Paul Ehrlich and PCSK9 inhibition: A Magic Bullet for CVD prevention? Jacques Genest MD Cardiovascular Research Laboratories McGill University Health Center Endocrinology Rounds 19 Nov 2015
Disclosure J. Genest MD 2016 Advisory Board, Speaker’s Bureau, Consultant, Grants, Clinical Trials Merck * Sanofi/Regeneron * Pfizer Lilly Novartis * Valeant AMGEN * Aegerion * Cerenis * Ascati Stock ownership: none; Off label use: none * Scientific Advisory Relevant disclosure: JUPITER, IMPROVE-IT, CANTOS , CAPREE steering Committees; REVEAL , ACCELERATE, AMG145 , Lilly Clinical Trials.
Monoclonal Antibodies (mAbs) 101
Paul Ehrlich (1854-1915) • Gram stain • Arsphenamine (first Rx for Syphilis) • Anti-serum against dyphteria • Concept of “ magische Kugel” – magic bullet Nobel Prize 1908
Polyclonal Antibodies B cell (humoral) immune responses are polyclonal Polyclonal Abs: • Recognize multiple epitopes on same antigen • Usually high affinity BUT • Show major batch to batch variability • Can include relatively non-specific antibodies
Monoclonal Antibodies (MAbs) Monoclonal Abs: • High specificity; detect only one epitope on antigen • High homogeneity; once made, antibodies are constant, all batches identical • Can be produced in unlimited quantities
Alirocumab Manufacturing – Production / Purification Thaw 3 days 7 days 6-8 days Vial of Cells Shaker Flask WAVE Bioreactor Seed Train Production Bioreactors: Bioreactor: 50-3000L 10,000L Through a series of centrifugation, filtration membranes, and chromatographic Production: 13-14 days steps, the antibody is purified to the desired quality for human use. 10,000L Bioreactor 14 Days
Antibody technology has evolved over past decades Red = mouse e.g. Abciximab Blue = human e.g. Bococizumab Immunogenicity e.g. Highly Immunogenic Evolocumab and Alirocumab Chimeric, Still very immunogenic Can be time-consuming to create repeated dosing possible “Fully” Human Fully Mouse Chimeric Humanized 1 st generation 2 nd generation 3 rd generation 4 th generation 8 Nomenclature: Prefix (Pharma) C (Cardiovascular) UMAB
Monoclonal antibodies in the clinic Cumulative number of human monoclonal Over 30 monoclonal antibodies antibodies entering clinical study between 1985 approved for clinical use by and 2008 European/US regulatory agencies in, 150 All human monoclonal antibodies for example: 140 • Asthma Antineoplastic only 130 • Autoimmune diseases Immunomodulatory only 120 • Oncology 110 Anti-infectious only Number of clinical candidates • Ophthalmic disorders 100 Other indications 90 80 70 Approximately 235 monoclonal 60 antibodies in active trials, for example: 50 • Alzheimer’s disease 40 • Cardiovascular disease 30 • Infectious disease 20 • Osteoporosis 10 0 Year 1. Adapted from: Nelson AL et al. Nat Rev Drug Discov 2010;9:325 – 38; 2. Landes Bioscience (2014). mAbs: About this journal. Available at: http://www.landesbioscience.com/journals/mabs/about/. Accessed July 2014; 3. ClinicalTrials.gov (July 2014). Available at: http://www.clinicaltrials.gov/.
The biologics explosion TNF Inhibitors Etanercept Emerging non-TNF Biologics Adalimumab • Sarilimab (IL6R) Infliximab • Olokizumab (IL6) Golimumab • Clazakizumab (IL6) Certolizumab • Sirukumab (IL6) • Secukinumab (IL-17) • Brodalumab Non-TNF Biologics (IL-17R) • Tocilizumab (IL-6) Emerging non-MAb Biologics • Rituximab (B cell CD20) • Small molecules • Abatacept (B7-CTLA4Ig) • Tofacitinib (JAK1/3) • Anakinra (IL1) • Biosimilars Canakinumab IL-1 b ) •
PCSK9
PCSK9: A Canadian Discovery Nature Genetics 34 , 154 - 156 (2003) Dr. Nabil Seidah IRCM
Proprotein Convertase Subtilisin/Kexin Type 9 Bacillus amyloliquefaciens saccharomyces cerevisiae Homo sapiens Evolutionary Conservation: Must be important
PCSK9 LDL-R A: LDL-R pathway in absence of PCSK9 LDL Degradation apoB Lysosome Endosome B: Intracellular PCSK9 route PCSK9 C: Mature PCSK9 Extracellular pre-PCSK9 PCSK9 route ER TGN
PCSK9 as a Target Cohen JC, et al. NEJM 2006;354:1264
Patients with Genetically Lower LDL have Correspondingly Better CV Event Reduction Greater effect than Pharmacologically Lower LDL-C 30% − Possibly due to Lifetime Lower LDL levels Proportional Risk Reduction (SE) log scale Genetically Lower LDL-C PCSK9 46L rs11591147 20% NPC1L1 LDL-C Score HMGCR LDL-C Score Pharmacologically Lower LDL-C LDLR rs2228671 LDLR A to Z GISSI-P rs6511720 10% ABCG5/8 PCSK9 Combined rs4299376 rs11206510 NPC1L1 & HMGCR LDL-C Score HMGCR ALLHAT-LLT rs12916 PCSK9 HMGCR LDL-C Score rs2479409 IMPROVE-IT NPC1L1 LDL-C Score NPC1L1 SEARCH rs217386 0 .003 .005 .078 .104 .130 .155 .181 .207 .233 .259 .285 .311 .330 .363 .389 .389 .440 .466 .492 .518 .544 Lower LDL-C (mmol/L) Ference BA, et al. J Am Coll Cardiol. 2015;65(15):1552-1561.
LDLR
Clinical Data
ODYSSEY Long-Term: Alirocumab Plus Statin Achieved a 62% Reduction in LDL-C over Placebo+Statin at 24 weeks 3.60 3.17 mmol/L 3.08 mmol/L 3.00 0.8% 3.6% Median LDL-C (mmol/L) 2.40 62% reduction , P<0.001 Absolute reduction: 1.2 mmol/L 1.80 1.50 mmol/L 1.25 mmol/L -52.4% 1.20 -61.0% 0.60 Alirocumab + statin therapy at maximum tolerated dose ± other LLT (150 mg q2w) Placebo + statin therapy at maximum tolerated dose ± other LLT 0.00 0 4 8 12 16 24 36 52 64 78 No. of patients with Week data available Placebo 780 754 747 746 716 708 694 676 659 652 Alirocumab 1530 1473 1458 1436 1412 1386 1359 1349 1324 1269 Robinson J, et al. N Engl J Med. 2015;372(16):1489-99.
ODYSSEY Long-Term: Reduction in the Rate of Cardiovascular Events- Post-hoc Analysis Kaplan-Meier Estimates for Time to First Adjudicated Major CV Event Kaplan-Meier Estimates for Time to First Adjudicated Major CV Event* 0.06 Safety Analysis † 0.05 Cox model analysis Cumulative probability of event HR 0.46 95% CI: 0.26 to 0.82 0.04 P<0.01 Alirocumab + max-tolerated statin ± other LLT (150 mg q2w) Placebo + max-tolerated statin ± other LLT 0.03 54% RRR 0.02 0.01 0.00 0 12 24 36 48 60 72 84 Weeks No. at Risk 788 776 731 703 682 667 321 127 Placebo 1550 1534 1446 1393 1352 1335 642 252 Alirocumab *Primary endpoint for the ODYSSEY OUTCOMES trial: CHD death, Non-fatal MI, Fatal and non-fatal ischemic stroke, Unstable angina requiring hospitalization. LLT, lipid-lowering therapy † ≥52 weeks for all patients continuing treatment, incl. 607 patients who completed W78 visit Robinson J, et al. N Engl J Med. 2015;372(16):1489-99.
Ratio of LDL Lowering to CV Event Reduction with PCSK9 Inhibitors Holds True to the “LDL Hypothesis” 70% 60% OSLER Proportional reduction in event rate (SE) 50% ODYSSEY Long-Term 40% 30% 20% IMPROVE-IT 10% 0% 0.5 1.0 1.5 2.0 Reduction in LDL cholesterol (mmol/L) -10% Waters DD. Hsue PY. Circ Res. 2015;16:1643-1645.
Am J Cardiol 2015;115:1212e1221)
Bococizumab Christie M. Ballantyne, et al. Results of Bococizumab, A Monoclonal Antibody Against Proprotein Convertase Subtilisin/Kexin Type 9, from a Randomized, Placebo-Controlled, Dose-Ranging Study in Statin-Treated Subjects With Hypercholesterolemia The American Journal of Cardiology, Volume 115, Issue 9, 2015, 1212 – 1221
Bococizumab Figure 4. Mean percentage change from baseline in LDL-C. Change over time is shown for the (A) Q14 days and (B) Q28 days placebo and bococizumab dose groups . Ballantyne CM. The American Journal of Cardiology, 2015;115:1212 – 1221
Bococizumab: AE
PCSK9 mAb FDA approves Praluent to treat certain patients with high cholesterol
PCSK9 mAb (US) Repatha is approved for use in addition to diet and maximally- Praluent is approved for use in addition to diet and maximally tolerated statin therapy in adult tolerated statin therapy in adult patients with heterozygous patients with heterozygous familial hypercholesterolemia familial hypercholesterolemia (HeFH), homozygous familial hypercholesterolemia (HoFH), or (HeFH) or patients with clinical atherosclerotic cardiovascular clinical atherosclerotic disease such as heart attacks or cardiovascular disease, such as strokes, who require additional heart attacks or strokes, who lowering of LDL cholesterol. require additional lowering of LDL cholesterol.
Anti-drug Antibodies (ADA)
Anti-drug antibodies (ADA): the challenge Immunogenicity: Anti-drug antibody The potential for an antigen to formation induce an immune response Antibody Fab (Neutralizing) Immunogenicity against therapeutic proteins that are not in the normal human repertoire is a normal immune response. Anti-PSCK9 Reaction to neo-antigens Proteins are non-human Fusion proteins create new epitopes Antibody Fc Unusual glycosylation
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