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Nucleic Acids as Therapeutic Targets and Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
At the time of writing, Alnylam has ten siRNA-based products in its pipeline, and the next most likely candidate for approval is inclisiran, a PCSK9-targeted agent developed by The Medicines Company Inc based on RNAi technology licensed from Alnylam. Inclisiran produced sufficiently robust data in late-stage clinical trials for Novartis to acquire the company in late 2019 for $9.7 billion. In clinical trials the agent lowered LDL-cholesterol by up to 54–58% and is on track for regulatory approval for patients with high-risk atherosclerotic cardiovascular disease or familial hypercholesterolaemia. If approved, inclisiran will compete with evolocumab (Amgen Inc.) and alirocumab (Sanofi and Regeneron Inc.), both PCSK9-lowering antibodies approved in 2015. These antibodies have not lived up to their blockbuster expectations, owing to their cost, slow patient uptake and remaining questions about their benefit for hard cardiovascular end points. The UK government is planning to launch a major clinical trial of inclisiran in 2020 with a view to making it available to NHS patients from 2021 after it is approved.
Statin associated muscle symptoms (SAMS): strategies for prevention, assessment and management
Published in Expert Review of Cardiovascular Therapy, 2023
Iulia Iatan, G. B. John Mancini, Eunice Yeoh, Robert A. Hegele
Inclisiran is a small interfering RNA (siRNA) that inhibits the cellular production of PCSK9 that reduces LDL-C by 44–55% over baseline therapy [102]. A single subcutaneous injection reduces both circulating PCSK9 and LDL-C for up to 6 months [102]. Pooled data from three RCTs of 3660 patients with hypercholesterolemia or ASCVD showed that inclisiran reduced ASCVD events risk by 24% [103], although these results are hypothesis generating and need to be confirmed in proper RCTs. A four-year study reported an overall LDL-C reduction by inclisiran of 44% with good tolerability [104]. However, there are no double-blind RCTs of inclisiran in statin intolerant patients. Two large RCTs of ASCVD outcomes with inclisiran – namely ORION-4 (NCT03705234) and VICTORION-2P (NCT05030428) – are underway and should be completed in 2025 and 2027, respectively. The drug appears to be well tolerated and effective but it is costly and requires parenteral administration in a health-care setting by a health-care provider, which may present as barriers to an already overburdened health-care system. Inclisiran is approved in the United Kingdom and North America for patients with familial hypercholesterolemia with varying approval conditions for statin intolerance.
Clinical pharmacology of siRNA therapeutics: current status and future prospects
Published in Expert Review of Clinical Pharmacology, 2022
Ahmed Khaled Abosalha, Jacqueline Boyajian, Waqar Ahmad, Paromita Islam, Merry Ghebretatios, Sabrina Schaly, Rahul Thareja, Karan Arora, Satya Prakash
Since its discovery in the late twentieth century by American pioneers, Andrew Fire and Craig Mello, RNA interference (RNAi) has revolutionized the medical and pharmaceutical fields drastically [1]. Its use became widespread as researchers around the world from numerous institutions began employing RNAi as a silencer for a wide variety of genes for the management of several related diseases. RNAi involves the utilization of 21–25-nucleotide, double-stranded RNA molecule known as ‘siRNA’ to regulate the post-transcriptional expression of the mRNA of the targeted gene. The siRNA is composed of two strands: a passenger strand (i.e. sense) and a guide strand (i.e. antisense) that is complementary to the mRNA of the gene of interest [2,3]. The siRNA with the aid of a multiprotein complex known as RNA-Induced Silencing Complex (RISC) recognizes the targeted mRNA and destroys it into nonfunctional moieties [4–6]. Despite the prominent mechanism of gene silencing via siRNA and its consistency for each target gene, only four siRNA products have been approved by FDA for human use. Patisiran was the first FDA-approved siRNA in 2018 [7], followed by the approval of Givosiran in 2019 [8] and Lumasiran as the third (2020) accredited siRNA [9]. Recently, Inclisiran has been approved for the treatment of hypercholesterolemia. The limited number of currently authorized formulations may be attributed to the difficulty of synthesizing a controlled drug delivery system that can carry siRNA safely and efficiently to the desired tissue while using a suitable concentration for a reproducible therapeutic effect.
Homozygous familial hypercholesterolemia and its treatment by inclisiran
Published in Expert Opinion on Orphan Drugs, 2020
A David Marais, Dirk J Blom, Frederick J Raal
It is clear that the reduction of the activity of PCSK9 by any means will favor LDL receptor recycling and lower LDL concentration. The differences between the approaches of suppression of synthesis and neutralization of secreted PCSK9 by monoclonal antibodies (alirocumab, evolocumab) were recently contrasted [58]. While both strategies require subcutaneous injection, the intervals between injections that will obtain effective control with monoclonal antibodies are 2 to 4 weekly while for inclisiran they are 3 to 6 monthly. It should be noted that inclisiran will result in the diminished intracellular effects of PCSK9 in the hepatocyte but the importance of this intracellular processing of the LDL receptor remains to be established. Initially, the plasma may contain more (bound) PCSK9 when neutralizing antibodies are injected while the administration of inclisiran results in very low concentrations of PCSK9 ab initio.