Familial Hypercholesterolemia New treatments

Transcription

1 Familial Hypercholesterolemia New treatments Prof. Shlomo Keidar Head Internal Medicine A Rambam Health Care Campus IAS, Haifa May 2013

2 Effect of treatment on CV survival in Familial Hypercholesterolemia

3 Effect of Lipid-Lowering Treatment on Natural History of Heterozygous Familial Hypercholesterolemia in Past Three Decades 327 patients, 60% men, 38±14 mean age at diagnosis 15±8 years follow up Treatment statin monotherapy - 24% statin plus another agent 55% triple therapy 21% LDL-C mean reduction of 55% from baseline Elis et al. Am J Cardiol Jul 15;108(2):223-6

4 The decrease in the mean LDL cholesterol levels during the 30-year period Elis et al. Am J Cardiol Jul 15;108(2):223-6

5 Evaluation of Cholesterol Lowering Treatment of Patients with Familial Hypercholesterolemia 443 patients with heterozygous familial hypercholesterolemia (172 men) mean age 40±15 years, who referred to outpatient Lipid Unit and were followed up for 8±2 years. Only 14% of the patients achieved an LDL goal <100 mg/dl Metaxa V, et al. Eur Heart J 2011;32

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7 PCSK9* Regulates the Surface Expression of LDLRs by Targeting for Lysosomal Degradation *PCSK9 Proprotein Convertase Subtilisin/Kexin Type 9

8 Key research on PCSK9 came from Helen Hobbs, an endocrinologist and genetics researcher at Southwestern Medical Center in Dallas and her colleague Jonathan Cohen, a geneticist at the medical center. Hobbs and Cohen had been gathering DNA from 3500 Americans for a heart study While many researcher were looking for common gene variants that modestly influence heart risk in broad populations, Hobbs went looking for rare genetic mutations that had a dramatic effect.

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13 More PCSK9=More ATHEROSCLEROSIS Denis et al. Circulation 2012

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16 % patients achieving treatment target Attainment of treatment target in FH patients LDL-C <100mg/dL placebo SAR 50 mg SAR 100 mg SAR 150 mg

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24 PCSK9 inhibitors AMG145 (Amgen ) REGN727/ SAR (Sanofi /Regeneron ) RN316 (Pfizer ) LGT209 (Novartis) RG7652 (Roche / Genentech ) Administration sc injection sc injection iv injection LDL lowering 41-66% 14-72% 15-56% FDA/EU approval x4 phaseii trials completed at 2012 *Start PhaseIII PhaseII PhaseII PhaseII Pricing: > 10,000 USD/patient/year Could achieve peak sales of $2.5bn-plus if it reaches the market as an add-on to statin therapy * Cost of phase III - about half a billion dollars

25 Homozygous familial hypercholesterolemia in Lebanon: A genotype/phenotype correlation Fahed AC, et al. Mol Genet Met 2011;102(2):181 Khachadurian AK. Am J Med 1964;37:402

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27 Brook GJ, Keidar S, et al. Clin Cardiol 1989;12(6):333

28 Brook GJ, Keidar S, et al. Clin Cardiol 1989;12(6):333

29 LDL Apheresis is Current Recommended Care for HoFH Heparin Pump Re-Priming Solution Regeneration Solution Regeneration Pump Blood Pump Plasma Pump Plasma Separator Dextran sulfate columns Blood Return Plasma Line Waste Line

30 Fluctuation of LDL-C levels following a single apheresis procedure Adapted from Thompson et al. Lancet.1995;345(8953):

31 The effect of apheresis on CV complications in HoFH The incidence of major coronary events is reduced by 50-72%, although no difference in total mortality was observed. Thompson GR. LDL apheresis. Atherosclerosis 2003;167:1 13.

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36 MTP Inhibition and Lomitapide 2013 Aegerion Pharmaceuticals, Inc.

37 Assembly and Release of Apo B Containing Lipoproteins and MTP Ribosome TG Liver Cell Apo B100 MTP TG Cytoplasm ER Lumen Ribosome Intestinal Epithelial Cell Apo B48 MTP TG TG Cytoplasm ER Lumen Hussain M, et al. J Lipid Res. 2003:44;22-32.

38 Predicted Effects of MTP Inhibition TG results in hepatic fat TG Blood Vessel Liver Cell Cytoplasm ER Lumen Apo B100 Degraded MTP TG contributes to GI tolerability issues Intestinal Epithelial Cell Apo B48 Degraded MTP TG Cytoplasm ER Lumen Lower VLDL, LDL, chylomicrons, and chylomicron remnants Hussain M, et al. J Lipid Res. 2003:44;22-32.

39 Phase 3 Study Patient Demographic and Baseline Characteristics Parameter Value Min, Max Mean Age (years) 30.7± , 55.0 Gender (M/F) 16/13 Race (Caucasian/Asian/Black/Other) 25/2/1/1 Mean (SD) BMI (kg/m 2 ) 25.8 ± , 41.3 Mean (SD) baseline LDL-C (mg/dl) 336 ± , 564 Receiving apheresis, n (%) 18 (62%) Receiving lipid lowering drugs (LLDs), n (%) Statins Ezetimibe (all in combination with statins) 27 (93%) 27 (93%) 22 (76%) Cuchel, M. et al. Lancet 2013; 381: (published online: 02 Nov 2012); Juxtapid (lomitapide) capsules [US prescribing information]. Cambridge, MA: Aegerion Pharmaceuticals; 2012

40 Phase 3 Study Cardiovascular History of Patients CVD History Total Patients N=29 n(%) History of CVD at baseline 27 (93) Undergone CABG surgery 10 (35) 21 years of age 5 (17) < 8 years of age 3 (10) Undergone multiple CABG surgeries 3 (10) Coronary angioplasty 3 (10) Aortic valve replacement 3 (10) Mitral valve replacement or repair 3 (10) Cuchel, M. et al. Lancet 2013; 381: (published online: 02 Nov 2012);

41 Mean % Change from Baseline (95%CI) Phase 3 Study Results Change in LDL-C Through Week 78 (Completer Population, N=23) Efficacy Phase Safety Phase 0% -10% -20% -30% -40% -50% -60% -70% Mean Dose (LOCF) (mg): Study Week Cuchel, M. et al. Lancet 2013; 381: (published online: 02 November 2012)

42 Rader DJ. J Clin Lipid. 2012:6:282 3; Data on File, Aegerion Pharmaceuticals 4 Treatment-emergent adverse events System organ class preferred term Efficacy phase 26 weeks Safety phase >26 78 weeks n % n % At least one adverse event Gastrointestinal disorders Infections and infestations Investigations (e.g. weight loss, lab abnormalities) General disorders and administrative site conditions Musculoskeletal and connective tissue disorders Injury, poisoning, and procedural complications Nervous system disorders Cardiac disorders Hepatobiliary disorders

43 Phase 3 Hepatic Fat Content as Measured by MRS (Safety Population, N=29) N: Mean (%): Range (%): to to to to 19.0 Aegerion Pharmaceuticals, Data on File

44 Orphan drugs for HoFH Juxtapid /Lomitapide (Aegerion Pharmaceuticals) Kynamro / Mipomersen (Genzyme and Isis Pharmaceuticals) Mode oral sc injection LDL lowering 50% 25% FDA/EU approval Mid 2013 Jan 2013 Pricing USD/patient/year 295, ,000

45 לסיכום הטיפול בחולים עם היפרקולסטרולמיה עיכוב של נתיבים שונים כגון: קשה כולל PCSK9 ApoB100 MTP חלק מהתרופות החדשות נמצאות כבר בשימוש וחלקן צפויות להיכנס לשימוש בעוד שנים בודדות.