7/14/2014. SOLIRIS (eculizumab) SOLIRIS PNH Clinical Studies. SOLIRIS Blocks Terminal Complement. 86% Reduction in LDH: TRIUMPH and SHEPHERD

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1 Proximal Terminal Lactate Dehydrogenase (U/L) 7/1/1 SOLIRIS (eculizumab) Humanized First in Class Anti - C5 Antibody SOLIRIS (eculizumab) Human Framework Regions No mutations Germline SOLIRIS is a Complement Inhibitor Indicated for the Treatment of Patients With PNH to Reduce Hemolysis Hinge Complementarity Determining Regions (murine origin) SOLIRIS is the First and Only Approved Therapy for PNH Human IgG Heavy Chain Constant Region 1 and Hinge (Eliminates Fc receptor binding) CH CH Human IgG Heavy Chain Constant Regions and (Eliminates complement activation) Rother R et al. Nat Biotech 7;5:15 SOLIRIS Blocks Terminal Complement SOLIRIS PNH Clinical Studies Complement Cascade C Ca Cb C5 C5a C5b-9 C5b Cause of Hemolysis in PNH SOLIRIS SOLIRIS binds with high affinity to C5 Terminal complement - C5a and C5b-9 activity blocked Proximal functions of complement remain intact Weak anaphylatoxin Immune complex clearance Microbial opsonization Pilot Study NEJM. N = 11 Primary endpoint: reduction of hemolysis TRIUMPH NEJM. Pivotal Phase III, Double-Blind, Placebo-Controlled Trial, N = 7 SHEPHERD Blood. Broader patient population, including those receiving minimal transfusions or with thrombocytopenia, N = 97 Long-Term Extension Trial Hillmen Blood. 7 Evaluated long-term safety, efficacy and effect on thrombosis; Placebo patients switched to SOLIRIS N = 17 Figueroa JE, Densen P. Clin Microbiol Rev. 1991;(): Walport MJ. N Engl J Med. 1;(1):15-. Rother RP et al. Nature Biotech. 7;5(11):15-. Dosing Schedule Pretreatment Induction Phase Maintenance Phase weeks before induction Neisseria meningitidis vaccination Week SOLIRIS dose, mg 9 and every weeks thereafter 9 X 9 X 9 In clinical trials all patients received a meningococcal vaccination SOLIRIS should be administered via IV infusion over 5 minutes every 7 days during induction and every 1 days during maintenance SOLIRIS dose adjustment to every 1 days may be necessary for some patients to maintain LDH reduction Concomitant medications allowed: Steroids, immunosuppressant drugs, anti-clotting agents and hematinics % Reduction in LDH: TRIUMPH and SHEPHERD 1% response after the first dose TRIUMPH Placebo/Extension TRIUMPH SOLIRIS /Extension SHEPHERD SOLIRIS Time, Weeks TRIUMPH placebo patients switched to SOLIRIS after week. All TRIUMPH patients entered the long-term extension study. P<.1 at all measured time points. 1. Hillmen P et al. N Engl J Med. ;5(): Hillmen P et al. Blood. 7;11(1):1-. 1

2 Hemoglobin, g/dl Thrombotic Events (#) Median Units Transfused Change from Baseline Standard Effect Size (SES) Cognitive Pain Insomnia Constipation Nausea Diarrhea 7/1/1 P<.1. 7% Reduction in Mean Units Transfused Across all Subgroups: TRIUMPH Patients not on SOLIRIS (n=) SOLIRIS (n=) Transfusion data obtained during 1 months before treatment; values were normalized for a -month period 1. Hillmen P et al. N Engl J Med. ;55;1-1.. Schubert J. Br. J Haematol. ;1():-7. (n=7) (n=) (n=5) (n=) Overall >5 Pre-treatment Transfusion Strata 51% of SOLIRIS patients achieved transfusion independence vs % of patients not on SOLIRIS 1 Patients with concomitant bone marrow dysfunction may continue to require minimal transfusions 7 P<.5. P<.1. Patients Report Rapid and Sustained Improvement Across Broad Range of Measures FACIT-Fatigue EORTC Fatigue Global Health Physical Role Dyspnea EORTC Functioning Brodsky R et al. Blood. ;1(11): Abstract 77. Data on file. Alexion Pharmaceuticals. EORTC Symptoms Large Moderate Small 9% Reduction in Thrombotic Events Pre-SOLIRIS Treatment N=195 P=.1 SOLIRIS Treatment Is the Primary Cause of Fatigue in PNH Anemia or Hemolysis? % of patients received concomitant anticoagulants 1 The effect of anticoagulant withdrawal was not studied Events observed in both venous and arterial sites PI: There were fewer thrombotic events with SOLIRIS treatment than during the same period of time prior to treatment. 1.Brodsky R et al. Blood. ;111():1-7..SOLIRIS (eculizumab) [package insert]. Alexion Pharmaceuticals; 9..Hillmen P, et al. Blood. 7;11: TRIUMPH Demonstrated that Improvement in Fatigue Occurred Independent of Hemoglobin Response or more points denotes a clinically significant improvement P< Hgb Level - What Is The Long-Term Experience with SOLIRIS? Time, Weeks SOLIRIS (n=) Patients not on SOLIRIS (n=) SOLIRIS Hgb In SHEPHERD, 7% patients reported a significant improvement in fatigue 1 FACIT = Functional Assessment of Chronic Illness Therapy Adapted from: Hillmen P et al. NEJM. ;55:1-. Brodsky R et al. Blood Rev. ; : 5-7. Hill A et al. Haematologica. ; 9 (Suppl 1): 59. Abstract Brodsky R et al. Blood. ;111:

3 7/1/1 SOLIRIS PNH Clinical Studies % Reduction in LDH Sustained Out Past ½ Years: Long-Term Extension Results Pilot Study NEJM. N = 11 Primary endpoint: reduction of hemolysis TRIUMPH NEJM. Pivotal Phase III, Double-Blind, Placebo-Controlled Trial, N = 7 SHEPHERD Blood. Broader patient population, including those receiving minimal transfusions or with thrombocytopenia, N = 97 Long-Term Extension Trial Hillmen Blood. 7 Evaluated long-term safety, efficacy and effect on thrombosis; Placebo patients switched to SOLIRIS N = 17 Patient (n) Study Year P<.1 P=. 17/ patients who participated in the pilot study demonstrated sustained reduction in LDH out past 5 years Patients followed for up to 5 months 1 Socié G et al. Blood. 7;11(11): Abstract 7. Summary of Clinical Efficacy In clinical trials, SOLIRIS significantly reduced hemolysis 1 the underlying cause of morbidity and mortality in PNH % sustained reduction in hemolysis as measured by LDH Fewer thrombotic events were observed with SOLIRIS in clinical trials 1, The majority of patients (%) received concomitant anticoagulant therapy 1 The effect of anticoagulant withdrawal during SOLIRIS treatment has not been studied 1 7% clinically meaningful improvement in fatigue Fatigue in PNH impacted by hemolysis Significant improvement noted in pain and dyspnea along with a broad range of QoL measures 7% reduction in need for transfusions across all patient populations Important Safety Information About SOLIRIS All Patients Should Receive a Medication Guide Before Starting SOLIRIS Treatment 1.. Hillmen P et al. N Engl J Med. ;55:1-.. Hillmen P et al. Blood. 7;11(1):1-.. Socie G et al. Blood. 7;11(11)::Abstract Please See Full Prescribing Information for SOLIRIS Warning WARNING: SERIOUS MENINGOCOCCAL INFECTION SOLIRIS increases the risk of meningococcal infections. Meningococcal infection may become rapidly lifethreatening or fatal if not recognized and treated early. Vaccinate patients with a meningococcal vaccine at least weeks prior to receiving the first dose of SOLIRIS Revaccinate according to current medical guidelines for vaccine use Monitor patients for early signs of meningococcal infections, evaluate immediately if infection is suspected, and treat with antibiotics if necessary Safety: Contraindications SOLIRIS is contraindicated for patients with unresolved serious Neisseria meningitidis infection or who are not currently vaccinated against Neisseria meningitidis 17 1

4 7/1/1 Safety: Warnings and Precautions SOLIRIS therapy increases the risk of meningococcal infections. Meningococcal infection may become rapidly lifethreatening or fatal if not recognized and treated early All patients must be vaccinated against Neisseria meningitidis weeks prior to receiving SOLIRIS Use caution when administering SOLIRIS to patients with any systemic infection Other infections: SOLIRIS blocks terminal complement; therefore patients may have increased susceptibility to infections, especially with encapsulated bacteria Use caution when administering SOLIRIS to patients with any systemic infection Safety: Warnings and Precautions (cont) The effect of withdrawal of anticoagulant therapy during SOLIRIS treatment has not been established. Therefore, treatment with SOLIRIS should not alter anticoagulant management Patients who discontinue SOLIRIS must be monitored closely for signs of serious hemolysis If serious hemolysis occurs after SOLIRIS discontinuation, consider the following procedures/treatments: blood transfusion (packed RBCs), or exchange transfusion if the PNH RBCs are >5% of the total RBCs by flow cytometry; anticoagulation; corticosteroids; or reinstitution of SOLIRIS In clinical trials, 1 of 19 PNH patients discontinued SOLIRIS treatment; no serious hemolysis was observed 19 Safety: Warnings and Precautions (cont) LDH levels may be used to monitor hemolysis SOLIRIS dose adjustment to every 1 days may be necessary for some patients to maintain LDH reduction Infusion reactions may occur In clinical trials, no patients experienced infusion reactions that required discontinuation SOLIRIS treatment should be interrupted in all patients experiencing severe infusion reactions and appropriate medical therapy administered Serious Adverse Events: Clinical Trial Experience Meningococcal infections are the most important adverse events that may be experienced by patients receiving SOLIRIS In clinical studies, out of 19 patients developed serious meningococcal infections while receiving treatment with SOLIRIS Both patients had been vaccinated In clinical studies among non-pnh patients, meningococcal meningitis occurred in one patient, who was unvaccinated In post-marketing experience, cases of serious or fatal meningococcal infections have been reported 1 Adverse Reactions Reported in 5% of SOLIRIS Treated Patients in TRIUMPH Patients, n (%) Reaction SOLIRIS (n = ) Placebo (n = ) Headache 19 () 1 (7) Nasopharyngitis 1 () (1) Back pain (19) (9) Nausea 7 (1) 5 (11) Fatigue 5 (1) 1 () Cough 5 (1) (9) Herpes simplex virus infections (7) Sinusitis (7) Respiratory tract infection (7) 1 () Constipation (7) (5) Myalgia (7) 1 () Pain in extremity (7) 1 () Influenza-like illness (5) 1 () Patient Counseling Prior to treatment, patients should be informed and fully understand: The risks and benefits of SOLIRIS, in particular the risk of meningococcal infection Meningococcal vaccine does not prevent all meningococcal infections They are required to receive a meningococcal vaccination at least weeks prior to receiving the first dose of SOLIRIS, if they have not previously been vaccinated There is a potential for serious hemolysis when SOLIRIS is discontinued and that they will be monitored by their healthcare professional for at least weeks following SOLIRIS discontinuation

5 7/1/1 SOLIRIS OneSource Program OneSource provides education, assistance with access and treatment support for people living with paroxysmal nocturnal hemoglobinuria (PNH) and their caregivers. It is staffed by Alexion Nurse Case Managers, who are registered nurses with healthcare and insurance experience. Patients should be informed that they will be provided with a Patient Safety Card Patients should carry the card with them at all times The card describes symptoms, which if experienced, should prompt the patient to seek immediate medical attention Instruct patients to show the card to all health care providers involved in their care Patient Safety Card 5 Global, observational, non-interventional study to collect real world safety, effectiveness and QoL data Open to all physicians treating patients with PNH regardless of therapy Objectives: Database for publications to enhance understanding of disease and improve outcomes Promote evidence-based medicine Current enrollment: Over 5 patients enrolled Participation in 1 countries, including the United States, Argentina, Denmark, Netherlands, Belgium, Australia, France, New Zealand, Germany, and Taiwan Enrollment information: () 91-9 or Thank You Jack Goldberg M.D. FACP Clinical Professor of Medicine University of Pennsylvania 7 5