Alemtuzumab risk:benefit
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Alemtuzumab risk:benefit

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Summary presentation of the risks and benefits of alemtuzumab treatment in my

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  • 1. ALEMTUZUMAB RISK: BENEFIT Professor Gavin Giovannoni Blizard Institute, Barts and The London School of Medicine and Dentistry
  • 2. Disclosures Professor Giovannoni has received personal compensation for participating on Advisory Boards in relation to clinical trial design, trial steering committees and data and safety monitoring committees from: Abbvie, Bayer-Schering Healthcare, Biogen-Idec, Canbex, Eisai, Elan, Fiveprime, Genzyme, Genentech, GSK, GW Pharma, Ironwood, Merck-Serono, Novartis, Pfizer, Roche, Sanofi-Aventis, Synthon BV, Teva, UCB Pharma and Vertex Pharmaceuticals. Regarding www.ms-res.org survey results in this presentation: please note that no personal identifiers were collected as part of these surveys and that by completing the surveys participants consented for their anonymous data to be analysed and presented by Professor Giovannoni. Professor Giovannoni would like to acknowledge and thank Biogen-Idec, Genzyme and Novartis for making available data slides on natalizumab, alemtuzumab and fingolimod for this presentation.
  • 3. Risks vs. Benefits
  • 4. Coles et al. J Neurol. 2006 Jan;253(1):98-108.. Window of therapeutic efficacy
  • 5. Alemtuzumab for the treatment of RRMS • Alemtuzumab is indicated for adult patients with relapsing remitting multiple sclerosis (RRMS) with active disease defined by clinical or imaging features1. • Alemtuzumab is a humanized monoclonal antibody that selectively targets CD52, a protein abundant on the surface of B and T lymphocytes2 • A phase 2 & 3 clinical trial program was implemented to establish efficacy and safety in MS patients • Completed 3 head-to-head trials vs. high-dose subcutaneous interferon beta-1a (SC IFNB-1a) in patients with active relapsing-remitting multiple sclerosis (RRMS) 3-6 1. SMPC – EMA label; 2. Hu Y et al. Immunology 2009;128:260-70; 3. Coles AJ et al. N Engl J Med 2008;359:1786-801; 4. Coles AJ et al. Lancet 2012;380:1819-1828; 5. Coles AJ et al. Lancet 2012;380(1829-1839); 6. Brinar V et al. Presented at 21st Meeting of the European Neurological Society, 2011.
  • 6. Alemtuzumab mode of action
  • 7. Overview of Alemtuzumab MoA 1. Selection • In animal studies, innate immune cells that express lower levels of CD52 were affected minimally or transiently by Alemtuzumab2 2. Depletion Decreases MS inflammation • Alemtuzumab selectively depletes circulating T and B cells2,3 • Significant numbers of lymphocytes remain present in lymphoid organs after Alemtuzumab treatment2,3 3. Repopulation Reduces MS disease activity • CLP cells are presumed unaffected by Alemtuzumab2,4,5 • Distinctive pattern of T-, B-cell repopulation begins within weeks, potentially changing the balance of the immune system2,4,5 CD52 B CD52T BT HSC CLP NK/T cell precursor Pre/Pro B cell BCD52 T CD52 Monocyte Macrophage Neutrophil NKT Targets T and B cells thought to mediate MS inflammation1 The exact mechanism of action of alemtuzumab is not fully elucidated. CLP, common lymphoid progenitor; HSC, hematopoietic stem cell; MOA, mechanism of action; NK, natural killer. 1. Weber MS, Hemmer Bl. Results Probl Cell Differ. 2010;51:115-126; 2. Hu Y, et al. Immunology. 2009;128:260-270; 3.Turner MJ, et al. J Neuroimmunol. 2013;261:29-36; 4. Cox AL, et al. Eur J Immunol. 2005;35:3332-3342; 5. Fox EJ. Exp Rev Neurotherapeutics. 2010;10:1789-1797.
  • 8. Selective binding to CD52 • Little or no CD52 detected on neutrophils, plasma cells, BM stem cells1,2 • Limited, transient effect on innate immunity3 • Greater effect on circulating cells; lesser degree of depletion in lymphoid tissue3 CD52 Expression on Immune Cell Populations2 ©2009 Immunology. Used with permission. Placebo Alemtuzumab TotalImmuneCells(×108) 3 2 1 Blood BM Lymph nodes Thymus Spleen BM, bone marrow; NTG, nontransgenic. 1. Alemtuzumab Summary of Product Characteristics. Oxford, UK: Genzyme Therapeutics, Ltd; 2013. 2. Hu Y, et al. Immunology. 2009;128:260-270; 3. Turner MJ, et al. J Neuroimmunol. 2013;15;261:29-36. Post-Alemtuzumab: More Immune Cells Remain in Lymphoid Tissue vs Peripheral Blood3 6 4 2 0 CD52MoleculesperCell(×105) CD4singlepos. CD8singlepos. Doublepos. Doubleneg. Macrophages Neutrophils NKcells Stemcells CD8Tcells NTG Bcells CD4Tcells CD4Treg Spleen BM Thymus
  • 9. Alemtuzumab depletes circulating T and B cells • Alemtuzumab depleted lymphocytes rapidly and selectively after each treatment course1 • Occurred via antibody-dependent cellular cytolysis, complement-mediated lysis2,3 White Blood Cell Counts Time After Alemtuzumab, mo CARE-MS I: White Blood Cell Counts Following Alemtuzumab1 0 1 2 3 4 5 6 7 8 9 10 11 12 0.0 0.5 1.0 1.5 2.0 4.0 4.5 5.0 MeanCellCount(109/L) Basophils NR, (0-0.2)4 Eosinophils NR, (0-0.5)4 Monocytes NR, (0-0.8)4 Lymphocytes NR, 0.8-4.15 Neutrophils NR, 1.8-7.74 NR, normal range. 1. Kovarova I, et al. Presented at: European Neurological Society; 2012; Prague; P341; 2. Minagar A, et al. Expert Opin Biol Ther. 2010;10:421-429; 3. Freedman MS, et al. J Clin Cell Immunol. 2013;4:152; 4. Coles A, et al. Presented at: American Academy of Neurology; 2010; Toronto; PO6.172. 5. Data on file, Genzyme Therapeutics, Ltd; Oxford, UK;
  • 10. Repopulation changes the balance of the immune system • After Alemtuzumab, distinctive pattern of T-, B-cell repopulation emerged within weeks1-3 — B cells return to baseline within 6 months — T cells generally do not reach baseline by 12 months • Relative increase in proportion of Treg cells1,4 • Relative increase in proportion of memory T, B lymphocytes1,4 • Effects similar after repeated courses4 LLN, lower limit of normal. 1. Alemtuzumab Summary of Product Characteristics. Oxford, UK: Genzyme Therapeutics, Ltd; 2013; 2. Cox AL, et al. Eur J Immunol. 2005;35:3332-3342. 3. Turner MJ, et al. J Neuroimmunol. 2013;261:29-36; 4. Hartung HP, et al. Presented at: European Committee for Research and Treatment in Multiple Sclerosis; 2012; Lyon; P935; 5. Kovarova I, et al. Presented at: European Neurological Society; 2012; Prague; P341. May change balance of immune system to reduce MS disease activity1,3 CARE-MS I: Mean Treg Cells as Percentage of Total CD4+ Count4* 2 6 10 14 CD4+TregCellCount,% 4 8 12 16 Alemtuzumab 12 mg 0.0 1 0.2 0.4 0.6 0.8 1.0 1.2 0 3 6 9 1213 15 18 21 24 Time, mo CARE-MS I: Mean Lymphocyte Counts After Alemtuzumab5* CD4+ T cells CD19+ B cells CD19+ LLN CD4+ LLN IFNB-1a 44 μg 10 3 6 9 1213 15 18 21 24 Time, mo CellCount(109/L)
  • 11. Alemtuzumab pharmacokinetics in MS Clinical effects persist after Alemtuzumab is cleared from circulation • Alemtuzumab serum concentrations low or undetectable within ~30 days after treatment Alemtuzumab 12 mg administered at time 0 and 12 months. Kovarova I, et al. Presented at: European Neurological Society; 2012; Prague; P341. CARE-MS I: Mean Serum Concentration Over Time Time on Study, mo 4,000 0 2,000 3,000 1,000 0 1 3 6 9 12 2415 18 21 Concentration(ng/mL) 13 Alemtuzumab 12 mg Alemtuzumab 12 mg
  • 12. Efficacy of Alemtuzumab
  • 13. Clinical development program 20172005 201320092003 2007 2011 2015 CAMMS2231 CARE-MS I3 CAMMS223 Extension2 CARE-MS II4 CARE-MS Extension5 • Included patients with active RRMS who relapsed on prior therapy and those who were naïve to treatment1-4 • Efficacy and safety established vs high-dose IFNB-1a SC (no placebo used) in 3 rater-blinded RCTs1-4 RCT, randomized controlled trial; SC, subcutaneous. 1. Coles, AJ et al. N Engl J Med. 2008;359:1786-1801; 2. Coles AJ, et al. Neurol. 2012;78:1069-1078; 3. Cohen JA, et al. Lancet. 2012;380:1819- 1828; 4. Coles AJ, et al. Lancet. 2012;380:1829-1839; 5. Data on file, Genzyme Therapeutics, Ltd; Oxford, UK.
  • 14. Alemtuzumab vs high-dose IFNB-1a SC MRI inclusion criteria:5 CARE-MS II: MS diagnosis per McDonald criteria; white matter lesions attributable to MS; ≥9 T2 lesions ≥3 mm, any axis; Gd-enhancing lesion ≥3 mm, any axis, with ≥1 brain T2 lesions; spinal cord lesion with ≥1 brain T2 lesions; CARE–MS I: MS diagnosis per McDonald criteria; cranial MRI demonstrating white matter lesions attributable to MS (within 5 y of screening); CAMMS223: MS diagnosis per McDonald criteria, including cranial MRI; ≥1 enhancing lesion on any of ≤4 Gd-enhanced brain scans during ≤3-mo run-in period (including baseline scan). NA, not applicable; TIW, 3 times per week. aTreatment with beta interferon or glatiramer acetate for ≥6 months. bThrough month 13. 1. Alemtuzumab Summary of Product Characteristics. Oxford, UK: Genzyme Therapeutics, Ltd; 2013. 2. Coles AJ, et al. Lancet. 2012;380:1829-1839; 3. Cohen JA, et al. Lancet. 2012;380:1819-1828; 4. Coles AJ, et al. N Engl J Med. 2008;359:1786-1801; 5. Data on file. Genzyme Therapeutics, Ltd; Oxford, UK. CARE-MS II1,2 Phase III CARE-MS I1,3 Phase III CAMMS2231,4 Phase II Total patients, n (% completed) Alemtuzumab 12 mg/d 426 (94) 376 (96) 108 (85b) IFNB-1a SC 44 μg TIW 202 (78) 187 (88) 107 (62b) Patient population Active RRMS, relapse on prior therapya Active RRMS, treatment-naïve Active RRMS, treatment-naïve Eligibility ≥2 clinical episodes in prior 2 y, ≥1 relapse in prior y ≥2 clinical episodes in prior 2 y, ≥1 relapse in prior y ≥2 clinical episodes in prior 2 y, ≥1 Gd-enhancing lesion at baseline Mean age, y 35 33 32 EDSS range (mean) 0.0-5.0 (2.7) 0.0-3.0 (2.0) 0.0-3.0 (1.9) Mean disease duration, y (median) 4.5 (3.8) 2.0 (1.6) 1.3 (NA)
  • 15. Phase II study design CAMMS223 • Rater-blinded, comparator- controlled trial1 — No placebo used • 334 treatment-naïve patients with early, active RRMS1 aReceived study drug. Note: All treatment arms received 1 g methylprednisolone qd ×3 d at months 0, 12, and 24. 1. Coles AJ, et al. N Engl J Med. 2008;359:1786-1801; 2. Coles AJ, et al. Neurology. 2012;78:1069-1078. • Co-primary endpoints: ARR, time to 6-month SAD1 • Safety, efficacy assessments continued in extension phase beyond 36 months2 105 QD×3 0 12 24 36 Extension Phase2Study Duration (mo)1 60 Alemtuzumab 12 mg/d IV 102 101n=108a QD×3QD×5 24 77 92 67 Alemtuzumab 24 mg/d IV 104n=108a QD×5 22 82 92 74 IFNB-1a 44 µg TIW SC n=107a 95 80 4266
  • 16. Durable efficacy over 5 years CAMMS223 aCo-primary endpoints. Coles AJ, et al. Neurology. 2012;76:1069-1078. 0.35 0.12 0 0.1 0.2 0.3 0.4 0.5 38% 16% 0 10 20 30 40 50 0.46 -0.15 -0.4 -0.2 0 0.2 0.4 0.6 0.8 P<0.0001 P=0.0005 P=0.0056 Mean EDSS Score6-Month SADaARRa Months 0-60Months 0-60 Months 0-60 66% reduction 69% reduction IFNB-1a 44 μg Alemtuzumab12 mg
  • 17. Phase III study design • Rater-blinded RCTs1,2 • Comparator-controlled (no placebo used) • Scoring by blinded raters1,2 • Relapse, EDSS every 3 months • MSFC every 6 months • MRI annually • Education, safety monitoring program for patients, physicians1,2 — Surveys, urinalysis, CBC monthly — Thyroid testing quarterly • In CARE-MS II only, 24-mg arm included but discontinued to accelerate recruitment into other arms; thereafter deemed exploratory1 Both treatment arms received 1 g methylprednisolone qd ×3 d at months 0 and 12. CBC, complete blood count; IV, intravenous. 1. Coles AJ, et al. Lancet. 2012;380:1829-1839; 2. Cohen JA, et al. Lancet. 2012;380:1819-1828 Image adapted from Hartung HP, Arnold DL. Presented at: European Neurological Society; 2012; Prague. Alemtuzumab 12 mg IV Daily ×5 Daily ×3 TIW IFNB-1a 44 µg SC Study Duration (mo) 0 12 24 Randomized Alemtuzumab 24 mg IV Daily ×5 Daily ×3
  • 18. Phase III efficacy endpoints ARR, annualised relapse rate; MSFC, Multiple Sclerosis Functional Composite; SAD, sustained accumulation of disability; SRD, sustained reduction in disability. 1. Cohen JA, et al. Lancet. 2012;380:1819-1828; 2. Coles AJ, et al. Lancet. 2012;380:1829-1839; 3. Data on file. Genzyme Therapeutics, Ltd; Oxford, UK; 4. Alemtuzumab Summary of Product Characteristics. Oxford, UK: Genzyme Therapeutics, Ltd; 2013. Co-Primary Endpoints1,2 Secondary Endpoints1,2 Select Tertiary Endpoints1-3 • ARR • Time to 6-month SAD, defined as increase of ≥1.0 point on EDSS from baseline of ≥1.0 (or ≥1.5 point from baseline of 0), confirmed twice during 6-month period • Proportion of patients relapse-free at study completion • Change in EDSS score from baseline • Percent change in T2 hyperintense lesion volume from baseline to study completion • Change in MSFC from baseline • Time to first relapse • Proportion of patients with no MS disease activity (MRI, relapse, SAD) at years 1, 2 • Time to 6-month SRD • Change in MSFC components plus Sloan charts from baseline • MRI measures of MS-related brain measures • A priori efficacy objective met if statistically significant treatment effect demonstrated for Alemtuzumab over IFNB-1a SC on either or both co-primary efficacy endpoint(s)4
  • 19. Significant reduction in ARR Lower rates of SAD in treatment-naïve patients CARE-MS I 0.39 0.18 Risk reduction: 55% P<0.0001 AdjustedARR(95%CI) 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Alem (n=376) IFNB-1a (n=187) 187 376 185 376 181 372 177 368 170 368 164 357 162 352 158 345 149 336 25 15 10 5 0 20 PatientsWithSAD(%) 8% 11% 30% reduction P=0.22 (NS) IFNB-1a 44 μg Alemtuzumab12 mg ARR: Years 0-21,2a Time to 6-Month SAD1a Alem IFNB-1a 0 3 6 9 12 15 18 21 24 Follow-Up Month aCo-primary endpoints. Alem: alemtuzumab 1. Cohen JA, et al. Lancet. 2012;380:1819-1828; 2. Fox EJ, et al. Presented at: American Academy of Neurology; 2012; New Orleans, LA; PD5.004.
  • 20. Reduced MRI activity across select markers CARE-MS I • Alemtuzumab reduced the proportion of patients with new MRI lesion activity Endpoint1,2 Alemtuzumab INFB-1a SC P Value Patients with no new or newly enlarging T2 lesions, %a 52 42 0.035 Patients with no new Gd-enhancing lesions, %a 85 73 0.001 Patients with no new T1-hypointense lesions, %a 76 69 NS Change from baseline in BPF, %a -0.867 -1.488 <0.0001 Change from baseline in T2 hyperintense lesion volume, %b -9.3 -6.5 NS aTertiary endpoint.2 bSecondary endpoint.2 1. Alemtuzumab Summary of Product Characteristics; Oxford, UK: Genzyme Therapeutics, Ltd; 2013; 2. Cohen JA, et al. Lancet. 2012;380:1819-1828.
  • 21. Alemtuzumab patients more likely free of MS disease activity CARE-MS I OR: 1.75 P=0.0064 P=0.0388 OR: 2.36 P<0.0001 42 56 27 51 74 39 0 10 20 30 40 50 60 70 80 90 100 Patients(%) MRI activity-freea MS disease activity-freec Clinical disease activity-freeb IFNB-1a 44 μg Alemtuzumab12 mg aAbsence of new Gd-enhancing lesion or new or enlarging T2 hyperintense lesion. bAbsence of relapse or SAD. cAbsence of CDA or MRI activity. CDA, clinical disease activity; OR, odds ratio Giovanni G, et al. Presented at: European Neurological Society; 2012; Prague.
  • 22. Alemtuzumab significantly reduced ARR & SAD CARE-MS II Time to 6-Month SADa Alem IFNB-1a 202 426 200 426 184 412 175 404 167 392 162 384 155 380 145 375 131 354 PatientsWithSAD(%) 0 3 6 9 12 15 18 21 24 25 15 10 5 0 20 Follow-Up Month 13% 21% 42% reduction P=0.0084 aCo-primary endpoints. Alem: alemtuzumab Coles AJ, et al. Lancet. 2012;380:1829-1839. 0.52 0.26 0.0 0.2 0.4 0.6 0.8 ARR(95%CI) ARR: Years 0-2a Alem (n=426) IFNB-1a (n=202) IFNB-1a 44 μg Alemtuzumab 12 mg
  • 23. Alemtuzumab improved pre-existing disability CARE-MS II aSecondary endpoint; defined as decrease of ≥1 EDSS point lasting at least 6 months, assessed in patients with baseline EDSS ≥2.0. bTertiary endpoint. cMeasured by SRD score in relapsing patients. Coles AJ, et al. Lancet. 2012;380:1829-1839. IFNB-1a 44 μg Alemtuzumab12 mg ‒0.17 P<0.0001 +0.24 EDSSScore,mean 3.25 3.00 2.75 2.50 2.25 Follow-Up Month 0 3 6 9 12 15 18 21 24 40 30 20 10 0 PatientsWith6-MonthSRD(%) 29% 13% P=0.0002 Mean EDSS Change From Baselinea SRDb‎ Follow-Up Month 0 3 6 9 12 15 18 21 24 Alemtuzumab is the first and currently only MS therapy to demonstrate sustained improvement in preexisting disability vs an active comparator (in 2 of 3 clinical trials)
  • 24. Reduced MRI activity across select markers CARE-MS II • Alemtuzumab reduced the proportion of patients with new MRI lesion activity aTertiary endpoint.2. bSecondary endpoint.2 BPF, brain parenchymal fraction; NS, non significant 1. Alemtuzumab Summary of Product Characteristics; Oxford, UK: Genzyme Therapeutics, Ltd; 2013; 2. Coles AJ, et al. Lancet. 2012;380:1829-1839. Endpoints1,2 Alemtuzumab INFB-1a SC P Value Patients with no new or newly enlarging T2 lesions, %a 54 32 <0.001 Patients with no new Gd-enhancing lesions, %a 82 66 <0.001 Patients with no new T1-hypointense lesions, %a 80 62 <0.001 Change from baseline in BPF, %a -0.615 -0.810 0.012 Change from baseline in T2 hyperintense lesion volume, %b -1.3 -1.2 NS
  • 25. Alemtuzumab patients more likely free of MS disease activity CARE-MS II aAbsence of new Gd-enhancing lesion or new or enlarging T2 hyperintense lesion. bAbsence of relapse or SAD. cAbsence of CDA or MRI activity. CDA, clinical disease activity; OR, odds ratio Hartung HP, et al. Presented at: American Academy of Neurology; 2013, San Diego, CA; P07.093. 32 41 14 53 60 32 0 10 20 30 40 50 60 70 80 90 100 Patients(%) OR: 3.03 P<0.0001 OR: 2.14 P<0.0001 OR: 0.39 P<0.0001 MRI activity-freea MS disease activity-freec Clinical disease activity-freeb IFNB-1a 44 μg Alemtuzumab12 mg
  • 26. Reduction in brain atrophy on Alemtuzumab
  • 27. Superior efficacy for Alemtuzumab in head-2-head trials vs high-dose IFNB-1a SC • 49% reduction in ARR over IFNB-1a SC at 2 years (P<0.0001) • 42% reduction in SAD over IFNB-1a SC at 2 years (P=0.0084) • Significant improvement in preexisting disability as measured by SRD score vs IFNB-1a SC (29% vs 13%, P=0.0002) • Reduced MRI activity across select markers • 66% reduction in ARR over IFNB-1a SC at 5 years (P<0.0001) • 69% reduction in SAD over IFNB-1a SC at 5 years (P=0.0005) • 55% reduction in ARR over IFNB-1a SC at 2 years (P<0.0001) • Low rates of SAD for both Alemtuzumab and IFNB-1a SC at 2 years (P=not significant) • Reduced MRI activity across select markers CARE-MS II1,2 Alemtuzumab (n=426) IFNB-1a SC (n=202) CAMMS2234,5 Alemtuzumab (n=108) IFNB-1a SC (n=107) CARE-MS I1,3 Alemtuzumab (n=376) IFNB-1a SC (n=187) Patients with active RRMS who relapsed on prior therapy Patients with active RRMS who are naïve to treatment 1. Alemtuzumab Summary of Product Characteristics, Oxford, UK: Genzyme Therapeutics, Ltd; 2013. 2. Coles AJ, et al. Lancet. 2012;380:1829-1839; 3. Cohen JA, et al. Lancet. 2012;380:1819-1828; 4. Coles AJ, et al. Neurology. 2012;78:1069-1078; 5. Data on file. Genzyme Therapeutics, Ltd; Oxford, UK.
  • 28. Safety of Alemtuzumab
  • 29. Safety Issues 0 12 24 36 ObservationTreatment Cycles Duration (mo) 60Alemtuzumab 12 mg/d IV QD×3QD×5 ? QD×3 Short-term Infusion reactions Infections: viral and opportunistic Travel Baseline De-risking VZV Live vaccines Latent TB HPV Pregnancy Intermediate-term 2° autoimmunity Pregnancy Pulsed steroids Travel ? Long-term Immune senescence 2° malignancy Risks Monitoring & prophylaxis Baseline bloods VZV serology CXR & quantiferon TB assay Cervical smear Pregnancy test Monthly FBC & urinalysis 3-monthly TFTs Annual MRI Pretreatment with steroids, anti- histamines and paracetamol Herpes prophylaxis x 28 days Listeriosis prevention diet Pre-planned rapid access to haematology, nephrology, dermatology, etc. Patient education Baseline counselling Signed consent Engaged with self-monitoring Lifelong monitoring Active public engagement programme
  • 30. Overall AE rates in clinical trials • Rate of AEs with Alemtuzumab 12 mg, including those leading to treatment discontinuation, generally similar to those with IFNB-1a SC aIncludes CAMMS223, CARE-MS I, and CARE-MS II. AE, adverse event. Data on file. Genzyme Therapeutics, Ltd; Oxford, UK. 2-year active-controlled experiencea • AE profiles similar for treatment-naïve patients and those who relapsed on prior therapy AEs IFNB-1a SC 44 μg n=496 Alemtuzumab 12 mg n=919 AEs, n (%) 469 (94.6) 896 (97.5) Grade 1 (mild) 400 (80.6) 815 (88.7) Grade 2 (moderate) 402 (81.0) 831 (90.4) Grade 3 (severe) 106 (21.4) 227 (24.7) Grade 4 (very severe) 10 (2.0) 27 (2.9) AEs leading to treatment discontinuation, n (%) 39 (7.9) 21 (2.3) Serious AEs, n (%) 91 (18.3) 168 (18.3) Serious AEs leading to treatment discontinuation, n (%) 10 (2.0) 7 (0.8) Deaths 0 3
  • 31. IARs common with Alemtuzumab • Defined as any AE that occurred during or within 24 hours of Alemtuzumab administration1 • Majority may be due to cytokine release during infusion1 • mAb-mediated apoptosis causes release of cytokines2,3 • Cytokine release then generates clinical signs and symptoms described as IARs2 mAb - monoclonal antibody. 1. Alemtuzumab Summary of Product Characteristics; Oxford, UK: Genzyme Therapeutics, Ltd; 2013; 2. Breslin S. Clin J Onc Nurs. 2007;11(suppl):37-42; 3. Maggi E, et al. Expert Rev Immunol. 2011;7:55-63 • Headache • Rash • Pyrexia • Nausea • Urticaria • Pruritus • Insomnia • Chills • Flushing Common Symptoms1
  • 32. Rate of AEs over time • Rate of AEs was similar in IFNB-1a- and Alemtuzumab-treated patients, except during month following Alemtuzumab administration, due to IARs1 — IAR rates lower with second vs first treatment course of Alemtuzumab1 • Similar pattern observed in CARE-MS II2 and CAMMS2233 Time, mo RateofAEs (totalevents/totalperson-months) CARE-MS I1 0 1 2 3 4 5 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Both treatment arms received 1 g methylprednisolone qd ×3 d at months 0 and 12. 1. Coles AJ, et al. Presented at: American Academy of Neurology; 2012; New Orleans, LA; 2. LaGanke CC, et al. Presented at: American Academy of Neurology; 2013; San Diego, CA. P01.174 3. Data on file, Genzyme Therapeutics, Ltd; Oxford, UK
  • 33. Overview of IARs in clinical trials CARE-MS I and II (Pooled)1 AverageNumberofIARSymptoms Infusion Number Course 1 Course 2 0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 1 2 3 4 5 1 2 3 • To manage IAR severity: — Pretreat with corticosteroids, (ie, methylprednisolone) immediately before infusion with Alemtuzumab for first 3 days of any treatment course1 — Consider pretreatment with antihistamines and/or antipyretics • Observe patient for IARs during and for 2 hours after Alemtuzumab infusion • Physician and patient education Premedication and Monitoring2 • Predominantly mild to moderate;decreased with each treatment course3 • 3% serious: pyrexia, urticaria, atrial fibrillation, nausea, chest discomfort, hypotension2 1. Data on file. Genzyme Therapeutics, Ltd; Oxford, UK; 2. Alemtuzumab Summary of Product Characteristics. Oxford, UK: Genzyme Therapeutics, Ltd; 2013; 3. Caon C. et al. Presented at: Consortium of Multiple Sclerosis Centers; 2012; San Diego, CA; DX41.
  • 34. No increase in infection rate over 2 years Time, mo IncidenceofInfections 0.0 0.1 0.2 0.3 0.4 0.5 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 IFNB-1a Alem12 mg 389 811 388 811 387 811 386 811 384 811 379 811 377 811 375 811 373 811 372 810 371 810 368 810 363 810 362 807 358 807 357 806 355 805 354 804 353 803 352 803 352 797 351 796 349 785 342 761 CARE-MS I and II (pooled data) IFNB-1a 44g Alemtuzumab12 mg Alem: alemtuzumab Havrdova E, et al. Presented at: European Committee for Research and Treatment in Multiple Sclerosis; 2013, Copenhagen; P603. • Risk highest in first month after first treatment; rates decreased over time • No increase in infection risk that would indicate cumulative immunosuppressive effects
  • 35. Overview of infections in clinical trials • More frequent with Alemtuzumab vs INFB-1a (71% vs 53%)1 • Predominately mild to moderate1 • Generally of typical duration, resolved following conventional treatment1 • Did not correlate with lymphocyte counts3 • Total or subgroups CD4, CD8, CD19 2-year active-controlled experience2a,b IFNB-1a SC 44 μg n=496 Alemtuzumab 12 mg n=919 Grade 1, 2 258 (52.0) 618 (67.2) Grade 3 6 (1.2) 33 (3.6) Grade 4 0 (0.0) 1 (0.1) Serious AEs, n (%) 5 (1.0) 25 (2.7) Nasopharyngitis 82 (16.5) 216 (23.5) Urinary tract infection 40 (8.1) 162 (17.7) Upper respiratory tract infection 57 (11.5) 141 (15.3) Sinusitis 34 (6.9) 100 (10.9) Oral herpes 6 (1.2) 79 (8.6) Influenza 25 (5.0) 77 (8.4) Bronchitis 16 (3.2) 64 (7.0) Herpes zoster 4 (0.8) 38 (4.1) Gastroenteritis 5 (1.0) 36 (3.9) Pharyngitis 7 (1.4) 36 (3.9) • Prophylaxis with oral anti-herpes agent (acyclovir 200 mg twice a day used in clinical trials) starting first day of treatment, continuing for 1 mo after treatment course Risk Mitigation (Monitoring)1 aInfections with incidence of ≥5.0% in any treatment group shown. bIncludes CAMMS223, CARE-MS I, and CARE-MS II. cEvents occurring in ≥5% of Alemtuzumab-treated patients, based on all available follow-up. 1. Alemtuzumab Summary of Product Characteristics. Oxford, UK: Genzyme Therapeutics, Ltd; 2013; 2. Data on file. Oxford, UK: Genzyme Therapeutics, Ltd; 3. Havrdova E, et al. Presented at: European Committee for Research and Treatment in Multiple Sclerosis; 2013; Copenhagen; P603.
  • 36. Autoimmunity: ITP • Characterized by antibody-, cell-mediated platelet destruction; suppression of platelet production1-3 — If untreated, may lead to life-threatening bleeding3 • Diagnosed via measurement of platelet levels (<100109/L), exclusion of non-autoimmune causes of thrombocytopenia1,2 — Response to ITP-specific therapy is most compelling diagnostic evidence2 • Treatment goal: hemostatic platelet count (>20-30109/L for most patients), minimization of treatment-related morbidity2,4 aHemoptysis may be indicative of ITP or anti-GBM disease; appropriate differential diagnosis required.5 IVIG, intravenous immunoglobulin; anti-Rh(D), anti-D immunoglobulin; TPO, thrombopoietin. 1. Cines DB, et al. Blood. 2009;113:6511-6521; 2. Cuker A, Cines DB. Hematology Am Soc Hematol Educ Prgm. 2010;2010:377-384; 3. Cuker A, et al. Blood. 2011;118:6299-6305; 4. Provan D, et al. Blood. 2010;115:168-186; 5. Alemtuzumab Summary of Product Characteristics. Oxford, UK: Genzyme Therapeutics Ltd; 2013. • Easy bruising • Petechiae • Spontaneous mucocutaneous bleeding — Epistaxis, hemoptysisa • Heavier than normal or irregular menstrual bleeding Symptoms5
  • 37. Autoimmunity:‎ITP‎(cont’d) • ITP observed with Alemtuzumab more closely resembles childhood vs adult ITP in general population1 — Does not appear to recur after first event (in contrast, in adults, ITP often is chronic) • Index case in CAMMS2232 — Symptoms (bruising, petechia) unreported until patient presented with ultimately fatal intracranial hemorrhage • Subsequently, monitoring program implemented2 • CBC with differential before starting Alemtuzumab treatment • Monthly CBCs with differential until 48 months after last treatment course; immediate CBC if ITP suspected • Physician/patient education and reporting Risk Mitigation (Monitoring)3 CBC, complete blood count. 1. Cuker A, et al. Blood. 2011;118:6299-6305. 2. Coles AJ, et al. N Engl J Med. 2008;359:1786-1801. 3. Alemtuzumab Summary of Product Characteristics. Oxford, UK: Genzyme Therapeutics Ltd; 2013.
  • 38. ITP cases in detail (phase II and III studies) aIndex case excluded. bCR: first recovery of platelet count ≥100 x 109/L after onset of ITP. CR, complete response. 1. Cuker A, et al. Blood. 2011;118:6299-6305; 2. Data on file, Genzyme Corporation, Ltd; Oxford, UK; 3. Cohen JA, et al. Lancet. 2012;389:1819-1828; 4. Coles AJ, et al. Lancet. 2012;380:1829-1839. Trial (ITP cases; Alemtuzumab patients) Time from last dose to ITP onset (mo) Nadir platelet count (109/L) Time from ITP onset to CRb (mo) In CR at last follow-up Yes/No (n) CAMMS2231 (5; 216)a 1-15 1-41 1-8 Yes (5) CARE-MS I2 (3; 376) 7-17 1-42 0.4-2.7 Yes (3) CARE-MS II2 (8; 596) 3-13 1-37 0.2-1 Yes (7) No (1) CAMMS2231 CARE-MS I3 CARE-MS II4 Following implementation of mandatory monitoring (after index case)3: • 2 cases detected by visible ITP symptoms • 3 patients diagnosed by monthly CBC − 2 symptomatic; 1 presented with cutaneous symptoms • All in CR at last follow-up (response to standard therapy or spontaneous recovery) • 1 case had initial platelet drop that resolved spontaneously, recurred 6 months later, and responded to prednisolone • All presented with visible signs • All in CR at last follow-up (response to standard therapy) • 3 cases initially presented with visible signs • 4 cases initially detected by monthly CBC • 6 of 7 in CR at last follow-up; 1 patient remained on corticosteroids
  • 39. Autoimmunity: Nephropathies • Rare cases of kidney disease associated with Alemtuzumab in clinical trials1,2 — Anti-GBM disease (n=2) — Membranous glomerulonephritis (n=2) • Anti-GBM disease3 — Rare condition that can cause severe kidney damage — If untreated, can lead to morbidity or mortality from renal failure — Prompt diagnosis, intervention may improve outcomes1 — Treatment aims to remove circulating autoantibodies, prevent further ongoing autoimmune activity using plasma exchange, steroids, cyclophosphamide • Membranous glomerulonephritis4 — Usually results in indolent nephrotic syndrome; frequently resolves spontaneously — Treatment directed at nephrotic state; includes salt and protein restriction, ACEI, blood pressure control, diuretics • May include: — elevation in serum creatinine — haematuria and/or — proteinuriaa Clinical Manifestations1 • Assess serum creatinine levels, monitor urinalyses with microscopy before starting Alemtuzumab treatment and each month afterward until 48 mo after last infusion1 • Physician/patient education and reporting Risk Mitigation (Monitoring)1 aAlthough not observed in Alemtuzumab clinical trials, alveolar hemorrhage manifesting as hemoptysis may occur with anti-GBM disease. ACEI, acetylcholinesterase inhibitor. 1. Alemtuzumab Summary of Product Characteristics. Oxford, UK: Genzyme Therapeutics, Ltd; 2013; 2. Wynn D, et al. Presented at: European Committee for Treatment and Research in Multiple Sclerosis; 2013; Copenhagen; P597; 3. Cui Z, Zhao M-H. Nat Rev Nephrol. 2011;7:697-705; 4. Fervenza FC, et al. Clin J Am Soc Nephrol. 2008;3:905-919.
  • 40. Nephropathy cases in detail aCreatinine normal range, 0.6-1.1 mg/dL. CKD, chronic kidney disease; URTI, upper respiratory tract infection. Wynn D, et al. Presented at: European Committee for Research and Treatment in Multiple Sclerosis; 2013; Copenhagen; P597. Age/Sex/ Trial Months From Last Dose Dose (Courses; Cumulative Dose) Serum Creatinine at Diagnosis mg/dL (mol/L) Prodrome Treatment  Outcome Anti-GBM cases 35 yr/female/ CAMMS223 39 12 mg (2 courses; 96 mg) 1.8 (163) URTI, rash, hematuria Standard Rx  CKD3a 23 yr/female/ Extension 4 12 mg (3 courses; 132 mg) 0.7 (63) (Normal)a Proteinuria; hematuria Standard Rx  CKD 1 Membranous nephropathy 26 yr/female/ CARE-MS II 5 12 mg (2 courses; 96 mg) 0.6 (54) (Normal)a Proteinuria, hematuria, hypoalbuminemia, peripheral edema Furosemide + ACEI  Symptoms improved 58 yr/female/ CAMMS3409 EXT 13 12 mg (2 courses; 96 mg) 1.5 (135) Proteinuria, hematuria, edema Initial: diuretics + albumin Ongoing: diuretics All cases (0.3% in clinical trials) detected by safety monitoring program; none resulted in renal failure Monitoring, education essential for early detection, effective management
  • 41. Autoimmunity: Thyroid disorders • Autoimmune thyroid abnormalities observed in pilot studies of alemtuzumab in MS patients1,2 • Thus, thyroid function monitored quarterly3 • Most frequently reported: hyperthyroidism, hypothyroidism Basedow’s (Graves’) disease, decreased TSH4 • Hyperthyroidism5 • Marked by elevated synthesis, secretion of thyroid hormones • Common causes include Graves’ disease, toxic multinodular goiter, toxic adenoma, thyroiditis • Treatment options • Radioactive iodine, anti-thyroid drugs (methimazole, propylthiouracil), subtotal thyroidectomy • β blockers, iodides (adjunctive, symptomatic therapy) • Hypothyroidism6 • Most common cause worldwide is environmental iodine deficiency; in areas of iodine sufficiency, most common cause is chronic autoimmune thyroiditis (Hashimoto’s thyroiditis). • Managed with thyroid hormone replacement (levothyroxine) TSH, thyroid-stimulating hormone. 1. Coles AJ, et al. Lancet. 1999;354:1691-1695; 2. Coles AJ. J Neurol. 2006;253:98-108; 3. Alemtuzumab Package leaflet: Information for the patient. Oxford, UK: Genzyme Therapeutics, Ltd; 2013; 4. Data on file. Genzyme Therapeutics, Ltd; Oxford, UK; 5. Bahn RS, et al. Endocr Pract. 2011;17:456-520; 6. Garber JR, et al. Endocr Pract. 2012;18:998- 1028. • Excessive sweating • Unexplained weight loss/gain • Eye swelling • Nervousness • Fast heartbeat • Feeling cold • Worsening tiredness • Newly occurring constipation Symptoms3
  • 42. Autoimmunity: Thyroid disorders • Most AEs mild to moderate in severity; most managed with conventional medical therapy, however some patients required surgical intervention1 • Higher incidence in patients with medical history of thyroid disorders1 • Anti-TPOa antibody status prior to treatment not indicative of thyroid AE development1 • Patients who developed thyroid events permitted to receive retreatment with Alemtuzumab1 • Experience limited, but generally no worsening in severity of disorders1 • Thyroid AEs did not affect efficacy2 • Relapse suppression comparable among patients with thyroid AEs and full Alemtuzumab cohort • Relapse reduction among Alemtuzumab-treated patients who developed thyroid AEs superior to that of IFNB-1a patients 1. Alemtuzumab Summary of Product Characteristics, Oxford, UK: Genzyme Therapeutics, Ltd; 2013; 2. Habek M, et al. Presented at: European Neurological Society; 2012, Prague; P340. • Obtain thyroid function tests (ie, TSH levels), before starting treatment and every 3 months thereafter for 48 months following the last infusion • Physician/patient education and reporting Risk Mitigation (Monitoring)1
  • 43. Autoimmune-related thyroid AE incidence Phase II through complete follow-up (6.7 years) • Occurred in 34% of patients taking Alemtuzumab vs 6.5% of those taking INFB (P<0.0001)1 • Majority were hyperthyroidism1 • 4 events identified as serious (0.4 events per 100 person-years)2 • Delayed onset: peaked in third year after initial Alemtuzumab treatment, declined thereafter1,2 Phase III Studies3 CARE-MS I CARE-MS II Rebif 44 µg N=187 Alemtuzumab 12 mg N=376 Rebif 44 µg N=202 Alemtuzumab 12 mg N=435 Any thyroid AEa (n, %) 12 (6.4) 68 (18.1) 10 (5.0) 69 (15.9) Hyperthyroidism 3 (1.6) 31 (8.2) 1 (0.5) 19 (4.4) Hypothyroidism 6 (3.2) 29 (7.7) 3 (1.5) 29 (6.7) Goiter 0 6 (1.6) 1 (0.5) 6 (1.4) Thyroid mass 0 1 (0.3) 0 0 Lab investigations 5 (2.7) 21 (5.6) 6 (3.0) 22 (5.1) Thyroid SAE (n, %) 0 4 (1.1) 0 2 (0.5) Thyroid carcinoma (n, %) 0 2 (1) 0 1 (<1) aSome patients had >1 episode of thyroid dysfunction; for example, treatment of one hyperthyroidism case in CARE-MS II resulted in development of hypothyroidism. SAE, serious adverse event. 1. Daniels GH, et al. J Clin Endocrinol Metab. 2014;99:80-89; 2. Coles AJ, et al. Neurology. 2012;78:1069-1078; 3. Habek M, et al. Presented at: European Neurological Society; 2012; Prague; P340.
  • 44. Risks identified in clinical trials aThrough 48 mo after first exposure. ITP, immune thrombocytopenia; GBM, glomerular basement membrane; mAb, monoclonal antibody. 1. Alemtuzumab Summary of Product Characteristics. Oxford, UK: Genzyme Therapeutics, Ltd; 2013; 2. Wynn D, et al. Presented at: European Committee for Treatment and Research in Multiple Sclerosis; 2013; Copenhagen; P597; 3. Coles AJ, et al. Neurology. 2012;78:1069-1078. Identified Risk Rate in Alemtuzumab- Treated Patients Notes ITP AutoimmuneEvents ~1% (1 fatality prior to implementation of monitoring program)1 • Onset generally occurred 14-36 mo after first exposure1 • Most cases responded to first-line medical therapy1 0.3% (anti-GBM n=2)1 • Generally occurred within 39 mo after last administration1 • Responded to timely medical treatment and did not develop permanent kidney failure2 Nephropathies Thyroid disorders (Hypo-/hyper-) ~36%a (serious, 1%)1 • Onset occurred 6-61 mo after first Alemtuzumab exposure; peaked in year 3 and declined thereafter3 • Most mild to moderate, most managed with conventional medical therapy, however, some patients required surgical intervention1 • Higher incidence in patients with history of thyroid disorders1 IARs >90% (serious, 3%)1 • Occurred within 24 h of Alemtuzumab administration1 • Most mild to moderate; rarely led to treatment discontinuation1 • May be caused by cytokine release following mAb-mediated cell lysis1 Infections 71% (serious, 2.7%)1 • Incidence highest during first mo after infusion; rate decreased over time2 • More common with Alemtuzumab; mostly mild to moderate1 • Generally of typical duration; resolved following conventional medical treatment1
  • 45. Alemtuzumab safety summary Monitoring Detection Management 1. Coles AJ, et al. New Engl J Med. 2008;359:1786-1801; 2. Cohen JA, et al. Lancet. 012:380:1819-1828; 3. Coles AJ, et al. Lancet. 2012;380:1829-1839; 4. Alemtuzumab Summary of Product Characteristics. Oxford, UK: Genzyme Therapeutics, Ltd; 2013; 5. Data on File. Genzyme Therapeutics, Ltd; Oxford, UK; 6. Havrdova E, et al. Presented at: ECTRIMS; 2013; Copenhagen; P603. • Safety, tolerability consistent across controlled clinical trials in MS1-3 • Most common AEs mild to moderate IARs1-4 • Autoimmune AEs detected via safety monitoring program4 • Thyroid-related events (~36%) • ITP (~1%) • Nephropathies (0.3%) • Low rates of serious infection consistent with relative sparing of innate immune cells and specific lymphocyte subpopulations5,6 • Proactive risk minimization procedures helped attain early detection, management of identified risks5
  • 46. Consistent safety profile Adverse‎reactions‎observed‎in‎≥0.5%‎of‎Alemtuzumab 12 mg patients across 3 clinical trials1 Asterisk (*) indicates adverse reaction reported as IAR. IAR, infusion-associated reaction. Alemtuzumab Summary of Product Characteristics. Oxford, UK: Genzyme Therapeutics, Ltd; 2013.
  • 47. Consistent safety profile (cont’d) Asterisk (*) indicates adverse reaction reported as IAR. . Alemtuzumab Summary of Product Characteristics. Oxford, UK: Genzyme Therapeutics, Ltd; 2013. Adverse‎reactions‎observed‎in‎≥0.5%‎of‎Alemtuzumab 12 mg patients across 3 clinical trials1