Alnylam Research Articles

DIRECT COST VARIANCE ANALYSIS OF PER-ORAL ENDOSCOPIC MYOTOMY VERSUS HELLER’S MYOTOMY FOR MANAGEMENT OF ACHALASIA: A TERTIARY REFERRAL CENTER EXPERIENCE

Syedreza Haider: NO financial relationship with a commercial interest | Gregory Bills: NO financial relationship with a commercial interest | Passisd Laoveeravat: NO financial relationship with a commercial interest | Jordan Miller: NO financial relationship with a commercial interest | Samir Softic: YES financial relationship with a commercial interest;Alnylam Pharmaceuticals:Grant/Research Support;AstraZeneca:Grant/Research Support | Moamen Gabr: NO financial relationship with a commercial interest

1167-P: Burden of Cardiorenal Complications (CRCs) in T2D: Take Care of Me Programme

Rationale: CRCs are known to be key determinants of patient outcomes in T2D; however, the burden of undiagnosed CRCs in unselected T2D population remains unclear, particularly in low-to-middle income countries (LMICs) . ‘Take CaRe of Me’ (TCOM) programme aims to determine the global burden and treatment patterns of CRCs in people with T2D without prior history of cardiovascular (CV) and renal disease. Methods: TCOM programme records data in a cloud based repository after being reported by primary care physicians on albuminuria, eGFR, CV risk, echocardiography and treatment patterns in adults with T2D and no CRCs at index visit for early identification of CRCs. We present a descriptive analysis (up to Dec 2021) of baseline cardiorenal factors from 6 LMICs. Results: We recruited 11335 adults (mean [±SD] age, 54.8±11.4 yrs; 57.9% women, mean T2D duration, 9.8±8.0 yrs) . Mean HbA1c was 8.3±2.2% (65.8% with HbA1c >7%) . Individuals with moderate-to-high renal risk (per urine albumin-creatinine ratio) ranged from 24.8% (Mexico) to 45.1% (Philippines) and with high/very high CV risk (per ESC 2019) ranged from 31.6% (Philippines) to 45.0% (Egypt) (Table) . Discussion: There is high burden of unrecognized CRCs in T2D in real-world setting, with >35% having moderate-to-high renal and high/very high CV risks. Our results point at the unmet need for early diagnosis, risk factor management and use of cardiorenoprotective glucose lowering drugs. Disclosure K.Khunti: Consultant; Abbott, Amgen Inc., AstraZeneca, Bayer AG, Berlin-Chemie AG, Boehringer Ingelheim International GmbH, Lilly, Merck Sharp & Dohme Corp., Napp Pharmaceuticals Limited, Novartis AG, Novo Nordisk, Roche Diabetes Care, Sanofi-Aventis Deutschland GmbH, Servier Laboratories, Research Support; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly, Merck Sharp & Dohme Corp., Novartis AG, Novo Nordisk, Sanofi-Aventis Deutschland GmbH. A.I.Silva: Employee; AstraZeneca. F.Surmont: Employee; AstraZeneca. H.Vasnawala: None. E.Vazquez-mendez: None. P.Fenici: Employee; AstraZeneca. S.Goncalves: None. H.L.Heerspink: Consultant; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Chinook Therapeutics Inc., CSL Behring, Gilead Sciences, Inc., Goldfinch Bio, Inc., Janssen Research & Development, LLC, Mitsubishi Tanabe Pharma Corporation, Mundipharma, Traveere Pharmaceuticals, Research Support; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk A/S. S.Joshi: Advisory Panel; Abbott, Boehringer Ingelheim International GmbH, Dr. Reddy’s Laboratories Ltd., Eli Lilly and Company, Novo Nordisk, Roche Diabetes Care, Consultant; Biocon, Glenmark Pharmaceuticals, Sanofi, USV Private Limited. M.N.Kosiborod: Advisory Panel; Amgen Inc., Applied Therapeutics, Bayer AG, Eli Lilly and Company, ESPERION Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Pharmacosmos A/S, Sanofi, Vifor Pharma Management Ltd., Consultant; Alnylam Pharmaceuticals, Inc., Other Relationship; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk. C.S.Lam: Other Relationship; Prosciento Inc, Radcliffe Group Ltd., Roche Diagnostics, Sanofi, Siemens Healthcare Diagnostics, Abbott, Actelion, Amgen, AnaCardio , Applied Therapeutics, AstraZeneca, Bayer, Boehringer, Boston Scientific, Cytokinetics, Darma., EchoNous, Impulse Dynamics, Ionis Pharma, Janssen R&D, Medscape/WebM, Us2.ai. A.Nicolucci: Board Member; AstraZeneca, Research Support; Novo Nordisk, PIKDARE S.p.A., Sanofi, Shionogi & Co., Ltd., Swedish Orphan Biovitrum AB, Speaker's Bureau; Eli Lilly and Company. L.Ramirez: Employee; AstraZeneca. Funding TCoM study was funded by AstraZeneca International

172-OR: Eligibility and Utilization of SGLT2i and GLP1-RA in T2D by Cardiovascular and Renal Indications

Background: SGLT2i and GLP1-RA improve cardiovascular (CV) and renal outcomes in patients with T2D who are at elevated cardiac or renal risk; however, prescription rates are low despite guidelines recommending their use. We aimed to evaluate the eligibility for and utilization of SGLT2i and GLP-1 in a large health system (HS) . Methods: The electronic health record (EHR) at a quaternary HS in the Northeastern US was queried to identify patients with T2D with CV, renal disease, or at high CV risk based on comorbidities and 10-year atherosclerotic CV disease (ASCVD) risk score. Demographics, medications, comorbidities, indications, and contraindications for SGLT2i and/or GLP1-RA therapy were assessed. Results: The population of individuals with T2D on metformin therapy consists of 122,537 patients: 55% male, 8% Black, 13% non-English speaking. Of patients eligible for SGLT2i, 12% were prescribed an SGLT2i. Of patients eligible for GLP1-RA therapy, 17% were prescribed GLP1-RA. Of patients eligible for either SGLT2i or GLP1-RA therapy not currently receiving either therapy, 41% had 10-year ASCVD risk >10%, 56% had ASCVD, 29% had chronic kidney disease (CKD) , and 18% had heart failure. Conclusion: While advantages of novel therapies have demonstrated benefits, opportunities from provider, patient, and systems to eliminate barriers to uptake and dissemination of therapy to improve outcomes for patients exist. Disclosure A.Blood: None. D.J.Wexler: Other Relationship; Elsevier, Novo Nordisk, UpToDate. B.M.Scirica: Consultant; Allergan, Boehringer Ingelheim International GmbH, ESPERION Therapeutics, Inc., Hanmi Pharm. Co., Ltd., Novo Nordisk, Research Support; Better Therapeutics, Eisai Co., Ltd., Merck & Co., Inc., Novo Nordisk, Pfizer Inc., Stock/Shareholder; Heath At Scale. F.Waterman: Employee; Novo Nordisk. G.Stern: None. D.Zelle: None. L.Chang: Consultant; Alosa Health, Pri-Med LLC, Other Relationship; Applied Therapeutics, Better Therapeutics, Eli Lilly and Company, Fractyl Health, Inc., Sanofi, Research Support; Boehringer Ingelheim International GmbH, Novo Nordisk. C.A.Colling: None. D.Gabovitch: None. C.M.Hamersky: Employee; Novo Nordisk. E.Durden: Employee; Novo Nordisk A/S. C.Holt: Employee; Novo Nordisk. J.Noone: Employee; Novo Nordisk. C.P.Cannon: Advisory Panel; Alnylam Pharmaceuticals, Inc., Amarin Corporation, Amgen Inc., Amryt Pharma Plc, Applied Therapeutics, Ascendis Pharma A/S, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Lexicon Pharmaceuticals, Inc., Merck & Co., Inc., Pfizer Inc., Rhoshan, Sanofi, Research Support; Amgen Inc., Better Therapeutics, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company, Daiichi Sankyo, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk, Pfizer Inc. Funding Novo Nordisk

1405-P: Bacteroides thetaiotaomicron Fortifies the Gut Mucosa and Improves Host Metabolism in Dietary Obese Mice

Disruption of the intestinal mucosa contributes to insulin resistance in obesity and Type 2 diabetes. Probiotic supplementation, which restores gut microbiota composition and fortifies intestinal barrier function, has therapeutic potential to treat obesity and metabolic disease. Treatment of mice on a chow diet or high fat diet (HFD) with Palmitic Acid Hydroxystearic Acids (PAHSAs) improves insulin sensitivity. These effects are mediated, at least in part, by changes in the gut microbiome. We used this paradigm to identify new microbes that may have beneficial metabolic effects. Metagenome sequencing of the cecum from mice treated with PAHSAs identified Bacteroides thetaiotaomicron (Bt) to be most strongly associated with insulin sensitivity. Here, we aimed to determine whether Bt supplementation in mice on a HFD diet has beneficial effects on energy balance and/or glucose homeostasis. Daily oral Bt supplementation in female mice fed a HFD resulted in less weight gain, lower adiposity, and improved glucose tolerance compared to vehicle-treated mice. Additionally, Bt supplementation preserved colonic mucus thickness, an indicator of gut health; increased the number of Goblet cells which are the cells that secrete mucin2, the predominant mucus protein that forms the intestinal mucosal barrier; and increased protein levels of mucin2 in the distal gut compared to vehicle-treated controls. These improvements in distal gut barrier architecture were associated with a reduction in circulating levels of pro-inflammatory lipopolysaccharide (LPS) and interleukin-6 (IL-6) . These beneficial effects of Bt were observed in female and not in male HFD-fed mice. These studies indicate that Bt has sex-specific effects to improve host metabolism in the setting of dietary obesity. Bt represents a next-generation probiotic and novel gut-based therapeutic strategy which could improve metabolic health in women. Disclosure J.Lee: None. K.Wellenstein: None. B.B.Kahn: Advisory Panel; Janssen Pharmaceuticals, Inc., Consultant; Mellicell, Other Relationship; Alnylam Pharmaceuticals, Inc. Funding NIH KDK114162; JPB Foundation

865-P: Long-Term Ertugliflozin Treatment and Incidence of Hypoglycemia: Analyses from VERTIS CV

This analysis assessed the incidence and total events of hypoglycemia in VERTIS CV (NCT01986881) , the cardiovascular (CV) outcome trial for ertugliflozin (ERTU) in patients (pts) with type 2 diabetes and atherosclerotic CV disease. Hypoglycemia was categorized as level 1, a documented symptomatic event with plasma glucose (PG) ≤70 mg/dL (prespecified) ; level 2, a documented event with PG <54 mg/dL (post hoc) ; level 3, a severe event requiring assistance (prespecified) . Time to first HYPO-broad (levels 1+2+3) and HYPO-strict (levels 2+3) were analyzed by a Cox proportional hazards model. Kaplan-Meier estimates were plotted. Exposure-adjusted event rates for total (first + recurrent) HYPO-broad and -strict were analyzed. Overall, 8246 pts were randomized, mean follow-up was 3.5 yrs. The incidence rate (ERTU vs PBO) of first HYPO-broad was 14.3 vs. 16.2/100 pt-yrs; adjusted hazard ratio [aHR], 95% CI: 0.93 [0.85, 1.00] and HYPO-strict was 9.5 vs. 11.1/100 pt-yrs; aHR: 0.89 [0.81, 0.97] [Figure A]. Exposure-adjusted event rates were lower in ERTU vs PBO [Figure B]. The increase in percentage of insulin users (end of study vs. baseline) was less with ERTU (3.5% 5 + 15 mg) compared with PBO (6.2%) . In VERTIS CV, pts randomized to ERTU had a lower risk of hypoglycemia, including first and recurrent events, than PBO-treated pts. This may in part be due to the lesser increase in insulin users with ERTU vs. PBO. Disclosure S.Dagogo-jack: Consultant; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Janssen Pharmaceuticals, Inc., Medtronic, Merck & Co., Inc., Sanofi. R.E.Pratley: Other Relationship; Bayer AG, Corcept Therapeutics, Dexcom, Inc., Hanmi Pharm. Co., Ltd., Merck & Co., Inc., Metavention, Novo Nordisk, Pfizer Inc., Poxel SA, Sanofi, Scohia Pharma Inc., Sun Pharmaceutical Industries Ltd. C.P.Cannon: Advisory Panel; Alnylam Pharmaceuticals, Inc., Amarin Corporation, Amgen Inc., Amryt Pharma Plc, Applied Therapeutics, Ascendis Pharma A/S, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Lexicon Pharmaceuticals, Inc., Merck & Co., Inc., Pfizer Inc., Rhoshan, Sanofi, Research Support; Amgen Inc., Better Therapeutics, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company, Daiichi Sankyo, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk, Pfizer Inc. D.Cherney: Other Relationship; AbbVie Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Janssen Research & Development, LLC, Lilly, Maze, BMS, CSL-Behring, Merck, Otsuka, Novartis and Novo-Nordisk , Mitsubishi Tanabe Pharma Corporation, Sanofi, Research Support; Boehringer Ingelheim-Lilly, Merck, Janssen, Sanofi, AstraZeneca and Novo-Nordisk. F.Cosentino: Advisory Panel; Merck Sharp & Dohme Corp., Pfizer Inc., Speaker's Bureau; AstraZeneca, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company, Lilly, Merck Sharp & Dohme Corp., Novo Nordisk. D.K.Mcguire: Consultant; AstraZeneca, Boehringer Ingelheim International GmbH, CSL Behring, ESPERION Therapeutics, Inc., Lexicon Pharmaceuticals, Inc., Lilly, Merck & Co., Inc., Novo Nordisk, Pfizer Inc., Sanofi. J.Liu: Employee; Merck & Co., Inc. C.Liu: Employee; Merck & Co., Inc., Stock/Shareholder; Merck & Co., Inc. R.Frederich: Employee; Pfizer Inc., Stock/Shareholder; Bristol-Myers Squibb Company, Pfizer Inc. J.P.Mancuso: Employee; Pfizer Inc., Stock/Shareholder; Pfizer Inc. Funding This study was sponsored by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and Pfizer Inc., New York, NY, USA.

720-P: Change in Body Weight from Baseline with Tirzepatide: Sex Subgroup Analysis of the SURPASS Studies

Five Phase 3 SURPASS trials have shown robust efficacy of novel dual GIP/GLP-1 receptor agonist, tirzepatide, in glycaemic control and body weight (BW) loss in adults with Type 2 Diabetes (T2D) . A key secondary endpoint investigated the effect of tirzepatide (5, 10, and 15 mg) versus placebo or active comparators on mean BW change from baseline to endpoint. To determine whether weight-lowering effects of tirzepatide depend on the sex of study participants, we conducted a post-hoc subgroup analysis of SURPASS (S) -1 to -5 trials. BW change in the sex subgroups was assessed in patients while on treatment without rescue medication (efficacy estimand) in the modified intention-to-treat (mITT) population, defined as all randomized patients who received at least one dose of study drug. All tirzepatide doses significantly reduced BW compared to placebo or active comparators regardless of the sex of study participants (S-1 to -5 p<0.001) . The most frequent AEs were mild-to-moderate, GI-related, and occurred during the dose-escalation period. Disclosure A.W.Plat: None. N.Rasouli: Advisory Panel; Eli Lilly and Company, Novo Nordisk, Sanofi, Research Support; Allergan, Eli Lilly and Company, Novo Nordisk. J.Peleshok: Employee; Eli Lilly and Company, Eli Lilly and Company. H.Sapin: Employee; Eli Lilly and Company. J.Wilding: Advisory Panel; Alnylam Pharmaceuticals, Inc., AstraZeneca, Eli Lilly and Company, Mundipharma, Novo Nordisk A/S, Rhythm Pharmaceuticals, Inc., Sanofi, Research Support; AstraZeneca, Speaker's Bureau; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly Diabetes, Novo Nordisk A/S, Takeda Pharmaceutical Company Limited. Funding Eli Lilly and Company

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22-OR: Finerenone in Patients across the Spectrum of CKD and T2D by GLP-1RA Use

Introduction: Finerenone reduced risk of cardiorenal outcomes in patients with CKD and T2D in the FIDELIO-DKD and FIGARO-DKD studies. In FIDELIO-DKD the effects of finerenone on kidney and CV outcomes were consistent irrespective of glucagon-like peptide-1 receptor agonist (GLP-1RA) use, but analyses were better powered to evaluate change in urine albumin-to-creatinine ratio (UACR) . Here, we extend these analyses to patients in both studies (FIDELITY analysis) , thus encompassing a larger population with broader inclusion criteria. Methods: Patients with T2D and CKD (UACR ≥30-<300 mg/g and eGFR ≥25-≤90 mL/min/1.73 m2, or UACR ≥300-≤5000 mg/g and eGFR ≥25 mL/min/1.73 m2) , treated with optimized renin-angiotensin system blockade, were randomized to finerenone or placebo. The effects of finerenone on CV (CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure) and kidney (kidney failure, sustained ≥57% eGFR decline, or renal death) composite outcomes, and on UACR at month 4, were analyzed by GLP-1RA use. Results: Of 13026 patients, 944 (7.2%) received GLP-1RAs at baseline. Results were consistent irrespective of GLP-1RA use at baseline for the CV composite outcome (hazard ratio [HR] 0.76; 95% CI 0.52-1.with GLP-1RA; HR 0.87, 95% CI 0.79-0.96 without GLP-1RA; p-interaction 0.63) , and the kidney composite outcome (HR 0.82; 95% CI 0.45-1.48 with GLP-1RA; HR 0.77, 95% CI 0.67-0.89 without GLP-1RA; p-interaction 0.79) . A greater reduction in UACR was observed with finerenone in patients taking GLP-1RA at baseline (placebo-corrected change -38% with GLP-1RA and -31% without GLP-1RA use; p-interaction 0.03) . Incidence of hyperkalemia was similarly increased with finerenone irrespective of GLP-1RA use at baseline. Conclusion: The benefits of finerenone on composite CV and kidney outcomes in patients with CKD and T2D are not modified by GLP-1RA use at baseline, with an increased effect observed for UACR reduction, suggesting a different mechanism of reduction in albuminuria. Disclosure P.Rossing: Consultant; Astellas Pharma Inc., AstraZeneca, Bayer AG, Gilead Sciences, Inc., Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi, Speaker's Bureau; Eli Lilly and Company. P.Viswanathan: Employee; Bayer AG. R.Lawatscheck: None. A.Joseph: Employee; Bayer AG. G.Bakris: Consultant; Alnylam Pharmaceuticals, Inc., AstraZeneca, DiaMedica Therapeutics, Inc., Horizon Therapeutics plc, Ionis Pharmaceuticals, Merck & Co., Inc., Other Relationship; Novo Nordisk. S.Anker: Consultant; Bayer AG, Boehringer Ingelheim International GmbH, Novartis AG, Novo Nordisk, Vifor Pharma Management Ltd., Research Support; Abbott. G.Filippatos: Other Relationship; Amgen Inc., Amgen Inc., Bayer AG, Boehringer Ingelheim International GmbH, Medtronic, Novartis AG, Servier Laboratories, Vifor Pharma Management Ltd. B.Pitt: Advisory Panel; Merck & Co., Inc., Consultant; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Lexicon Pharmaceuticals, Inc., Vifor Pharma Management Ltd. L.M.Ruilope: Consultant; Bayer AG. V.Fonseca: Consultant; Abbott, Asahi Kasei Corporation, Bayer AG, Novo Nordisk, Sanofi, Research Support; Fractyl Health, Inc., Jaguar Gene Therapy, Stock/Shareholder; Abbott, Amgen Inc., BRAVO4Health, Mellitus Health. G.E.Umpierrez: Research Support; AstraZeneca, Dexcom, Inc., Novo Nordisk. L.Caramori: Advisory Panel; Bayer AG, Consultant; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk, Research Support; Bayer AG, Novartis AG. M.Lambelet: Other Relationship; Bayer AG.

826-P: Effect of Finerenone on Occurrence of Vision-Threatening Events in Patients with DR

Finerenone is a potent and selective mineralocorticoid receptor (MR) antagonist that slowed progression of CKD and reduced risk of CV outcomes vs. placebo in patients with CKD and T2D in the FIDELIO-DKD and FIGARO-DKD phase 3 trials. MR overactivation is involved in DR pathogenesis. To evaluate potential benefits of oral finerenone on progression of DR, two studies of identical observational design (ReFineDR and DeFineDR) retrospectively collected data from patients with DR in FIDELIO-DKD/FIGARO-DKD at selected centers. Eligible patients had a routine ophthalmological examination showing NPDR in ≥1 eye performed 6 months prior to 1 month post-randomization in FIDELIO-DKD/FIGARO-DKD, and ≥1 subsequent ophthalmological assessment. Patients with advanced DR were excluded; inclusion was blinded to FIDELIO-DKD/FIGARO-DKD treatment assignment. Primary endpoint was occurrence of vision-threatening events (ASN, DME or PDR) at 2 years. Overall, 134 patients received finerenone and 1received placebo, of whom 68.7% and 71.8% had mild/moderate NPDR, 3.0% and 10.0% had severe NPDR, 27.6% and 15.5% had NPDR of unknown severity and 70.1% and 64.5% had HbA1c >7.5%, at baseline (mean HbA1c 8.25 [SD 1.41] and 8.18 [SD 1.34]) . At 2 years, 5 (3.7%) and 7 (6.4%) patients in the finerenone and placebo groups had a vision-threatening event in ≥1 eye (difference -0.026, 95% CI -0.082 to 0.029, p=0.3550) . The number of events increased after 2 years, with trends in Kaplan-Meier estimated cumulative incidence probabilities in favor of finerenone at 30 and 36 months (post hoc) . Results were generally consistent across components of the primary endpoint and subgroups with baseline HbA1c ≤ and >7.5%, UACR 30-<300 and ≥300 mg/g, and mild/moderate and severe NPDR. Fewer finerenone vs. placebo patients had required ocular interventions (4 [3%] vs. 17 [15.5%]) , with trends for favorable probabilities at 24, 30, and 36 months (post hoc) . Observed trends for benefit of finerenone on progression of DR were independent of HbA1c. Disclosure P.Rossing: Consultant; Astellas Pharma Inc., AstraZeneca, Bayer AG, Gilead Sciences, Inc., Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi, Speaker's Bureau; Eli Lilly and Company. D.Finis: Employee; Bayer AG. S.Leal: Employee; Bayer Consumer Care AG. T.Schmelter: Employee; Bayer AG, Stock/Shareholder; Bayer AG. G.Bakris: Consultant; Alnylam Pharmaceuticals, Inc., AstraZeneca, DiaMedica Therapeutics, Inc., Horizon Therapeutics plc, Ionis Pharmaceuticals, Merck & Co., Inc., Other Relationship; Novo Nordisk. S.Anker: Consultant; Bayer AG, Boehringer Ingelheim International GmbH, Novartis AG, Novo Nordisk, Vifor Pharma Management Ltd., Research Support; Abbott. J.G.Garweg: Advisory Panel; AbbVie Inc., Research Support; Roche Pharmaceuticals, Speaker's Bureau; Bayer AG, Novartis AG. T.Osonoi: Research Support; Bayer AG, Eli Lilly and Company, Gilead Sciences, Inc., Kowa Company, Ltd., Novo Nordisk, Ono Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited, Speaker's Bureau; Novo Nordisk. B.Pitt: Advisory Panel; Merck & Co., Inc., Consultant; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Lexicon Pharmaceuticals, Inc., Vifor Pharma Management Ltd. S.Rosas: Advisory Panel; AstraZeneca, Teladoc Health, Other Relationship; Bayer AG, Research Support; AstraZeneca, Bayer AG. L.M.Ruilope: Consultant; Bayer AG. D.Zhu: n/a. M.Brinker: Employee; Bayer AG.

866-P: Efficacy of Dapagliflozin by Baseline Diabetes Medications: A Prespecified Analysis from the DAPA-CKD Study

Background: The sodium-glucose cotransporter 2 inhibitor dapagliflozin improved kidney and cardiovascular (CV) outcomes in persons with chronic kidney disease (CKD) with and without type 2 diabetes (T2D) in the DAPA-CKD study. In this prespecified analysis we investigate the effects of dapagliflozin on kidney, CV, and mortality outcomes according to baseline diabetes drug class or number of diabetes drugs. Methods: We enrolled participants with CKD with eGFR 25-75 ml/min/1.73m2 and UACR 200-5000 mg/g, and included those with T2D at baseline in this analysis. The primary endpoint was a composite of sustained decline in eGFR of ≥50%, end-stage kidney disease, or death from kidney or CV causes. Secondary outcomes included a kidney-specific composite (the same as the primary without CV death) , composite of hospitalizations for heart failure and CV mortality, and all-cause mortality. We determined the effect of dapagliflozin, compared with placebo, in subgroups by use or not of diabetes drug classes at baseline: metformin, sulfonylureas, DPP4 inhibitors, GLP-1 receptor agonists and insulin, and by the number of diabetes medications at baseline. Results: Of 43participants enrolled 29 (68%) had T2D, of which 1598 (55%) were on insulin, 1244 (43%) on metformin, 774 (27%) on sulfonylureas, 742 (26%) on DPP4 inhibitors, and 122 (4%) on GLP-1 receptor agonists. At baseline 327 (11%) were without diabetes treatment, 1442 (50%) were treated with one diabetes drug, 943 (32%) with two drugs and 194 (7%) with three or more. The effect of dapagliflozin on the primary composite outcome was consistent across comparisons of baseline drug class (all pint>0.19) , and according to number of drugs (pint=0.08) . Similarly, we found consistent benefit of dapagliflozin compared to placebo on the secondary endpoints regardless of background drug class or number of drugs. Conclusion: Dapagliflozin reduced kidney and CV events in T2D with CKD independent of baseline diabetes drug class or number. Disclosure F.Persson: Advisory Panel; Amgen Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk A/S, Research Support; Boehringer Ingelheim International GmbH, Novo Nordisk A/S, Speaker's Bureau; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk A/S, Sanofi. R.D.Toto: Advisory Panel; Bayer AG, Boehringer Ingelheim International GmbH, Chinook Therapeutics Inc., Lilly, Consultant; Amgen Inc., AstraZeneca, Medscape, Vifor Pharma Management Ltd., Other Relationship; Akebia Therapeutics, Inc., Otsuka America Pharmaceutical, Inc., Reata Pharmaceuticals, Inc. A.Langkilde: Employee; AstraZeneca, Stock/Shareholder; AstraZeneca. D.C.Wheeler: Advisory Panel; Bayer AG, Boehringer Ingelheim International GmbH, Gilead Sciences, Inc., GlaxoSmithKline plc., Janssen Global Services, LLC, Merck Sharp & Dohme Corp., Mundipharma, Tricida, Inc., Vifor Pharma Management Ltd., Consultant; AstraZeneca, Speaker's Bureau; Amgen Inc., Astellas Pharma Inc. H.L.Heerspink: Consultant; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Chinook Therapeutics Inc., CSL Behring, Gilead Sciences, Inc., Goldfinch Bio, Inc., Janssen Research & Development, LLC, Mitsubishi Tanabe Pharma Corporation, Mundipharma, Traveere Pharmaceuticals, Research Support; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk A/S. Dapa-ckd trial committees and investigators: n/a. P.Rossing: Consultant; Astellas Pharma Inc., AstraZeneca, Bayer AG, Gilead Sciences, Inc., Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi, Speaker's Bureau; Eli Lilly and Company. N.Jongs: None. G.M.Chertow: Other Relationship; AstraZeneca. F.Hou: Other Relationship; AstraZeneca. P.Vart: None. J.J.Mcmurray: Other Relationship; Abbott, Alkem Metabolics, Alnylam Pharmaceuticals, Inc., Amgen Inc., AstraZeneca, AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company, Cardurion, Cytokinetics Inc., DalCor Pharmaceuticals, Eris Lifesciences Ltd., GlaxoSmithKline plc., Ionis Pharmaceuticals, KBP Bioscience, Lupin Pharmaceuticals, Inc., Medscape, Novartis AG, ProAdWise Communications, Radcliffe Group, Servier Laboratories, Sun Pharmaceutical Industries Ltd., The Corpus, Theracos, Inc. R.Correa-rotter: Advisory Panel; Boehringer Ingelheim International GmbH, Consultant; Bayer AG, Other Relationship; AstraZeneca, GlaxoSmithKline plc., Novo Nordisk, Speaker's Bureau; AbbVie Inc., Amgen Inc., Janssen Pharmaceuticals, Inc., Sanofi. B.Stefansson: Employee; AstraZeneca. Funding AstraZeneca

16-LB: Effects of Finerenone in Patients with CKD and T2D Are Independent of HbA1c at Baseline, HbA1c Variability, and Duration of Diabetes

Introduction: Finerenone reduced the risk of cardiovascular (CV) and kidney outcomes, without affecting HbA1c, in CKD and T2D patients in the FIDELITY prespecified pooled analysis of the FIDELIO-DKD and FIGARO-DKD studies. Here, we evaluate the effect of finerenone by baseline HbA1c, HbA1c variability, and diabetes duration. Methods: Patients with T2D and CKD (UACR ≥30-≤5000 mg/g and eGFR ≥25 mL/min/1.73 m2) were randomized to finerenone or placebo. Effects of finerenone vs. placebo on CV (CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure) and kidney (kidney failure, sustained ≥57% eGFR decline from baseline, or renal death) composite outcomes were analyzed by baseline HbA1c quartiles, HbA1c variability (first year of treatment) , and diabetes duration quartiles. Results: In 13,026 patients included in the analysis, mean baseline HbA1c was 7.7% and diabetes duration was 15.4 years. Higher baseline HbA1c quartiles had longer diabetes duration and more diabetes-related complications. Risk reductions in the CV and kidney composite outcomes with finerenone vs. placebo were consistent across HbA1c (p-interaction 0.52 and 0.09, respectively) and diabetes duration (p-interaction 0.12 and 0.75) quartiles. HbA1c variability in the first year of treatment was associated with higher cardiorenal risks; each 1 unit increase in mean absolute residual of HbA1c was associated with a 20% increased risk of a CV event (HR 1.20; 95% CI 1.07-1.35; p=0.0016) and a 36% increased risk of a kidney event (HR 1.36; 95% CI 1.21-1.52; p<0.001) . The CV and kidney benefits of finerenone were not modified by HbA1c variability (p-interaction 0.48 and 0.09, respectively) . Conclusion: Greater variability in HbA1c was associated with increased risks of cardiorenal outcomes. Risk reductions in the CV and kidney outcomes with finerenone in patients with CKD and T2D were not modified by baseline HbA1c, HbA1c variability, or duration of diabetes. Disclosure J. B. Mcgill: Advisory Panel; Gilead Sciences, Inc., Lilly Diabetes, MannKind Corporation, Novo Nordisk A/S, Provention Bio, Inc., Salix Pharmaceuticals, Consultant; Bayer AG, Boehringer Ingelheim International GmbH, Research Support; Dexcom, Inc., Novo Nordisk. M. Brinker: Employee; Bayer AG. A. Joseph: Employee; Bayer AG. A. Z. Lage: None. R. Lawatscheck: None. C. Scott: Employee; Bayer AG. P. Rossing: Consultant; Astellas Pharma Inc., AstraZeneca, Bayer AG, Gilead Sciences, Inc., Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi, Speaker’s Bureau; Eli Lilly and Company. R. Agarwal: Advisory Panel; Akebia Therapeutics, Inc., Bayer AG, Board Member; Chinook Therapeutics Inc., DiaMedica Therapeutics, Inc., Vertex Pharmaceuticals Incorporated, Consultant; Boehringer Ingelheim International GmbH, Reata Pharmaceuticals, Inc., Vifor Pharma Management Ltd. S. Anker: Consultant; Bayer AG, Boehringer Ingelheim International GmbH, Novartis AG, Novo Nordisk, Vifor Pharma Management Ltd., Research Support; Abbott. G. Bakris: Consultant; Alnylam Pharmaceuticals, Inc., AstraZeneca, DiaMedica Therapeutics, Inc., Horizon Therapeutics plc, Ionis Pharmaceuticals, Merck & Co., Inc., Other Relationship; Novo Nordisk. G. Filippatos: Other Relationship; Amgen Inc., Amgen Inc., Bayer AG, Boehringer Ingelheim International GmbH, Medtronic, Novartis AG, Servier Laboratories, Vifor Pharma Management Ltd. B. Pitt: Advisory Panel; Merck & Co., Inc., Consultant; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Lexicon Pharmaceuticals, Inc., Vifor Pharma Management Ltd. L. M. Ruilope: Consultant; Bayer AG. A. L. Birkenfeld: None. L. Caramori: Advisory Panel; Bayer AG, Consultant; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk, Research Support; Bayer AG, Novartis AG.

481-P: Eligibility for Icosapent Ethyl in Patients with Type 2 Diabetes and Atherosclerotic Cardiovascular Disease: An Analysis of VERTIS CV

Among patients with type 2 diabetes (T2D) treated with statins, residual cardiovascular (CV) risk remains. Because icosapent ethyl (IPE) has been shown to decrease CV risk in patients on statin therapy, we explored potential eligibility for IPE therapy in VERTIS CV (NCT01986881) , the CV outcomes trial of ertugliflozin in which all patients had T2D and atherosclerotic CV disease (ASCVD) . We analyzed eligibility for IPE based on REDUCE-IT trial inclusion criteria (on statin, fasting triglyceride of 135 to 499 mg/dL and low-density lipoprotein cholesterol of 41 to 100 mg/dL) . Among 8246 patients randomized, the mean age was 64 years and 30% were female. At baseline, 6747 (81.8%) patients used statins, while 293 (3.6%) used ezetimibe, 389 (4.7%) used fish oil, and 8 (0.1%) used IPE. The REDUCE-IT trial inclusion criteria were met by 2444 (29.6%) patients at baseline and an additional 2500 (30.3%) did not fully meet the criteria but had baseline triglyceride level >135 mg/dL (Figure) . In conclusion, this analysis of the VERTIS CV trial population identified important opportunities to reduce residual CV risk: consideration of adding statin therapy in 18% of patients and of adding IPE based on the REDUCE-IT trial inclusion criteria or triglyceride level threshold in 60% of patients. These findings highlight the need to optimize lipid therapies in patients with T2D and ASCVD. Disclosure J.M.Kim: Other Relationship; Pfizer Inc. R.Frederich: Employee; Pfizer Inc., Stock/Shareholder; Bristol-Myers Squibb Company, Pfizer Inc. J.P.Mancuso: Employee; Pfizer Inc., Stock/Shareholder; Pfizer Inc. C.P.Cannon: Advisory Panel; Alnylam Pharmaceuticals, Inc., Amarin Corporation, Amgen Inc., Amryt Pharma Plc, Applied Therapeutics, Ascendis Pharma A/S, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Lexicon Pharmaceuticals, Inc., Merck & Co., Inc., Pfizer Inc., Rhoshan, Sanofi, Research Support; Amgen Inc., Better Therapeutics, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company, Daiichi Sankyo, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk, Pfizer Inc. D.L.Bhatt: Research Support; Afimmune Limited, Amarin Corporation, Amgen Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Chiesi USA, Inc., Lexicon Pharmaceuticals, Inc., Lilly, Novartis AG, Sanofi. S.Dagogo-jack: Consultant; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Janssen Pharmaceuticals, Inc., Medtronic, Merck & Co., Inc., Sanofi. D.Cherney: Other Relationship; AbbVie Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Janssen Research & Development, LLC, Lilly, Maze, BMS, CSL-Behring, Merck, Otsuka, Novartis and Novo-Nordisk , Mitsubishi Tanabe Pharma Corporation, Sanofi, Research Support; Boehringer Ingelheim-Lilly, Merck, Janssen, Sanofi, AstraZeneca and Novo-Nordisk. F.Cosentino: Advisory Panel; Merck Sharp & Dohme Corp., Pfizer Inc., Speaker's Bureau; AstraZeneca, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company, Lilly, Merck Sharp & Dohme Corp., Novo Nordisk. D.K.Mcguire: Consultant; AstraZeneca, Boehringer Ingelheim International GmbH, CSL Behring, ESPERION Therapeutics, Inc., Lexicon Pharmaceuticals, Inc., Lilly, Merck & Co., Inc., Novo Nordisk, Pfizer Inc., Sanofi. R.E.Pratley: Other Relationship; Bayer AG, Corcept Therapeutics, Dexcom, Inc., Hanmi Pharm. Co., Ltd., Merck & Co., Inc., Metavention, Novo Nordisk, Pfizer Inc., Poxel SA, Sanofi, Scohia Pharma Inc., Sun Pharmaceutical Industries Ltd. C.Liu: Employee; Merck & Co., Inc., Stock/Shareholder; Merck & Co., Inc. N.B.Cater: Employee; Pfizer Inc., Stock/Shareholder; Pfizer Inc. Funding Merck Sharp & Dohme Corp.

747-P: Baseline Characteristics of Subjects in the Once-Weekly (OW) Semaglutide FLOW Kidney Outcomes Trial

Chronic kidney disease (CKD) is a common complication of type 2 diabetes (T2D) that increases the risk of kidney failure and cardiovascular (CV) disease. Data from CV outcomes trials suggest that glucagon-like peptide-1 receptor agonists have kidney-protective effects. The FLOW trial (NCT03819153) will evaluate kidney outcomes with OW semaglutide in subjects with T2D and CKD. FLOW is an ongoing randomized, double-blinded, multinational, phase 3b trial. Subjects (N=3,535) with T2D, estimated glomerular filtration rate (eGFR) ≥25-≤75 mL/min/1.73 m2, and urine albumin-to-creatinine ratio >100-<5,000 mg/g were assigned 1:1 to OW semaglutide 1.0 mg or placebo, plus standard-of-care. The primary endpoint is time to first occurrence of kidney failure (as measured by persistent eGFR <15 mL/min/1.73 2 or initiation of chronic dialysis or kidney transplantation) ; ≥50% persistent eGFR reduction compared with baseline; kidney or CV death. At baseline, 68.6% of subjects had HbA1c >7.0%, diabetes complications were common, and 15.5% were taking a sodium-glucose co-transporter-2 inhibitor (Table) . The majority of subjects (68.2%) were at very high risk for CKD progression (Kidney Disease: Improving Global Outcomes criteria) . Subjects enrolled in FLOW had substantial diabetes burden and risk for CKD progression. FLOW will assess kidney outcomes with OW semaglutide in this population. Disclosure R.E.Pratley: Other Relationship; Bayer AG, Corcept Therapeutics, Dexcom, Inc., Hanmi Pharm. Co., Ltd., Merck & Co., Inc., Metavention, Novo Nordisk, Pfizer Inc., Poxel SA, Sanofi, Scohia Pharma Inc., Sun Pharmaceutical Industries Ltd. V.Perkovic: Advisory Panel; Astellas Pharma Inc., Baxter, DURECT Corporation, Merck & Co., Inc., Metavant Sciences, Mundipharma, Relypsa Inc., Other Relationship; AbbVie Inc., AstraZeneca, Bayer AG, Bristol-Myers Squibb Company, Dimerix, Eli Lilly and Company, Eli Lilly and Company, Gilead Sciences, Inc., GlaxoSmithKline plc., Janssen Research & Development, LLC, Mitsubishi Tanabe Pharma Corporation, Novartis Pharma K.K., Novo Nordisk, Novo Nordisk, Otsuka America Pharmaceutical, Inc., Pfizer Inc., Sanofi, Servier Laboratories, Tricida, Inc., UpToDate. F.M.M.Baeres: Employee; Novo Nordisk, Stock/Shareholder; Novo Nordisk. G.Bakris: Consultant; Alnylam Pharmaceuticals, Inc., AstraZeneca, DiaMedica Therapeutics, Inc., Horizon Therapeutics plc, Ionis Pharmaceuticals, Merck & Co., Inc., Other Relationship; Novo Nordisk. J.Lawson: Employee; Novo Nordisk A/S. K.W.Mahaffey: Consultant; Novo Nordisk. J.F.Mann: Advisory Panel; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Novo Nordisk A/S. H.Mersebach: Employee; Novo Nordisk A/S. P.Rossing: Consultant; Astellas Pharma Inc., AstraZeneca, Bayer AG, Gilead Sciences, Inc., Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi, Speaker's Bureau; Eli Lilly and Company. K.R.Tuttle: Advisory Panel; Boehringer Ingelheim International GmbH, Gilead Sciences, Inc., Consultant; AstraZeneca, Eli Lilly and Company, Research Support; Bayer AG, Goldfinch Bio, Inc., Novo Nordisk, Travere.

719-P: Tirzepatide Induces Weight Loss in Patients with Type 2 Diabetes Regardless of Baseline BMI: A Post Hoc Analysis of SURPASS-1 through -5 Studies

Tirzepatide (TZP) is a novel once-weekly dual GIP and GLP-1 receptor agonist evaluated in patients with type 2 diabetes (T2D) . Five Phase 3 SURPASS (S) trials have demonstrated safety and shown robust efficacy of TZP in improvement of glycaemic control and body weight (BW) in adults with T2D. To understand whether the weight-lowering effects of TZP are dependent on baseline BMI, we conducted subgroup analyses of S-1 through -5. BW change in the BMI subgroups (Subgroup 1 [<27 or ≥27 kg/m2] and Subgroup 2 [<30; ≥30 to <35; ≥35 kg/m2]) at primary endpoint was assessed in patients while on treatment without rescue medication (efficacy estimand) in the modified intention-to-treat (mITT) population, defined as all randomized patients who received at least one dose of study drug. All TZP doses (5, 10, 15 mg) lowered BW in patients with T2D irrespective of baseline BMI in both subgroups (p<0.001) . The weight reductions were generally dose-dependent and absolute weight change was generally greater in higher BMI categories. TZP-treated patients with T2D experienced weight loss across a spectrum of mean baseline BMI values in S-1 through -5 studies. The most frequent adverse events were GI-related events that were mild to moderate in severity and occurred during the dose-escalation period. Disclosure A.Kwan: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. J.M.Maldonado: Employee; Eli Lilly and Company. H.Wang: None. N.Rasouli: Advisory Panel; Eli Lilly and Company, Novo Nordisk, Sanofi, Research Support; Allergan, Eli Lilly and Company, Novo Nordisk. J.Wilding: Advisory Panel; Alnylam Pharmaceuticals, Inc., AstraZeneca, Eli Lilly and Company, Mundipharma, Novo Nordisk A/S, Rhythm Pharmaceuticals, Inc., Sanofi, Research Support; AstraZeneca, Speaker's Bureau; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly Diabetes, Novo Nordisk A/S, Takeda Pharmaceutical Company Limited. Funding Eli Lilly and Company

Breaking new ground in the clinical application of CRISPR/Cas9

David McCall, Commissioning Editor, Cell & Gene Therapy Insights, speaks to Laura Sepp-Lorenzino, Executive Vice President and Chief Scientific Officer, Intellia Therapeutics.Laura Sepp-Lorenzino, PhD, has served as our executive vice president, chief scientific officer since May 2019. Prior to joining Intellia, Dr Sepp-Lorenzino was vice president, head of nucleic acid therapies, research leadership and a member of the external innovation team at Vertex Pharmaceuticals, Inc. from September 2017 to May 2019. From April 2014 to September 2017, Dr Sepp-Lorenzino was vice president, entrepreneur-in-residence and head of the hepatic infectious disease strategic therapeutic area at Alnylam Pharmaceuticals, Inc. Since October 2018, she has been a member of the scientific advisory board of Thermo Fisher Scientific, and in December 2020 she joined the board of directors of Taysha Gene Therapies, a biopharmaceutical company focused on developing treatments for monogenic CNS diseases. She is also a member of the BOD for Oligonucleotide Therapeutics Society and the Alliance for Regenerative Medicine. Dr Sepp-Lorenzino earned a professional degree in biochemistry from the Universidad de Buenos Aires in Argentina and a PhD in biochemistry from New York University.

FC010: Multicentric Experience with RNA Interference Medication (OXLUMO®) in Patients with Primary Hyperoxaluria Type 1

Abstract BACKGROUND AND AIMS Primary hyperoxaluria type 1 (PH1) is a rare metabolic disorder of the glyoxylate metabolism in the liver inducing severe endogenous oxalate overproduction. Massive hyperoxaluria leads to recurrent urolithiasis and/or nephrocalcinosis and often early end-stage kidney failure. Current treatment options were scarce until the first RNA interference drug, Oxlumo® (Lumasiran, Alnylam Pharmaceuticals, USA) can now be prescribed. Oxlumo® targets the mRNA of glycolate oxidase and, thus, prevents its translation. This reduces production of glyoxylate (i.e. the precursor to oxalate) and thus oxalate production. However, glycolate production increases. METHOD We herein report our current clinical experience with s.c. administration of Oxlumo adhering to provide dosage recommendation. A total of 25 PH1 patients were included. Seven patients were on haemodialysis, 1 patient on peritoneal dialysis and 17 were on stable kidney function at start of Oxlumo medication (eGFR > 30 and <55 mL/min in 2 patients and >70 mL/min in all others). The male: female ratio was 15:10, and the age range was 1–62 years of age at start of treatment. In both groups plasma oxalate (Pox) and glycolate (Pglyc) were determined before the first and every next Oxlumo dosage. In non-dialysis patients, urinary oxalate (Uox) and urinary glycolate in 24 h urines were analysed at same interval plus monthly collection until month 6 of treatment and thereafter in 6 weeks’ intervals, if Uox did not reach near normalisation, or had increased again at end of dosing interval (3 monthly). Oxalate and glycolate were determined using ion chromatography/mass spectrometry in the same lab. RESULTS We now report data of those patients, who have received at least four dosages of Oxlumo (n = 15). Non-dialysis patients: Uox was normal (<0.5 mmol/1.73 m2/d) in two patients, in five patients it was near normal (1.5 times the upper limit, <0.75) and in three patients Uox was above 0.75 mmol/1.73 m2/d. Pox was normal in seven and above 7.4 µmol/L in three patients. In seven patients data were available at fifth to seventh dosage interval. Here, one patient had a normal Uox; in all other patients Uox was above 0.75 mmol/1.73 m2/d before next dosage. In the seven dialysis patients median Pox did not really decline over time (median of 45.1 at baseline, n = 7; and 39.9 post fourth dosage, n = 5), as was median Pglyc (86.05/71.1). Patient-specific follow-up differed and must also be related to co-medication with B6. For example, one dialysis patient remained stable with Pglyc below 2 µmol/L (under B6) and another patient experienced Pglyc > 1 mmol/L (without B6). CONCLUSION Oxlumo® has reduced Uox in 7/10 patients after the fourth dosage. However, adjustment of dosage intervals or dosage per se are necessary in the majority of patients to reach the goal of treatment, e.g. at least near normalisation of urinary oxalate excretion. In dialysis patients lack of reduction of Pox maybe because patients dissolve systemic oxalate deposits. However, specific imaging (bone MRI) in three of the dialysis patients did not show improvement of oxalate osteopathy over 6 and 9 months, respectively.

Givosiran for the treatment of acute hepatic porphyria

Introduction Acute hepatic porphyrias (AHPs) are a family of rare inherited disorders characterized by enzyme dysfunctions in the hepatic pathway of heme biosynthesis. In AHPs, accumulation of the neurotoxic porphyrin precursors delta-aminolevulinic acid and porphobilinogen, caused by enhanced activity of hepatic aminolevulinate synthase 1 (ALAS1), is associated with acute, potentially life-threatening neurovisceral attacks. Symptoms during and between attacks dramatically reduce patients’ quality of life (QoL). Givosiran is the first mRNA-targeted treatment for AHPs, silencing ALAS1 expression. Areas covered For givosiran, this review summarizes its chemistry, mechanism of action, pharmacokinetics, pharmacodynamics, safety, preclinical and clinical data in AHP, postmarketing surveillance, and regulatory status. A literature search of public and internal databases was performed, bibliographies of retrieved articles were manually searched to identify additional studies of relevance, and information was also provided by Alnylam Pharmaceuticals. Expert opinion Givosiran is a small interfering RNA (siRNA) therapeutic that reduces hepatic activity of ALAS1 and decreases accumulation of neurotoxic porphyrin precursors in patients with AHPs, ultimately reducing the number of acute attacks and improving symptoms and QoL between attacks. As AHPs are lifelong diseases, long-term safety data are needed for givosiran as an siRNA-based therapy.

GSK and Novo Nordisk invest in RNAi

A decade ago , drug firms were becoming disenchanted with RNA interference (RNAi) technology, which uses small interfering RNA (siRNA) molecules to turn down the expression of disease-causing genes. But the RNAi company Alnylam Pharmaceuticals has launched three commercial siRNA therapies in the past 3 years, and companies are investing in the genetic technology once again. GlaxoSmithKline has signed an agreement with the RNAi company Arrowhead Pharmaceuticals to develop an siRNA therapy for nonalcoholic steatohepatitis (NASH), a form of fatty liver disease. The therapy, currently in a Phase 1/2 clinical trial, targets a gene, HSD17B13 , that encodes an enzyme linked to inflammation in NASH. GSK will pay Arrowhead $120 million initially and up to $910 million in milestone payments. And Novo Nordisk will acquire the RNAi company Dicerna Pharmaceuticals for $3.3 billion . The two firms began collaborating in 2019 on siRNAs that target more than 30 genes in

Outcomes Following Biochemical or Clinical Progression in Patients with Multiple Myeloma

Outcomes Following Biochemical or Clinical Progression in Patients with Multiple Myeloma

Ocular Toxicity of Commercially Available Belantamab Mafodotin in Patients with Advanced Multiple Myeloma

Ocular Toxicity of Commercially Available Belantamab Mafodotin in Patients with Advanced Multiple Myeloma