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• W1916502715 abstract "The targeted silencing of protein expression by interfering with the degradation of specific coding mRNA sequences is an emerging mechanism of action for therapeutics. The two most common “classes” of mRNA silencing agents are the antisense oligonucleotides (ASOs) and short-interfering RNA (siRNA) therapeutics. Although these therapeutic strategies have slightly different mechanisms, each can achieve the same outcome of decreasing target protein expression. Research in the late 70s by Zamecnik and Stephenson1 studying respiratory syncytial virus, suggested that ASOs could be utilized as an antiviral treatment. This research was the basis for the evaluation of these agents as a potential new class of drugs. ASOs developed for clinical use are generally composed of up to ∼ 30 nucleotides of DNA and/or RNA in a single-strand and are chemically modified (eg. phosphorothioates) to prevent degradation from endogenous nucleases. The standard route of non-local administration for an ASO is by subcutaneous (SC) injection. Absorption into the intracellular compartment of target cells is thought to occur by endocytosis. Intracellularly, ASOs can silence target protein expression via various mechanisms that are structurally dependent. One common intracellular mechanism for the marketing approved generation of ASOs is via the enzyme RNase H. Once inside the cell, therapeutic ASOs bind their complementary mRNA within the nucleus. This double-stranded DNA-mRNA or RNA-mRNA hybridization renders the RNA strand(s) within the duplex amenable to degradation by RNase H. Target protein expression is then decreased due to lack of translation from mRNA. Current FDA approved ASO therapeutics include fomivirsen (Vitravene) for cytomegalovirus retinitis, and mipomersen (Kynamro) for homozygous familial hypercholesterolemia. In addition to these agents, there are a number of ASOs in development for ocular, cardiovascular, metabolic, inflammatory, oncologic and rare disease indications. In contrast to the single-stranded ASOs, siRNAs are composed of double-stranded (ds) RNA of up to ∼25 nucleotides per sense and antisense, including a 2 nucleotide overhang on one of the strands to facilitate activity. In some cases, a few DNA nucleotides may be added, but the primary makeup of the duplex is typically RNA. The site of action of siRNAs is within the cytoplasm and does not include a nuclear mechanistic component as utilized by ASOs. The seminal work that led to identification of the process underlying the mechanism of siRNA agents, and ultimately the awarding of a Nobel Prize, was published in 1998 by Andrew Fire and Craig Mello. Fire and Mello's work described the injection of dsRNA into Caenorhabditis elegans leading to a degradation of sequence-specific mRNA that was located in the cytoplasm2. This work in nematodes was then followed by similar findings in a mammalian system3. Delivery of the siRNAs is most commonly via two general mechanisms, lipid-based formulations that are administered intravenously (IV) or via conjugation to a molecule that targets the siRNA to the specific cell type expressing the protein of interest. Conjugated siRNAs can be administered SC, an advantage for certain indications. Local administration can also be achieved such as for ocular indications. Once available systemically, siRNA gains access to cells via fusing with the cell membrane or via endocytosis, depending on the delivery mechanism. Intracellularly siRNA is loaded into the RNAi-induced silencing complex (RISC) and the sense strand is cleaved by a protein, Argonaute 2 (AGO2), within the complex, leaving the antisense strand available for hybridization to the complimentary target mRNA. Once the target mRNA binds the antisense strand within RISC, the target mRNA is then cleaved by AGO2 thereby preventing the translation of the target protein. As of the preparation of this article, no siRNAs have been approved by the FDA or EMA. Several biopharmaceutical companies have siRNAs in late stage development covering various therapeutic areas such as cardiovascular/metabolic, infectious disease, oncology and rare diseases. In the development of small molecule and large molecule biologics such as antibodies, it is the role of the Clinical Pharmacologist to characterize the human ADME properties. Current FDA guidance documents exist in the small molecule and the biologics space, clarifying the types of in vitro and in vivo ADME assessments necessary to understand the human disposition of these classes of agents. Within the nucleic acid therapeutics field, the path is not as clear at this point in time. Scientific reasoning to guide the path forward is paramount; unfortunately with lack of regulatory guidances, this approach on its own could be associated with high risk if it is in contrast to the opinion of health authorities. When considering biotransformation, ASOs and siRNAs are metabolized via endogenous nuclease digestion; CYP and UGT mediated pathways have not been found to be relevant for their metabolism4. Standard pharmacokinetic drug-drug interactions (DDIs) whereby the metabolism of ASOs and siRNAs could be influenced by CYPs or UGTs, is not of concern based on current data5. In terms of perpetrating a DDI via inhibition or induction of these metabolic routes, there is similar low likelihood of an interaction and no currently published data suggests such liability. In addition to in vitro metabolism studies, evaluation of clinical DDIs involving healthy volunteers has also been completed for mipomersen4; there were no clinically meaningful findings from these DDI studies. Although DDIs at the pharmacokinetic level involving standard drug metabolizing enzymes are unlikely, pharmacodynamic interactions must still be considered if the ASO or siRNA mechanistically may directly or indirectly impact the activity of drug metabolizing enzymes. Another area of consideration are QT studies and their applicability to nucleic acid therapies. A review of mipomersen prescribing information and published literature indicate a QT study was conducted in 60 healthy volunteers and showed no exposure related impact of mipomersen on the QTc interval6. Historically, the E14 guidance7 was developed primarily for small molecule therapeutics following the identification of drugs such as terfenadine that prolonged the QT interval triggering torsades de pointes and possible sudden death. The E14 guidance was a mechanism to help rule out drug-induced QT prolongation. While efforts are underway by various working groups to evaluate the appropriate battery of assessments needed to characterize the cardiac safety of drugs, a key question is what is the applicability of QT studies for nucleic acid therapeutics. The DDI and QTc study examples are not the only clinical pharmacology questions unique for nucleic acid therapies. What about characterizing mass balance? Is this necessary for nucleic acid therapies? If so, how should such molecules be radiolabeled, especially those that are double-stranded? Are preclinical studies sufficient? This just highlights some of the other questions that come to mind. In characterizing the ADME properties across a wide variety of drug molecule types, one size does not fit all. In clinical research we need to balance out the question we are addressing with the potential safety risks associated with exposing healthy volunteer subjects and/or patients. Unnecessary exposure of healthy volunteers or patients just to “check a box” is not the ethical or justified. Safety is of foremost importance in drug development. Valid scientific rationale needs to factor into the development of these new agents. Existing guidances focus heavily on small molecules – for good reason – and are not always applicable, and in some cases frankly vague when biologic therapies are mentioned. Biologic therapies in and of themselves vary greatly. From small peptides to larger antibody molecules, there is no one size that fits all. There are also significant economic costs to non-focused “check a box” development strategies. A recent study by the Tufts Center for the Study of Drug Development noted that the cost of developing a drug from R&D through marketing approval is approximately $2,558M8. In order for new innovative therapies to be developed for patients in need, these development costs are passed along in pricing of medicines and ultimately, overall expense of health care. Streamlining the questions that truly need to be addressed will impact the economics. All of us in industry, academics and government agencies, need to continue to collaborate closely, have discussion forums and dialog so that we can efficiently deliver new therapies to the many patients who count on all of us each day. Monette M. Cotreau Waltham, MA" @default.
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• W1916502715 date "2015-09-01" @default.
• W1916502715 modified "2023-10-17" @default.
• W1916502715 title "Developing antisense oligonucleotide and short-interfering RNA therapeutics - a few considerations" @default.
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