<ul><li>Eric Bruckert </li></ul><ul><li>Hôpital Pitié-Salpêtrière </li></ul><ul><li>Paris </li></ul>Thérapeutique des hype...
Capillary endothelium Muscle Lipoprotein Lipase (LPL): Mechanism of action <ul><li>LPL is synthesized e.g. in muscle cells...
LPLD is a severe disease <ul><ul><li>Pancreatitis (potentially lethal) </li></ul></ul><ul><ul><li>Diabetes mellitus  </li>...
Pancreatitis over 350 times more common in LPLD than in healthy controls Gaudet et al Atherosclerosis Suppl 2010 Severe Hy...
Postprandial Chylomicronemia Causes Pancreatitis in LPL Deficiency fat intake high levels of newly-formed chylomicrons in ...
How Glybera Works Persistent Gene Expression Systemic LPL Activity Improved CM Metabolism IM Injection Glybera LPL Protein...
Glybera  Administration Injections ultrasound or electro-physiologically guided  Spinal anesthesia
Objectives clinical studies <ul><li>To assess safety profile of AMT-010/AMT-011  (Glybera) </li></ul><ul><li>Triglyceride ...
Safety Profile <ul><li>Glybera was well tolerated </li></ul><ul><ul><li>Most adverse events were  transient and related to...
TG in CT-AMT-011-01 over time
Yet, Persistent LPL expression  after TG reversal Injected muscle Non-injected muscle 3x10 11  gc/kg (subj007) 3x10 11  gc...
Glybera Reduces  Postprandial Chylomicronemia  <ul><ul><ul><ul><li>Reduced circulating levels of newly-formed chylomicrons...
Reduction of risk of events adjudicated as definite, probable pancreatitis & abd. pain <ul><ul><ul><ul><li>Consistent 56 -...
Reduction of risk of events adjudicated as definite and probable pancreatitis <ul><ul><ul><ul><li>Consistent 62 - 69% risk...
Reduction of risk of events adjudicated as definite pancreatitis <ul><ul><ul><ul><li>Consistent 51 - 59% risk reduction </...
Conclusion <ul><li>First gene therapy in hyperchylomicronemia </li></ul><ul><li>Well tolerated </li></ul><ul><li>Transient...
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12 ème journée-Hyperchylomicronémie : nouvelles perspectives de thérapie génique

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12 ème journée-Hyperchylomicronémie : nouvelles perspectives de thérapie génique

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  • AMT-011 study
  • The observed lack of effect within twoyears prior to therapy can be attributed to small numbers not burn out.
  • 12 ème journée-Hyperchylomicronémie : nouvelles perspectives de thérapie génique

    1. 1. <ul><li>Eric Bruckert </li></ul><ul><li>Hôpital Pitié-Salpêtrière </li></ul><ul><li>Paris </li></ul>Thérapeutique des hyperchylomicronémies par déficit en LPL Perspectives de thérapie génique Conflict of interest. EB has received fees for presentation and participation to advisory boards from Astra Zeneca, MSD, AMT, GSK, Genzyme, Sanofi Aventis, Novo Nordisk, Lilly, Pfizer, Takeda.
    2. 2. Capillary endothelium Muscle Lipoprotein Lipase (LPL): Mechanism of action <ul><li>LPL is synthesized e.g. in muscle cells and transported and bound to the capillary endothelium </li></ul><ul><li>At the endothelium, LPL breaks down triglycerides from chylomicrons/VLDL; resulting free fatty acids (FFA) are absorbed by underlying tissues for energy and storage </li></ul><ul><li>LPL (w/remnants) (downstream) promotes lipoprotein clearance </li></ul>Heparan Sulphate/ GPIHBP1 LPL ApoCII
    3. 3. LPLD is a severe disease <ul><ul><li>Pancreatitis (potentially lethal) </li></ul></ul><ul><ul><li>Diabetes mellitus </li></ul></ul><ul><ul><li>Atherosclerosis ? </li></ul></ul><ul><ul><li>Hyperviscosity syndrome </li></ul></ul><ul><ul><li>(Other) Presenting S&S: </li></ul></ul><ul><ul><ul><li>Lipaemia </li></ul></ul></ul><ul><ul><ul><li>Lipaemia retinalis </li></ul></ul></ul><ul><ul><ul><li>Abdominal pain </li></ul></ul></ul><ul><ul><ul><li>Hepatosplenomegaly </li></ul></ul></ul><ul><ul><ul><li>Xanthomas </li></ul></ul></ul>Lipemia retinalis Eruptive xanthomas <ul><ul><li>Current management ineffective: - low fat diet does not eliminate complications entirely and niacin/fibrates/statins do not lower lipids significantly </li></ul></ul>
    4. 4. Pancreatitis over 350 times more common in LPLD than in healthy controls Gaudet et al Atherosclerosis Suppl 2010 Severe HyperTG (> 10.0 mmol/L) n = 354 Moderate HyperTG (5.0 - 9.0 mmol/L) n = 487 All n = 354 LPLD only n = 28 15.8 ± 16.3 (0.008) 55.8 ± 56.9 (< 0.001) 361.4 ± 401.2 (< 0.001) Odd Ratio ± SE (p-value)
    5. 5. Postprandial Chylomicronemia Causes Pancreatitis in LPL Deficiency fat intake high levels of newly-formed chylomicrons in circulation post meal lodging of aggregates in capillaries - reduced blood flow - oedema - increased pressure acute pancreatitis
    6. 6. How Glybera Works Persistent Gene Expression Systemic LPL Activity Improved CM Metabolism IM Injection Glybera LPL Protein in Muscle <ul><li>Glybera: </li></ul><ul><ul><ul><ul><li>Adeno Associated Virus derived vector </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Naturally occurring human gain-of-function LPL gene variant </li></ul></ul></ul></ul>Reduced Risk of Pancreatitis
    7. 7. Glybera Administration Injections ultrasound or electro-physiologically guided Spinal anesthesia
    8. 8. Objectives clinical studies <ul><li>To assess safety profile of AMT-010/AMT-011 (Glybera) </li></ul><ul><li>Triglyceride levels down on top of a low fat diet </li></ul><ul><ul><li>Bring fasting TG to a level less than or equal to 10 mmol/l (890 mg/dL) OR </li></ul></ul><ul><ul><li>Reduce median fasting plasma triglyceride concentration (vs PREP-study result) by 40% </li></ul></ul><ul><li>Secondary objectives </li></ul><ul><li>To determine the biologic activity and expression of LPL S447X </li></ul><ul><li>To evaluate potential immune responses against LPL S447X and AAV vector </li></ul><ul><li>To assess shedding of AMT-010/011 </li></ul>
    9. 9. Safety Profile <ul><li>Glybera was well tolerated </li></ul><ul><ul><li>Most adverse events were transient and related to administration procedure itself (edema, bruising, sensitivity) </li></ul></ul><ul><ul><li>All but 4 of 27 LPLD patients are continuing in (follow up) studies (1 withdrawal for personal reasons, 1 lost to follow up, 2 deaths during long term follow up) </li></ul></ul><ul><ul><li>No functional or biochemical or MRI changes of injected muscle; muscle biopsies show minor signs of cellular infiltrate 3-12 months post injection </li></ul></ul><ul><li>Transient shedding indicating rapid vector clearance </li></ul><ul><li>No clinically relevant immune responses </li></ul>
    10. 10. TG in CT-AMT-011-01 over time
    11. 11. Yet, Persistent LPL expression after TG reversal Injected muscle Non-injected muscle 3x10 11 gc/kg (subj007) 3x10 11 gc/kg (subj008) (32 weeks after administration) (26 weeks after administration) CT AMT-010 Immunohistochemistry using specific anti-LPL antibody (5D2)
    12. 12. Glybera Reduces Postprandial Chylomicronemia <ul><ul><ul><ul><li>Reduced circulating levels of newly-formed chylomicrons (CM) for 24 hours following intake of fat </li></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>indicative of systemic LPL </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>providing plausible mechanistic explanation for a reduction in pancreatitis risk </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><li>All tested patients showed a persistent response </li></ul></ul></ul></ul>Time after meal (hrs) N=5 N=5 PRE POST (wk 52) POST (wk 14) N=3 CM-[ 3 H]-Activity
    13. 13. Reduction of risk of events adjudicated as definite, probable pancreatitis & abd. pain <ul><ul><ul><ul><li>Consistent 56 - 67% risk reduction </li></ul></ul></ul></ul><ul><ul><ul><ul><li>p-values 0.001 - 0.007 </li></ul></ul></ul></ul>Bruckert - Glybera | 25 May 2011 | CONFIDENTIAL SLIDE SLIDE SLIDE
    14. 14. Reduction of risk of events adjudicated as definite and probable pancreatitis <ul><ul><ul><ul><li>Consistent 62 - 69% risk reduction </li></ul></ul></ul></ul><ul><ul><ul><ul><li>p-values 0.007 - 0.043 </li></ul></ul></ul></ul>
    15. 15. Reduction of risk of events adjudicated as definite pancreatitis <ul><ul><ul><ul><li>Consistent 51 - 59% risk reduction </li></ul></ul></ul></ul><ul><ul><ul><ul><li>p-values 0.032 - 0.087 </li></ul></ul></ul></ul>
    16. 16. Conclusion <ul><li>First gene therapy in hyperchylomicronemia </li></ul><ul><li>Well tolerated </li></ul><ul><li>Transient effect on circulating Tg </li></ul><ul><li>Effect on pancreatitis leading to new hypothesis on the role of chylomicron on pancreatitis </li></ul>

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