Alnylam Research Articles

796-P: Cardiorenal Outcomes with Ertugliflozin by Baseline Cardiorenal Medications: An Analysis from VERTIS CV

VERTIS CV was a placebo-controlled cardiovascular (CV) outcome trial evaluating the SGLT2 inhibitor ertugliflozin. The aim of current analyses was to examine pre-specified CV and kidney outcomes by Cox proportional hazard assessment according to use of renin-angiotensin-aldosterone system inhibitors (RAASi), diuretics, and mineralocorticoid receptor antagonists (MRA) at baseline. Among 8246 randomized patients, at baseline 6686 (81%) were treated with RAASi, 3542 (43%) with diuretics, including 1252 (15%) with loop diuretics, and 674 (8%) with MRA. No significant interactions were observed for cardiorenal outcomes by baseline use of RAASi or MRA (Pinteraction > 0.05 for all; FIGURE). Nominally significant interactions for first event of hospitalization for heart failure (HHF) and HHF/CV death were observed with baseline use of diuretics, including loop diuretics, with an increased benefit of ertugliflozin vs. placebo. In VERTIS CV, baseline use of diuretics, including loop diuretics, appeared to be associated with greater benefit of ertugliflozin on first HHF and HHF/CV death, with no modification of effect based on baseline use of RAASi or MRA.View largeDownload slideView largeDownload slide DisclosureD. Cherney: Other Relationship; Self; AbbVie Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Janssen Scientific Affairs, LLC., Lilly Diabetes, Merck & Co., Inc., Mitsubishi-Tanabe, Maze Inc, Prometic, Novo Nordisk, Sanofi. I. Gantz: Employee; Self; Merck & Co., Inc. R. Frederich: Employee; Self; Pfizer Inc., Other Relationship; Self; Merck Sharp & Dohme Corp., Stock/Shareholder; Self; Bristol-Myers Squibb Company, Pfizer Inc. J. P. Mancuso: Employee; Self; Pfizer Inc., Employee; Spouse/Partner; Pfizer Inc., Stock/Shareholder; Self; Pfizer Inc., Stock/Shareholder; Spouse/Partner; Pfizer Inc. U. Masiukiewicz: Employee; Self; Pfizer Inc. C. P. Cannon: Advisory Panel; Self; Aegerion Pharmaceuticals Inc., Amarin Corporation plc, Corvidia Therapeutics, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Pfizer Inc., Sanofi, Consultant; Self; Alnylam Pharmaceuticals, Inc., Amgen Inc., Applied Therapeutics, Ascendis Pharma A/S, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, HLS Therapeutics Inc., Kowa Company, Ltd., Research Support; Self; Amgen Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Daiichi Sankyo, Janssen Research & Development, LLC, Kowa Company, Ltd., Merck & Co., Inc., Novo Nordisk Pharma Ltd., Pfizer Inc. F. Cosentino: Advisory Panel; Self; AstraZeneca, Merck Sharp & Dohme Corp., Pfizer Inc., Speaker’s Bureau; Self; Bayer AG, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company, Mundipharma International, Novo Nordisk. D. K. Mcguire: Consultant; Self; Applied Therapeutics, AstraZeneca, Boehringer Ingelheim (Canada) Ltd., CSL Behring, Eli Lilly and Company, Lexicon Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk, Pfizer Inc., Sanofi. B. Charbonnel: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly Diabetes, Merck & Co., Inc., Mundipharma International, Novo Nordisk, Sanofi, Speaker’s Bureau; Self; Takeda Pharmaceutical Company Limited. S. Dagogo-jack: Consultant; Self; Abbott, AstraZeneca, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Sanofi US, Stock/Shareholder; Self; Aerami Therapeutics, Jana Care Inc. R. E. Pratley: Other Relationship; Self; Hanmi Pharmaceutical, Merck Sharp & Dohme Corp., Metavention, Monster Energy Company, Inc., Novo Nordisk, Pfizer Inc., Poxel SA, Sanofi, Scohia Pharma Inc., Sun Pharmaceutical Industries Ltd. W. J. Shih: None. M. Maldonado: Employee; Self; Merck Sharp & Dohme Corp. A. Pong: None.

783-P: Cardiorenal Outcomes with Ertugliflozin by Baseline (BL) Glucose-Lowering Agent (GLA): An Analysis from VERTIS CV

VERTIS CV was the cardiovascular (CV) outcome trial for the SGLT2 inhibitor ertugliflozin, conducted in patients with type 2 diabetes (T2D) and atherosclerotic CV disease. In the overall population, ertugliflozin was noninferior to placebo for major adverse CV events (MACE). Although superiority for the composite endpoint of CV death or hospitalization for heart failure (HHF) and the renal composite (that included doubling of serum creatinine from BL) were not met, the prespecified secondary objective of HHF showed a 30% risk reduction and a prespecified exploratory renal composite (sustained ≥40% decrease in eGFR from BL, dialysis/transplantation, or renal death) showed improved kidney outcomes. This analysis assessed cardiorenal endpoints of VERTIS CV by BL GLA.Among 8246 patients in VERTIS CV, at BL 6292 (76%) used metformin, 3900 (47%) insulin, 3390 (41%) sulfonylureas (SU), and 911 (11%) dipeptidyl peptidase-4 inhibitors (DPP4i), alone or in combination therapy (67% used >1 GLA at BL). For each of the GLAs, metformin, insulin, SU, and DPP4i, no significant differences were observed for cardiorenal outcomes by BL use (yes, no) of the GLA (FIGURE; all interaction P values >0.05). Cardiorenal outcomes were generally similar across the BL GLA subgroups.In VERTIS CV, the effects of ertugliflozin on cardiorenal outcomes in patients with T2D were generally consistent regardless of BL GLA.View largeDownload slideView largeDownload slide DisclosureB. Charbonnel: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly Diabetes, Merck & Co., Inc., Mundipharma International, Novo Nordisk, Sanofi, Speaker’s Bureau; Self; Takeda Pharmaceutical Company Limited. I. Gantz: Employee; Self; Merck & Co., Inc. R. Frederich: Employee; Self; Pfizer Inc., Other Relationship; Self; Merck Sharp & Dohme Corp., Stock/Shareholder; Self; Bristol-Myers Squibb Company, Pfizer Inc. J. P. Mancuso: Employee; Self; Pfizer Inc., Employee; Spouse/Partner; Pfizer Inc., Stock/Shareholder; Self; Pfizer Inc., Stock/Shareholder; Spouse/Partner; Pfizer Inc. R. E. Pratley: Other Relationship; Self; Hanmi Pharmaceutical, Merck Sharp & Dohme Corp., Metavention, Monster Energy Company, Inc., Novo Nordisk, Pfizer Inc., Poxel SA, Sanofi, Scohia Pharma Inc., Sun Pharmaceutical Industries Ltd. S. Dagogo-jack: Consultant; Self; Abbott, AstraZeneca, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Sanofi US, Stock/Shareholder; Self; Aerami Therapeutics, Jana Care Inc. C. P. Cannon: Advisory Panel; Self; Aegerion Pharmaceuticals Inc., Amarin Corporation plc, Corvidia Therapeutics, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Pfizer Inc., Sanofi, Consultant; Self; Alnylam Pharmaceuticals, Inc., Amgen Inc., Applied Therapeutics, Ascendis Pharma A/S, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, HLS Therapeutics Inc., Kowa Company, Ltd., Research Support; Self; Amgen Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Daiichi Sankyo, Janssen Research & Development, LLC, Kowa Company, Ltd., Merck & Co., Inc., Novo Nordisk Pharma Ltd., Pfizer Inc. D. Cherney: Other Relationship; Self; AbbVie Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Janssen Scientific Affairs, LLC., Lilly Diabetes, Merck & Co., Inc., Mitsubishi-Tanabe, Maze Inc, Prometic, Novo Nordisk, Sanofi. F. Cosentino: Advisory Panel; Self; AstraZeneca, Merck Sharp & Dohme Corp., Pfizer Inc., Speaker’s Bureau; Self; Bayer AG, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company, Mundipharma International, Novo Nordisk. D. K. Mcguire: Consultant; Self; Applied Therapeutics, AstraZeneca, Boehringer Ingelheim (Canada) Ltd., CSL Behring, Eli Lilly and Company, Lexicon Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk, Pfizer Inc., Sanofi. W. J. Shih: None. J. Liu: Employee; Self; Merck Sharp & Dohme Corp. A. Pong: None.FundingMerck Sharp & Dohme Corp

133-LB: Canagliflozin Improves Cardiovascular and Renal Outcomes across Broad Geographic Regions: Results from CREDENCE

Background: Diabetes is the most common cause of kidney disease in people requiring renal replacement therapy (RRT). RRT is projected to dramatically increase globally, with the greatest increase in Asia. CREDENCE showed canagliflozin reduces kidney and cardiovascular (CV) events in individuals with type 2 diabetes (T2DM) and chronic kidney disease (CKD). Methods: We explored canagliflozin efficacy across geographic regions. A Cox proportional-hazards model was used to analyze the primary outcome (composite of end-stage kidney disease [dialysis, transplantation, or a sustained eGFR of Results: A total of 4401 participants were enrolled across North America (n=1182, 27%), Central and South America (n=941, 21%), Eastern Europe (n=947, 21%), Western Europe (n=421, 10%), Asia (n=749, 17%), and Other (n=161, 4%). Placebo event rates ranged widely, with 32 and 77 events/1000 patient-years in Western Europe and Asia, respectively. Canagliflozin consistently reduced the risk of the primary outcome in all geographic regions (see Figure, previously reported data on race also included). Conclusions: Event rates varied two-fold across regions and needs further study. Canagliflozin reduces the risk of kidney and CV events in all geographic regions. Disclosure K. Cardoza: None. B. Zinman: Advisory Panel; Self; Abbott Diabetes, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Novo Nordisk, Sanofi. M. J. Jardine: Advisory Panel; Self; AstraZeneca, Bayer Inc., Boehringer Ingelheim International GmbH, Chinook, CSL Behring, Janssen Pharmaceuticals, Inc., Vifor Pharma Management Ltd., Research Support; Self; Amgen Inc., Dimerix, Eli Lilly and Company, Merck & Co., Inc., Speaker’s Bureau; Self; Amgen Inc. C. Arnott: None. A. Levin: Advisory Panel; Self; AstraZeneca, Johnson & Johnson, Research Support; Self; Boehringer Ingelheim International GmbH. K. W. Mahaffey: Consultant; Self; Abbott, Amgen Inc., Anthos, AstraZeneca, Baim Institute for Clinical Research, Bayer Healthcare Pharmaceuticals Inc., Boehringer Ingelheim Pharmaceuticals, Inc., CSL Behring, Elsevier, Inova, Intermountain Health, Johnson & Johnson, Medscape, Mount Sinai, Mundipharma International, MyoKardia, National Institutes of Health, Novartis Pharmaceuticals Corporation, Novo Nordisk, Otsuka America Pharmaceutical, Inc., Portola Pharmaceuticals, Inc., Regeneron Pharmaceuticals Inc., SmartMedics, Theravance Biopharma, Research Support; Self; Afferent, AHA, Amgen Inc., Apple, AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Cardiva Medical, Inc, Eidos, Ferring Pharmaceuticals Inc., Gilead Sciences, Inc., Google, Johnson & Johnson, Luitpold Pharmaceuticals, Inc., Medtronic, Merck & Co., Inc., National Institutes of Health, Novartis Pharmaceuticals Corporation, Sanifit, Sanofi, St. Jude Medical. A. Kang: None. B. Smyth: None. T. Yi: None. G. Di tanna: Consultant; Self; Amgen Inc. C. A. Pollock: None. D. De zeeuw: Consultant; Self; Boehringer Ingelheim International GmbH, Fresenius Medical Care, Retrophin, Inc., Other Relationship; Self; Bayer Healthcare Pharmaceuticals Inc. D. C. Wheeler: Advisory Panel; Self; Merck Sharp & Dohme Corp., Consultant; Self; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, GlaxoSmithKline plc., Janssen Global Services, LLC., Mundipharma International, Tricida, Inc., Speaker’s Bureau; Self; Amgen Astellas BioPharma, Astellas Pharma Inc., Napp Pharmaceuticals, Vifor Pharma Management Ltd. C. P. Cannon: Advisory Panel; Self; Aegerion Pharmaceuticals Inc., Amarin Corporation plc, Corvidia Therapeutics, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Pfizer Inc., Sanofi, Consultant; Self; Alnylam Pharmaceuticals, Inc., Amgen Inc., Applied Therapeutics, Ascendis Pharma A/S, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, HLS Therapeutics Inc., Kowa Company, Ltd., Research Support; Self; Amgen Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Daiichi Sankyo, Janssen Research & Development, LLC, Kowa Company, Ltd., Merck & Co., Inc., Novo Nordisk Pharma Ltd., Pfizer Inc.

189-OR: FIDELIO-DKD Study: Analysis of Effects of Finerenone by Baseline A1C

Introduction: Patients with CKD and T2D are at high risk of morbidity and mortality despite the use of guideline-directed therapies. Finerenone, a novel, selective, nonsteroidal mineralocorticoid receptor antagonist, reduced the risk of adverse kidney and CV outcomes in patients with CKD and T2D; here we report outcomes by baseline A1C. Methods: FIDELIO-DKD (NCT02540993) randomized 5734 patients from 48 countries to receive oral finerenone or placebo. Eligible patients had T2D, with a UACR of ≥30-≤5000 mg/g, eGFR ≥25‍-‍<75 mL/min/1.73 m2 and received optimized RAS blockade. Patients with A1C >12% at screening were excluded. The primary outcome was a composite of kidney failure, sustained ≥40% decrease in eGFR from baseline, or renal death. The key secondary outcome was a composite of CV death, non-fatal MI, non-fatal stroke, or hospitalization for HF. Results: In the 5674 patients analyzed, the mean baseline A1C was 7.7% and mean diabetes duration was 16.6 years; finerenone did not affect A1C during the trial. Overall, 2948 patients had A1C ≤7.5% and 2715 patients had A1C >7.5% at baseline. Patients with higher A1C levels were more likely to use insulin and had a longer duration of diabetes. After a median follow-up of 2.6 years, the primary outcome occurred in fewer patients treated with finerenone compared with placebo, this was observed in both the A1C ≤7.5% and >7.5% groups (18.7% vs. 21.5% patients with A1C of ≤7.5% [HR 0.86; 95% CI 0.73-1.01]; 16.9% vs. 20.7% patients with A1C >7.5% [HR 0.79; 95% CI 0.66-0.94]; P-interaction 0.47). Finerenone also reduced the incidence of the key secondary CV outcome compared with placebo regardless of baseline A1C (HR 0.88; 95% CI 0.71-1.07 for A1C ≤7.5% and HR 0.83; 95% CI 0.69-1.01 for A1C >7.5%; P-interaction 0.73). Reduction in UACR was consistent across subgroups. Overall, hyperkalemia events were independent of A1C level. Conclusion: In patients with CKD and T2D, treatment with finerenone reduced the risk for developing adverse kidney and CV outcomes independent of baseline A1C. Disclosure P. Rossing: Advisory Panel; Self; Astellas Pharma Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Gilead Sciences, Inc., Merck KGaA, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi, Vifor Pharma Management Ltd. M. Brinker: Employee; Self; Bayer AG, Stock/Shareholder; Self; Bayer AG. C. Scott: Employee; Self; Bayer PLC. G. Bakris: Consultant; Self; Alnylam Pharmaceuticals, Inc., Bayer AG, Ionis Pharmaceuticals, Merck & Co., Inc., Vascular Dynamics Inc. E. Burgess: Advisory Panel; Self; Bayer Inc. R. Agarwal: Advisory Panel; Self; Akebia Therapeutics, Inc., Bayer Healthcare Pharmaceuticals Inc., Diamedica, Relypsa Inc., Sanofi US, Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Reata Pharmaceuticals, Inc., Other Relationship; Self; AstraZeneca, Chinook. S. Anker: Consultant; Self; Abbott, Bayer AG, Boehringer Ingelheim International GmbH, Cardiac Dimensions Pty. Ltd., Impulse Dynamics, Novartis AG, Servier Laboratories, Vifor Pharma Management Ltd., Other Relationship; Self; Abbott, Vifor Pharma Management Ltd. G. Filippatos: Other Relationship; Self; Bayer AG, Boehringer Ingelheim International GmbH, Servier Laboratories. B. Pitt: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Lilly Diabetes, Consultant; Self; AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Lexicon Pharmaceuticals, Inc., Lexicon Pharmaceuticals, Inc., Sanofi. L. M. Ruilope: None. P. Gillard: None. A. Joseph: Employee; Self; Bayer AG. Funding Bayer AG

405-P: Efficacy and Safety of Finerenone in Patients with CKD and T2D by Baseline Insulin Treatment

Introduction: Finerenone is a novel, selective, nonsteroidal mineralocorticoid receptor antagonist that significantly reduced the risk of kidney and CV outcomes in patients with CKD and T2D in the FIDELIO-DKD trial, with no effect on blood glucose. In advanced T2D, insulin is often used to control glycemia. This analysis will report outcomes from the FIDELIO-DKD trial by baseline insulin treatment. Methods: In FIDELIO-DKD (NCT02540993), 5734 patients with T2D, UACR 30-5000 mg/g, eGFR 25-<75 mL/min/1.73 m2 and treated with optimized RAS blockade were randomized to oral finerenone or placebo. The primary outcome was a composite of kidney failure, a sustained ≥40% eGFR decline from baseline, or renal death. The key secondary outcome was a composite of CV death, non-fatal MI, non-fatal stroke, or hospitalization for HF. Results: Of the 5674 patients analyzed, 3637 (64.1%) were treated with insulin or insulin analogues at baseline. Patients treated with insulin at baseline had a higher A1C and a longer duration of diabetes, with higher proportions of statin and GLP-1RA use, and lower use of other anti-hyperglycemic agents than those who were not. Finerenone did not affect A1C during the trial. The primary and key secondary CV outcome occurred in fewer patients treated with finerenone, with no between-group interaction (primary outcome: HR 0.85, 95% CI 0.73-0.98 with insulin; HR 0.79, 95% CI 0.64-0.96 without insulin; P-value for interaction 0.56; CV outcome: HR 0.82, 95% CI 0.69-0.97 with insulin; HR 0.95, 95% CI 0.74-1.23 without insulin; P-value for interaction 0.33). Hyperkalemia events were similar between groups (mean treatment difference between finerenone and placebo for treatment-emergent serum potassium >5.5 mmol/L, 11.1% with insulin and 13.4% without insulin), with a low incidence of hyperkalemia-related treatment discontinuation. Conclusion: Finerenone has a beneficial effect on kidney and CV outcomes in patients with CKD and T2D, irrespective of insulin use at baseline. Disclosure P. Rossing: Advisory Panel; Self; Astellas Pharma Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Gilead Sciences, Inc., Merck KGaA, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi, Vifor Pharma Management Ltd. L. Roessig: Employee; Self; Bayer AG. C. Scott: Employee; Self; Bayer PLC. G. Bakris: Consultant; Self; Alnylam Pharmaceuticals, Inc., Bayer AG, Ionis Pharmaceuticals, Merck & Co., Inc., Vascular Dynamics Inc. R. Agarwal: Advisory Panel; Self; Akebia Therapeutics, Inc., Bayer Healthcare Pharmaceuticals Inc., Diamedica, Relypsa Inc., Sanofi US, Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Reata Pharmaceuticals, Inc., Other Relationship; Self; AstraZeneca, Chinook. S. Anker: Consultant; Self; Abbott, Bayer AG, Boehringer Ingelheim International GmbH, Cardiac Dimensions Pty. Ltd., Impulse Dynamics, Novartis AG, Servier Laboratories, Vifor Pharma Management Ltd., Other Relationship; Self; Abbott, Vifor Pharma Management Ltd. G. Filippatos: Other Relationship; Self; Bayer AG, Boehringer Ingelheim International GmbH, Servier Laboratories. B. Pitt: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Lilly Diabetes, Consultant; Self; AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Lexicon Pharmaceuticals, Inc., Lexicon Pharmaceuticals, Inc., Sanofi. L. M. Ruilope: None. R. Macisaac: Advisory Panel; Self; AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Novo Nordisk, Servier Laboratories, Speaker’s Bureau; Self; Boehringer Ingelheim International GmbH, Novo Nordisk. J. Wainstein: Board Member; Self; Novo Nordisk, Research Support; Self; Bayer Healthcare Pharmaceuticals Inc., Kowa Company, Ltd., Speaker’s Bureau; Self; Novo Nordisk. A. Joseph: Employee; Self; Bayer AG. Funding Bayer AG

791-P: Ertugliflozin in Older Patients with Type 2 Diabetes (T2D): An Analysis from VERTIS CV

VERTIS CV was a cardiovascular (CV) outcome trial of ertugliflozin vs. placebo in patients (pts) with T2D and atherosclerotic CV disease. Here we analyzed the cardiorenal outcomes and safety of ertugliflozin in older pts.Among 8238 pts randomized and treated with ertugliflozin 5 mg, 15 mg, or placebo, 4093 (49.7%) were <65 yrs, 4145 (50.3%) were ≥65 yrs, with 903 (11.0%) ≥75 yrs. Baseline characteristics were similar across treatment groups within each age group; mean eGFR was lower in older pts (82.2, 69.9, and 63.6 mL/min/1.73m2 for pts <65, ≥65, and ≥75 yrs, respectively). Cardiorenal outcomes for ertugliflozin vs. placebo did not differ between pts ≥65 and <65 yrs, with interaction P values >0.05 for all outcomes assessed (FIGURE). The incidences of adverse events (AEs), serious AEs (including deaths), and discontinuations due to an AE were higher in older vs. younger pts, but generally similar across treatment groups in pts ≥65 and ≥75 yrs. The incidence of renal-related AEs was similar across treatment groups in younger and older pts. The incidences of genital mycotic infection and urinary tract infection were higher with ertugliflozin vs. placebo in older pts. The incidences of hypovolemia AEs with ertugliflozin vs. placebo in pts ≥65 was 5.3% vs. 4.5% and in pts ≥75 yrs was 6.9% vs. 5.8%.Cardiorenal outcomes were similar in pts ≥65 and <65 yrs. Ertugliflozin was generally well tolerated in pts ≥65 and ≥75 yrs.View largeDownload slideView largeDownload slide DisclosureR. E. Pratley: Other Relationship; Self; Hanmi Pharmaceutical, Merck Sharp & Dohme Corp., Metavention, Monster Energy Company, Inc., Novo Nordisk, Pfizer Inc., Poxel SA, Sanofi, Scohia Pharma Inc., Sun Pharmaceutical Industries Ltd. I. A. Adamsons: Employee; Self; Merck Sharp & Dohme Corp. D. Lawrence: Employee; Self; Pfizer Inc., Employee; Spouse/Partner; Becton, Dickinson and Company. W. J. Shih: None. C. P. Cannon: Advisory Panel; Self; Aegerion Pharmaceuticals Inc., Amarin Corporation plc, Corvidia Therapeutics, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Pfizer Inc., Sanofi, Consultant; Self; Alnylam Pharmaceuticals, Inc., Amgen Inc., Applied Therapeutics, Ascendis Pharma A/S, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, HLS Therapeutics Inc., Kowa Company, Ltd., Research Support; Self; Amgen Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Daiichi Sankyo, Janssen Research & Development, LLC, Kowa Company, Ltd., Merck & Co., Inc., Novo Nordisk Pharma Ltd., Pfizer Inc. S. Dagogo-jack: Consultant; Self; Abbott, AstraZeneca, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Sanofi US, Stock/Shareholder; Self; Aerami Therapeutics, Jana Care Inc. B. Charbonnel: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly Diabetes, Merck & Co., Inc., Mundipharma International, Novo Nordisk, Sanofi, Speaker’s Bureau; Self; Takeda Pharmaceutical Company Limited. D. Cherney: Other Relationship; Self; AbbVie Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Janssen Scientific Affairs, LLC., Lilly Diabetes, Merck & Co., Inc., Mitsubishi-Tanabe, Maze Inc, Prometic, Novo Nordisk, Sanofi. F. Cosentino: Advisory Panel; Self; AstraZeneca, Merck Sharp & Dohme Corp., Pfizer Inc., Speaker’s Bureau; Self; Bayer AG, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company, Mundipharma International, Novo Nordisk. D. K. Mcguire: Consultant; Self; Applied Therapeutics, AstraZeneca, Boehringer Ingelheim (Canada) Ltd., CSL Behring, Eli Lilly and Company, Lexicon Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk, Pfizer Inc., Sanofi. M. N. Essex: Employee; Self; Pfizer Inc., Stock/Shareholder; Self; Pfizer Inc. P. L. S. Jones: Employee; Self; Pfizer Inc. J. Liu: Employee; Self; Merck Sharp & Dohme Corp.FundingMerck Sharp & Dohme Corp

209-OR: Physical Activity and Nerve Structure and Function in Patients with Long-Standing Type 1 Diabetes

Physical activity (PA) is recommended for patients with diabetes to improve glycemic control. In prediabetes and T2D there is a causal relationship between PA and peripheral nerve health; however, the effect of PA on nerve structure and function in longstanding T1D is unclear. We aimed to determine the relationship between PA and small nerve fiber morphology, large nerve fiber function and cardiac autonomic function in this population. Data from 75 participants was collected as part of the Canadian Study of Longevity in T1D. Participants completed a physical exam, medical history and neuropathy assessment including nerve conduction studies (NCS), corneal confocal microscopy measurement of corneal nerve fiber length (CNFL) and assessment of heart rate variability. Participants also reported their daily PA from the preceding 12-months. There were 41(55%) female participants, mean ± SD age was 66 ± 8 years, median duration of diabetes was 54 [52,58] years, BMI was 26.6 ± 3.8, HbA1c of 7.3 ± 0.8. 65(89%) participants met the criteria for diagnosis of diabetic neuropathy. The weekly mean PA time was 156 ± 132 min and 35(47%) reported ≧150 minutes/week. PA time was associated with a greater cooling detection threshold (r=0.24; p=0.043), higher peroneal and sural amplitude (r=0.36; p=0.0017, rs=0.26; p=0.024) and conduction velocity (rs=0.28; p=0.015, r=0.23; p=0.050). Vibration perception threshold at the toe was inversely associated with PA (r=-0.31; p=0.025), whereas there was no association at the finger. There was no association between PA time and heart rate variability (r=-0.040; p=0.74) or CNFL (r=0.23; p=0.055). Linear regression for NCS, adjusting for age and A1c, showed that for each 30 min of PA there was an 0.09 mv higher peroneal amplitude (p=0.032) and 0.048 ms lower peroneal F-wave latency (p=0.022). In individuals with longstanding T1D, PA is associated with substantially better large nerve fiber function in the lower limbs and some better measures of small nerve fiber function. Disclosure E. J. H. Lewis: Board Member; Self; Nutarniq Corp, Board Member; Spouse/Partner; Nutarniq Corp, Research Support; Self; Canadian Institutes of Health Research. B. A. Perkins: Advisory Panel; Self; Abbott Diabetes, Boehringer Ingelheim International GmbH, Insulet Corporation, Novo Nordisk Canada Inc., Other Relationship; Self; Abbott Diabetes, Medtronic, Novo Nordisk Canada Inc. L. Lovblom: None. S. O. Lanctot: None. D. Scarr: None. N. Cardinez: None. A. Weisman: None. M. H. Brent: Advisory Panel; Self; Novartis Pharmaceuticals Canada Inc., Roche Canada, Research Support; Self; Bayer AG, Novartis Pharmaceuticals Canada Inc. V. Bril: Advisory Panel; Self; Akcea Therapeutics, Alnylam Pharmaceuticals, Inc., CSL Behring, Sanofi Genzyme, Consultant; Self; Janssen Research &amp; Development, LLC, Research Support; Self; Takeda Canada. D. Cherney: Other Relationship; Self; AbbVie Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Janssen Scientific Affairs, LLC., Lilly Diabetes, Merck &amp; Co., Inc., Mitsubishi-Tanabe, Maze Inc, Prometic, Novo Nordisk, Sanofi. Funding JDRF (17-2013-312)

Lumasiran, an RNAi Therapeutic for Primary Hyperoxaluria Type 1

BackgroundPrimary hyperoxaluria type 1 (PH1) is a rare genetic disease caused by hepatic overproduction of oxalate that leads to kidney stones, nephrocalcinosis, kidney failure, and systemic oxalosis. Lumasiran, an investigational RNA interference (RNAi) therapeutic agent, reduces hepatic oxalate production by targeting glycolate oxidase.MethodsIn this double-blind, phase 3 trial, we randomly assigned (in a 2:1 ratio) patients with PH1 who were 6 years of age or older to receive subcutaneous lumasiran or placebo for 6 months (with doses given at baseline and at months 1, 2, 3, and 6). The primary end point was the percent change in 24-hour urinary oxalate excretion from baseline to month 6 (mean percent change across months 3 through 6). Secondary end points included the percent change in the plasma oxalate level from baseline to month 6 (mean percent change across months 3 through 6) and the percentage of patients with 24-hour urinary oxalate excretion no higher than 1.5 times the upper limit of the normal range at month 6.ResultsA total of 39 patients underwent randomization; 26 were assigned to the lumasiran group and 13 to the placebo group. The least-squares mean difference in the change in 24-hour urinary oxalate excretion (lumasiran minus placebo) was −53.5 percentage points (P<0.001), with a reduction in the lumasiran group of 65.4% and an effect seen as early as month 1. The between-group differences for all hierarchically tested secondary end points were significant. The difference in the percent change in the plasma oxalate level (lumasiran minus placebo) was −39.5 percentage points (P<0.001). In the lumasiran group, 84% of patients had 24-hour urinary oxalate excretion no higher than 1.5 times the upper limit of the normal range at month 6, as compared with 0% in the placebo group (P<0.001). Mild, transient injection-site reactions were reported in 38% of lumasiran-treated patients.ConclusionsLumasiran reduced urinary oxalate excretion, the cause of progressive kidney failure in PH1. The majority of patients who received lumasiran had normal or near-normal levels after 6 months of treatment. (Funded by Alnylam Pharmaceuticals; ILLUMINATE-A ClinicalTrials.gov number, NCT03681184.)

216 - The Impact of Bridging Therapy Prior to CAR-T Cell Therapy on Clinical Outcomes of Patients with Relapsed Refractory Large B-Cell Lymphoma

Introduction:Chimeric antigen receptor T-cell (CAR-T) therapy has become an important treatment modality for patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL). However, many of these patients have aggressive disease and require a form of bridging therapy (BT) for disease control during CAR-T manufacturing. There is limited data in the literature on the most appropriate form of BT and the impact of BT on clinical outcomes. Methods:We retrospectively analyzed data on 75 patients that received CAR-T therapy at our institution. BT was defined as therapy administered between apheresis and CAR-T infusion. 52 patients received bridging therapy (BT) and 23 did not receive BT (NBT). BT included 10 high dose (HD) steroids, 28 chemotherapy-based regimen (CT), and 14 radiation therapy (RT). CT included cytotoxic chemotherapy, immunotherapy, and targeted therapy. IRB approval was obtained for this study. Statistical analysis was conducted with SAS v9.4. Univariate analysis Cox proportional hazard model was used and p-values for response rate were generated from Fisher's exact test. The methods of generalized linear model and logistic regression were used to associate the toxicity grades and cytopenias with BT, respectively. Results:Many patient and disease characteristics between BT and NBT groups were similar, with minor, non-statistically significant differences (See Fig. 1a). Although while the incidence of stage III/IV patients in the BT and NBT group was comparable (p=0.79), in subgroup analysis, there were significantly more stage III/IV patients in the CT subgroup and NBT than in the RT and HD steroids subgroups (p=0.03). There was a higher incidence of bulky disease (≥10cm) in the BT and all BT subgroups versus (vs) NBT, although this was not significant (p=0.58 and p=0.92). The number of prior lines of therapy was comparable between the BT and NBT groups (p=0.99). However, in subgroup analysis there were significantly more patients in the CT subgroup and NBT that received ≥4 lines of therapy compared with RT and HD steroids subgroups (p=0.02). There was no significant difference in overall response rate (ORR) at last follow up between BT vs NBT and BT subgroups vs NBT with approximately 50% being in complete remission in all cases (p=0.48 and p=0.54). Progression free survival (PFS) and overall survival (OS) were similar in the BT vs NBT (one-year rates of 67% vs 64% and 83% vs 75%, respectively) and this was not statistically significant (p=0.52 and 0.89), see Fig. 1b and 1c. In subgroup analysis PFS was comparable in the BT subgroups (CT 69% and HD steroids 68%) vs NBT group (67%) while RT was lower (51%), although this was not statistically significant (p=0.54). In subgroup analysis OS was slightly worse in the BT subgroups (CT 77%, RT 76%, and HD steroids 72%) vs NBT group (83%) although was not statistically significant (p=0.93). The development of cytokine release syndrome (CRS) was comparable in the BT vs NBT group and in BT subgroups vs NBT (p=0.18 and p=0.53). The median grade of immune effector cell-associated neurotoxicity syndrome (ICANS) was higher in BT than NBT (grade 2 vs 0) and trended towards statistical significance (p=0.09). The development of cytopenias at day +180 following CAR-T therapy was significantly higher in BT (50%) vs NBT (13.3%) and was statistically significant (p= 0.038). Subgroup analysis also showed significantly increased cytopenias at day +180 in CT (58.3%) and RT (57.1%) subgroups (p= 0.04). Conclusion:In our single-institution experience, BT prior to CAR-T therapy is feasible and may preserve CAR-T candidacy in patients with rapidly progressive LBCL. BT does not appear to significantly affect ORR, PFS, and OS. The incidence of CRS was comparable, although there was a higher incidence of ICANS in BT, which trended towards significance, and could be contributed to higher tumor bulk in the BT group. BT patients receiving CT and RT for BT were more likely to experience prolonged cytopenias, likely due to the myelosuppressive impact of BT and previous lines of chemo-immunotherapy agents. In conclusion, in high-risk patients with advanced and/or aggressive disease, BT may provide disease stabilization to CAR-T with a similar toxicity profile compared to NBT patients, although BT patients are more likely to experience prolonged cytopenias after CAR-T therapy. Download : Download high-res image (352KB) Download : Download full-size image Disclosures Kansagra:Alnylam Pharmaceuticals, Bristol Myers Squibb /Celgene, GlaxoSmithKline, Janssen, Pharmacyclics, Takeda Pharmaceuticals, Pfizer, Karyopharm Therpeutics:Other: Advisory Board.Hardy:Incyte Corporation:Other: Advisory Board Member;American Gene Technologies:Other: DSMB Member;Kite/Gilead:Other: Advisory Board Member.

Lumasiran: First Approval.

Lumasiran (Oxlumo™) is a subcutaneously administered small interfering RNA (siRNA) targeting the mRNA for hydroxyacid oxidase 1 gene (HAO1; encodes glycolate oxidase) and was developed by Alnylam Pharmaceuticals for the treatment of primary hyperoxaluria type 1 (PH1). By silencing the gene encoding glycolate oxidase, lumasiran depletes glycolate oxidase and thereby inhibits the synthesis of oxalate, which is the toxic metabolite that is directly associated with the clinical manifestations of PH1. On 19 November 2020, lumasiran received its first global approval in the EU for the treatment of PH1 in all age groups. On 23 November 2020, lumasiran was approved in the USA for the treatment of adult and paediatric patients with PH1. This article summarizes the milestones in the development of lumasiran leading to this first approval.

Safety, Pharmacokinetics, and Pharmacodynamics of Oral Venglustat in Patients With Parkinson's Disease and a &lt;i&gt;GBA&lt;/i&gt; Mutation: Results From Part 1 of the Randomised, Double-Blinded, Placebo-Controlled MOVES-PD Trial

Safety, Pharmacokinetics, and Pharmacodynamics of Oral Venglustat in Patients With Parkinson's Disease and a &lt;i&gt;GBA&lt;/i&gt; Mutation: Results From Part 1 of the Randomised, Double-Blinded, Placebo-Controlled MOVES-PD Trial

Givosiran to treat acute porphyria

Porphyrias are a family of rare diseases chiefly due to inborn errors of heme biosynthesis. The porphyrias are generally characterized either by the main site of overproduction of heme precursors (hepatic or erythropoietic) or the main clinical manifestations (acute or cutaneous). The regulation of 5- (or δ)-aminolevulinic acid synthase 1 (ALAS1) plays a key role in the pathway of normal hepatic heme synthesis, providing insight into the pathophysiologic mechanisms and potential therapeutic targets for the treatment of the porphyrias. Givosiran (Givlaari; Alnylam Pharmaceuticals) is an ALAS1-directed small interfering RNA (siRNA) which has been developed for the treatment of acute hepatic porphyria (AHP). It was first approved in 2019 by the U.S. Food and Drug Administration (FDA) for the treatment of adult patients with AHP, and it received also approval in the E.U. in 2020 for the treatment of AHP in adults and adolescents aged 12 years and older.

645. Absence of Toxemia in Clostridioides difficile infection: Results from Ultrasensitive Toxin Assay of Serum

Background Clostridioides difficile infection (CDI) is the major cause of hospital-acquired bacterial infectious diarrheacaused by Toxin A (TcdA) and Toxin B (Tcd B), secreted from pathogenic strains of C.difficle bacteria. This infection can vary greatly in symptom severity and presentation. In fulminant CDI, these toxins lead to systemic complications such as toxemia, however, identification of toxemia in CDI patients is extremely rare. We hypothesized that this rarity of detection may be due to low concentrations of circulating toxins in the blood, below the limit of detection of commercially available assays.MethodsThe previously developed Single Molecule Array (Simoa) assay, capable of detecting TcdA and TcdB in stool, was modified for the detection of toxins in serum and applied to a panel of serum samples from patients with confirmed CDI.ResultsOur cohort included 169 patients with a median age of 68 years (IQR 54-78), most with severe CDI and many with severe clinical outcomes attributed to CDI (Table 1). We found no detectable TcdA or TcdB in the serum of our patient cohort despite a wide range of toxin concentrations in paired stool (Figure 1). The detection of toxin may be limited by the interference of anti-toxin anti-bodies circulating in serum. When serum samples were spiked with TcdA and/or TcdBvarying amounts of IgA, IgG or IgM anti-toxin, high serum anti-toxin antibody concentrations were associated with loss of Simoa signal, suggesting substantial inhibition of toxin measurements.Table 1. Demographics, Baseline Laboratory Values, and Clinical Outcomes for the cohort Figure 1. Comparison of TcdA and TcdB concentrations, as measured by Simoa, in serum and stool. Clinical cutoffs are shown: stool, 20 pg/ml for TcdA and for TcdB; serum 15.0 pg/ml for TcdA and is 26.7 pg/ml for TcdB. Signals below these cut-offs are below backgrounds and so negative. ConclusionIn contrast to earlier published findings which reported on the presence of detectable toxin in the serum of a small number of patients with CDI, our work did not support this observation. Although Simoa is highly sensitive for detection of picogram quantities of TcdA or TcdB it was unable to detect either toxin in serum during CDI. This result does not support the hypothesis that toxemia develops even in severe C. difficile infection.DisclosuresAlice Banz, Ph.D, BioMerieux (Employee) Kevin W. Garey, PharmD, MS, FASHP, Merck & Co. (Grant/Research Support, Scientific Research Study Investigator) Carolyn D. Alonso, MD, FIDSA, Alnylam Pharmaceuticals (Employee)Merck (Research Grant or Support) Ciarán Kelly, MD, Artugen (Consultant)Facile Therapeutics (Consultant)Finch (Consultant)First Light Biosciences (Consultant)Matrivax (Consultant)Merck (Consultant)Vedanta (Consultant)

Long-term safety and efficacy of patisiran for hereditary transthyretin-mediated amyloidosis with polyneuropathy: 12-month results of an open-label extension study

Hereditary transthyretin-mediated amyloidosis is a rare, inherited, progressive disease caused by mutations in the transthyretin (TTR) gene. We assessed the safety and efficacy of long-term treatment with patisiran, an RNA interference therapeutic that inhibits TTR production, in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy. This multicentre, open-label extension (OLE) trial enrolled patients at 43 hospitals or clinical centres in 19 countries as of Sept 24, 2018. Patients were eligible if they had completed the phase 3 APOLLO or phase 2 OLE parent studies and tolerated the study drug. Eligible patients from APOLLO (patisiran and placebo groups) and the phase 2 OLE (patisiran group) studies enrolled in this global OLE trial and received patisiran 0·3 mg/kg by intravenous infusion every 3 weeks with plans to continue to do so for up to 5 years. Efficacy assessments included measures of polyneuropathy (modified Neuropathy Impairment Score +7 [mNIS+7]), quality of life, autonomic symptoms, nutritional status, disability, ambulation status, motor function, and cardiac stress, with analysis by study groups (APOLLO-placebo, APOLLO-patisiran, phase 2 OLE patisiran) based on allocation in the parent trial. The global OLE is ongoing with no new enrolment, and current findings are based on the interim analysis of the patients who had completed 12-month efficacy assessments as of the data cutoff. Safety analyses included all patients who received one or more dose of patisiran up to the data cutoff. This study is registered with ClinicalTrials.gov, NCT02510261. Between July 13, 2015, and Aug 21, 2017, of 212 eligible patients, 211 were enrolled: 137 patients from the APOLLO-patisiran group, 49 from the APOLLO-placebo group, and 25 from the phase 2 OLE patisiran group. At the data cutoff on Sept 24, 2018, 126 (92%) of 137 patients from the APOLLO-patisiran group, 38 (78%) of 49 from the APOLLO-placebo group, and 25 (100%) of 25 from the phase 2 OLE patisiran group had completed 12-month assessments. At 12 months, improvements in mNIS+7 with patisiran were sustained from parent study baseline with treatment in the global OLE (APOLLO-patisiran mean change -4·0, 95 % CI -7·7 to -0·3; phase 2 OLE patisiran -4·7, -11·9 to 2·4). Mean mNIS+7 score improved from global OLE enrolment in the APOLLO-placebo group (mean change from global OLE enrolment -1·4, 95% CI -6·2 to 3·5). Overall, 204 (97%) of 211 patients reported adverse events, 82 (39%) reported serious adverse events, and there were 23 (11%) deaths. Serious adverse events were more frequent in the APOLLO-placebo group (28 [57%] of 49) than in the APOLLO-patisiran (48 [35%] of 137) or phase 2 OLE patisiran (six [24%] of 25) groups. The most common treatment-related adverse event was mild or moderate infusion-related reactions. The frequency of deaths in the global OLE was higher in the APOLLO-placebo group (13 [27%] of 49), who had a higher disease burden than the APOLLO-patisiran (ten [7%] of 137) and phase 2 OLE patisiran (0 of 25) groups. In this interim 12-month analysis of the ongoing global OLE study, patisiran appeared to maintain efficacy with an acceptable safety profile in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy. Continued long-term follow-up will be important for the overall assessment of safety and efficacy with patisiran. Alnylam Pharmaceuticals.

Eighteen-Month Interim Analysis of Efficacy and Safety of Givosiran, an RNAi Therapeutic for Acute Hepatic Porphyria, in the Envision Open Label Extension

Eighteen-Month Interim Analysis of Efficacy and Safety of Givosiran, an RNAi Therapeutic for Acute Hepatic Porphyria, in the Envision Open Label Extension

Long-Term Durability, Safety and Efficacy of Fitusiran Prophylaxis in People with Hemophilia a or B, with or without Inhibitors - Results from the Phase II Study

Long-Term Durability, Safety and Efficacy of Fitusiran Prophylaxis in People with Hemophilia a or B, with or without Inhibitors - Results from the Phase II Study

Dosing, Patient Satisfaction and Other Patient-Reported Outcomes after Switching to Rurioctocog Alfa Pegol in Athn 2: A Longitudinal, Observational Study of Previously Treated Hemophilia Patients Switching Coagulation Replacement Factor Products

Dosing, Patient Satisfaction and Other Patient-Reported Outcomes after Switching to Rurioctocog Alfa Pegol in Athn 2: A Longitudinal, Observational Study of Previously Treated Hemophilia Patients Switching Coagulation Replacement Factor Products

Distinct Genetic Pathways Define Leukemia Predisposition Versus Adaptive Clonal Hematopoiesis in Shwachman-Diamond Syndrome

Background: Shwachman-Diamond Syndrome (SDS) is a bone marrow failure disorder caused by impaired removal of EIF6 from the nascent 60S ribosome subunit, resulting in defective ribosome assembly. SDS patients have a high risk of myeloid neoplasms (MN) and the prognosis of those that develop MN is poor. Knowledge of the kinetics and functional consequences of somatic mutation acquisition in SDS may offer insight into mechanism of transformation and the potential for therapuetic intervention. Methods: We performed whole exome sequencing of 45 samples from 30 patients, and validated recurrent somatically mutated genes using targeted sequencing with error suppression in prospectively collected samples from 110 patients in the North American SDS Registry. We correlated mutation status with clinical outcome and performed functional studies to understand the consequence of somatic mutations in SDS. Results: We detected somatic mutations in 74 of 98 (76%) patients with germline biallelic SBDS mutations (median 2 mutations/patient, range 0-21). We found no mutations in patients with SDS-like disease; those who have clinical features of SDS without disease defining mutations. Of the 83 patients with SDS without a MN diagnosis, 60 (72%) had detectable clonal hematopoiesis (CH), 40 of whom had more than one mutation (median 3, range 1-21). The most frequently mutated genes were EIF6 (60/98, 61%),TP53 (44/98, 45%), PRPF8 (12/98, 12%), and CSNK1A1 (6/98, 6%). Among SDS patients with TP53 mutated CH, 90.9% (30 of 33) had concurrent EIF6 mutations. To determine whether EIF6 and TP53 mutations occur in the same or different clones, we performed single cell DNA sequencing. Among the 47 clones identified with either EIF6 or TP53 mutations, 24 had a sole EIF6 mutation, and 21 had a sole TP53 mutation, showing that these mutations arise in separate clones. To study the functional consequences of EIF6 missense mutations, we cloned 7 patient-derived mutations and generated cell lines expressing wild-type or mutant EIF6 cDNA. We found six mutants (I13N, R67W, G69S, P73R, A194T, G196R) reduced levels of EIF6 protein compared with wild type EIF6, despite comparable abundance of mRNA. The most common recurrent mutation, N106S, was found in 20% of patients and, by contrast to others listed above, did not change protein expression. This mutation is located at the EIF6/60S protein interface and disrupted the interaction of N106S-EIF6 with the 60S subunit as measured by polysome profiling followed by western blotting. To compare the effects of EIF6 versus TP53 somatic mutations in context of SDS deficient translation, we measured ribosome maturation and translation in SDS cells containing shRNAs targeting EIF6 or TP53. EIF6 knockdown ameliorated the SDS defect, reflected by improved ribosome joining (normalization of the 80:60s ratio) and enhanced protein translation (increased O-propargyl-puromycin incorporation), whereas TP53 knockdown had no effect. Knockdown of EIF6 in SDS deficient cells decreased p53 pathway activation as demonstrated by decreased CDKN1A expression. TP53 mutations were significantly associated with MN diagnosis (p=0.023), but were also common in SDS CH and typically stable over time. To identify the characteristics associated with transformation, we analyzed exomes from 7 patients with TP53 mutated myeloid malignancy for allelic imbalances at the TP53 locus and found that all 7 had biallelic alteration of TP53. Using single cell DNA sequencing from serial samples, we observed that TP53 LOH can precede transformation by several years and can distinguish pre-leukemic clones from indolent clones with monoallelic TP53 alterations. Somatic EIF6 mutations were not found in the leukemic clones. These results suggest early detection of TP53 LOH may distinguish clones with leukemic potential. Conclusions: In SDS, impairment of ribosome maturation drives selection of clones with somatic EIF6 or TP53 mutations. EIF6 mutations promote competitive fitness by rescuing the SDS ribosome defect and decreasing p53 pathway activation, and do not contribute to malignant transformation. TP53 mutations decrease checkpoint activation without affecting ribosome assembly. These results provide genetic evidence that germline SBDS deficiency causes a global, disease-specific HSC fitness constraint that drives parallel development of somatic CH and provides a mechanistic rationale for clinical surveillance. Disclosures Dale: Emendo BioTherapeutics: Consultancy; X4 Pharmaceuticals: Research Funding; X4 Pharmaceuticals: Honoraria. Gansner:Alnylam Pharmaceuticals: Current Employment, Current equity holder in private company. Edwards:Jazz Pharmaceuticals: Consultancy, Honoraria. Fleming:DISC Medicine: Consultancy, Membership on an entity's Board of Directors or advisory committees. Lindsley:MedImmune: Research Funding; Takeda Pharmaceuticals: Consultancy; Bluebird Bio: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding.

Genotype Analysis of Adolescents with Heavy Menstrual Bleeding and Low Von Willebrand Activity - Report of a Multi-Center Study

Introduction: Low von Willebrand factor (VWF) activity is prevalent in adolescents with heavy menstrual bleeding (HMB). There is a need to better genetically characterize these patients and improve our understanding of the pathophysiology of their bleeding risk. Methods: One of the main objectives of this multi-center, single arm, observational cohort study was to genotype adolescent females with HMB and low VWF (≥ 30 and ≤ 50 IU/dL) by means of whole exome sequencing (WES), to identify variants throughout the exome that may modulate risk for bleeding. Post-menarchal females &amp;lt; 21 years with HMB (defined as PBAC score &amp;gt;100) and low VWF were eligible for the study. All patients were enrolled by participating centers where blood samples were collected. Exome data for 86 cases and 900 unrelated pediatric (&amp;lt;21 years) controls taken from a genetic study on Chiari 1 Malformation (CM1) were aligned and sorted, and variants called using the Sentieon software package. Annotation including allele frequencies, function, amino acid change and Clinvar rating among others was obtained using ANNOVAR. Variants were retained if there was a genotype call rate of &amp;gt;0.8, GQ&amp;gt;20, AB between 0.3-0.7 and min DP&amp;gt;8. Case/control analyses included common and rare SNP associations, gene burden analysis of both rare nonsynonymous variants and ClinVar 'pathogenic' variants, and gene-set burden analyses. Variants were considered rare if they had a minor allele frequency of &amp;lt;1% in the Genome Aggregation Database (gnomAD). Count differences between cases/controls were determined by Fisher's Exact test. Results: Of the 113 subjects enrolled, 86 had sufficient blood samples collected for WES. The median age was 16.2 years (range: 11.5-19.6). 36% of cases showed variants in VWF vs. 26% of controls (p=0.14). After multiple test correction, WES revealed a significant common variant association in FERMT2 with an LD block with a frequency of 24% in cases and 6% in controls (p=7.5x10-7). Rare variant analysis showed a significant association with an intronic variant in ABCA13 (p=1.6x10-7). Among the gene burden analysis using rare nonsynonymous variants, 2 genes of interest passed multiple test correction: IL12B and DTNBP1. When using ClinVar 'pathogenic' variants as the input for the gene burden analysis, 4 genes of interest passed multiple test correction: HBM, MYLK, RUNX1 and CD36. Gene-set burden analysis revealed 5 significant pathways of interest, including platelet degranulation, platelet alpha granule lumen and erythrocyte differentiation. We then focused a subset of known risk genes and compared the number of missense, nonsense and ClinVar 'pathogenic' variants between cases and controls. GP6, and MTHFR had significantly more missense variants in controls vs. cases (p=0.003 and 0.01, respectively), and F13B approached significance, with more missense variants in controls than cases (p=0.07). Conclusion: We found VWF variants in 36% of subjects, in accordance with previous reports. We found novel SNP associations with variants in FERMT2 and ABCA13.FERMT2 encodes for the integrin, Kindlin 2, which has been shown to be critical for supporting vascular integrity. Several other relevant genes passed multiple test correction in gene burden analyses, including genes known to cause Hermansky-Pudlak syndrome (DTNBP1), familial platelet disorder (RUNX1), platelet glycoprotein IV deficiency (CD36) and aortic aneurysm (MYLK). This association with platelet disorders was strengthened by our gene-set burden results, which implicate several platelet-related pathways. These data suggest that while a subset of HMB patients may have their bleeding explained by variants in VWF, there is a role for other hemostasis, platelet biology and vascular integrity related gene variants which can contribute to the variation in bleeding severity in adolescents with low-VWF related HMB. Study supported by an investigator-initiated research grant from Shire US Inc., now part of Takeda Disclosures O'Brien: Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees. Mullins:Takeda, Bayer: Other: Advisory Board. Sidonio:Takeda: Research Funding. Ragni:Sangamo: Consultancy, Research Funding; Takeda: Research Funding; Bioverativ: Consultancy, Research Funding; Spark: Consultancy, Research Funding; BioMarin: Consultancy, Research Funding; Alnylam/Sanofi, ATHN, BioMarin, Bioverativ, Sangamo, Spark: Research Funding; Alnylam/Sanofi, BioMarin, Bioverativ, Spark: Consultancy; Alnylam Pharmaceuticals Inc., Baxalta/Takeda, BioMarin, Bioverativ, and Spark Therapeutics: Membership on an entity's Board of Directors or advisory committees; American Thrombosis Hemostasis Network: Other: Committee work; Baxalta/Takeda, CSL Behring, Genentech, a member of the Roche Group, OPKO Biologics, and Vascular Medicine Institute: Research Funding. Kulkarni:Sanofi/ Bioverativ, Bayer, Biomarin, Shire/Takeda, Novo Nordisk, Freeline: Other: clinical trial research grants ; Bioverativ/Sanofi, BPL, Genentech, Kedrion, Novo Nordisk, Octapharma, Pfizer, Takeda, Catalyst Bioscience Bayer: Membership on an entity's Board of Directors or advisory committees. Srivaths:Shire US Inc., now part of Takeda: Research Funding.

Outcomes By Cardiac Stage in Newly Diagnosed AL Amyloidosis: Results from Andromeda

Outcomes By Cardiac Stage in Newly Diagnosed AL Amyloidosis: Results from Andromeda