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Gene therapy with alipogene tiparvovec (glybera®) for the prevention of LPLD induced pancreatitis: Follow-up data suggests long-term clinical benefit
Abstracts / Atherosclerosis 235 (2014) e11–e26 a Medicine Division of Endocrinology Diabetes & Metabolism, University of Pennsylvania, Philadephia, USA; b Medicine Division of Translational Medicine & Human Genetics, University of Pennsylvania, Philadelphia, USA; c Medicine Division of Endocrinology Diabetes & Metabolism, University of Pennsylvania, Philadelphia, USA; d Biochemistry & Biophysics, University of Pennsylvania, Philadelphia, USA; e Robarts Research Institute, University of Western Ontario, London, Canada; f Medicine Division of Translational Medicine & Human Genetics, University of Pennsylvania, Philadephia, USA
Objectives: Loss-of-function mutations affecting the cholesterol transporter ABCA1 impair cellular cholesterol efflux and are associated with reduced HDL-C levels. ABCA1 may also be important in regulating b-cell cholesterol homeostasis and insulin secretion. We sought to determine whether loss-of-function ABCA1 mutations affect b-cell secretory capacity in humans. Methods: The acute insulin response to 5 g iv arginine was measured fasting (AIRarg) and during 230 and 340 mg/dl (AIRpot and AIRmax ) glucose clamps in 3 subjects homozygous for ABCA1 mutations, 8 heterozygous subjects, and 8 normal controls pair-matched to the heterozygous carriers. To account for any effect of low HDL cholesterol on insulin secretion, 9 subjects with isolated low HDL-C with no ABCA1 mutations, and matched controls were also evaluated. Additional tests performed included oral glucose tolerance and frequently sampled intravenous glucose tolerance (FSIGT) tests. Results: Under glucose clamp conditions, insulin secretory capacity was greater in homozygous and heterozygous carriers of ABCA1 mutations than controls (AIRpot 195 33 vs 122 20 and AIRmax 219 30 vs 173 34 mU/ml, heterozygous vs controls respectively, p < 0.05 for both). Insulin sensitivity was not different. Subjects with isolated low HDL-C demonstrated greater AIR than controls under both basal (AIRarg) and clamp conditions (p < 0.05 and <0.001 respecively), but in contrast to ABCA1 carriers, exhibited impaired insulin sensitivity (measured as insulin-dependent glucose disposal during FSIGT) when compared to controls (4.97 0.66 vs 7.15 1.19 [(mU/ml)-1$min-1] respectively, p < 0.05 ), supporting compensatory b-cell adaptation for increased insulin demand. Conclusion: These data indicate that in humans loss-of-function mutations in ABCA1 may be associated with enhanced b-cell secretory capacity and normal insulin sensitivity, and support the importance of cellular cholesterol homeostasis in regulating b-cell insulin secretion. Clinical & late breaking session II EAS-1153. GENE THERAPY WITH ALIPOGENE TIPARVOVEC (GLYBERAÒ) FOR THE PREVENTION OF LPLD INDUCED PANCREATITIS: FOLLOW-UP DATA SUGGESTS LONG-TERM CLINICAL BENEFIT D. Gaudeta, E. Stroesb, M. Brunoc, M. Andersend, H. Petrye, C. Meyerd a Ecogene-21 Clinical Research Center, University of Montreal, Montreal, Canada; b Department of Vascular Medicine, Academic Medical Center, Amsterdam, Netherlands; c Department of Gastroenterology & Hepatology, University Medical Center Rotterdam, Rotterdam, Netherlands; d Clinical Department, uniQure B.V., Amsterdam, Netherlands; e Department of Research and Development, uniQure B.V., Amsterdam, Netherlands
Objectives: In 13 LPLD patients with severe and recurrent acute pancreatitis and treated with GlyberaÒ (AAV1-LPL-S447X), follow-up data for up to 6 years pre- and post-treatment (median 5.8 years) were collected retrospectively to determine the frequency and severity of acute pancreatitis episodes. Methods: Information about acute abdominal pain events resulting in hospitalization was collected from hospital case notes including: date; nature of pain, symptoms, and triggers; diagnosis at time of event; laboratory and imaging data, treatment and interventions (opiates, ICU admission, duration of hospital stay, IV support, and fasting). An independent adjudication panel reviewed blindly each event with
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categorization as either ’documented pancreatitis event according to Atlanta Consensus Criteria.(ACC)’ or ’acute abdominal pain event consistent with pancreatitis’. Events with documented non-pancreatic cause or due to insufficient detail where categorized as ’other’. Results: A total of 60 events classified as documented or consistent with pancreatitis were identified in 8 out of 13 patients. 8 events were classified as ’other’. It was possible to document 24 acute abdominal pain events as pancreatitis events (ACC). In 36 events not all data were available for definite ACC classification, but symptoms and disease course were highly compatible with pancreatitis, typically in patients with prior documented pancreatitis. 5 patients had no events in the observation period. 41 events occurred during the pre-administration period, 19 after GlyberaÒ administration. 1 severe pancreatitis event was observed before treatment, but none after treatment.
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Conclusion: A retrospective analysis of hospital records in 13 patients with LPLD shows that up to 6 years after a single administration of GlyberaÒ the frequency of documented pancreatitis events and acute abdominal pain events consistent with pancreatitis is 59% and 50% lower, respectively, than prior to therapy. Long-term reduction in the frequency of pancreatitis events may be achieved with a single intramuscular administration of GlyberaÒ. Clinical & late breaking session II EAS-1134. EFFECTS OF CER-001 ON CAROTID ATHEROSCLEROSIS BY 3TMRI IN HOMOZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA (HOFH): THE MODIFYING ORPHAN DISEASE EVALUATION (MODE) STUDY G.K. Hovingha, E.S. Stroesa, D. Gaudetb, C. Stefanuttic, H. Sorand, S. Kwokd, J. de Graafe, J.J.P. Kastelijnf, J. Frickg, H. Kleppg, C. Keyserlingg, J. Paolinig, J.L. Dasseuxg a
Vascular Medicine, Academic Medical Center, Amsterdam, Netherlands; Vascular Medicine, Centre Hospitalier Affilie Universitaire Regional, Chicoutimi, Canada; c Department of Molecular Medicine - Lipid Clinic and Atherosclerosis Prevention Centre - Extracorporeal Therapeutic Techniques Unit - Immunohematology and Transfusion Medicine, Sapienza University of Rome, Rome, Italy; d Trial Unit Internal Medicine, University of Glasgow, Glasgow, United Kingdom; e Internal Medicine, University Nijmegen, Nijmegen, Netherlands; f Vascular Medicine, Academic Medical Center, Amsterdam, Netherlands; g Cerenis, Cerenis, Toulouse, France b
Objectives: Patients suffering from HoFH are characterized by extreme progressive atherosclerosis, leading to premature death. HDL has been shown to exert anti-atherogenic effects. We set out to investigate the effect of infusions of CER-001, an engineered pre-beta HDL mimetic, on atherosclerosis by carotid 3T MRI. Methods: Genetically defined HoFH subjects on maximally tolerated LDL lowering therapy underwent twelve biweekly infusions of CER-001 (8 mg/ kg). 3TMRI was performed at baseline and at 6 months. The primary outcome parameter was change in carotid Mean Vessel Wall Area. Secondary parameters included other MRI-derived measurements of the carotids. Results: 23 subjects were enrolled in the study (6 male, 17 female, aged 39 14 years) and the infusions were well tolerated.Results for carotid wall measurements in the 18 subjects who qualified for the modified intent-totreat analyses are shown in the table below.
Objectives: Loss-of-function mutations affecting the cholesterol transporter ABCA1 impair cellular cholesterol efflux and are associated with reduced HDL-C levels. ABCA1 may also be important in regulating b-cell cholesterol homeostasis and insulin secretion. We sought to determine whether loss-of-function ABCA1 mutations affect b-cell secretory capacity in humans. Methods: The acute insulin response to 5 g iv arginine was measured fasting (AIRarg) and during 230 and 340 mg/dl (AIRpot and AIRmax ) glucose clamps in 3 subjects homozygous for ABCA1 mutations, 8 heterozygous subjects, and 8 normal controls pair-matched to the heterozygous carriers. To account for any effect of low HDL cholesterol on insulin secretion, 9 subjects with isolated low HDL-C with no ABCA1 mutations, and matched controls were also evaluated. Additional tests performed included oral glucose tolerance and frequently sampled intravenous glucose tolerance (FSIGT) tests. Results: Under glucose clamp conditions, insulin secretory capacity was greater in homozygous and heterozygous carriers of ABCA1 mutations than controls (AIRpot 195 33 vs 122 20 and AIRmax 219 30 vs 173 34 mU/ml, heterozygous vs controls respectively, p < 0.05 for both). Insulin sensitivity was not different. Subjects with isolated low HDL-C demonstrated greater AIR than controls under both basal (AIRarg) and clamp conditions (p < 0.05 and <0.001 respecively), but in contrast to ABCA1 carriers, exhibited impaired insulin sensitivity (measured as insulin-dependent glucose disposal during FSIGT) when compared to controls (4.97 0.66 vs 7.15 1.19 [(mU/ml)-1$min-1] respectively, p < 0.05 ), supporting compensatory b-cell adaptation for increased insulin demand. Conclusion: These data indicate that in humans loss-of-function mutations in ABCA1 may be associated with enhanced b-cell secretory capacity and normal insulin sensitivity, and support the importance of cellular cholesterol homeostasis in regulating b-cell insulin secretion. Clinical & late breaking session II EAS-1153. GENE THERAPY WITH ALIPOGENE TIPARVOVEC (GLYBERAÒ) FOR THE PREVENTION OF LPLD INDUCED PANCREATITIS: FOLLOW-UP DATA SUGGESTS LONG-TERM CLINICAL BENEFIT D. Gaudeta, E. Stroesb, M. Brunoc, M. Andersend, H. Petrye, C. Meyerd a Ecogene-21 Clinical Research Center, University of Montreal, Montreal, Canada; b Department of Vascular Medicine, Academic Medical Center, Amsterdam, Netherlands; c Department of Gastroenterology & Hepatology, University Medical Center Rotterdam, Rotterdam, Netherlands; d Clinical Department, uniQure B.V., Amsterdam, Netherlands; e Department of Research and Development, uniQure B.V., Amsterdam, Netherlands
Objectives: In 13 LPLD patients with severe and recurrent acute pancreatitis and treated with GlyberaÒ (AAV1-LPL-S447X), follow-up data for up to 6 years pre- and post-treatment (median 5.8 years) were collected retrospectively to determine the frequency and severity of acute pancreatitis episodes. Methods: Information about acute abdominal pain events resulting in hospitalization was collected from hospital case notes including: date; nature of pain, symptoms, and triggers; diagnosis at time of event; laboratory and imaging data, treatment and interventions (opiates, ICU admission, duration of hospital stay, IV support, and fasting). An independent adjudication panel reviewed blindly each event with
e13
categorization as either ’documented pancreatitis event according to Atlanta Consensus Criteria.(ACC)’ or ’acute abdominal pain event consistent with pancreatitis’. Events with documented non-pancreatic cause or due to insufficient detail where categorized as ’other’. Results: A total of 60 events classified as documented or consistent with pancreatitis were identified in 8 out of 13 patients. 8 events were classified as ’other’. It was possible to document 24 acute abdominal pain events as pancreatitis events (ACC). In 36 events not all data were available for definite ACC classification, but symptoms and disease course were highly compatible with pancreatitis, typically in patients with prior documented pancreatitis. 5 patients had no events in the observation period. 41 events occurred during the pre-administration period, 19 after GlyberaÒ administration. 1 severe pancreatitis event was observed before treatment, but none after treatment.
Ă
Conclusion: A retrospective analysis of hospital records in 13 patients with LPLD shows that up to 6 years after a single administration of GlyberaÒ the frequency of documented pancreatitis events and acute abdominal pain events consistent with pancreatitis is 59% and 50% lower, respectively, than prior to therapy. Long-term reduction in the frequency of pancreatitis events may be achieved with a single intramuscular administration of GlyberaÒ. Clinical & late breaking session II EAS-1134. EFFECTS OF CER-001 ON CAROTID ATHEROSCLEROSIS BY 3TMRI IN HOMOZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA (HOFH): THE MODIFYING ORPHAN DISEASE EVALUATION (MODE) STUDY G.K. Hovingha, E.S. Stroesa, D. Gaudetb, C. Stefanuttic, H. Sorand, S. Kwokd, J. de Graafe, J.J.P. Kastelijnf, J. Frickg, H. Kleppg, C. Keyserlingg, J. Paolinig, J.L. Dasseuxg a
Vascular Medicine, Academic Medical Center, Amsterdam, Netherlands; Vascular Medicine, Centre Hospitalier Affilie Universitaire Regional, Chicoutimi, Canada; c Department of Molecular Medicine - Lipid Clinic and Atherosclerosis Prevention Centre - Extracorporeal Therapeutic Techniques Unit - Immunohematology and Transfusion Medicine, Sapienza University of Rome, Rome, Italy; d Trial Unit Internal Medicine, University of Glasgow, Glasgow, United Kingdom; e Internal Medicine, University Nijmegen, Nijmegen, Netherlands; f Vascular Medicine, Academic Medical Center, Amsterdam, Netherlands; g Cerenis, Cerenis, Toulouse, France b
Objectives: Patients suffering from HoFH are characterized by extreme progressive atherosclerosis, leading to premature death. HDL has been shown to exert anti-atherogenic effects. We set out to investigate the effect of infusions of CER-001, an engineered pre-beta HDL mimetic, on atherosclerosis by carotid 3T MRI. Methods: Genetically defined HoFH subjects on maximally tolerated LDL lowering therapy underwent twelve biweekly infusions of CER-001 (8 mg/ kg). 3TMRI was performed at baseline and at 6 months. The primary outcome parameter was change in carotid Mean Vessel Wall Area. Secondary parameters included other MRI-derived measurements of the carotids. Results: 23 subjects were enrolled in the study (6 male, 17 female, aged 39 14 years) and the infusions were well tolerated.Results for carotid wall measurements in the 18 subjects who qualified for the modified intent-totreat analyses are shown in the table below.