familial hypercholesterolaemia is characterized by raised low - density lipoprotein cholesterol ( ldl - c ) and premature onset of cardiovascular disease . without effective lipid - lowering treatment ( llt ) , adults with heterozygous familial hypercholesterolaemia ( hefh ) have a very high risk of a coronary event by age 50 . statins can reduce this risk , but patients still have an approximately two - fold excess of coronary heart disease mortality vs. the general population . it is generally regarded as a last - resort option for patients with progressive cardiovascular disease and persistently elevated ldl - c . apheresis is expensive and can only be performed in specialized centres , the availability of which varies in different countries . as ldl - c concentrations quickly return to pre - treatment levels , patients must undergo a regular weekly or every 2 weeks ( q2w ) apheresis regimen , depending on the patient s ldl - c value and local practice . lipoprotein apheresis acutely lowers the ldl - c concentration by 5075% , but the time - averaged reduction approximates 30% . alirocumab is a fully human monoclonal antibody that binds pcsk9 and inhibits pcsk9-mediated hepatic catabolism of the low - density lipoprotein receptor . alirocumab as monotherapy or on a background of llt reduced ldl - c by 4458% in patients with and without hefh . the 150  mg q2w dose in combination with statin therapy with or without other llt reduced ldl - c by 6272% . these data showing robust decreases in ldl - c suggested that alirocumab may allow a reduction in the frequency of standard apheresis treatments ( weekly or q2w ) or remove the need for apheresis in patients with hefh . therefore , the objective of this study was to evaluate the effect of alirocumab 150  mg q2w vs. placebo on the standardized rate of apheresis treatments in patients with hefh . odyssey escape ( https://www.clinicaltrials.gov/ct2/show/nct023  26220 ) was a randomized , double - blind , placebo - controlled , parallel - group , phase 3 study in patients with hefh undergoing regular weekly or q2w lipoprotein apheresis . the study was conducted at 14 sites in the united states and germany ; screening started in march 2015 and was completed in september 2015 . eligible patients had hefh ( diagnosed by genotyping or clinical criteria ) , had undergone consistent lipoprotein apheresis weekly for  4 weeks or q2w for  8 weeks , and had maintained a stable background medical llt , diet , and exercise level for  8 weeks . patients undergoing all lipoprotein apheresis techniques were recruited ( for additional information , see supplementary material online , text s1 ) . patients continued to take their background llt and remained on a stable diet and exercise regimen from screening until the end of treatment visits . the study was approved by the local institutional review boards , and was conducted according to the declaration of helsinki , the international conference on harmonisation good clinical practice guidelines , and applicable local laws and regulations . all patients provided written informed consent . during the 2-week screening period , patients provided informed consent , were checked for eligibility , and underwent a lipid panel and other laboratory testing , safety evaluation , and dietary review . ldl - c was calculated using the friedewald formula ( for information on laboratory analyses , as well as the well - being analysis , see supplementary material online , text s1 ) . qualifying patients were randomly assigned ( 2:1 , respectively ) to receive alirocumab 150  mg or placebo subcutaneously q2w for 18 weeks during the double - blind treatment period . randomization was done centrally using an interactive voice or web response system and a permuted - block design to ensure even distribution of treatment assignment . randomization was stratified by frequency of apheresis procedure ( weekly or q2w ) and normal ( < 30  mg / dl ) or elevated ( 30  mg / dl ) lipoprotein ( a ) values . treatment injections ( in 1-ml volume ) were administered at the site by research staff using an autoinjector , starting on the day of randomization . the drug or placebo was administered immediately after completion of the apheresis procedure on days when the two coincided . the double - blind treatment period comprised two intervals : ( phase 1 ) from day 1 to week 6 , the apheresis rate was fixed according to the patient s established schedule ( weekly or q2w ) ; ( phase 2 ) from week 7 to week 18 , the apheresis rate was adjusted based on the patient s ldl - c response to treatment , determined by blinded point - of - care testing . apheresis was not performed when the ldl - c value at that visit was  30% lower than the baseline ( pre - apheresis ) ldl - c value , as described previously . site personnel and patients were blinded to the ldl - c value and treatment assignment , and only received an alert as to whether apheresis should be performed on the basis of coded and blinded point - of - care ldl - c results . patients in germany who completed the double - blind treatment period were offered an optional open - label extension ( to week 86 ) ( results for these patients are not currently available ) . the extension was not offered to patients in the united states because alirocumab is commercially available , but patients had the option to initiate clinical treatment with alirocumab or evolocumab . patients who were not eligible or who chose not to enter the extension were followed for 8 weeks after the end of the double - blind treatment period , or after premature discontinuation of study treatment . the primary efficacy endpoint was the rate of apheresis treatments over 12 weeks ( weeks 7 to 18 ) , standardized according to the number of planned treatments for each individual patient . safety was assessed based on adverse event reports and laboratory analyses during the treatment - emergent adverse event ( teae ) period ( defined as the time from the first dose of double - blind study treatment to the last injection plus 70 days [ 10 weeks ] , as alirocumab was anticipated to have a residual effect lasting for 10 weeks after the last injection ) . we estimated that a sample size of 63 patients ( alirocumab 42 : placebo 21 ) would have at least 85% power to detect a 33% difference in mean apheresis rates using a two - sided significance level and assuming a standard deviation ( sd ) of 40% . the primary efficacy analysis population was the primary intent - to - treat ( itt ) population , defined as all randomized patients . the secondary efficacy analysis population was based on randomized patients who had atleast one pre - apheresis calculated ldl - c value before the first dose of study drug ( or randomization , if the patient did not receive any study drug ) and at least one calculated ldl - c value in one of the pre - apheresis analysis windows up to week 6 . the statistical analysis was conducted when the last patient completed all efficacy assessments at week 18 . ldl - c data were analysed post 
 hoc using the kroon formula ( see supplementary material online , text s1 ) to estimate the interval means of ldl - c in weeks 618 ( after potential withdrawal of apheresis therapy ) . the standardized rate of apheresis treatments was analysed through the rate of treatments received during the 12-week period ( week 7 to week 18 ) , divided by the number of planned treatments ( 6 for q2w and 12 for weekly ) , using the ranked analysis of covariance ( ancova ) model . the standardized apheresis rate could range from 0 to 1 , with 0 indicating that the patient skipped all planned apheresis treatments between week 7 to week 18 , and 1 indicating that the patient received all planned treatments . a rate of 0.75 indicated that the patient received 75% of planned apheresis treatments ( and skipped 25% of planned treatments ) . patient drop - outs were accounted for as described in supplementary material online , text s1 . lehmann estimation and 95% confidence intervals ( cis ) using moses distribution - free ci ( see supplementary material online , text s1 ) . as the primary endpoint analysis was significant at the 5% alpha level , key secondary efficacy endpoints were tested sequentially ( see supplementary material online , table s2 ) . during the 2-week screening period , patients provided informed consent , were checked for eligibility , and underwent a lipid panel and other laboratory testing , safety evaluation , and dietary review . ldl - c was calculated using the friedewald formula ( for information on laboratory analyses , as well as the well - being analysis , see supplementary material online , text s1 ) . qualifying patients were randomly assigned ( 2:1 , respectively ) to receive alirocumab 150  mg or placebo subcutaneously q2w for 18 weeks during the double - blind treatment period . randomization was done centrally using an interactive voice or web response system and a permuted - block design to ensure even distribution of treatment assignment . randomization was stratified by frequency of apheresis procedure ( weekly or q2w ) and normal ( < 30  mg / dl ) or elevated ( 30  mg / dl ) lipoprotein ( a ) values . treatment injections ( in 1-ml volume ) were administered at the site by research staff using an autoinjector , starting on the day of randomization . the drug or placebo was administered immediately after completion of the apheresis procedure on days when the two coincided . the double - blind treatment period comprised two intervals : ( phase 1 ) from day 1 to week 6 , the apheresis rate was fixed according to the patient s established schedule ( weekly or q2w ) ; ( phase 2 ) from week 7 to week 18 , the apheresis rate was adjusted based on the patient s ldl - c response to treatment , determined by blinded point - of - care testing . apheresis was not performed when the ldl - c value at that visit was  30% lower than the baseline ( pre - apheresis ) ldl - c value , as described previously . site personnel and patients were blinded to the ldl - c value and treatment assignment , and only received an alert as to whether apheresis should be performed on the basis of coded and blinded point - of - care ldl - c results . patients in germany who completed the double - blind treatment period were offered an optional open - label extension ( to week 86 ) ( results for these patients are not currently available ) . the extension was not offered to patients in the united states because alirocumab is commercially available , but patients had the option to initiate clinical treatment with alirocumab or evolocumab . patients who were not eligible or who chose not to enter the extension were followed for 8 weeks after the end of the double - blind treatment period , or after premature discontinuation of study treatment . the primary efficacy endpoint was the rate of apheresis treatments over 12 weeks ( weeks 7 to 18 ) , standardized according to the number of planned treatments for each individual patient . safety was assessed based on adverse event reports and laboratory analyses during the treatment - emergent adverse event ( teae ) period ( defined as the time from the first dose of double - blind study treatment to the last injection plus 70 days [ 10 weeks ] , as alirocumab was anticipated to have a residual effect lasting for 10 weeks after the last injection ) . we estimated that a sample size of 63 patients ( alirocumab 42 : placebo 21 ) would have at least 85% power to detect a 33% difference in mean apheresis rates using a two - sided significance level and assuming a standard deviation ( sd ) of 40% . the primary efficacy analysis population was the primary intent - to - treat ( itt ) population , defined as all randomized patients . the secondary efficacy analysis population was based on randomized patients who had atleast one pre - apheresis calculated ldl - c value before the first dose of study drug ( or randomization , if the patient did not receive any study drug ) and at least one calculated ldl - c value in one of the pre - apheresis analysis windows up to week 6 . the statistical analysis was conducted when the last patient completed all efficacy assessments at week 18 . ldl - c data were analysed post 
 hoc using the kroon formula ( see supplementary material online , text s1 ) to estimate the interval means of ldl - c in weeks 618 ( after potential withdrawal of apheresis therapy ) . the standardized rate of apheresis treatments was analysed through the rate of treatments received during the 12-week period ( week 7 to week 18 ) , divided by the number of planned treatments ( 6 for q2w and 12 for weekly ) , using the ranked analysis of covariance ( ancova ) model . the standardized apheresis rate could range from 0 to 1 , with 0 indicating that the patient skipped all planned apheresis treatments between week 7 to week 18 , and 1 indicating that the patient received all planned treatments . a rate of 0.75 indicated that the patient received 75% of planned apheresis treatments ( and skipped 25% of planned treatments ) . patient drop - outs were accounted for as described in supplementary material online , text s1 . lehmann estimation and 95% confidence intervals ( cis ) using moses distribution - free ci ( see supplementary material online , text s1 ) . as the primary endpoint analysis was significant at the 5% alpha level , key secondary efficacy endpoints were tested sequentially ( see supplementary material online , table s2 ) . seventy - six patients with hefh undergoing regular weekly or q2w lipoprotein apheresis provided consent to participate and were screened ; 62 ( 71.6% ) patients were eligible for randomization in the study . forty - one patients were randomly assigned to alirocumab and 21 to placebo ( see supplementary material online , figure s1 ) . all randomized patients received double - blind study treatment and were included in the safety population . sixty patients completed the 6-week double - blind treatment period ( 40 [ 97.6% ] in the alirocumab group and 20 [ 95.2% ] in the placebo group ) ( i.e. when apheresis rate was determined by the patient s established schedule ) , and 57 completed the 18-week double - blind treatment period ( 37 [ 90.2% ] and 20 [ 95.2% ] , respectively ) , when the apheresis schedule was determined by ldl - c value previously achieved . of the five ( 8.1% ) patients who prematurely discontinued study treatment , one ( 4.8% ) was on placebo ( withdrawn due to adverse events ) and four ( 9.8% ) were on alirocumab ( two were withdrawn for adverse events and one for poor compliance , one patient withdrew consent ) . the mean  sd age of the population was 58.7    9.7 years , 36 ( 58.1% ) patients were men , and 60 ( 96.8% ) were white . the median ( minimum , maximum ) duration of apheresis treatments before entry into the study was 4.9 ( 0.5 , 32.9 ) years . the baseline characteristics were balanced between treatment groups ( table 1 and supplementary material online , table s3 ) . the mean calculated baseline ldl - c ( at study entry ) was 4.5    1.4  mmol / l ( 175.1  mg / dl ) in the alirocumab group and 5.0    1.8  mmol / l ( 191.6  mg / dl ) in the placebo group ( p  =  0.35 ) . twenty - seven ( 43.5% ) patients followed a weekly apheresis schedule at baseline and 35 ( 56.5% ) patients followed a q2w schedule . the mean ldl - c value in patients undergoing weekly apheresis was 3.9    1.3  mmol / l ( 151.3    51.3  mg / dl ) vs. 5.3    1.4  mmol / l ( 204.9    55.7  mg / dl ) in patients undergoing q2w apheresis . thirty - eight ( 61.3% ) patients had normal baseline lipoprotein ( a ) levels ( < 30  mg / dl ) and 24 ( 38.7% ) had elevated levels . thirty - four ( 54.8% ) patients were taking a statin at screening , 19 ( 55.9% ) of whom were on a maximum daily dose . baseline ldl - c values were 4.0    1.4  mmol / l ( 155.0    54.6  mg / dl ) among statin - treated patients compared with 5.4    1.4  mmol / l ( 208.0    53.2  mg / dl ) in patients not taking a statin . thirty patients ( 48.4% ) were from germany and 32 ( 51.6% ) from the united states ( see supplementary material online , table s4 ) . table 1baseline characteristics   ( randomized patients)characteristicalirocumab   ( n = 41)placebo   ( n = 21)age   ( years ) , mean    sd59.5    9.257.0    10.5men , n   ( % ) 26   ( 63.4)10   ( 47.6)race , n   ( % )  white39   ( 95.1)21   ( 100 )  black or african american2   ( 4.9)0body mass index   ( kg / m ) , mean    sd30.5    5.030.3    6.2country , n   ( % )  germany20   ( 48.8)10   ( 47.6 )  united states21   ( 51.2)11   ( 52.4)previous pci or cabg , n   ( % ) 35   ( 85.4)14   ( 66.7)time from hypercholesterolaemia diagnosis   ( years ) , mean    sd13.3    12.915.2    14.0frequency of apheresis , n   ( % )  weekly18   ( 43.9)9   ( 42.9 )  every 2 weeks23   ( 56.1)12   ( 57.1)time from first known apheresis treatment   ( years ) , median   ( iqr)4.5   ( 0.5 , 32.9)5.3   ( 0.5 , 27.3)background lipid - modifying therapy at randomization , n   ( % )  any statin19   ( 46.3)13   ( 61.9 )  high - intensity statin13   ( 31.7)12   ( 57.1 )  any llt other than statins   ( with or without statin)26   ( 63.4)16   ( 76.2)ldl - c at baseline , mean    sd or median   ( iqr ) ( mmol / l ) [ mg / dl ]  ldl - c   ( measured formula)4.5    1.3   [ 174.0    51.4]5.0    1.7   [ 195.0    66.9 ]  range1.46.8   [ 56265]2.38.1   [ 90313 ]  median   ( iqr)4.6   ( 3.3:5.7)[176.0   ( 129.0:219.0)]4.7   ( 3.6:6.2)[180.0   ( 140.0:240.0)]ldl - c   ( friedewald formula )   ( mmol / l )   [ mg / dl]4.5    1.4   [ 175.1    54.6]5.0    1.8   [ 191.6    68.9 ]  range1.47.1   [ 53275]2.18.2   [ 81316]cabg , coronary artery bypass graft ; iqr , interquartile range ; ldl - c , low - density lipoprotein cholesterol ; llt lipid - lowering therapy ; pci , percutaneous coronary intervention ; sd , standard deviation.athere were no clinically or statistically significant between - group differences.bself-reported.c4080  mg / day atorvastatin or 2040  mg / day rosuvastatin.dcolesevelam hydrochloride , colestipol , ezetimibe , fish oil , nicotinic acid , omega 3 fatty acids or omega-3-acid ethyl ester . baseline characteristics   ( randomized patients ) cabg , coronary artery bypass graft ; iqr , interquartile range ; ldl - c , low - density lipoprotein cholesterol ; llt lipid - lowering therapy ; pci , percutaneous coronary intervention ; sd , standard deviation . colesevelam hydrochloride , colestipol , ezetimibe , fish oil , nicotinic acid , omega 3 fatty acids or omega-3-acid ethyl ester . the mean    sd duration of injection exposure was 17.4    2.3 weeks ( 8.6    1.3 injections ) in the alirocumab group and 17.5    3.1 weeks ( 8.4    1.7 injections ) in the placebo group . the primary efficacy endpoint achieved statistically significant benefit in favour of alirocumab - treated patients , with a hodges  lehmann median estimate of the treatment difference vs. placebo of 0.75 ( 95% ci 0.670.83 ) . therefore , alirocumab - treated patients had a 0.75 ( 75% ) additional reduction in the standardized rate of apheresis treatments vs. placebo - treated patients ( p  <  0.0001 ) ( table 2 ) . the median treatment difference in the standardized rate of apheresis treatments from week 7 to week 18 , when apheresis treatment was determined by ldl - c concentration previously achieved , was 0.75 ( 95% ci 0.580.92 ) for patients who had been undergoing weekly apheresis and 0.67 ( 95% ci 0.501.00 ) for those on a q2w schedule , in favour of alirocumab . 
 table 2primary study endpoint and key secondary endpointalirocumab ( n = 41)placebo   ( n = 21)alirocumab vs. placebohodges  lehmann estimate of median treatment difference ( 95% moses distribution - free ci)p valueprimary endpoint : standardized rate of apheresis treatments over 12 weeks   ( from weeks 7 to 18 ) , median   ( minimum , maximum ) , % 0   ( 0 , 100)83   ( 42 , 100)0.75   ( 0.670.83)<0.0001key secondary endpoint : standardized rate of apheresis treatments during week 15 to week 18 , median   ( minimum , maximum ) , % 0   ( 0 , 0)100   ( 50 , 100)0.50   ( 0.501.00)<0.0001ci , confidence interval ; q2w , every 2 weeks.athe standardized rate of apheresis treatments was analysed through the rate of treatments received during the 12-week period   ( week 7 to week 18 ) , divided by the number of planned treatments   ( 6 for q2w and 12 for weekly ) . one patient on a q2w schedule was misstratified at the time of randomization ; on the basis of the itt approach , the data for this patient were included in the weekly group . primary study endpoint and key secondary endpoint ci , confidence interval ; q2w , every 2 weeks . the standardized rate of apheresis treatments was analysed through the rate of treatments received during the 12-week period   ( week 7 to week 18 ) , divided by the number of planned treatments   ( 6 for q2w and 12 for weekly ) . one patient on a q2w schedule was misstratified at the time of randomization ; on the basis of the itt approach , the data for this patient were included in the weekly group . the median treatment difference in the standardized rate of apheresis treatments over the 4-week period ( week 15 to week 18 ) was 0.50 ( 95% ci 0.50  1.00 ; p  <  0.0001 ) in favour of alirocumab , indicating a 50% reduction in the standardized rate of apheresis treatments vs. placebo ( table 2 ) . the individual patient reductions in apheresis over the 12-week period are illustrated in figure 1a . during this period , 63.4% of patients on alirocumab had no apheresis procedures , and 92.7% avoided at least half of the procedures ( figure 1b ) . the rate of apheresis treatments according to apheresis schedule is illustrated in supplementary material online , figure s2 . figure 1(a ) individual patients reductions in standardized rate of apheresis treatments from week 7 to week 18 ; ( b ) standardized rate of apheresis treatments from week 7 to week 18 ( intent - to - treat ) by randomized treatment . two patients ( one in each randomized treatment group ) terminated study treatments before week 6 , and their standardized apheresis rates were imputed as 1 ( i.e. 100% ) . ( a ) individual patients reductions in standardized rate of apheresis treatments from week 7 to week 18 ; ( b ) standardized rate of apheresis treatments from week 7 to week 18 ( intent - to - treat ) by randomized treatment . two patients ( one in each randomized treatment group ) terminated study treatments before week 6 , and their standardized apheresis rates were imputed as 1 ( i.e. 100% ) . the mean pre - apheresis ldl - c value decreased from 4.5  mmol / l ( 175  mg / dl ) at baseline to 2.3  mmol / l ( 90  mg / dl ) at week 6 in the alirocumab group ; corresponding data for patients in the placebo group are 5.0  mmol / l ( 192  mg / dl ) and 4.8  mmol / l ( 185  mg / dl ) ( figure 2 ) . the least square ( ls ) mean    standard error ( se ) ( 95% ci ) per cent change in pre - apheresis ldl - c from baseline at week 6 was 
 figure 2pre - apheresis low - density lipoprotein cholesterol values ( mean , with 95% ci ) achieved at 2-weekly time - points ( intent - to - treat analysis ) . the arrow indicates the time from which apheresis treatments could be avoided , when a    30% reduction in low - density lipoprotein cholesterol was achieved vs. baseline ( pre - apheresis ) . values below week 6 and week 18 data points indicate ls mean ( 95% ci ) per cent change from baseline . 53.7    2.3 ( 58.2 to 49.2 ) in the alirocumab group and 1.6    3.1 ( 4.7 to 7.9 ) in the placebo group ( ls mean    se per cent difference 55.3    3.9 , 0.0001 ) ( figure 2 and supplementary material online , table s5 ) . by week 18 , the mean ldl - c value in the alirocumab group had risen slightly , to 2.9  mmol / l ( 110  mg / dl ) , compared with 4.9  mmol / l ( 191  mg / dl ) in the placebo group ( ls mean    se per cent difference 46.4    7.9 , 95% ci 62.3 to 30.5 ; p  <  0.0001 ) ( figure 2 and supplementary material online , table s5 ) . results for other selected key secondary endpoints are shown in supplementary material online , table s5 . results from the well - being analysis are given in supplementary material online , text s2 and table s6 . pre - apheresis low - density lipoprotein cholesterol values ( mean , with 95% ci ) achieved at 2-weekly time - points ( intent - to - treat analysis ) . the arrow indicates the time from which apheresis treatments could be avoided , when a    30% reduction in low - density lipoprotein cholesterol was achieved vs. baseline ( pre - apheresis ) . values below week 6 and week 18 data points indicate ls mean ( 95% ci ) per cent change from baseline . a cross - validation , comparing point - of - care ldl - c values with central laboratory values , showed that both measures were highly correlated ( pearson s correlation 0.86 ) ( supplementary material online , text s3 ) . per cent change from baseline to week 18 in lipoprotein ( a ) was 5.7% for alirocumab vs. 3.0% for placebo among patients with normal baseline values , and 4.9% vs. 7.6% , respectively , in patients with elevated baseline values ( supplementary material online , table s7 ) . during weeks 718 , when apheresis treatment could be withdrawn , alirocumab treatment was associated with a lower mean    sd time - averaged ldl - c value ( using the kroon formula ) over the course of the ( potential ) apheresis interval of 2.4    1.3  mmol / l ( 92.7    50.2  mg / dl ) vs. 3.8    1.7  mmol / l ( 146.7    65.6  mg / dl ) for placebo ( p  <  0.0001 ) . in a post hoc analysis , the time - averaged ldl - c values in the alirocumab - treated patients were consistently lower than those in the placebo - treated patients ( supplementary material online , figure s3 ) . teaes were reported by 75.6% of patients in the alirocumab group and by 76.2% of patients in the placebo group , none of which were fatal ( table 3 ) . the rates of serious adverse events ( 9.8% for alirocumab and 9.5% for placebo ) and events leading to treatment discontinuation ( table 3teaes 
 and laboratory parameters   ( safety population ) at 18 weeksalirocumab ( n = 41)placebo ( n = 21)any teae , n   ( % ) 31   ( 75.6)16   ( 76.2)treatment - emergent serious adverse event , n   ( % ) 4   ( 9.8)2   ( 9.5)teae leading to death , n   ( % ) 00teae leading to treatment discontinuation , n   ( % ) 2   ( 4.9)1   ( 4.8)teaes by system organ class occurring in    2% of patients in either group , n   ( % )  general disorders and administration site conditions13   ( 31.7)4   ( 19.0 )  musculoskeletal and connective tissue disorders13   ( 31.7)4   ( 19.0 )  infections and infestations12   ( 29.3)8   ( 38.1 )  gastrointestinal disorders10   ( 24.4)3   ( 14.3 )  injury , poisoning and procedural complications8   ( 19.5)3   ( 14.3 )  respiratory , thoracic and mediastinal disorders8   ( 19.5)2   ( 9.5 )  nervous system disorders7   ( 17.1)1   ( 4.8 )  laboratory investigations5   ( 12.2)3   ( 14.3 )  cardiac disorders4   ( 9.8)3   ( 14.3 )  skin and subcutaneous tissue disorders4   ( 9.8)1   ( 4.8 )  blood and lymphatic system disorders2   ( 4.9)1   ( 4.8 )  metabolism and nutrition disorders2   ( 4.9)1   ( 4.8 )  psychiatric disorders2   ( 4.9)1   ( 4.8 )  vascular disorders1   ( 2.4)2   ( 9.5 )  immune system disorders1   ( 2.4)0  ear and labyrinth disorders1   ( 2.4)0  reproductive system and breast disorders1   ( 2.4)0  eye disorders01   ( 4.8)teaes occurring in    5% of patients in either group or teaes of interest , n   ( % )  fatigue6   ( 14.6)2   ( 9.5 )  nasopharyngitis4   ( 9.8)2   ( 9.5 )  diarrhoea4   ( 9.8)0  myalgia4   ( 9.8)1   ( 4.8 )  upper respiratory tract infection3   ( 7.3)4   ( 19.0 )  headache3   ( 7.3)1   ( 4.8 )  arthralgia3   ( 7.3)2   ( 9.5 )  nausea2   ( 4.9)3   ( 14.3 )  pruritus2   ( 4.9)1   ( 4.8 )  back pain2   ( 4.9)2   ( 9.5 )  injection site reaction1   ( 2.4)0  palpitations02   ( 9.5)laboratory parameters , n   ( % )  alanine aminotransferase > 3  uln00  creatine kinase > 3  uln3   ( 7.3)0teae , treatment - emergent adverse event ; uln , upper limit of normal.ateaes are adverse events that developed or worsened or became serious during the teae period.balanine aminotransferase increased , liver function test abnormal , blood creatine phosphokinase increased . teaes 
 and laboratory parameters   ( safety population ) at 18 weeks teae , treatment - emergent adverse event ; uln , upper limit of normal . teaes are adverse events that developed or worsened or became serious during the teae period . three patients ( 7.3% ) in the alirocumab group and none in the placebo group had two consecutive pre - apheresis calculated ldl - c values  < 0.7  mmol / l ( 25  mg / dl ) . two of these patients had at least one adverse event , one of which had several serious adverse events ( pneumonia , acute myocardial infarction , acute respiratory failure , congestive heart failure , sepsis , and aortic valve stenosis ) . twenty - seven patients ( 23 [ 56.1% ] on alirocumab and 4 [ 19.0% ] on placebo ) had two consecutive ldl - c values < 0.7  mmol / l after apheresis , of which 15 ( 65.2% ) and 2 ( 50.0% ) , respectively , had an adverse event . none of the events was serious but one patient ( 4.3% ) discontinued treatment with alirocumab . the primary efficacy endpoint achieved statistically significant benefit in favour of alirocumab - treated patients , with a hodges  lehmann median estimate of the treatment difference vs. placebo of 0.75 ( 95% ci 0.670.83 ) . therefore , alirocumab - treated patients had a 0.75 ( 75% ) additional reduction in the standardized rate of apheresis treatments vs. placebo - treated patients ( p  <  0.0001 ) ( table 2 ) . the median treatment difference in the standardized rate of apheresis treatments from week 7 to week 18 , when apheresis treatment was determined by ldl - c concentration previously achieved , was 0.75 ( 95% ci 0.580.92 ) for patients who had been undergoing weekly apheresis and 0.67 ( 95% ci 0.501.00 ) for those on a q2w schedule , in favour of alirocumab . table 2primary study endpoint and key secondary endpointalirocumab ( n = 41)placebo   ( n = 21)alirocumab vs. placebohodges  lehmann estimate of median treatment difference ( 95% moses distribution - free ci)p valueprimary endpoint : standardized rate of apheresis treatments over 12 weeks   ( from weeks 7 to 18 ) , median   ( minimum , maximum ) , % 0   ( 0 , 100)83   ( 42 , 100)0.75   ( 0.670.83)<0.0001key secondary endpoint : standardized rate of apheresis treatments during week 15 to week 18 , median   ( minimum , maximum ) , % 0   ( 0 , 0)100   ( 50 , 100)0.50   ( 0.501.00)<0.0001ci , confidence interval ; q2w , every 2 weeks.athe standardized rate of apheresis treatments was analysed through the rate of treatments received during the 12-week period   ( week 7 to week 18 ) , divided by the number of planned treatments   ( 6 for q2w and 12 for weekly ) . one patient on a q2w schedule was misstratified at the time of randomization ; on the basis of the itt approach , the data for this patient were included in the weekly group . primary study endpoint and key secondary endpoint ci , confidence interval ; q2w , every 2 weeks . the standardized rate of apheresis treatments was analysed through the rate of treatments received during the 12-week period   ( week 7 to week 18 ) , divided by the number of planned treatments   ( 6 for q2w and 12 for weekly ) . one patient on a q2w schedule was misstratified at the time of randomization ; on the basis of the itt approach , the data for this patient were included in the weekly group . the median treatment difference in the standardized rate of apheresis treatments over the 4-week period ( week 15 to week 18 ) was 0.50 ( 95% ci 0.50  1.00 ; p  <  0.0001 ) in favour of alirocumab , indicating a 50% reduction in the standardized rate of apheresis treatments vs. placebo ( table 2 ) . the individual patient reductions in apheresis over the 12-week period are illustrated in figure 1a . during this period , 63.4% of patients on alirocumab had no apheresis procedures , and 92.7% avoided at least half of the procedures ( figure 1b ) . the rate of apheresis treatments according to apheresis schedule is illustrated in supplementary material online , figure s2 . figure 1(a ) individual patients reductions in standardized rate of apheresis treatments from week 7 to week 18 ; ( b ) standardized rate of apheresis treatments from week 7 to week 18 ( intent - to - treat ) by randomized treatment . two patients ( one in each randomized treatment group ) terminated study treatments before week 6 , and their standardized apheresis rates were imputed as 1 ( i.e. 100% ) . ( a ) individual patients reductions in standardized rate of apheresis treatments from week 7 to week 18 ; ( b ) standardized rate of apheresis treatments from week 7 to week 18 ( intent - to - treat ) by randomized treatment . two patients ( one in each randomized treatment group ) terminated study treatments before week 6 , and their standardized apheresis rates were imputed as 1 ( i.e. 100% ) . the mean pre - apheresis ldl - c value decreased from 4.5  mmol / l ( 175  mg / dl ) at baseline to 2.3  mmol / l ( 90  mg / dl ) at week 6 in the alirocumab group ; corresponding data for patients in the placebo group are 5.0  mmol / l ( 192  mg / dl ) and 4.8  mmol / l ( 185  mg / dl ) ( figure 2 ) . the least square ( ls ) mean    standard error ( se ) ( 95% ci ) per cent change in pre - apheresis ldl - c from baseline at week 6 was 
 figure 2pre - apheresis low - density lipoprotein cholesterol values ( mean , with 95% ci ) achieved at 2-weekly time - points ( intent - to - treat analysis ) . the arrow indicates the time from which apheresis treatments could be avoided , when a    30% reduction in low - density lipoprotein cholesterol was achieved vs. baseline ( pre - apheresis ) . values below week 6 and week 18 data points indicate ls mean ( 95% ci ) per cent change from baseline . 53.7    2.3 ( 58.2 to 49.2 ) in the alirocumab group and 1.6    3.1 ( 4.7 to 7.9 ) in the placebo group ( ls mean    se per cent difference 55.3    3.9 , 95% ci 63.1 to 47.5 ; p  < 0.0001 ) ( figure 2 and supplementary material online , table s5 ) . by week 18 , the mean ldl - c value in the alirocumab group had risen slightly , to 2.9  mmol / l ( 110  mg / dl ) , compared with 4.9  mmol / l ( 191  mg / dl ) in the placebo group ( ls mean    se per cent difference 46.4    7.9 , 95% ci 62.3 to 30.5 ; p  <  0.0001 ) ( figure 2 and supplementary material online , table s5 ) . results for other selected key secondary endpoints are shown in supplementary material online , table s5 . results from the well - being analysis are given in supplementary material online , text s2 and table s6 . pre - apheresis low - density lipoprotein cholesterol values ( mean , with 95% ci ) achieved at 2-weekly time - points ( intent - to - treat analysis ) . the arrow indicates the time from which apheresis treatments could be avoided , when a    30% reduction in low - density lipoprotein cholesterol was achieved vs. baseline ( pre - apheresis ) . values below week 6 and week 18 data points indicate ls mean ( 95% ci ) per cent change from baseline . a cross - validation , comparing point - of - care ldl - c values with central laboratory values , showed that both measures were highly correlated ( pearson s correlation 0.86 ) ( supplementary material online , text s3 ) . per cent change from baseline to week 18 in lipoprotein ( a ) was 5.7% for alirocumab vs. 3.0% for placebo among patients with normal baseline values , and 4.9% vs. 7.6% , respectively , in patients with elevated baseline values ( supplementary material online , table s7 ) . during weeks 718 , when apheresis treatment could be withdrawn , alirocumab treatment was associated with a lower mean    sd time - averaged ldl - c value ( using the kroon formula ) over the course of the ( potential ) apheresis interval of 2.4    1.3  mmol / l ( 92.7    50.2  mg / dl ) vs. 3.8    1.7  mmol / l ( 146.7    65.6  mg / dl ) for placebo ( p  <  0.0001 ) . in a post 
 hoc analysis , the time - averaged ldl - c values in the alirocumab - treated patients were consistently lower than those in the placebo - treated patients ( supplementary material online , figure s3 ) . teaes were reported by 75.6% of patients in the alirocumab group and by 76.2% of patients in the placebo group , none of which were fatal ( table 3 ) . the rates of serious adverse events ( 9.8% for alirocumab and 9.5% for placebo ) and events leading to treatment discontinuation ( 4.9% and 4.8% , respectively ) were also similar in both groups . table 3teaes 
 and laboratory parameters   ( safety population ) at 18 weeksalirocumab ( n = 41)placebo ( n = 21)any teae , n   ( % ) 31   ( 75.6)16   ( 76.2)treatment - emergent serious adverse event , n   ( % ) 4   ( 9.8)2   ( 9.5)teae leading to death , n   ( % ) 00teae leading to treatment discontinuation , n   ( % ) 2   ( 4.9)1   ( 4.8)teaes by system organ class occurring in    2% of patients in either group , n   ( % )  general disorders and administration site conditions13   ( 31.7)4   ( 19.0 )  musculoskeletal and connective tissue disorders13   ( 31.7)4   ( 19.0 )  infections and infestations12   ( 29.3)8   ( 38.1 )  gastrointestinal disorders10   ( 24.4)3   ( 14.3 )  injury , poisoning and procedural complications8   ( 19.5)3   ( 14.3 )  respiratory , thoracic and mediastinal disorders8   ( 19.5)2   ( 9.5 )  nervous system disorders7   ( 17.1)1   ( 4.8 )  laboratory investigations5   ( 12.2)3   ( 14.3 )  cardiac disorders4   ( 9.8)3   ( 14.3 )  skin and subcutaneous tissue disorders4   ( 9.8)1   ( 4.8 )  blood and lymphatic system disorders2   ( 4.9)1   ( 4.8 )  metabolism and nutrition disorders2   ( 4.9)1   ( 4.8 )  psychiatric disorders2   ( 4.9)1   ( 4.8 )  vascular disorders1   ( 2.4)2   ( 9.5 )  immune system disorders1   ( 2.4)0  ear and labyrinth disorders1   ( 2.4)0  reproductive system and breast disorders1   ( 2.4)0  eye disorders01   ( 4.8)teaes occurring in    5% of patients in either group or teaes of interest , n   ( % )  fatigue6   ( 14.6)2   ( 9.5 )  nasopharyngitis4   ( 9.8)2   ( 9.5 )  diarrhoea4   ( 9.8)0  myalgia4   ( 9.8)1   ( 4.8 )  upper respiratory tract infection3   ( 7.3)4   ( 19.0 )  headache3   ( 7.3)1   ( 4.8 )  arthralgia3   ( 7.3)2   ( 9.5 )  nausea2   ( 4.9)3   ( 14.3 )  pruritus2   ( 4.9)1   ( 4.8 )  back pain2   ( 4.9)2   ( 9.5 )  injection site reaction1   ( 2.4)0  palpitations02   ( 9.5)laboratory parameters , n   ( % )  alanine aminotransferase > 3  uln00  creatine kinase > 3  uln3   ( 7.3)0teae , treatment - emergent adverse event ; uln , upper limit of normal.ateaes are adverse events that developed or worsened or became serious during the teae period.balanine aminotransferase increased , liver function test abnormal , blood creatine phosphokinase increased . teaes 
 and laboratory parameters   ( safety population ) at 18 weeks teae , treatment - emergent adverse event ; uln , upper limit of normal . teaes are adverse events that developed or worsened or became serious during the teae period . three patients ( 7.3% ) in the alirocumab group and none in the placebo group had two consecutive pre - apheresis calculated ldl - c values  < 0.7  mmol / l ( 25  mg / dl ) . two of these patients had at least one adverse event , one of which had several serious adverse events ( pneumonia , acute myocardial infarction , acute respiratory failure , congestive heart failure , sepsis , and aortic valve stenosis ) . twenty - seven patients ( 23 [ 56.1% ] on alirocumab and 4 [ 19.0% ] on placebo ) had two consecutive ldl - c values < 0.7  mmol / l after apheresis , of which 15 ( 65.2% ) and 2 ( 50.0% ) , respectively , had an adverse event . none of the events was serious but one patient ( 4.3% ) discontinued treatment with alirocumab . the odyssey escape study was conducted in hefh patients who had been undergoing regular lipoprotein apheresis . the study achieved the primary endpoint in the itt population of a statistically significant 75% reduction in the standardized rate of apheresis in favour of alirocumab ( p  <  0.0001 ) . the standardized rate of apheresis was at least halved in 39 of 41 ( 92.7% ) patients on alirocumab , with 63.4% having no apheresis procedures during the 12-week period . patients receiving alirocumab had lower time - averaged ldl - c values than placebo - treated patients . at week 6 , the pre - apheresis ldl - c concentration was reduced by 53.7% in patients on alirocumab , in line with the anticipated reduction . consequently , the percentage of patients on apheresis at week 7 dropped markedly in the alirocumab group . whereas 15 of the 21 placebo - treated patients avoided some of their planned apheresis treatments , three placebo - treated patients achieved a  50% reduction in the apheresis rate . the reasons for this reduction in the apheresis rate with placebo are unclear , but may reflect individual variation in ldl - c values , perhaps due to changes in diet or adherence to llt , the small sample size , and the fact that patients were in a supervised clinical trial . all of the patients in this study were at high cardiovascular risk and had taken llt previously , including statins . at screening , only 54.8% of the patients were taking a statin , 55.9% of whom were on a maximally tolerated dose . a large proportion of the overall population reported a history of down - titration of statin treatment due to tolerability issues ( 43.5% ) and 62.9% reported changing to a different statin . various reasons were given for not taking a statin or for not taking it at the maximum daily dose , ranging from muscle symptoms to anxiety about side - effects , and regional practices / local labelling , indicating that patients with hefh on apheresis present a diverse and difficult - to - treat population , with limited treatment options . patients in the usa showed different characteristics to those in germany , with higher baseline ldl - c , greater prevalence of statin intolerance , and a less frequent apheresis regimen . in the usa , lipoprotein apheresis for hefh is often only considered for patients who , after 6 months , do not have an adequate response to maximum tolerated drug therapy and have elevated ldl - c plus other cardiovascular risk factors . in germany , where apheresis centres are more common , apheresis is considered within 12 months of failure of diet and llt , and at a lower ldl - c threshold , and weekly is preferred to q2w apheresis . furthermore , recommendations for ldl - c lowering from europe are based on a risk - stratified treat - to - target approach , whereas us guidelines advocate a dose - adapted approach . in view of the approach adopted in european guidelines , in which the target ldl - c value is  < 1.8  mmol / l ( 70  mg / dl ) , german patients on alirocumab with ldl - c above this target value would still meet the criteria for apheresis . consequently , llt with alirocumab may prove complementary to lipoprotein apheresis in patients with very high ldl - c or who fail to meet the target ldl - c value . a small observational study involving three patients with hefh on long - term apheresis , who ceased apheresis treatment and received single injections of evolocumab 140  mg q2w subcutaneously over 7 weeks , reported similar results . the present study was conducted in two countries , with patients showing markedly different baseline and treatment characteristics . in order to account for these differences , the target level was based on per cent reduction from baseline in ldl - c rather than on achievement of a specific goal ( e.g. < 1.8  mmol / l[70  mg / dl ] ) for any given patient . thus , in some cases apheresis was interrupted despite the fact that specific ldl - cholesterol goals were not achieved . guideline - recommended threshold values may be achievable in individual patients through treatment with alirocumab alone or in combination with lipoprotein apheresis . furthermore , the study is limited by a relatively small sample size and the short trial duration . the present study was conducted in two countries , with patients showing markedly different baseline and treatment characteristics . in order to account for these differences , the target level was based on per cent reduction from baseline in ldl - c rather than on achievement of a specific goal ( e.g. < 1.8  mmol / l[70  mg / dl ] ) for any given patient . thus , in some cases apheresis was interrupted despite the fact that specific ldl - cholesterol goals were not achieved . guideline - recommended threshold values may be achievable in individual patients through treatment with alirocumab alone or in combination with lipoprotein apheresis . furthermore , the study is limited by a relatively small sample size and the short trial duration . lipoprotein apheresis was discontinued in 63.4% of patients on alirocumab who were previously undergoing regular apheresis every 1 or 2 weeks , and the standardized rate was reduced by at least 50% in an additional 29.3% of patients . pcsk9 inhibition maintained ldl - c at a significantly reduced plateau level as a function of antibody dose over time , whereas ldl - c levels following lipoprotein apheresis started to increase towards pre - procedure levels very rapidly regardless of the frequency of apheresis administration . this difference between pcsk9 inhibition and apheresis translates into a cumulative area under the curve ldl - c benefit in favour of alirocumab , and may be of clinical significance over the long term . the findings from this study suggest a role for alirocumab in the overall management of patients with hefh undergoing regular lipoprotein apheresis therapy , with the potential to avoid apheresis treatments or delay the requirement for such treatments . sanofi and regeneron pharmaceuticals , inc . the sponsor was involved in the study design ; in the writing of the report ; and in the decision to submit the article for publication . funding to pay the open access publication charges for this article was provided by sanofi and regeneron pharmaceuticals , inc . conflict of interest : dr moriarty reports grants and personal fees from regeneron , grants and personal fees from sanofi , grants and personal fees from amgen , grants and personal fees from ionis , grants and personal fees from genzyme , personal fees from duke , personal fees from esperion , personal fees from eliaz therapeutics , personal fees from alexion , grants from pfizer , grants from catabasis , grants from novartis , grants from kaneka , personal fees from aegerion , personal fees from amarin , personal fees from lilly , outside the submitted work . dr parhofer reports grants and personal fees from sanofi / regeneron , during the conduct of the study ; personal fees from sanofi - aventis , grants and personal fees from regeneron , personal fees from aegerion , grants and personal fees from merck , sharp & dohme , personal fees from amgen , personal fees from boehringer ingelheim , personal fees from pfizer , outside the submitted work . dr babirak reports other from sanofi , other from amgen , during the conduct of the study ; other from sanofi , other from amgen , outside the submitted work . dr duell reports grants from regeneron , during the conduct of the study ; personal fees from regeneron , personal fees from amgen , personal fees from kaneka , outside the submitted work . dr hohenstein reports personal fees from amgen gmbh , grants and personal fees from kaneka pharma europe n.v . , personal fees from miltenyi biotec gmbh , personal fees from fresenius medical care gmbh , grants and personal fees from b. braun avitum , personal fees from sanofi - aventis , grants and personal fees from novartis , personal fees from alexion pharma , outside the submitted work . dr ramlow reports grants and personal fees from amgen , grants and personal fees from fresenius , grants and personal fees from kaneka , personal fees from aegerion , personal fees from b. braun , personal fees from merck sharp & dohme , personal fees from regeneron pharmaceuticals inc . , personal fees from sanofi , outside the submitted work . dr schettler reports support for lectures from sanofi - aventis . dr steinhagen - thiessen reports nothing to disclose . dr thompson reports other from regeneron , other from sanofi , other from amgen , outside the submitted work . dr vogt reports other from sanofi / regeneron pharmaceuticals , during the conduct of the study ; other from sanofi / regeneron pharmaceuticals , other from sanofi / regeneron pharmaceuticals , outside the submitted work .
aimto evaluate the effect of alirocumab on frequency of standard apheresis treatments [ weekly or every 2 weeks ( q2w ) ] in heterozygous familial hypercholesterolaemia ( hefh).methods and resultsodyssey escape ( nct02326220 ) was a double - blind study in 62 hefh patients undergoing regular weekly or q2w lipoprotein apheresis . 
 patients were randomly assigned ( 2:1 , respectively ) to receive alirocumab 150  mg ( n  =  41 ) or placebo ( n  =  21 ) q2w subcutaneously for 18 weeks . from day 1 
 to week 6 , apheresis rate was fixed according to the patient s established schedule ; from weeks 7 to 18 , apheresis rate was adjusted based on the patient s low - density lipoprotein cholesterol ( ldl - c ) response in a blinded fashion . 
 apheresis was not performed when the ldl - c value was  30% lower than the baseline ( pre - apheresis ) value . 
 the primary efficacy endpoint was the rate of apheresis treatments over 12 weeks ( weeks 718 ) , standardized to number of planned treatments . in the alirocumab group the least square ( ls ) 
 mean    se ( 95% confidence interval [ ci ] ) per cent change in pre - apheresis ldl - c from baseline at week 6 was 53.7    2.3 ( 58.2 to    49.2 ) compared with 1.6    3.1 ( 4.7 to 7.9 ) in the placebo group . 
 the primary efficacy endpoint showed statistically significant benefit in favour of alirocumab ( hodges  lehmann median estimate of treatment difference : 0.75 ; 95% ci 0.670.83 ; p  <  0.0001 ) . therefore , alirocumab - treated patients had a 0.75 ( 75% ) additional reduction in the standardized rate of apheresis treatments vs. placebo - treated patients . during this period 
 , 63.4% of patients on alirocumab avoided all and 92.7% avoided at least half of the apheresis treatments . 
 adverse event rates were similar ( 75.6% of patients on alirocumab vs. 76.2% on placebo).conclusionslipoprotein apheresis was discontinued in 63.4% of patients on alirocumab who were previously undergoing regular apheresis , and the rate was at least halved in 92.7% of patients . 
 alirocumab was generally safe and well tolerated .