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Eric BruckertHôpital Pitié-Salpêtrière
Paris
Thérapeutique des hyperchylomicronémies Thérapeutique des hyperchylomicronémies par déficit en LPLpar déficit en LPL
Perspectives de thérapie géniquePerspectives 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.
Capillary endothelium Muscle
Lipoprotein Lipase (LPL): Mechanism of action
• LPL is synthesized e.g. in muscle cells and transported and bound to the capillary endothelium
• At the endothelium, LPL breaks down triglycerides from chylomicrons/VLDL; resulting free fatty acids (FFA) are absorbed by underlying tissues for energy and storage
• LPL (w/remnants) (downstream) promotes lipoprotein clearance
HeparanSulphate/GPIHBP1 LPL ApoCII
LPLD is a severe disease
• Pancreatitis (potentially lethal)• Diabetes mellitus • Atherosclerosis ?• Hyperviscosity syndrome
• (Other) Presenting S&S:• Lipaemia • Lipaemia retinalis• Abdominal pain• Hepatosplenomegaly• Xanthomas
Lipemia retinalis
Eruptive xanthomas
• Current management ineffective:- low fat diet does not eliminate complicationsentirely and niacin/fibrates/statins do not lower lipids significantly
Pancreatitis over 350 times more common in LPLD than in healthy
controls
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50
100
150
200
250
300
350
400
Severe HyperTG (> 10.0 mmol/L)n = 354
Moderate HyperTG (5.0 - 9.0 mmol/L)
n = 487
Alln = 354
LPLD onlyn = 28
15.8 ± 16.3 (0.008)
55.8 ± 56.9(< 0.001)
361.4 ± 401.2(< 0.001)
Od
d R
atio
± S
E(p
-val
ue)
Gaudet et al Atherosclerosis Suppl 2010
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
Postprandial Chylomicronemia Causes Pancreatitis in LPL Deficiency
How Glybera Works
Persistent Gene
Expression
Systemic LPL Activity
Improved CM
Metabolism
IM Injection Glybera
LPL Protein in Muscle
Glybera: Adeno Associated Virus derived vector
Naturally occurring human gain-of-function LPL gene variant
Reduced Risk of
Pancreatitis
Glybera Administration
Injections ultrasound or electro-physiologically guided Spinal anesthesia
Objectives clinical studies
• To assess safety profile of AMT-010/AMT-011 (Glybera)• Triglyceride levels down on top of a low fat diet
– Bring fasting TG to a level less than or equal to 10 mmol/l (890 mg/dL)OR
– Reduce median fasting plasma triglyceride concentration (vs PREP-study result) by 40%
Secondary objectives• To determine the biologic activity and expression of LPLS447X
• To evaluate potential immune responses against LPLS447X and AAV vector
• To assess shedding of AMT-010/011
Safety Profile
• Glybera was well tolerated– Most adverse events were transient and related to
administration procedure itself (edema, bruising, sensitivity)
– 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)
– No functional or biochemical or MRI changes of injected muscle; muscle biopsies show minor signs of cellular infiltrate 3-12 months post injection
• Transient shedding indicating rapid vector clearance
• No clinically relevant immune responses
TG in CT-AMT-011-01 over time
Injected muscle Non-injected muscle
Yet, Persistent LPL expression after TG reversal
3x1011 gc/kg
(subj007)
3x1011 gc/kg
(subj008)
(32 weeks after administration)
(26 weeks after administration)
CT AMT-010
Immunohistochemistry using specific anti-LPL antibody (5D2)
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0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0 5 10 15 20 25
Glybera Reduces Postprandial Chylomicronemia
– Reduced circulating levels of newly-formed chylomicrons (CM) for 24 hours following intake of fat
» indicative of systemic LPL
» providing plausible mechanistic explanation for a reduction in pancreatitis risk
– All tested patients showed a persistent response
Time after meal (hrs)
N=5
N=5
PRE
POST (wk 52)
POST (wk 14)
N=3
CM
-[3H
]-A
ctiv
ity
Bruckert - Glybera | 25 May 2011 | CONFIDENTIAL
SLIDE 13
SLIDE 13
SLIDE 13
Reduction of risk of events adjudicated as definite, probable pancreatitis & abd. pain
•
– Consistent 56 - 67% risk reduction
– p-values 0.001 - 0.007
0 1.00.2 0.4 0.6 0.8 1.2
3 Years
4 Years
5 Years
6 Years
7 Years
8 Years
9 Years
10 Years
Hazard Ratio with 95 % Confidence Interval
2 Years
1 Year
p < 0.001
p = 0.001
p < 0.001
p < 0.001
p < 0.001
p < 0.001
p < 0.001
p < 0.001
p = 0.007
p = 0.019
Reduction of risk of events adjudicated as definite and probable pancreatitis
0 1.00.2 0.4 0.6 0.8 1.2
3 Years
4 Years
5 Years
6 Years
7 Years
8 Years
9 Years
10 Years
Hazard Ratio with 95 % Confidence Interval
2 Years
p = 0.010
p = 0.010
p = 0.008
p = 0.025
p = 0.007
p = 0.017
p = 0.023
p = 0.026
p = 0.043
1 Year p = nsTreatment not selected
– Consistent 62 - 69% risk reduction
– p-values 0.007 - 0.043
Reduction of risk of events adjudicated as definite pancreatitis
0 1.00.2 0.4 0.6 0.8 1.2
3 Years
4 Years
5 Years
6 Years
7 Years
8 Years
9 Years
10 Years
Hazard Ratio with 95 % Confidence Interval
p = 0.087
p = 0.044
p = 0.032
p = 0.077
p = 0.061
p = 0.040
p = 0.042
p = 0.070
2 Years p = ns
1 Year p = ns
Treatment not selected
Treatment not selected
– Consistent 51 - 59% risk reduction
– p-values 0.032 - 0.087
Conclusion
• First gene therapy in hyperchylomicronemia
• Well tolerated
• Transient effect on circulating Tg
• Effect on pancreatitis leading to new hypothesis on the role of chylomicron on pancreatitis