, adds further credibility to the commercial potential of voclosporin. Our next steps are to confirm our Phase 3 transplant protocol with the FDA. As previously outlined, Isotechnika continues to explore strategic partnerships and/or licensing arrangements as a means to build value in our program and fund the continued development of our product."
Phase 2b Trial Design
PROMISE is a randomized, multicenter, open-label, concentration controlled, dose ranging, safety study of voclosporin and tacrolimus in de novo renal transplant patients. Patients received an initial dose of 0.4, 0.6 or 0.8 mg/kg of voclosporin twice daily or a standard dose of tacrolimus. All four arms of the study were then dosed to achieve trough blood concentration levels as dictated by the protocol. A total of 41 centers participated in the study, and 334 patients were enrolled. The primary endpoint was defined as non-inferiority in biopsy proven acute rejection (BPAR) episodes in de novo kidney transplant patients receiving voclosporin for six months as compared to tacrolimus control. Secondary endpoints examined clinical and laboratory parameters such as kidney function, NODAT, electrolytes, neurological effects and lipid parameters.
Efficacy Results:
BPAR is a measure of acute rejection in transplant. As a dose ranging study, the Phase 2b trial was successful in meeting the primary endpoint demonstrating non-inferiority in BPAR episodes as compared to tacrolimus control in all three dose groups at six months. As specified by the protocol, after six months, only the mid and high dose groups received a dose reduction as is often standard practice with this class of drugs.
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Patients with BPAR Patients with BPAR
Drug at 6 months between 6 and 12 months
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Low dose voclosporin 11% 2%
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Mid dose voclosporin 9% 8%
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High dose voclosporin 2% 3%
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Tacrolimus 6% 0%
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Data from a multicenter trial reported in 2008, suggest that rejection rates in patients on tacrolimus after one year are in the range of 16-23%. This indicates that the BPAR rates observed in all dose groups of voclosporin fall within the expected range.
Safety Results:
The safety profile of voclosporin compared to tacrolimus was evaluated again at 12 months by multiple assessments including renal function, NODAT, hypertension and hyperlipidemia. Based on these assessments no specific safety concerns were raised.
Renal Function
At 12 months, kidney function was well preserved in each of the three dose levels of voclosporin relative to tacrolimus. Based on Nankivell glomerular filtration rate (GFR) there were no statistical differences between any of the voclosporin dose groups and tacrolimus. A statistical difference was observed with iothalamate GFR in the high dose voclosporin group when compared to tacrolimus (53 versus 62 mL/min) which is not unexpected as this was a dose range finding study.
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Nankivell GFR (mL/min)
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Drug 6 Month Results 12 Month Results
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Low dose voclosporin 71 70
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Mid dose voclosporin 72 72
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High dose voclosporin 68 69
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Tacrolimus 69 73
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The results suggest that over a wide range of dosing, there are minimal changes in renal function.
New Onset Diabetes Mellitus After Transplant (NODAT)
NODAT is a serious complication in transplant patients and negatively impacts patient outcomes. Published literature shows that mean graft survival of 11 years decreases to eight years with NODAT. At 12 months there was a meaningful reduction in NODAT in the low dose group of 81% as compared to tacrolimus. Although not statistically significant, the mid dose group had a clinically meaningful lower incidence of NODAT with a 66% reduction in risk.
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Patients with NODAT
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Drug 6 Month Results 12 Month Results
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Low dose voclosporin 1.6% 3.2%
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Mid dose voclosporin 5.7% 5.7%
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High dose voclosporin 17.7% 21.0%
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Tacrolimus 16.4% 16.4%
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Hypertension
Systolic blood pressure was statistically significantly higher in voclosporin treated patients compared to tacrolimus treated patients, however there was no difference in the number of patients treated for hypertension. The absolute difference ranged from a 5 to 8 mmHg increase, and no dose dependency was seen. No statistical differences were noted in diastolic blood pressure.
Neurological Events
Voclosporin has consistently shown a lower proportion of patients experiencing insomnia and tremors at both six and 12 months as compared to tacrolimus.
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Tremors Insomnia
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Drug 6 Months 12 Months 6 Months 12 Months
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Low dose voclosporin 11.9% 13.1% 7.1% 7.1%
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Mid dose voclosporin 22.1% 23.4% 10.4% 10.4%
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High dose voclosporin 13.8% 13.8% 8.0% 6.8%
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Tacrolimus 22.1% 24.4% 14.0% 15.1%
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About Isotechnika
Edmonton-based Isotechnika Inc. is a biopharmaceutical company focused on the discovery and development of novel immunosuppressive therapeutics that are designed to offer advantages over other currently available treatments. There is a significant unmet medical need in the treatment of both solid organ transplantation and autoimmune disease. It is estimated that the market potential will exceed $4 billion annually in sales for calcineurin inhibitors such as voclosporin by 2010.
Voclosporin is a next generation calcineurin inhibitor, which recently completed a Phase 2b North American trial for the prevention of kidney rejection following transplantation. An extension to the Phase 2b trial and a combined Phase 3 European/Canadian trial for the treatment of moderate to severe psoriasis have been completed and data is being collected and analyzed. Our partner, Lux BioSciences, Inc., has recently completed three separate Phase 2/3 pivotal trials investigating voclosporin (referred to as LUVENIQ(TM) by Lux) for the treatment of uveitis. In addition to the uveitis trials, Lux BioSciences Inc. has also commenced a Phase 1 trial using their proprietary voclosporin ophthalmic solution (LX214) 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.
Isotechnika Inc. is a publicly traded company on the Toronto Stock Exchange under the symbol "ISA". More information on Isotechnika can be found at www.isotechnika.com or www.SEDAR.com.
Forward-Looking Statements
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This press release may contain forward-looking statements. Forward looking statements, including the Company's belief as to the potential of its products, the Company's expectations regarding the issuance of additional patents and the Company's ability to protect its intellectual property, involve known and unknown risks and uncertainties, which could cause the Company's actual results to differ materially from those in the forward looking statements. Such risks and uncertainties include, among others, the availability of funds and resources to pursue research and development projects, the ability to economically manufacture its products, the potential of its products, the success and timely completion of clinical studies and trials, the Company's ability to successfully commercialize its products, the ability of the Company to defend its patents from infringement by third parties, and the risk that the Company's patents may be subsequently shown to be invalid or infringe the patents of others. Investors should consult the Company's quarterly and annual filings with the Canadian commissions for additional information on risks and uncertainties relating to the forward- looking statements. Investors are cautioned against placing undue reliance on forward-looking statements.
%SEDAR: 00010508E -30- /For further information: Dr. Robert Foster, President & CEO, Isotechnika Inc., Phone: (780) 487-1600 Ext. 247, Fax: (780) 484-4105, Email: rfoster@isotechnika.com/
