- |||||||||| Kynamro (mipomersen) / Kastle Therap
Review, Journal: Lipoprotein(a) as a Risk Factor for Cardiovascular Diseases: Pathophysiology and Treatment Perspectives. (Pubmed Central) - Oct 1, 2023
Mipomersen decreases Lp(a) levels by 25-40%, but its use is burdened with important side effects...The aim of this review is to provide an update on the current state of the art with regard to Lp(a) pathophysiological mechanisms, focusing on the most effective strategies for lowering Lp(a), including new emerging alternative therapies. The purpose of this manuscript is to improve the management of hyperlipoproteinemia(a) in order to achieve better control of the residual cardiovascular risk, which remains unacceptably high.
- |||||||||| Review, Journal: Novel Pharmacological Therapies for the Management of Hyperlipoproteinemia(a). (Pubmed Central) - Sep 13, 2023
Traditional pharmacological interventions like niacin, statins, ezetimibe, aspirin, PCSK-9 inhibitors, mipomersen, estrogens and CETP inhibitors have not yet yielded satisfactory results...Pelacarsen is an antisense oligonucleotide, while olpasiran, LY3819469 and SLN360 are small interfering RNAs, all conjugated with a N-acetylgalactosamine molecule...The Lp(a) reduction achieved with novel RNA agents may exceed 95%. The results of ongoing and future clinical trials are eagerly anticipated, and it is hoped that guidelines for the tailored management of Lp(a) levels with these novel agents may not be far off.
- |||||||||| Journal: Established and Emerging Lipid-Lowering Drugs for Primary and Secondary Cardiovascular Prevention. (Pubmed Central) - Jul 24, 2023
Established pharmaceutical treatment options include the Niemann-Pick-C1 like-1 protein (NPC1L1) inhibitor ezetimibe, the protein convertase subtilisin-kexin type 9 (PCSK9) inhibitors alirocumab and evolocumab, fibrates as peroxisome proliferator receptor alpha (PPAR-?) activators, and the omega-3 fatty acid icosapent ethyl...For secondary prevention in hypertriglyceridemia, second-line options such as statin add-on or statin-intolerant treatments are icosapent ethyl and fenofibrate...Recent biotechnological advances have led to the development of innovative small molecules (bempedoic acid, lomitapide, pemafibrate, docosapentaenoic and eicosapentaenoic acid), antibodies (evinacumab), antisense oligonucleotides (mipomersen, volanesorsen, pelcarsen, olezarsen), small interfering RNA (inclisiran, olpasiran), and gene therapies for patients with dyslipidemia...Apart from statins, data on new drugs' use in primary cardiovascular prevention remain scarce. For their swift adoption into clinical routine, these treatments must demonstrate safety and efficacy as well as cost-effectiveness in randomized cardiovascular outcome trials.
- |||||||||| Review, Journal: Current Options and Future Perspectives in the Treatment of Dyslipidemia. (Pubmed Central) - Aug 27, 2022
This narrative review provides an overview of the new drugs for the treatment of dyslipidemia, their current status, ongoing clinical or preclinical trials, and their prospects. We also discuss the new alternative therapies for the treatment of dyslipidemia and their relevance to practice.
- |||||||||| olpasiran (AMG 890) / Amgen, pelacarsen (AKCEA-APO(a)-LRx) / Ionis, Novartis, Kynamro (mipomersen) / Kastle Therap
Review, Journal: Lipoprotein(a) and its Significance in Cardiovascular Disease: A Review. (Pubmed Central) - Jul 17, 2022
Nevertheless, emerging nucleic acid-based therapies, such as the antisense oligonucleotide pelacarsen and the small interfering RNA olpasiran, are generating interest because of their potent Lp(a)-lowering effects...Epidemiologic and genetic studies suggest a potentially causal association between elevated Lp(a) levels, atherosclerotic cardiovascular disease, and aortic valve stenosis. Emerging nucleic acid-based therapies have potent Lp(a)-lowering effects and appear safe; phase 3 trials will establish whether they improve cardiovascular outcomes.
- |||||||||| Review, Journal: The promising novel therapies for familial hypercholesterolemia. (Pubmed Central) - Jul 17, 2022
Emerging nucleic acid-based therapies have potent Lp(a)-lowering effects and appear safe; phase 3 trials will establish whether they improve cardiovascular outcomes. While the therapies based on different targets including protein, RNA, and DNA are on different stages of development, the mechanisms of these novel therapies may provide new ideas for precision medicine.
- |||||||||| FDA event, Journal: Absorption, distribution, metabolism, and excretion of FDA-approved antisense oligonucleotide drugs. (Pubmed Central) - Jun 25, 2022
Significance Statement Through a systematic analysis of the existing information of ADME parameters for ten FDA-approved ASO drugs, this review provides an overall view of the unique ADME characteristics of ASO drugs, which are distinct from small chemical drug ADME. This knowledge is useful for discovery and development of new ASO drugs as well as clinical use of current FDA-approved ASO drugs.
- |||||||||| FDA event, Journal, Adverse drug reaction: Adverse Drug Reactions and Toxicity of the FDA-approved Antisense Oligonucleotide Drugs. (Pubmed Central) - Jun 25, 2022
Significance Statement The current review provides a comprehensive analysis of unique and common ADRs and the toxicity of FDA-approved ASO drugs. The information can help better manage the risk of severe hepatotoxicity, kidney toxicity, and hypersensitivity reactions in the usage of currently approved ASO drugs and the discovery and development of new and safer ASO drugs.
- |||||||||| FDA event, Journal: Absorption, Distribution, Metabolism, and Excretion of FDA-approved Antisense Oligonucleotide Drugs. (Pubmed Central) - May 14, 2022
The summarized information provides the most updated knowledge of ADME characteristics of these ASO drugs, leading to a better understanding of their therapeutic efficacy and potential ADRs and toxicity. Numerous knowledge gaps, particularly on cellular uptake and subcellular trafficking and distributions are identified and future perspective and directions are discussed.
- |||||||||| Review, Journal: Deliver the promise: RNAs as a new class of molecular entities for therapy and vaccination. (Pubmed Central) - Feb 12, 2022
By overviewing individual RNA medications and vaccines approved by the FDA and some agents under development, we illustrate the unique compositions and pharmacological actions of RNA products. A new era of RNA research and development will likely lead to commercialization of more RNA agents for medical use, expanding the range of therapeutic targets and increasing the diversity of molecular modalities.
- |||||||||| Journal: Therapeutic targets in the treatment of dyslipidaemias: From statins to PCSK9 inhibitors. Unmet needs. (Pubmed Central) - Nov 16, 2021
In the present narrative review, a summary is presented on the current knowledge on the effects of the different cholesterol-lowering drugs, including those recently approved by European and American regulatory agencies, on lipid profile, and on cardiovascular risk. Since difficult-to-treat patients may benefit from new combination therapies as a result of the emergence of new drugs with clinical evidence, updates of the clinical guidelines would be recommended.
- |||||||||| Parmodia (pemafibrate) / Kowa
Journal: Atherosclerosis prevention: new therapeutic strategies on the horizon (Pubmed Central) - Nov 5, 2021
We discuss the mechanism of action, biological effects, and safety profile of these new drugs (bempedoic acid, lomitapide, inclisiran, evinacumab, vupanorsen, mipomersen, eicosapent ethyl, volanesorsen, pemafibrate, AKCEA-APO(a)-LRx, colchicine, semaglutide). Lastly, we briefly report therapeutic interventions based on biotechnological methods that could be implemented in the near future.
- |||||||||| Clinical, Review, Journal: Familial Hypercholesterolemia: Global Burden and Approaches. (Pubmed Central) - Sep 23, 2021
Additionally, novel agents bempedoic acid, inclisiran, and evinacumab expanded the treatment choices for some patients with FH...Despite major advances in our understanding of the disease and effective therapies, FH is still underdiagnosed and undertreated. Early initiation of LDL-C lowering by increased awareness of FH among the healthcare professionals, patients, and the public is necessary to achieve meaningful reduction in ASCVD morbidity and mortality in these patients.
- |||||||||| Review, Journal: Biologic therapy for dyslipidemia. (Pubmed Central) - Jul 20, 2021
Nowadays, they are targeting at various proteins that are involved in the synthesis, transport, or metabolism of lipoproteins. This review provides a statement of current options for the biological treatment of dyslipidemias and for other products that have the potential to broaden its spectrum in the near future.
- |||||||||| Kynamro (mipomersen) / Kastle Therap, Tegsedi (inotersen) / Ionis
Journal: Invention and Early History of Gapmers. (Pubmed Central) - Mar 18, 2021
Gapmers have also successfully entered clinical trials for various genetic disorders, with two already approved by the U.S. Food and Drug Administration for the treatment of familial hypercholesterolemia and transthyretin amyloidosis-associated polyneuropathy. Here, we review the events surrounding the early development of gapmers, from conception to their maturity, and briefly conclude with perspectives on their use in therapy.
- |||||||||| Clinical, Journal: Development and Clinical Applications of Antisense Oligonucleotide Gapmers. (Pubmed Central) - Mar 18, 2021
Many others are being tested in clinical trials or under preclinical development. This chapter will cover the development of mipomersen and inotersen in clinical trials, along with advancement in gapmer treatments for cancer, triglyceride-elevating genetic diseases, Huntington's disease, myotonic dystrophy, and prion diseases.
- |||||||||| Journal: Development of Antisense Oligonucleotide Gapmers for the Treatment of Dyslipidemia and Lipodystrophy. (Pubmed Central) - Mar 18, 2021
Volanesorsen, another 20-mer MOE gapmer has shown to be successful in lowering the levels of triglycerides (TGs) in several lipid disorders and has received conditional approval in the European Union for the treatment of Familial chylomicronemia syndrome (FCS) in May 2019 following successful results from phase II/III clinical trials. This chapter focuses on the clinical applications of gapmer AOs for genetic dyslipidemia and lipodystrophy.
- |||||||||| Journal: Novel emerging therapies in atherosclerosis targeting lipid metabolism. (Pubmed Central) - Jan 28, 2021
Inclisiran and pemafibrate show promise in the reduction of LDL-C and TG, respectively and results are pending in cardiovascular outcome trials. Combination strategies could improve outcomes, but the challenge will be balancing cost and selecting the correct patient population for each treatment modality to maximize benefit with the fewest medications.
- |||||||||| Juxtapid (lomitapide) / Amryt, Novelion, Kynamro (mipomersen) / Kastle
Journal: Low cholesterol syndrome and drug development. (Pubmed Central) - Sep 26, 2020
Orphan lipid disorders have provided insights into mechanisms involved in lowering cholesterol levels and the potential safety and efficacy of interventional processes. They have been not only enabled development of drugs to treat rare lipid disorders but also those finding wider use in general lowering of CVD risk.
- |||||||||| Kynamro (mipomersen) / Kastle, Waylivra (volanesorsen) / Novartis, inclisiran (ALN-PCSsc) / Alnylam, Novartis
Review, Journal: A NEW DAWN FOR MANAGING DYSLIPIDEMIAS: THE ERA OF RNA-BASED THERAPIES. (Pubmed Central) - Aug 27, 2020
The availability of specific ASOs lowering lipoprotein (a) [Lp(a)] levels will allow rigorous testing of the Lp(a) hypothesis; by dramatically reducing plasma triglyceride levels, volanesorsen (apoC-III) and angiopoietin-like 3 (ANGPTL3)-LRx will further clarify the causality of triglyceride-rich lipoproteins in ASCVD. The rapid progress to date heralds a new dawn in therapeutic lipidology, but outcome, safety and cost-effectiveness studies are required to establish the role of these new agents in clinical practice.
- |||||||||| Journal: Therapeutic Oligonucleotides: State of the Art. (Pubmed Central) - Jul 9, 2020
Expected final online publication date for the Annual Review of Pharmacology and Toxicology Volume 59 is January 6, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
- |||||||||| Kynamro (mipomersen) / Kastle
Journal: Structural Insight into Antisense Gapmer-RNA Oligomer Duplexes through Molecular Dynamics Simulations. (Pubmed Central) - Jul 4, 2020
Free energy calculations suggest that the oligomer, which contains LNA binds to the RNA strongly than other modifications as shown in experimental results. The MOE modified nucleotide, which although had a lower binding affinity but higher solvent accessible surface area (SASA) compared to the other modifications, may be influencing the toxicity and hence may be used it in Mipomersen, the second antisense molecule which is approved by FDA.
- |||||||||| Juxtapid (lomitapide) / Amryt, Novelion, Kynamro (mipomersen) / Kastle
Biomarker, Review, Journal: Lipoprotein(a) and Atherosclerotic Cardiovascular Disease: Current Understanding and Future Perspectives. (Pubmed Central) - Jun 8, 2020
The MOE modified nucleotide, which although had a lower binding affinity but higher solvent accessible surface area (SASA) compared to the other modifications, may be influencing the toxicity and hence may be used it in Mipomersen, the second antisense molecule which is approved by FDA. It is reasonable to measure Lp(a) levels to reclassify ASCVD risk and manage individuals with elevated Lp(a) to further reduce the residual risk of ASCVD, especially with IONIS-APO(a)-L.
- |||||||||| Juxtapid (lomitapide) / Amryt, Novelion, Kynamro (mipomersen) / Kastle
Review, Journal: Lomitapide and Mipomersen-Inhibiting Microsomal Triglyceride Transfer Protein (MTP) and apoB100 Synthesis. (Pubmed Central) - May 31, 2020
Mipomersen may cause injection-site and influenza-like reactions. The effect of lomitapide and mipomersen on cardiovascular outcomes has not been studied, but circumstantial evidence suggests that the LDL cholesterol lowering achieved with these two agents may reduce cardiovascular event rates.
- |||||||||| AKCEA-APO(a)-LRx / Ionis, Novartis, Kynamro (mipomersen) / Kastle
Review, Journal: Antisense Oligonucleotides Targeting Lipoprotein(a). (Pubmed Central) - May 7, 2020
Mipomersen has been shown to lower lipoprotein(a) by 20-50% in phase 3 studies...The treatment of elevated lipoprotein(a) levels with the newest antisense oligonucleotides seems promising; however, no improvement in cardiovascular disease risk has yet been shown. However, a phase 3 study of AKCEA-APO(a)-L is being planned with cardiovascular disease as outcome, and results are awaited with great anticipation.
- |||||||||| Review, Journal: Can Lp(a) Lowering Against Background Statin Therapy Really Reduce Cardiovascular Risk? (Pubmed Central) - Apr 10, 2020
Conclusive evidence is still lacking as to whether the treatment with PCSK9 inhibitors against background statin therapy actually additionally reduces ASCVD risk due to the lowering of Lp(a) or simply due to lowering LDL-C to levels much lower than high-intensity statin treatment as monotherapy. Ongoing trials will probably provide an answer to these questions.
- |||||||||| Kynamro (mipomersen) / Kastle Therap
Clinical, Journal: Safety and efficacy of mipomersen in patients with heterozygous familial hypercholesterolemia. (Pubmed Central) - Mar 26, 2020
This is counterbalanced by limited tolerability and increased hepatic transaminase levels in about 21% of patients. The thrice-weekly dosing regimen was associated with lower frequency of flu-like symptoms, which might help avert discontinuation in some patients, but otherwise had no major benefits.
- |||||||||| Kynamro (mipomersen) / Kastle
Retrospective data, Review, Journal: Efficacy and Safety of Mipomersen: A Systematic Review and Meta-Analysis of Randomized Clinical Trials. (Pubmed Central) - Nov 29, 2019
Despite favourable effects on the lipid profile, some concerns are reinforced from the safety profile. As a matter of fact, mipomersen therapy is more likely discontinued and associated with increased risk of injection-site reactions, hepatic steatosis, hepatic enzyme elevation, and flu-like symptoms.
- |||||||||| Juxtapid (lomitapide) / Amryt, Novelion, Kynamro (mipomersen) / Kastle
Journal: Multimodal treatment of homozygous familial hypercholesterolemia. (Pubmed Central) - Nov 23, 2019
The main treatment is LDL-C apheresis aided by ezetimibe and PCSK9 inhibitors. Lomitapide needs caution, and liver transplantation is an alternative as the last resort.
- |||||||||| Kynamro (mipomersen) / Kastle
Clinical, Journal: Familial Hypercholesterolemia in Children and Adolescents: Diagnosis and Treatment. (Pubmed Central) - Nov 23, 2019
The main gap of evidence remains the lack of longitudinal follow up studies investigating cardiovascular outcomes, side effects, and effectiveness of treatment starting from childhood. Evidence would be expected in the near future by cohort and registry studies.
- |||||||||| Journal: Lipid-Lowering Agents. (Pubmed Central) - Nov 21, 2019
Alipogene tiparvovec, pradigastat, and volanesorsen primarily target elevated triglycerides, whereas evinacumab and IONIS-ANGPTL3-L target both LDL cholesterol and triglyceride. IONIS-APO(a)-L targets Lp(a).
- |||||||||| Juxtapid (lomitapide) / Amryt, Novelion, Kynamro (mipomersen) / Kastle, Xenical (orlistat) / Roche, GSK
Journal: Monoacylglycerol Acyltransferase 2 (MGAT2) Inhibitors for the Treatment of Metabolic Diseases and Nonalcoholic Steatohepatitis (NASH). (Pubmed Central) - Oct 2, 2019
In addition, several inhibitors of diacylglycerol transferase 1 (DGAT1) have advanced to the clinic but were withdrawn due to poor GI tolerability. This perspective first discusses the biological rationale in support of inhibition of MGAT2 as a therapeutic approach that may offer a distinct and superior efficacy versus GI tolerability profile, and then reviews advances in the discovery of small molecule MGAT2 inhibitors for the treatment of metabolic diseases and non-alcoholic steatohepatitis (NASH).
|
