Abstract 14248: Efficacy and Safety of Bempedoic Acid in Patients Who Cannot Tolerate Statins: Pooled Analysis of 4 Phase 3 Clinical Trials

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Ulrich Laufs ◽  
Maciej Banach ◽  
Harold E Bays ◽  
Alberico L Catapano ◽  
P Barton Duell ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Adverse Events ◽  
Pooled Analysis ◽  
Lipid Lowering ◽  
Drug Discontinuation ◽  
Lipid Lowering Therapy ◽  
Efficacy And Safety ◽  
Statin Intolerance ◽  
Phase 3 ◽  
Additional Information

Introduction: Some patients cannot tolerate statins mainly because of statin-associated muscle symptoms (SAMS). Bempedoic acid (BA) is a prodrug activated in the liver and not in skeletal muscle. BA has been shown to significantly lower LDL-C by a mean of ~18% in patients receiving background maximally tolerated statins and a mean of ~25% in patients with statin intolerance. Objective: Determine efficacy and safety of BA in statin-intolerant patients receiving no background statin therapy across 4 phase 3 clinical trials. Methods: Data were pooled from 4 randomized (2:1), placebo-controlled studies evaluating oral BA 180 mg once daily vs placebo for 12 to 52 weeks. Primary efficacy endpoint was LDL-C % change from baseline to week 12. Safety assessments included treatment-emergent adverse events (TEAEs), adverse events of special interest (AESI), and laboratory values. For patients who reported SAMs, additional information around etiology and location were collected. Results: Of 3621 patients, 586 (394 BA; 192 placebo) reported intolerance to multiple statins because of SAMS or other AEs and received no statins during the studies. Mean baseline LDL-C was 148.7 mg/dL. After 12 weeks, BA significantly lowered LDL-C vs placebo (placebo-corrected, -26.5%; P < 0.001). Myalgia was the top reason for drug discontinuation, but was less common in the BA arm (17.7%) vs placebo (43.5%). CK > 5 х ULN was uncommon in both groups. Among AESIs (Table) , muscle disorders were reported by 12.7% (BA) vs 14.1% (placebo). Myalgia was less common with BA (4.6%) vs placebo (7.3%). Muscle spasms (4.1% vs 3.6%) and pain in extremity (3.3% vs 2.1%) were comparable between treatment groups. Muscular weakness was rare (0.5% BA, 1% placebo). Conclusion: Among the population of patients unable to use statins, BA significantly lowered LDL-C vs placebo without increasing muscle-related TEAEs. BA may be an appropriate lipid-lowering therapy for patients with hyperlipidemia who are statin intolerant.

scholarly journals Pooled safety and efficacy of inclisiran in patients with statin intolerance (ORION-10 and ORION-11)

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
R.S Wright ◽  
D Kallend ◽  
F.J Raal ◽  
R Stoekenbroek ◽  
W Koenig ◽  
...  
Keyword(s):  
Statin Therapy ◽  
Therapeutic Option ◽  
Lipid Lowering ◽  
Funding Source ◽  
Lipid Lowering Therapy ◽  
Statin Intolerance ◽  
Private Company ◽  
Phase 3 ◽  
Absolute Reduction ◽  
Secondary Endpoints

Abstract Introduction Statin-associated side effects prevent a substantial proportion of patients from being adequately treated with statin therapy and achieving adequate LDL-C reductions. Phase 3 trials showed that inclisiran, a new siRNA, durably lowers LDL-C by ≥50% on top of maximally tolerated statin therapy. Purpose To evaluate inclisiran's tolerability and LDL-C lowering effects among individuals who were not receiving statin therapy mainly because of statin intolerance. Methods The Phase 3 ORION-10 and ORION-11 trials randomized patients with established ASCVD (or risk-equivalents) with LDL-C &gt;70 mg/dl despite maximally tolerated statins to inclisiran or placebo (1:1). Inclisiran sodium 300 mg was administered s.c. at baseline, three months later, then every six months. The primary efficacy endpoints were % change in LDL-C from baseline to Day 510 and time adjusted % change in LDL-C from baseline after Day 90 and up to Day 540. Absolute LDL-C reductions were secondary endpoints. This analysis included individuals who were not on statin therapy at baseline. Results The trials included 252 (7.9% of the pooled trial populations; mean age 68; male 62%; lipid-lowering therapy 28%). AE rates and LDL-C reductions are shown in the Table. Overall, 12 (4.7%) patients had myalgia (4.8% in the inclisiran groups, 4.7% in the placebo groups). There were 8 discontinuations in the inclisiran groups (6.5%) and 3 in the placebo groups (2.3%). The placebo-adjusted mean reduction in LDL-C at Day 510 was 45.8%, an absolute reduction of 68.0 mg/dL (p&lt;0.0001). Conclusion Among statin intolerant individuals in ORION-10 and 11, inclisiran potently and durably lowered LDL-C with an adverse event profile comparable to placebo. Inclisiran may represent a new and potent therapeutic option for patients with elevated LDL-C unable to tolerate statins. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): The Medicines Company

scholarly journals Safety and reactogenicity of the adjuvanted recombinant zoster vaccine: experience from clinical trials and post-marketing surveillance

2021 ◽  
Vol 9 ◽  
pp. 251513552110574
Author(s):  
Joseph Fiore ◽  
Maribel Miranda Co-van der Mee ◽  
Andrés Maldonado ◽  
Lisa Glasser ◽  
Phil Watson
Keyword(s):  
Clinical Trials ◽  
Adverse Events ◽  
Pooled Analysis ◽  
Cell Transplant ◽  
Zoster Vaccine ◽  
Phase 3 ◽  
Pivotal Phase ◽  
Post Marketing Surveillance ◽  
Post Marketing ◽  
Recombinant Zoster Vaccine

An adjuvanted recombinant zoster vaccine (RZV) is licensed for the prevention of herpes zoster. This paper reviews its safety and reactogenicity. A pooled analysis of two pivotal randomized Phase-3 trials (NCT01165177, NCT01165229) in adults ⩾50 years found that more solicited adverse events (AEs) were reported with RZV than placebo. Injection site pain was the most common solicited AE (RZV: 78.0% participants; placebo: 10.9%). Grade-3 pain occurred in 6.4% of RZV and 0.3% of placebo recipients. Myalgia, fatigue, and headache were the most commonly reported general solicited AEs (RZV: 44.7%, 44.5%, and 37.7%, respectively; placebo: 11.7%, 16.5%, and 15.5%, respectively). Most symptoms were mild to moderate in intensity with a median duration of 2–3 days. The intensity of reactogenicity symptoms did not differ substantially after the first and second vaccine doses. The pooled analysis of the pivotal Phase-3 trials did not identify any clinically relevant differences in the overall incidence of serious adverse events (SAEs), fatal AEs or potential immune-mediated diseases (pIMDs) between RZV and placebo. Reactogenicity in five studies of immunocompromised patients ⩾18 years (autologous stem cell transplant, human immunodeficiency virus, solid tumors, hematological malignancies, and renal transplant; NCT01610414, NCT01165203, NCT01798056, NCT01767467, and NCT02058589) was consistent with that observed in the pivotal Phase-3 trials. There were no clinically relevant differences between RZV and placebo in the immunocompromised populations with regard to overall incidence of SAEs, fatal AEs, pIMDs, or AEs related to patients’ underlying condition. Post-marketing surveillance found that the most commonly reported AEs were consistent with the reactogenicity profile of the vaccine in clinical trials. Overall, the clinical safety data for RZV are reassuring. [Formula: see text]

Bempedoic acid: a promising novel agent for LDL-C lowering

2020 ◽  
Vol 16 (5) ◽  
pp. 361-371 ◽  
Author(s):  
Anandita Agarwala ◽  
Anne C Goldberg
Keyword(s):  
Clinical Trials ◽  
Cholesterol Biosynthesis ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Patient Characteristics ◽  
Lipid Lowering ◽  
Lipid Lowering Therapy ◽  
Statin Intolerance ◽  
Major Cardiovascular Events ◽  
Phase Ii And Iii

Bempedoic acid (ETC-1002) is a novel, first-in-class, oral, small molecule that inhibits cholesterol biosynthesis in the same pathway as statins, thereby lowering low-density lipoprotein cholesterol (LDL-C) by upregulating LDL receptors. Preclinical and completed Phase II and III clinical trials have demonstrated promising results regarding its safety and efficacy across a variety of patient characteristics including statin intolerance and on a background of lipid-lowering therapy. Bempedoic acid is currently being evaluated in a cardiovascular outcomes trial to evaluate its effect on major cardiovascular events in patients with or at high risk for cardiovascular disease and with statin intolerance. In this review, we will discuss the history and development of bempedoic acid, relevant clinical trials, and its potential role as a lipid-lowering medication in the context of other currently available lipid-lowering therapies.

Bempedoic Acid Efficacy and Safety in High CVD Risk Patients Treated With or Without Ezetimibe: Pooled Analysis of 4 Phase 3 Clinical Trials†

2020 ◽  
Vol 14 (4) ◽  
pp. 569-570
Author(s):  
Alberico Catapano ◽  
Harold Bays ◽  
Maciej Banach ◽  
P. Duell ◽  
Ulrich Laufs ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Pooled Analysis ◽  
Efficacy And Safety ◽  
Cvd Risk ◽  
Phase 3 ◽  
Risk Patients

scholarly journals Hypolipidemic therapy: evidence-based effectiveness and new perspectives

2020 ◽  
Vol 22 (10) ◽  
pp. 55-60
Author(s):  
Ekaterina V. Kudina ◽  
◽  
Irina A. Samkova ◽  
Vera N. Larina ◽  
◽  
...  
Keyword(s):  
Clinical Trials ◽  
Cardiovascular Diseases ◽  
Combination Therapy ◽  
Lipid Lowering ◽  
Lipid Lowering Therapy ◽  
Efficacy And Safety ◽  
Omega 3 ◽  
Pcsk9 Inhibitors ◽  
Lipid Lowering Drugs ◽  
Number Of Patients

Background. Hyperlipidemia is one of the most important risk factors for the onset and progression of cardiovascular diseases. Currently, several classes of drugs are used in lipid-lowering therapy, which have proven their effectiveness over the past decades. However, in a number of patients there is an intolerance to these drugs or it is not possible to achieve the target levels of the lipid spectrum against the background of the use of maximum doses and combination therapy. This dictates the need to create new lipid-lowering drugs. Aim. To present data on the proven efficacy of widely used drugs in the treatment of hyperlipidemia and the prospects for therapy of this pathology. Materials and methods. We analysed literature sources, included European and Russian guidelines in the last 10 years. Results. The article presents the results of multicenter international randomized clinical trials that studied the efficacy and safety of the main classes of lipid-lo-wering drugs, both in the form of mono- and combination therapy. The indications for the administration of fibrates, ezetimibe omega-3-fats and PCSK9 inhibitors, depending on clinical situations, are discussed. Information on the mechanisms of action of new lipid-lowering drugs – bempedoic acid and inclisiran is presented. The results of clinical trials studying the efficacy and safety of these drugs are presented. Conclusion. Achieving the target levels of lipid metabolism in patients with cardiovascular diseases is an important link in the program to reduce the risk of de-velopment and progression of cardiovascular diseases. At the moment, statins remain the main drugs for the treatment of hyperlipidemia. But in some patients, in order to achieve the goal, the appointment of a combination therapy is required, in which both the long-used fibrates, ezetimibe, omega-3-fats, and the most recent drugs: PCSK9 inhibitors, bempedoic acid and inclisiran can be used.

scholarly journals Neoadjuvant EGFR-TKI Therapy for EGFR-Mutant NSCLC: A Systematic Review and Pooled Analysis of Five Prospective Clinical Trials

2021 ◽  
Vol 10 ◽  
Author(s):  
Li Sun ◽  
Yi-Jia Guo ◽  
Jun Song ◽  
Yan-Ru Wang ◽  
Shu-Ling Zhang ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Adverse Events ◽  
Surgical Resection ◽  
Objective Response ◽  
Pooled Analysis ◽  
Phase Iii ◽  
Cochrane Library ◽  
Efficacy And Safety ◽  
Egfr Mutant ◽  
Egfr Tki

PurposeThe role of neoadjuvant epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) targeted therapy for patients with EGFR-mutant non-small cell lung cancer (NSCLC) has not been clarified. A pooled analysis of prospective clinical trials was conducted to evaluate the efficacy and safety of neoadjuvant EGFR-TKI therapy.MethodsThe PubMed, Embase, Web of Science, and Cochrane Library databases, as well as meeting abstracts were searched for prospective clinical trials evaluating the efficacy and safety of neoadjuvant EGFR-TKI for treatment of EGFR-mutant NSCLC. The main outcomes included the objective response rate (ORR), downstaging rate, surgical resection rate (SRR), pathologic complete response (pCR) rate, progression-free survival (PFS), and adverse events.ResultsA total of five, phase II, prospective, clinical trials involving 124 patients with resectable or potentially resectable EGFR-mutant NSCLC treated with neoadjuvant erlotinib or gefitinib treatment were included in this pooled analysis. The median neoadjuvant medication time was 42 (range, 21–56) days and the median time of response evaluation was 45 (range, 42–56) days. The pooled ORR was 58.5% [95% confidence interval (CI), 45.5%–71.8%] and the surgical resection and complete resection (R0) rates were 79.9% (95% CI, 65.3%–94.5%) and 64.3% (95% CI, 43.8%–84.8%), respectively. In the stage IIIA subgroup (n = 68), the pooled ORR, SRR, and R0 rate were 51.4%, 72.9%, and 57.0%, respectively, while the downstaging and pCR rates were 14.0% and 0.0%, respectively. The pooled median PFS and overall survival were 13.2 and 41.9 months, respectively. Of the most common grade 3/4 adverse events in the overall group, the incidences of hepatotoxicity and skin rash were 5.3% and 14.7%, respectively. The most commonly reported postoperative complications were lung infection, arrhythmia, and pneumothorax.ConclusionNeoadjuvant EGFR-TKI therapy provides a feasible treatment modality for patients with resectable or potentially resectable EGFR-mutant NSCLC, with satisfactory surgical outcomes and low toxicity. Although further phase III clinical trials are needed to confirm these findings, it is necessary to explore the feasibility of a more effective EGFR-TKI combination neoadjuvant therapy given the modest downgrade and pCR rates for EGFR-TKI alone.

scholarly journals A Systematic Review and Meta-Analysis: Efficacy and Toxicity Profile of Ixazomib for Treatment of Multiple Myeloma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5639-5639
Author(s):  
Madeeha Shafqat ◽  
Faiza Jamil ◽  
Zunairah Shah ◽  
Ali Younas Khan ◽  
Seren Durer ◽  
...  
Keyword(s):  
Systematic Review ◽  
Multiple Myeloma ◽  
Clinical Trials ◽  
Peripheral Neuropathy ◽  
Adverse Events ◽  
Meta Analysis ◽  
Drug Regimen ◽  
Pooled Analysis ◽  
Efficacy And Safety ◽  
Free Survival

Abstract Background: Ixazomib (Ixa) is the first FDA approved oral proteasome inhibitor to be used for relapsed and refractory multiple myeloma (MM). We conducted a comprehensive systematic review and meta-analysis of all published prospective clinical trials to analyze the efficacy and safety of ixazomib in newly diagnosed multiple myeloma (NDMM) and relapsed/refractory multiple myeloma (RRMM). Method: After review of literature (last updated June 30, 2018) using database searches (Pubmed, Embase, Cochrane Library, Web of Science and Clinical Trials.gov), from a total of 1290 studies, only fifteen clinical trials (n=1387) met the inclusion criteria for RRMM and eight clinical trials (n=537) met criteria for NDMM. CMA software v.3 was used for meta-analysis. Heterogeneity among studies was assessed using the I2 test. A random-effect model was applied. Result: Based on pooled analysis, an overall response rate (ORR) of 40.6% (95% CI:19.4-66.0) with a very good partial response or better (≥VGPR) of 15.7% (95% CI: 6.8-32.1) in RRMM and ORR (CR+VGPR+PR) of 77.5% (95% CI: 73.1-81.4, I2=48.05) in NDMM was observed. Most common grade (G) ≥ 3 adverse events (AE) based on regimen were calculated using pooled analysis in MM patients. Ixazomib Based Regimen in RRMM: Ixazomib as monotherapy: Four studies (n=192) evaluated the efficacy of ixazomib as a single agent. On subgroup pooled analysis on Ixa as monotherapy, an ORR of 22.7% (95% CI: 13.3-35.9, I2=45%) was observed with ≥VGPR of 7.8% (95% CI: 2.7-20.3). Pooled analysis for safety profile on most common G ≥ 3 adverse events (AEs) were thrombocytopenia 32.3% (95% CI: 22.4-44.2), neutropenia 21.5% (95% CI: 12.6-34.1), diarrhea 13.1% (95% CI: 6.8-23.9), fatigue 11.6% (95% CI: 7.4-17.7) and peripheral neuropathy 2.2% (95% CI: 0.7-6.6). Ixazomib in two drug regimen: In RRMM, two clinical trials (n=92) evaluated the efficacy of Ixa weekly with dexamethasone (D). In this subgroup pooled analysis, ORR of 40.7% (95% CI: 22.8-61.5, I2=41.76%) with ≥VGPR of 19.5% (95% CI: 4.6-52) was calculated. One study reported event-free survival (EFS) of 8.4 months(4.5-12.8) with a 1-year overall survival rate of 96% (95% CI: 91-100). In our analysis for safety (n=102), common G≥ 3 AEs calculated was thrombocytopenia in 20% (95% CI: 7.5-43.7), neutropenia in 14.3% (95% CI: 3.7-41.6), fatigue in 9.1% (95% CI: 5.0-16.2), diarrhea in 5.7% (1.1-25.5), nausea in 5.7% (95% CI: 1.4-20.2) and peripheral neuropathy in 5.7% (95% CI: 1.4-20.2). Ixazomib in three drug regimen: In RRMM, the efficacy of Ixa was evaluated inten clinical trials (n=646), an ORR of 56.3% (95% CI: 41.8-65.5, I2=82%) with ≥VGPR of 22.8% (95% CI: 13.2-36.4) was noted. Best response was seen when Ixa was used in combination with lenalidomide (R) and dexamethasone, with reported ORR of 78.3%. Common AEs were neutropenia 23.5% (95% CI: 16-33.1), thrombocytopenia 18.8% (95% CI: 13.4-25.6) anemia 10.5% (95% CI: 8.2-13.2), diarrhea 6.3% (95% CI: 3.4 -11.3), fatigue 4.2% (95% CI:2.7-6.4), nausea 1.8% (95% CI: 0.9-3.5) and peripheral neuropathy 2.3% (95% CI: 1.3-3.9). Ixazomib Based Regimen In NDMM: Pooled analysis of subgroup study for combination regimen of Ixa as IRD, Ixa-Thalidomide (T)-D, Ixa-Cyclophosphamide (C)-D, and with Ixa -melphalan-prednisone (IMP), their estimated ORR was 83.7% (95% CI: 75.6-89.5), 80.8% (95% CI: 72.8-86.9), 75% (95% CI: 66.6-82) and 66% (95% CI: 52.4-77.4) respectively. We also measured the efficacy of Ixa as a maintenance therapy, estimated ORR was 81.5% (95% CI: 36.6-97.1, I2=90.5%). In one phase II maintenance study (n=64), a combination of IR receiving patients (n=34), an ORR of 90.4% with VGPR of 53% was reported. Median progression-free survival (PFS) was not reached after a median follow up of 37.8 months and estimated 2-year PFS was 81%. Common G≥3 AEs in NDMM patients were neutropenia 21.6% (95% CI: 11.2-37.6), thrombocytopenia 15.9% (95% CI: 4.7- 42), infections 15.2% (95% CI: 10.3-21.9) and peripheral neuropathy 7.9% (95% CI: 4.7-13). Conclusion: In our pooled analysis (95%CI), Ixazomib has shown promising efficacy both in NDMM as well as RRMM. Especially in three drug regimen it showed an estimated ORR of 84.8% in NDMM and 56.3% RRMM.Cytopenia was a common side effect.Peripheral neuropathy was noted to be a rare side-effect (2.6%) in RRMM. Further studies are required to evaluate efficacy and safety of ixazomib in combination therapies in NDMM. Disclosures No relevant conflicts of interest to declare.

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