EPM September/October 2020

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APIs/HPAPIs

How innovation in pharma is enabling RNA therapeutics’ rapid move to the clinic

Clinically significant

I Author: DANNY GALBRAITH - head of New Services and Technology Management at Merck KGaA, Darmstadt, Germany

nnovation in the biopharmaceutical industry has always been rapid; however, this pace is accelerating with the global call to action to develop therapies to prevent and treat Covid-19. As the industry continues to look to novel modalities as a solution to Covid-19 and other diseases, a new class of therapeutic molecule is capturing attention -- nucleic acid, particularly Ribonucleic Acid (RNA). These molecules have demonstrated several clinical mechanisms of action in the treatment of a multitude of illnesses. For example, anti-sense or interfering RNA therapies have been used in oncology treatment and the use of the RNA to act as a means of gene delivery is showing promise. First described in 1961, RNA is the least developed of the biologically active molecules as a therapeutic. Compared with DNA delivered gene vectors, RNA has the advantage of being biologically active in both dividing and non-dividing cells and as

such would be the preferred tool to deliver expression of gene encoding proteins. They also have the advantage of no “foreign” genetic materials such as promoters on many DNA vectors. These molecules can be surprisingly easy to manufacture. Producer cells are transfected with an appropriate plasmid DNA and RNA polymerase, and these drive the production of RNA. The purification of the RNA away from the other host and manufacturing materials requires multiple steps but fortunately requires little in the way of the development of novel technologies, allowing a faster path to the clinic. A significant downside to RNA molecules, however, is their fragility in biological systems. The largest challenge with these drugs is the delivery system to achieve adequate survival of the biologically active molecule to the cells where the gene transfer and expression can be delivered. Many innovative compounds are being developed to enable these therapies to move to the clinic safely. The pharmacokinetics of naked RNA is well understood. With a half-life of around seven hours, this type of molecule is rapidly degraded in the extracellular space by a variety of RNase mediated mechanisms. If the molecule survives to reach a cell it requires to translocate across the plasma membrane into the cytosol where the protein can be translated and initiate its therapeutic target. However, these naked RNA molecules are negatively charged and compose a high molecular weight; both characteristics mean that passive movement across the charged cell

membrane is incredibly low. For these reasons naked RNA is no longer considered an option for drug developers. To combat these challenges, two strategies are used to create RNA therapy and delivery systems for the clinic. Firstly, modifications of the RNA molecule can increase stability during transportation to the cell. These modifications have included changes to the 5’ cap and 5’ and 3’ UTR regions to enhance stability and modification of the Poly-A tail. These modifications can enhance the potency of the molecule as well as reducing degradation. However, modifications in the genomic construct alone are seldom enough to improve the pharmacokinetics of the drug. One of the more interesting approaches has been the use of


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