voclosporin and Psoriasis

Isotechnika is developing the immunosuppressive drug ISA 247, a calcineurin inhibitor that is undergoing clinical development for the treatment of psoriasis (phase III) and prevention of organ rejection after transplantation (phase II). Preclinical development for uveitis is also underway. Other autoimmune disease indications that could be explored include arthritis, type I diabetes and Crohn's disease. ISA 247 was being co-developed as R 1524 by Isotechnika and Roche. However, Roche is no longer involved in the development of this compound. Based on analysis of previously collected data, the trans-ISA 247 isomer was found to be more bioavailable and it is expected that this isomer can be administered at a lower dose compared with the previous formulation that consisted of an equivalent mixture of the two geometric isomers (cis and trans). Preclinical observations indicate that ISA 247 has the potential to be more potent and less toxic than other marketed immunosuppressants in its class used for the prevention of transplant rejection. Experiments to date suggest that ISA 247 is about three times as potent as ciclosporin, while genotoxicity studies in animals have shown that the compound has a significantly reduced tendency to cause renal toxicity. The combination of reduced toxicity and improved potency would give ISA 247 a therapeutic benefit over existing calcineurin-based treatments. Isotechnika and Roche entered into a co-development and commercialisation agreement in April 2002, with Roche gaining the exclusive worldwide marketing rights for ISA 247; Isotechnika received milestone payments of $US4 million and $CAN21.9 million in September 2002 and May 2003, respectively. The agreement was restructured in April 2004, under which Isotechnika will now solely manage and fund the clinical development of trans-ISA 247. Upon successful completion of these trials, Isotechnika will conduct at its own expense a phase IIb study in renal transplantation and phase III studies in psoriasis. Roche will have the right to opt-in to the development and commercialisation of trans-ISA 247 for transplant indications up to the end of the phase IIb renal transplantation trial. Isotechnika retains all rights to develop and commercialise the product outside of transplant indications. Under an agreement signed with Cellgate Inc. on 25 April 2006, Isotechnika has the option to obtain an exclusive licence to develop and commercialise conjugates consisting of Cellgate's patented

Topics: Animals; Calcineurin Inhibitors; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Cyclosporine; Graft Rejection; Humans; Immunosuppressive Agents; Psoriasis; Rabbits; Randomized Controlled Trials as Topic; Skin Diseases

Topics: Adalimumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Biological Products; Cyclosporine; Dermatologic Agents; Forecasting; Fumarates; Humans; Infliximab; Nicotinic Acids; Psoriasis; Receptors, Tumor Necrosis Factor; Receptors, Tumor Necrosis Factor, Type I; Tacrolimus; Tumor Necrosis Factor Decoy Receptors; Ustekinumab

ISAtx-247 is a ciclosporin A analog under development by Isotechnika and Roche as an immunosuppressant for the potential prevention of organ rejection after transplantation, and for the potential treatment of autoimmune diseases such as rheumatoid arthritis, psoriasis and type 1 diabetes. A phase II renal transplantation study had been completed by June 2003.

Topics: Animals; Arthritis, Experimental; Calcineurin Inhibitors; Clinical Trials as Topic; Cyclosporine; Diabetes Mellitus, Type 1; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Lymphocyte Activation; Psoriasis; Structure-Activity Relationship

Systems for determining psoriasis severity in clinical trials have not been sufficiently validated against patients' perceived quality of life.. To validate three systems of physician-determined psoriasis severity (the Lattice System Physician's Global Assessment [LS-PGA], Psoriasis Area and Severity Index [PASI] and static Physician's Global Assessment [sPGA]).. Data were from a 24-week randomized, double-blind, placebo-controlled, multicenter trial of therapy with oral calcineurin inhibitors in 445 patients. Construct validity was measured by correlations of the three severity scores with patients' self-reported quality of life (QoL) from the Dermatology Life Quality Index (DLQI) and a DLQI item about psoriasis symptoms.. All severity systems were moderately and positively correlated with QoL, indicating construct validity. QoL was most consistently related to physicians' assessments of body surface area involved with psoriasis (iBSA) followed by, in the order of consistency, plaque elevation, erythema and scale.. The LS-PGA weights iBSA and aspects of plaque morphology in concert with their relative effects on QoL. The LS-PGA, sPGA and PASI are validated by their relationship to QoL in a clinical trial.

Topics: Administration, Oral; Calcineurin Inhibitors; Clinical Competence; Cyclosporine; Dose-Response Relationship, Drug; Double-Blind Method; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Male; Physicians; Psoriasis; Quality of Life; Severity of Illness Index; Time Factors

Accurate and reliable assessment of changes in psoriasis severity is critical in clinical trials of therapies.. To compare Psoriasis Area and Severity Index (PASI), static Physician's Global Assessment (sPGA), and the Lattice System Physician's Global Assessment (LS-PGA) in a trial of systemic treatments for plaque psoriasis vulgaris and to assess whether they measure change in psoriasis induced by therapy.. Patients were randomized to voclosporin or cyclosporine for 24 weeks (the '24-week-treatment' group, n = 366), or placebo for 12 weeks followed by voclosporin for 12 weeks (the 'initial-placebo' group, n = 89).. All scoring systems changed in concert and were sensitive enough to detect reductions in severity during placebo therapy as well as with active therapy (P < 0.01 for each measurement). At study onset, there were poorer correlations of sPGA with PASI (r = 0.45) and LS-PGA (r = 0.39) than between PASI and LS-PGA (r = 0.68). After therapy, all correlations were stronger, but sPGA continued to be less well correlated (with PASI, r = 0.85; with LS-PGA, r = 0.79) than LS-PGA with PASI (r = 0.90). Two- or three-step improvements in LS-PGA showed very good to excellent accuracy in corresponding to PASI-50 and PASI-75, respectively, and were more accurate than comparable changes in sPGA.. PASI, sPGA and LS-PGA are responsive to the varying degrees of improvement in psoriasis induced by either placebo or active therapy. While the three systems capture similar information, each has different reasons for use in a clinical trial.

Topics: Adult; Clinical Competence; Cyclosporine; Double-Blind Method; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Male; Middle Aged; Physicians; Psoriasis; Severity of Illness Index; Time Factors; Treatment Outcome

Topics: Calcineurin Inhibitors; Cyclosporine; Drug-Related Side Effects and Adverse Reactions; Humans; Psoriasis; PUVA Therapy; Treatment Outcome

The use of systemic calcineurin inhibitors for the treatment of patients with psoriasis is limited by toxicity, particularly nephrotoxicity. ISA247, a novel inhibitor, was effective and well tolerated in a phase II study of patients with plaque psoriasis. Therefore its efficacy was assessed in this phase III study.. 451 patients aged 18-65 years with plaque psoriasis involving at least 10% of the body surface area were randomly assigned in equal proportions to receive placebo or ISA247 at 0.2 mg/kg, 0.3 mg/kg, or 0.4 mg/kg orally twice a day in dermatology clinics. The primary endpoint was a 75% reduction in the psoriasis area and severity index (PASI 75) score at week 12. Treatment allocation was concealed from patient and physicians doing the assessments by use of sealed envelopes. The method of analysis was by modified intention to treat. The trial is registered at ClinicalTrials.gov, number NCT00244842.. 107, 113, and 116 patients were assigned to the ISA247 0.2 mg/kg, 0.3 mg/kg, and 0.4 mg/kg groups, respectively, and 115 to the placebo group. At week 12, PASI 75 scores were achieved in the ISA247 0.2 mg/kg, 0.3 mg/kg, and 0.4 mg/kg groups by 14 (16%; 95% CI 9-24) of 105, 26 (25%; 17-24) of 111, and 44 (47%; 27-57) of 113 patients, respectively, and in the placebo group by 4 (4%; 0-8) of 113 patients. Efficacy was maintained during 24 weeks. Mild to moderate glomerular filtration rate reductions were noted in seven patients in the ISA247 0.4 mg/kg group and in one in the ISA247 0.3 mg/kg group. ISA247 blood concentrations showed a strong correlation with mean percentage reduction in PASI.. ISA247 was safe and effective in the treatment of patients with moderate to severe psoriasis during 24 weeks, with the highest dose providing the best efficacy. The strong correlation between ISA247 concentrations and efficacy might allow for accurate dosing of patients compared with existing calcineurin inhibitors.

Topics: Adolescent; Adult; Aged; Blood Pressure; Calcineurin Inhibitors; Cyclosporine; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Male; Middle Aged; Psoriasis; Severity of Illness Index

Use of current oral calcineurin inhibitors for the treatment of psoriasis is limited by toxicity.. Evaluate the safety and efficacy of ISA247, a new oral calcineurin inhibitor, in plaque psoriasis patients.. This 12-week, randomized, double-blind, placebo-controlled, parallel-group study included 201 plaque psoriasis patients with > or = 10% body surface area involvement. Patients were randomized to placebo, ISA247 0.5 mg/kg/d, and ISA247 1.5 mg/kg/d groups. End points included a 2-point reduction in the Static Global Assessment score and a 75% reduction in the Psoriasis Area and Severity Index.. A 2-point SGA reduction was achieved in 0% (placebo), 15.6% (0.5 mg/kg/d), and 45.1% (1.5 mg/kg/d) (P < .0001). A 75% reduction in the Psoriasis Area and Severity Index was achieved in 0% (placebo), 18.2% (0.5 mg/kg/d), and 66.7% (1.5 mg/kg/day) (P < .0001). While serum creatinine increased in patients treated with ISA247 1.5 mg/kg/d, it remained within the normal range.. Longer-term studies are needed to evaluate the effect of ISA247 on renal function.. ISA247 appears safe and effective for treating moderate to severe psoriasis.

Topics: Adolescent; Adult; Aged; Calcineurin Inhibitors; Cyclosporine; Double-Blind Method; Female; Humans; Male; Middle Aged; Psoriasis

Topics: Calcineurin Inhibitors; Cyclosporine; Humans; Placebos; Psoriasis; Randomized Controlled Trials as Topic; Risk Factors; Triglycerides

Topics: Cyclosporine; Drug Industry; Humans; Insulin-Like Growth Factor I; Neoplasm Proteins; Psoriasis; Receptors, Tumor Necrosis Factor; Receptors, Tumor Necrosis Factor, Type I; Receptors, Tumor Necrosis Factor, Type II; Technology, Pharmaceutical; Tumor Necrosis Factor Decoy Receptors