A randomized controlled double-blinded split-face prospective clinical trial to assess the efficacy, safety, and tolerability of a novel 3-step routine compared to benzoyl peroxide for the treatment of mild to moderate acne vulgaris.

Adult acne vulgaris affects up to 43-51% of individuals. While there are numerous treatment options for acne including topical, oral, and energy-based approaches, benzoyl peroxide (BPO) is a popular over the counter (OTC) treatment. Although BPO monotherapy has a long history of efficacy and safety, it suffers from several disadvantages, most notably, skin irritation, particularly for treatment naïve patients. In this prospective, randomized, controlled, split-face study, we evaluated the comparative efficacy, safety, and tolerability of a novel 3-step azelaic acid, salicylic acid, and graduated retinol regimen versus a common OTC BPO-based regimen over 12 weeks. A total of 37 adult subjects with self-reported mild to moderate acne vulgaris were recruited. A total of 21 subjects underwent a 2-week washout period and completed the full study with 3 dropping out due to product irritation from the BPO routine, and 13 being lost to follow-up. Detailed tolerability surveys were conducted at Week 4. Additional surveys on tolerability and product preferences were collected monthly, at Week 4, Week 8, and Week 12. A blinded board-certified dermatologist objectively scored the presence and type of acne lesions (open or closed comedones, papules, pustules, nodules, and cysts) at baseline, Week 4, Week 8, and Week 12. Patients photographed themselves and uploaded the images using personal mobile phones. Detailed Week 4 survey results showed across 25 domains of user-assessed product performance, the novel routine outperformed the BPO routine in 19 (76%) which included domains in preference (e.g. "I would use this in the future) and performance ("my skin improved" and "helped my acne clear up faster"). Users of the novel routine reported less facial redness, itching, and burning, though differences did not reach statistical significance. In terms of efficacy, both products performed similarly, reducing total acne lesions by 36% (novel routine) and 40% (BPO routine) by Week 12. Overall, accounting for user preferences and tolerability the novel routine was more preferred than the BPO routine in 79% of domains (22/28). Differences in objective acne lesion reduction were not statistically significant (p = 0.97). In a randomized split-face study, a 3-step azelaic acid, salicylic acid, and graduated retinol regimen delivered similar acne lesion reduction, fewer user dropouts, greater user tolerability, and higher use preference compared to a 3-step BPO routine based in a cohort of participants with mild-to-moderate acne vulgaris.

755-nm picosecond laser plus topical 20% azelaic acid compared to topical 20% azelaic acid alone for the treatment of melasma: a randomized, split-face and controlled trial.

PURPOSE: Melasma remains a refractory skin condition that needs to be actively explored. Azelaic acid has been used for decades as a topical agent to improve melasma through multiple mechanisms, however, there is a lack of research on its combination with laser therapy. This study evaluated the effectiveness of isolated treatment with topical 20% azelaic acid and its combination with 755-nm picosecond laser in facial melasma patients. METHODS: A randomized, evaluator-blinded, controlled study was conducted on 30 subjects with facial melasma in a single center from October 2021 to April 2022. All subjects received topical 20% azelaic acid cream (AA) for 24 weeks, and after 4 weeks, a hemiface was randomly assigned to receive 755-nm picosecond (PS) laser therapy once every 4 weeks for 3 treatments. Treatment efficacy was determined by mMASI score evaluations, dermoscopic assessment, reflectance confocal microscopy (RCM) assessments and patient's satisfaction assessments (PSA). RESULTS: Treatment with 20% azelaic acid, with or without picosecond laser therapy, significantly reduced the hemi-mMASI score (P < 0.0001) and resulted in higher patient satisfaction. Improvements in dermoscopic and RCM assessments were observed in both sides of the face over time, with no difference between the two sides. RCM exhibited better dentritic cell improvement in the combined treatment side. No patients had serious adverse effects at the end of treatment or during the follow-up period. CONCLUSION: The additional use of picosecond laser therapy showed no clinical difference except for subtle differences detected by RCM assessments.The study was registered in the Chinese Clinical Trial Registry (ChiCTR2100051294; 18 September 2021).

Dicarboxylic Acid Dietary Supplementation Protects against AKI.

SIGNIFICANCE STATEMENT: In this study, we demonstrate that a common, low-cost compound known as octanedioic acid (DC 8 ) can protect mice from kidney damage typically caused by ischemia-reperfusion injury or the chemotherapy drug cisplatin. This compound seems to enhance peroxisomal activity, which is responsible for breaking down fats, without adversely affecting mitochondrial function. DC 8 is not only affordable and easy to administer but also effective. These encouraging findings suggest that DC 8 could potentially be used to assist patients who are at risk of experiencing this type of kidney damage. BACKGROUND: Proximal tubules are rich in peroxisomes, which are damaged during AKI. Previous studies demonstrated that increasing peroxisomal fatty acid oxidation (FAO) is renoprotective, but no therapy has emerged to leverage this mechanism. METHODS: Mice were fed with either a control diet or a diet enriched with dicarboxylic acids, which are peroxisome-specific FAO substrates, then subjected to either ischemia-reperfusion injury-AKI or cisplatin-AKI models. Biochemical, histologic, genetic, and proteomic analyses were performed. RESULTS: Both octanedioic acid (DC 8 ) and dodecanedioic acid (DC 12 ) prevented the rise of AKI markers in mice that were exposed to renal injury. Proteomics analysis demonstrated that DC 8 preserved the peroxisomal and mitochondrial proteomes while inducing extensive remodeling of the lysine succinylome. This latter finding indicates that DC 8 is chain shortened to the anaplerotic substrate succinate and that peroxisomal FAO was increased by DC 8 . CONCLUSIONS: DC 8 supplementation protects kidney mitochondria and peroxisomes and increases peroxisomal FAO, thereby protecting against AKI.

Quinazoline-containing Hydrazydes of Dicarboxylic Acids and Products of Their Structural Modification: A Novel Class of Anti-inflammatory Agents.

The synthesis of hydrazides formed by quinazolin-4(3H)-ylidenehydrazine and dicarboxylic acids, as well as their further modification are described in the present manuscript. It was shown that above-mentioned hydrazides may be obtained via acylation of initial quinazolin-4(3H)-ylidenehydrazine by corresponding acylhalides, cyclic anhydrides and imidazolides of dicarboxylic acids monoesters. Obtained hydrazides were converted into [1,2,4]triazolo[1,5-c]quinazolines that were used as initial compounds for chemical modification aimed to the introduction of amide fragment to the molecule. The IR, 1H NMR and chromato-mass spectral data of obtained compounds were studied and discussed. Obtained substances were studied for anti-inflammatory activity using carrageenan-induced paw inflammation model. Amides of ([1,2,4]triazolo[1,5-c]quinazoline-2-yl)alkyl carboxylic acids were detected as promising class of anti-inflammatory agents for further purposeful synthesis and profound study of anti-inflammatory activity.

Evaluating pharmacokinetics of bempedoic acid in the treatment of hypercholesterolemia.

Introduction: Bempedoic acid is a first-in-class low-density lipoprotein cholesterol (LDL-C) lowering agent which offers an important opportunity for further LDL-C lowering in statin-intolerant patients or in patients requiring further LDL-C reduction despite maximally tolerated statin therapy.Areas covered: In this review, we examined the pharmacodynamics, pharmacokinetics, clinical efficacy, and safety of bempedoic acid, based on randomized clinical phase III clinical studies and their meta-analyses.Expert opinion: Unlike statins, bempedoic acid is administered as a prodrug and is converted to active form by a liver-specific enzyme. For the liver-specific mechanism of action, bempedoic acid has the potential to reduce the risk of muscle-related adverse events which can limit the utilization and effectiveness of statin therapy.

Lipid lowering with bempedoic acid added to a proprotein convertase subtilisin/kexin type 9 inhibitor therapy: A randomized, controlled trial.

BACKGROUND: Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9is) lower low-density lipoprotein cholesterol (LDL-C) in patients with hypercholesterolemia. However, some patients receiving PCSK9i therapy might require additional lipid-lowering therapy (LLT) to reach LDL-C goals. Bempedoic acid is an oral, once-daily, ATP-citrate lyase inhibitor that significantly lowers LDL-C in patients with hypercholesterolemia when given alone or as add-on therapy to statins and/or ezetimibe. OBJECTIVE: Assess safety and efficacy of bempedoic acid added to PCSK9i (evolocumab) background therapy in patients with hypercholesterolemia. METHODS: This phase 2, randomized, double-blind, placebo-controlled study was conducted in three phases: 1.5-month screening/washout period including discontinuation of all LLTs, a 3-month period wherein patients initiated background PCSK9i therapy, and a 2-month treatment period in which patients were randomized 1:1 to receive bempedoic acid 180 mg or placebo once daily while continuing PCSK9i therapy. RESULTS: Of 59 patients randomized, 57 completed the study. Mean baseline LDL-C after 3 months of PCSK9i background therapy was 103.1 ± ±â€¯30.4 mg/dL. Bempedoic acid added to background PCSK9i therapy significantly lowered LDL-C by 30.3% (P < .001) vs placebo. Compared with placebo, bempedoic acid significantly lowered apolipoprotein B, non-high-density lipoprotein cholesterol, and total cholesterol (nominal P < .001 for all), and high-sensitivity C-reactive protein (P = .029). When added to background PCSK9i therapy, the safety profile of bempedoic acid was comparable to that observed for placebo. CONCLUSIONS: When added to a background of PCSK9i therapy, bempedoic acid significantly lowered LDL-C levels with a safety profile comparable to placebo in patients with hypercholesterolemia.

Clinical development of bempedoic acid: phase 2 and phase 3 clinical trials. / Desarrollo clínico de ácido bempedoico: estudios fase 2 y fase 3.

We review all the phase II and III studies carried out with bempedoic acid at the dose of 180mg, alone or in combination with different lipid-lowering drugs and in different subgroups of patients that unequivocally show the efficacy and safety of the drug. We point out some of the potential advantages of its use in clinical practice in patients with statin intolerance and the efficacy in reducing LDL-c when combined with statins, and with statins and ezetimibe, as well as in reducing inflammation markers pending the results of the CV Clear Outcomes trial that will end in 2022.

Bempedoic acid. Mechanism of action and pharmacokinetic and pharmacodynamic properties. / Ácido bempedoico. Mecanismo de acción y propiedades farmacocinéticas y farmacodinámicas.

Bempedoic acid acts by inhibiting adenosine triphosphate-citrate lyase (ACL) and consequently cholesterol biosynthesis, leading to increased expression of LDL receptors and increasing low-density lipoproteins (LDL-C) plasma clearence. It is a prodrug for oral administration with intracellular activation. It is activatedin liver cells and to a lesser extent in kidney cells, being absent in adipose tissue and muscle cells. Therefore, unlike statins, its potential myotoxic effect is very limited. It has recently been approved as a lipid-lowering drug in combination with diet, with statins, or with other lipid-lowering drugs in patients with hypercholesterolaemia, mixed dyslipidaemia, statin intolerance, or when these are contraindicated. The marketing of bempedoic acid implies, in clinical practice, having a new family of lipid-lowering drugs.

Bempedoic Acid: a cholesterol lowering agent with a novel mechanism of action.

INTRODUCTION: Dyslipidemia is a common condition that increases the risk of heart diseases and stroke. High levels of low-density lipoprotein-cholesterol (LDL-C) are correlated with a higher risk for heart disease. A drug class known as 'statins' is the gold standard for LDL-C-lowering, but its use in some patients is limited by its adverse effects of myalgias and myopathies. Use of other LDL-C-lowering agents is frequently limited by cost and degree of efficacy. Additionally, many high-risk atherosclerotic cardiovascular disease patients fail to meet LDL-C goals despite maximally tolerated statin therapy with or without the addition of a non-statin agent. AREAS COVERED: This review covers the pharmacology, pharmacokinetics, clinical trials, and clinical implications of bempedoic acid. A PubMed search was conducted using the terms bempedoic, bempedoic acid, Nexletol, ETC-1002, and adenosine triphosphate citrate lyase inhibitor. Additional data were obtained from the prescribing information and relevant guidelines. All clinical trials were included. EXPERT OPINION: Bempedoic acid has not been shown to cause myalgias or myopathies and is likely to be competitively affordable compared to other LDL-C-lowering agents. Bempedoic acid has been shown to be superior compared to placebo and provides additional LDL-C lowering on top of maximally tolerated statin therapy or combined with ezetimibe alone.

Azelaic Acid Promotes Caenorhabditis elegans Longevity at Low Temperature Via an Increase in Fatty Acid Desaturation.

PURPOSE: Azelaic acid (AzA) is a dicarboxylic acid naturally occurring in various grains having anti-inflammatory and anti-oxidation properties. Recently, AzA is shown to reduce high-fat diet-induced adiposity in animals. However, its physiological role in lipid metabolism and aging in various environmental stresses is unknown. METHODS AND RESULTS: Using C. elegans as an invertebrate animal model, we demonstrate that AzA suppresses fat accumulation with no effect on lifespan at normal temperatures. Moreover, AzA promotes lifespan at low temperatures by elevation of unsaturated long-chain fatty acids and expression of genes in fatty acid desaturation. We further find that genes encoding fatty acid desaturases such as fat-1, fat-5, fat-6, and fat-7 are crucial for the lifespan-extending effect of AzA at low temperature. CONCLUSIONS: Taken together, our results suggest that AzA promotes adaption to low temperature in C. elegans via shifting fatty acid profile to unsaturated long-chain fatty acids.

Bempedoic Acid: A New Drug for an Old Problem.

OBJECTIVE: To review the pharmacology, pharmacokinetics, safety, and efficacy of bempedoic acid for low-density lipoprotein cholesterol (LDL-C) reduction. DATA SOURCES: A PubMed search was conducted from January 2000 to June 15, 2020, using the keyword bempedoic acid for phase III clinical trials published in the English language. STUDY SELECTION AND DATA EXTRACTION: Articles related to the Food and Drug Administration (FDA) approval of bempedoic acid and other trials relating to the safety and efficacy of this drug were included. DATA SYNTHESIS: The findings from this review show that bempedoic acid is a safe and effective option for lowering LDL-C levels in patients requiring LDL-C lowering for primary or secondary prevention of cardiovascular events. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: Statin therapy remains the mainstay of treatment for both primary and secondary prevention. However, many patients cannot tolerate statin therapy because of statin-associated muscle symptoms. Bempedoic acid may be a reasonable adjunct for LDL-C reduction, though further evaluation of cardiovascular outcomes with bempedoic acid in this population is needed. CONCLUSIONS: The recent FDA approval of bempedoic acid offers an additional option for lowering LDL-C levels in patients with atherosclerotic cardiovascular disease or heterozygous familial hyperlipidemia. Additional data regarding effect on long-term cardiovascular outcomes with bempedoic acid are currently being studied.

Bempedoic Acid and Ezetimibe for the Treatment of Hypercholesterolemia: A Systematic Review and Meta-Analysis of Randomized Phase II/III trials.

BACKGROUND AND OBJECTIVE: A limited number of trials have evaluated the efficacy of a fixed-dose combination of bempedoic acid and ezetimibe for the treatment of hypercholesterolemia. The aim of this meta-analysis of existing studies was to evaluate the efficacy and safety of fixed-dose bempedoic acid and ezetimibe combination therapy for the treatment of hypercholesterolemia. METHODS: A systematic literature search was conducted to identify randomized controlled trials (RCTs) comparing bempedoic acid and ezetimibe, versus placebo or ezetimibe alone, to 30 August 2020. A meta-analysis was conducted to investigate the efficacy of bempedoic acid and ezetimibe on lipid parameters and highly sensitive C-reactive protein (hsCRP) levels in patients with hypercholesterolemia or established atherosclerotic cardiovascular disease (ASCVD). Mean differences (MDs) or relative risk (RR) with their corresponding 95% confidence intervals (CIs), using random-effects models, were used to provide pooled estimates. RESULTS: A total of three phase II and III RCTs, comprising 388 patients, of whom 49.2% were treated with bempedoic acid and ezetimibe, and 197 controls, were identified. The duration of treatment was 12 weeks. Bempedoic acid and ezetimibe significantly reduced low-density lipoprotein cholesterol (MD - 29.14%, 95% CI - 39.52 to - 18.76; p < .001), total cholesterol (MD - 15.78%, 95% CI - 20.84 to - 10.72; p = 0.01), non-high-density lipoprotein cholesterol (MD - 18.36%, 95% CI - 24.60 to - 12.12; p = 0.01), and hsCRP levels (MD - 30.48%, 95% CI - 44.69 to - 16.28; p = 0.04). No significant effects on triglycerides (MD - 8.35%, 95% CI - 16.08 to - 0.63; p = 0.72) and improvement in high-density lipoprotein cholesterol (MD 1.63%, 95% CI - 4.03 to 7.28; p = 0.92) were observed with the fixed-dose combination therapy. Regarding safety, bempedoic acid and ezetimibe combination was associated with a non-significant increased risk of drug-related adverse events (RR 1.61, 95% CI 0.86-2.35) and overall adverse events (RR 1.16. 95% CI 0.97-1.35); however, the incidence of discontinuation of therapy (RR 0.75, 95% CI 0.35-1.49) was lower. CONCLUSION: This review found bempedoic acid and ezetimibe significantly lowered lipid parameters, attenuated hsCRP levels, and had an acceptable safety profile for the treatment of hypercholesterolemia and ASCVD.

Efficacy and safety of bempedoic acid alone or combining with other lipid-lowering therapies in hypercholesterolemic patients: a meta-analysis of randomized controlled trials.

BACKGROUND: Bempedoic acid is a new drug that reduces cholesterol synthesis via inhibiting ATP citrate lyase. It remains unclear whether the combination of bempedoic acid and other lipid-lowering drugs is better than these drugs alone. This study systematically reviewed the efficacy and safety of bempedoic acid monotherapy or combination togethers in hypercholesterolemic patients. METHODS: Randomized controlled trials were searched across Medline, Embase, Cochrane library, web of science, etc. The net change scores [least squares mean (LSM) percentage change] in LDL-C level were meta-analyzed using weighted mean difference. The reductions in other lipids including total cholesterol (TC), non-high-density lipoprotein cholesterol (non-HDL-C) and apolipoprotein (ApoB) and high sensitivity C reactive protein (hsCRP) were also assessed. Odds ratio (OR) of the incidence of adverse events (AEs) were calculated to evaluate the safety of bempedoic acid. RESULTS: A total of 13 trials (4858 participates) were included. Pooled data showed that the combination togethers resulted in greater reductions in LDL-C level than monotherapies (bempedoic acid + statin vs. statin: LSM difference (%), - 18.37, 95% CI, - 20.16 to - 16.57, I2 = 0; bempedoic acid + ezetimibe vs. ezetimibe: LSM difference (%), - 18.89, 95% CI, - 29.66 to - 8.13, I2 = 87%). But the difference in efficacy between bempedoic acid and ezetimibe was not obvious. Meta-regression analysis showed the treatment duration was a source of heterogeneity (adj R2 = 16.92, 95% CI, 0.04 to 0.72). Furthermore, the background therapy of statin before screening decreased the efficacy of bempedoic acid. In addition, bempedoic acid also resulted in a significant reduction in TC, non-HDL-C, ApoB and hsCRP level. The OR of muscle-related AEs by the combination of bempedoic acid and statin was 1.29 (95% CI, 1.00 to 1.67, I2 = 0) when compared with statin alone. CONCLUSION: This study showed the efficacy of combination togethers were similar but stronger than these drugs alone. Of note, a trend of high risk of muscle-related AEs by the combination of bempedoic acid and statin was observed, though it is not statistically significant, such risk is needed to be confirmed by more trials, because it is important for us to determine which is the better combinative administration for statin-intolerant patients.

Evidence-based topical treatments (azelaic acid, salicylic acid, nicotinamide, sulfur, zinc, and fruit acid) for acne: an abridged version of a Cochrane systematic review.

OBJECTIVE: The effects of topical azelaic acid, salicylic acid, nicotinamide, sulfur, zinc, and fruit acid (alpha-hydroxy acid) for acne are unclear. We aimed to assess the effects of these topical treatments by collecting randomized controlled trials. METHODS: We searched The Cochrane Skin Group Specialised Register, CENTRAL, MEDLINE, Embase, and LILACS up to May 2019. We also searched five trials registers. Two review authors independently extracted data and assessed risk of bias. Meta analyses were performed by using Review Manager 5 software. RESULTS: We included a total of 49 trials involving 3880 participants. In terms of treatment response (measured using participants' global self-assessment of acne improvement, PGA), azelaic acid was probably less effective than benzoyl peroxide (RR = 0.82, 95% CI 0.72-0.95). However, there was probably little or no difference in PGA when comparing azelaic acid to tretinoin (RR = 0.94, 95% CI 0.78-1.14). There may be little or no difference when comparing salicylic acid to tretinoin (RR = 1.00, 95% CI 0.92-1.09). There were no studies measured PGA when evaluating nicotinamide. With respect to alpha-hydroxy acid, there may be no difference in PGA when comparing glycolic acid to salicylic-mandelic acid (RR = 1.06, 95% CI 0.88-1.26). We were uncertain about the effects of sulfur and zinc. Adverse events associated with these topical treatments were always mild and transient. CONCLUSIONS: Moderate-quality evidence was available for azelaic acid and low- to very-low-quality evidence for other topical treatments. Risk of bias and imprecision limit our confidence in the evidence.

Pharmaceutical salts/cocrystals of enoxacin with dicarboxylic acids: Enhancing in vitro antibacterial activity of enoxacin by improving the solubility and permeability.

Base on improving the solubility and permeability of enoxacin (EX) to enhance the antibacterial activity in vitro, three new pharmaceutical salts/cocrystals of EX with oxalic acid (EX·0.5(C2H2O4)·2(H2O)), malonic acid ((HEX)·C3H3O4) and fumaric acid ((HEX)·C4H3O4) have been designed, synthesized and characterized. Comprehensive analysis structure and Hirshfeld surface reveal that the hydrogen bonds/CAHBs formed by the N atom in the piperazine ring from EX molecule with the carboxylic acid group in the coformer could form a stable crystal structure. It is universally acknowledged that improving the solubility of the EX (BCS class II) to make it a BCS class I drug would obtain a Bioequivalence of immunity to the drug trial. The solubilities of three pharmaceutical salts/cocrystals of EX with dicarboxylic acids are consistent with expectation that they are dramatically improved in pure water than pure enoxacin, and the solubility order of three pharmaceutical salts/cocrystals of EX is consistent with coformers solubility. The permeabilities of three pharmaceutical salts/cocrystals of EX are improved compared with the pure enoxacin, and the variation tendency is consistent with the solubilities of three pharmaceutical salts/cocrystals of EX. In addition, the antibacterial activities in vitro of three pharmaceutical salts/cocrystals of EX are improved compared with the corresponding parent compound (EX), which change the order is consistent with the solubility and permeability. Simultaneously, the hygroscopic stabilities of three pharmaceutical salts/cocrystals are surpassing pure EX, and the hygroscopic stability of molecular cocrystal EX-OXA is better than ionic cocrystal EX-MLO and EX-FUM. This implies that preparation of the pharmaceutical salts/cocrystals of EX with oxalic acid, malonic acid and fumaric acid could not only enhance the antibacterial activity of EX, which base on improving the solubility and permeability of EX, but also improve the hygroscopic stability of EX.

Oral Azelaic Acid Ester Decreases Markers of Insulin Resistance in Overweight Human Male Subjects.

BACKGROUND/AIM: Insulin resistance (IR) is linked to increased risk of cardiovascular disease and cancer. We examined safety and efficacy of the natural product diethyl azelate (DEA) in overweight males with a varying degree of IR. PATIENTS AND METHODS: Seventeen subjects [age 18-42, hemoglobin A1c (A1c) of 5.2-6.2%] received orally 1 mg/kg DEA daily for 21 days. Blood plasma glucose, insulin and lipid levels were assessed before and after treatment. RESULTS: DEA was well tolerated without hypoglycemia or adverse effects except transient diarrhea (n=1). DEA significantly reduced fasting glucose by 6.06 mg/dl (n=8) and insulin by 37.8% (n=8) in subjects with IR and/or A1c ≥5.6%. Furthermore, it improved cholesterol/HDL, LDL/HDL, and non-cholesterol HDL/HDL by 5.4, 6.5, and 6.6%, respectively in all subjects, and by 8.0, 9.8, and 9.8%, respectively in 9 subjects with A1c ≥5.6%. CONCLUSION: DEA efficacy correlates with the degree of IR. DEA holds promise as a novel treatment for the management of IR.

Safety, Tolerability and Pharmacokinetics of Vidofludimus calcium (IMU-838) After Single and Multiple Ascending Oral Doses in Healthy Male Subjects.

BACKGROUND AND OBJECTIVE: Vidofludimus is a potent and selective inhibitor of human mitochondrial enzyme dihydroorotate dehydrogenase (DHODH). The clinical efficacy and safety profile of vidofludimus has been analyzed in patients suffering from rheumatoid arthritis and Crohn's disease and ulcerative colitis. In previous sudies, hematuria at higher doses occurred in close temporal relationship to vidofludimus administration and appeared to be dose related. The present report describes the results from two phase 1 studies conducted in healthy male subjects to investigate the safety, tolerability and pharmacokinetics after single and multiple ascending (SAD and MAD) oral doses of IMU-838 (vidofludimus calcium, tablets containing a specific polymorph). The effect of food on the pharmacokinetics of IMU-838 was also assessed in the SAD study. METHODS: In the SAD study, 12 subjects received single doses of IMU-838 under fasting (10-40 mg) or fed (10 mg) condition in an open-label, partial parallel group design. In the MAD study, 52 subjects received multiple doses of IMU-838 (30-50 mg) in a double-blind, placebo-controlled, parallel group design. RESULTS: IMU-838 showed dose-proportional pharmacokinetics after single and multiple oral dosing in both SAD and MAD studies. IMU-838 was well absorbed after single daily doses. Food did not impact the pharmacokinetics of IMU-838. The accumulation factor for multiple daily dosing was approximately 2. Steady-state concentrations were reached within about 6-8 days for 30-50 mg groups. The geometric mean plasma half-life of IMU-838 at steady state was approximately 30 h, which supports its use for once-daily dosing regimen. Single and multiple oral doses of IMU-838 were safe and well tolerated. CONCLUSION: Overall, oral IMU-838 was generally well tolerated in SAD and MAD studies in healthy subjects over a wide dose range of 10-50 mg. IMU-838 was well absorbed after single daily doses. IMU-838 showed dose proportional pharmacokinetics after single and multiple oral dosing.

A Review of the Efficacy and Tolerability of Bempedoic Acid in the Treatment of Hypercholesterolemia.

Despite the widespread use of statins and ezetimibe to decrease low-density lipoprotein cholesterol (LDL-C) levels and associated atherosclerotic cardiovascular disease (ASCVD), many patients do not achieve adequate LDL-C lowering as per the recommended American College of Cardiology (ACC)/American Heart Association (AHA) and European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) guidelines and demonstrate residual cardiovascular risk. The introduction of proprotein convertase subtilisin/kexin type 9 (PCSK-9) inhibitors in 2015 was a promising addition to hypercholesterolemia therapies, but their cost and subcutaneous administration has limited their use, and therefore, new affordable and patient friendly treatment strategies are crucial to help reduce ASCVD risk. Bempedoic acid, a drug currently under investigation, is a small molecule that has been shown to upregulate LDL receptors, decrease LDL-C, and reduce atherosclerotic plaque formation in hypercholesterolemic patients. Furthermore, bempedoic acid is a prodrug that becomes activated by an enzyme expressed primarily in the liver, allowing it to avoid the potential myotoxicity associated with statin therapy. The purpose of this review is to summarize the major clinical studies evaluating bempedoic acid and describe its potential addition to currently approved lipid-lowering therapies.

Bempedoic acid plus ezetimibe fixed-dose combination in patients with hypercholesterolemia and high CVD risk treated with maximally tolerated statin therapy.

AIMS: The aim of this study was to evaluate the low-density lipoprotein cholesterol lowering efficacy and safety of a bempedoic acid 180 mg and ezetimibe 10 mg fixed-dose combination in patients with hypercholesterolemia and a high risk of cardiovascular disease receiving maximally tolerated statin therapy. METHODS: This phase 3, double-blind clinical trial enrolled adult patients at high risk of cardiovascular disease due to atherosclerotic cardiovascular disease, heterozygous familial hypercholesterolemia, or multiple cardiovascular disease risk factors. Patients were randomly assigned (2:2:2:1) to treatment with the fixed-dose combination, bempedoic acid 180 mg, ezetimibe 10 mg or placebo added to stable background statin therapy for 12 weeks. The primary efficacy endpoint was the percentage change from baseline to week 12 in low-density lipoprotein cholesterol. RESULTS: Among the 301 patients included in the primary analysis, the mean baseline low-density lipoprotein cholesterol level was 3.87 mmol/L (149.8 mg/dL). At week 12, the fixed-dose combination lowered low-density lipoprotein cholesterol (-36.2%) significantly more than placebo (1.8% (placebo-corrected difference -38.0%); P < 0.001), ezetimibe alone (-23.2%; P < 0.001) or bempedoic acid alone (-17.2%; P < 0.001). The fixed-dose combination lowered low-density lipoprotein cholesterol levels similarly across subgroups, including patients receiving high-intensity, other-intensity or no statin therapy. Improvements with the fixed-dose combination were also observed in secondary efficacy endpoints, including high-sensitivity C-reactive protein. In this trial, fixed-dose combination treatment had a generally similar safety profile compared with bempedoic acid, ezetimibe or placebo. CONCLUSION: The bempedoic acid and ezetimibe fixed-dose combination significantly lowered low-density lipoprotein cholesterol versus placebo or other oral monotherapies and had a favourable safety profile when added to maximally tolerated statin therapy in patients with hypercholesterolemia and high cardiovascular disease risk. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03337308.