Lipid-Reduction Variability and Antidrug-Antibody Formation with Bococizumab
Paul M Ridker, Jean-Claude Tardif, Pierre Amarenco, William Duggan, Robert J Glynn, J Wouter Jukema, John J P Kastelein, Albert M Kim, Wolfgang Koenig, Steven Nissen, James Revkin, Lynda M Rose, Raul D Santos, Pamela F Schwartz, Charles L Shear, Carla Yunis, SPIRE Investigators, Alberto Lorenzatti, Diego Conde, David Colquhoun, Luc Missault, José Carlos Nicolau, Jean Grégoire, Runlin Gao, Miguel Urina, Miroslav Solar, Michal Vrablik, Henrik Kjaerulf Jensen, Diederick Grobbee, Markku Savolainen, François Schiele, Gilles Montalescot, Istvan Edes, Gavin Blake, Chaim Lotan, Aldo Maggioni, Stefano Savonitto, Cheol Whan Lee, Jose Luis Leiva Pons, Harvey White, Piotr Ponikowski, Gheorghe-Andrei Dan, Yuri Karpov, Jan Murin, Pravin Manga, Fernando Civeira, Jordi Bruguera Cortada, Linda Mellbin, Thomas Kahan, Stephane Noble, Juey-Jen Hwang, Piyamitr Sritara, Arend Mosterd, Lale Tökgozoğlu, Handrean Soran, Marcus Flather, Michael Miller, R Scott Wright, Lisa Tarasenko, Jeffrey S Borer, Henry Black, Rafael Carmena, Karen L Furie, John McMurray, James Neaton, Faiez Zannad, Blair O’Neill, Francine Welty, Robert McNamara, Hyung Chun, J Dawn Abbott, Daniel Jacoby, Craig McPherson, Farid Jadbabaie, Duane Pinto, Louise McCullough, Isaac E Silverman, Lauren H Sansing, Jennifer Dearborn-Tomazos, Joanne Foody, Josephy Schinder, Gregory Piazza, Anjan Chakrabarti, Yuri Pride, Eli Gelfand, Dan Baultrukonis, Ellen Wang, Takaharu Yamabe, Paul M Ridker, Jean-Claude Tardif, Pierre Amarenco, William Duggan, Robert J Glynn, J Wouter Jukema, John J P Kastelein, Albert M Kim, Wolfgang Koenig, Steven Nissen, James Revkin, Lynda M Rose, Raul D Santos, Pamela F Schwartz, Charles L Shear, Carla Yunis, SPIRE Investigators, Alberto Lorenzatti, Diego Conde, David Colquhoun, Luc Missault, José Carlos Nicolau, Jean Grégoire, Runlin Gao, Miguel Urina, Miroslav Solar, Michal Vrablik, Henrik Kjaerulf Jensen, Diederick Grobbee, Markku Savolainen, François Schiele, Gilles Montalescot, Istvan Edes, Gavin Blake, Chaim Lotan, Aldo Maggioni, Stefano Savonitto, Cheol Whan Lee, Jose Luis Leiva Pons, Harvey White, Piotr Ponikowski, Gheorghe-Andrei Dan, Yuri Karpov, Jan Murin, Pravin Manga, Fernando Civeira, Jordi Bruguera Cortada, Linda Mellbin, Thomas Kahan, Stephane Noble, Juey-Jen Hwang, Piyamitr Sritara, Arend Mosterd, Lale Tökgozoğlu, Handrean Soran, Marcus Flather, Michael Miller, R Scott Wright, Lisa Tarasenko, Jeffrey S Borer, Henry Black, Rafael Carmena, Karen L Furie, John McMurray, James Neaton, Faiez Zannad, Blair O’Neill, Francine Welty, Robert McNamara, Hyung Chun, J Dawn Abbott, Daniel Jacoby, Craig McPherson, Farid Jadbabaie, Duane Pinto, Louise McCullough, Isaac E Silverman, Lauren H Sansing, Jennifer Dearborn-Tomazos, Joanne Foody, Josephy Schinder, Gregory Piazza, Anjan Chakrabarti, Yuri Pride, Eli Gelfand, Dan Baultrukonis, Ellen Wang, Takaharu Yamabe
Abstract
Background: Bococizumab, a humanized monoclonal antibody targeting proprotein convertase subtilisin-kexin type 9 (PCSK9), reduces levels of low-density lipoprotein (LDL) cholesterol. However, the variability and durability of this effect are uncertain.
Methods: We conducted six parallel, multinational lipid-lowering trials enrolling 4300 patients with hyperlipidemia who were randomly assigned to receive 150 mg of bococizumab or placebo subcutaneously every 2 weeks and who were followed for up to 12 months; 96% were receiving statin therapy at the time of enrollment. The patients were assessed for lipid changes over time, stratified according to the presence or absence of antidrug antibodies detected during the treatment period.
Results: At 12 weeks, patients who received bococizumab had a reduction of 54.2% in the LDL cholesterol level from baseline, as compared with an increase of 1.0% among those who received placebo (absolute between-group difference, -55.2 percentage points). Significant between-group differences were also observed in total cholesterol, non-high-density lipoprotein cholesterol, apolipoprotein B, and lipoprotein(a) (P<0.001 for all comparisons). However, high-titer antidrug antibodies developed in a substantial proportion of the patients who received bococizumab, which markedly diminished the magnitude and durability of the reduction in LDL cholesterol levels. In addition, among patients with no antidrug antibodies, there was wide variability in the reduction in LDL cholesterol levels at both 12 weeks and 52 weeks. Major cardiovascular events occurred in 57 patients (2.5%) who received bococizumab and in 55 (2.7%) who received placebo (hazard ratio, 0.96; 95% confidence interval, 0.66 to 1.39; P=0.83). The most common adverse event among patients who received bococizumab was injection-site reaction (12.7 per 100 person-years).
Conclusions: In six multinational trials evaluating bococizumab, antidrug antibodies developed in a large proportion of the patients and significantly attenuated the lowering of LDL cholesterol levels. Wide variation in the relative reduction in cholesterol levels was also observed among patients in whom antidrug antibodies did not develop. (Funded by Pfizer; SPIRE ClinicalTrials.gov numbers, NCT01968954 , NCT01968967 , NCT01968980 , NCT02100514 , NCT02135029 , and NCT02458287 .).
Source: PubMed