PCSK9 inhibition in homozygous familial hypercholesterolaemia

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1 PCSK9 inhibition in homozygous familial hypercholesterolaemia Slide deck kindly supplied as an educational resource by Dr Evan A Stein MD PhD Director Emeritus Metabolic & Atherosclerosis Research Center Cincinnati, Ohio USA

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3 Background Ø >95% of clinical HoFH patients have mutations in the LDLr, <5% in apolipoprotein B, <0.5% in PCSK9. Ø True genetic HoFH is not uncommon, but the majority are compound heterozygotes. Ø Residual LDLr activity, either negative (<2% function) or (2% to 25% function), is associated with the degree of LDLc elevation and propensity for early CVD. Ø Approximately 70% to 75% of HoFH patients are LDLr and 10% are LDLR negative, the rest unknown. Ø As PCSK9 monoclonal antibodies bind to LDL receptors and increase their activity, it is unknown and uncertain if PCSK9 inhibition will be effective in HoFH patients who have minimal or no LDLr function. Ø We evaluated the efficacy and safety of AMG 145 in an open-label, singlearm, multicenter, dose-scheduling pilot study in patients with HoFH.

4 TESLA: Study Design Ø Evolocumab (AMG 145) 420 mg SC Q4W for 12 weeks (NCT ), maintained for an additional 12 weeks of treatment at 4-week intervals, and then 12 weeks with AMG mg SC Q2W (NCT ) Administration of AMG mg * Week 2 and week 10 study visits are optional. Red rectangles indicate prespecified cutoff dates for efficacy and safety analyses. SC = subcutaneous; Q4W = every 4 weeks; Q2W = every 2 weeks; LDL-C = low-density lipoprotein cholesterol Stein et al Circulation. 2013;128:

5 TESLA: Patient Genotype and LDLR Activity Patient Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6* Patient 7* Patient 8 Mutation Allele 1 (Estimated LDLR Function) Asp266Glu (15%-30%) G>A (Not determined) Asp224Asn (<2% ) Deletion Exon 4-18 (Not determined) Asp221Gly (<2%) Asp175Asn (Not determined) Mutation Allele 2 (Estimated LDLR Function) Asp266Glu (15%-30%) Asp266Glu (15%-30%) Cys296Tyr (Not determined) Cys197Gly (Not determined) # Confirmed by fibroblast culture Mutation at splice acceptor site 10 nucleotides upstream of the first nucleotide of exon 9, 1187 *True homozygous patient; patients share the same genotype Overall LDLR Function Negative # Negative # Stein et al Circulation. 2013;128:

6 PCSK9 mab in HoFH: Change in mmol/l from baseline in LDL-C, weeks 4,, 8, and 12 of the 4-week and 2-week dosing periods 6 Stein et al Circulation. 2013;128:

7 TESLA: LDL-C, Apo B, and Lp(a) Based on LDLR Status Mutation Status Percentage Change from Baseline, %, Mean (SD) Week 12 Q4W Dosing Week 12 Q2W Dosing UC LDL-C Apolipoprotein B Lipoprotein (a) UC LDL-C Apolipoprotein B Lipoprotein (a) Defective LDLR (n=6) (17.5) (14.9) (11.5) (7.6) (18.0) (14.1) Negative LDLR (n=2) 2.6 (3.7) -4.5 (3.5) (8.0) 15.3 (34.7) 3.4 (14.0) (5.3) Average of Week 4, 8, and 12 Q4W Dosing Average of Week 4, 8, and 12 Q2W Dosing UC LDL-C Apolipoprotein B Lipoprotein (a)* UC LDL-C Apolipoprotein B Lipoprotein (a) Defective LDLR (n=6) (15.5) p= (13.1) (11.5) (20.4) p= (18.7) (12.1) Negative LDLR (n=2) 4.4 (10.3) 1.4 (5.6) (8.0) 11.0 (23.6) 2.1 (7.9) (11.2) Signed-rank test; * Lipoprotein (a) was only collected at week 12 for every-4-week dosing. UC = ultracentrifugation; Q4W = every 4 weeks; Q2W = every 2 weeks; LDLR = low-density lipoprotein receptor Stein et al Circulation. 2013;128:

8 Comparison of absolute (mg/dl) LDL-C reductions in HoFH: Apo B antisense 1, MTP inhibitor 2 and PCSK9 inhibition 3 Mipomersen + Lomitapide* AMG 145 # Absolute change from baseline (mg/dl) wk 26 wk 26 wk 52 wk 72 wk pts LOCF * 23 of 26 completers # 6 LDLr 8 1 Raal et al Lancet : Cuchel et al Lancet : Stein et al Circulation. 2013;128:

9 TESLA: CK Elevations and Liver Enzymes Adverse events, no. of patients (%) Laboratory Test Data ALT or AST >3 x ULN any post-baseline visit CK >5 x ULN any post-baseline visit AMG 145 (N = 8) 0 (0) 0 (0) Stein et al Circulation. 2013;128:

10 TESLA: Conclusions Ø This study demonstrated, for the first time, that significant LDLc lowering is achievable with a PCSK9 monoclonal antibody in HoFH patients with LDLr activity. Ø AMG 145, even at a dose of 420 mg Q2W, was well tolerated and was not associated with any notable side effects or increased hepatic transaminases. Ø Based on the results of this proof-of-concept trial, a larger, double-blind, randomized and placebo-controlled trial of evolocumab in HoFH has commenced and is fully recruited. Stein et al Circulation. 2013;128: