Developing siRNA Therapies: A Technical Forum - Pharmaceutical Technology

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Developing siRNA Therapies: A Technical Forum
Pharmaceutical Technology talked to experts in siRNA-drug development to gain insight into the characteristics, processes, and challenges of this class of therapeutics.

Pharmaceutical Technology
Volume 34, Issue 8, pp. 39-41

Manufacturing and administration

PharmTech: How are siRNA therapies manufactured? How stable is the finished dosage form?

Tracy (Alnylam): siRNAs are manufactured as the active pharmaceutical ingredient with standardized chemical synthetic procedures. LNP formulations are produced by mixing defined components of specific lipids and siRNAs to achieve a defined drug product. The final product is stable at refrigerated conditions (2 to 8 C) for up to two years or longer.

Houston (MDRNA): The drug product, which includes the delivery agents and the siRNA, is manufactured using an impinging stream process whereby the siRNA and delivery agents (DiLA2 and other components) are combined forming the initial particles. The intermediate product is incubated for a prescribed time under conditions that favor formation of highly active and physically stable liposomes. The formulations undergo filtration and concentration steps prior to sterile fill–finish steps. The formulation allows the drug product to be frozen and stored as a concentrate. Under these conditions, greater than one year stability at –20 C has been demonstrated.

Thompson (Quark): Quark's systemically administered drug is formulated at 25 mg/ml in phosphate-buffered saline. In this formulation the drug has exhibited excellent stability for three years at room temperature. Our siRNAs are very well behaved drugs in terms of manufacturing and stability. We're now extending our current stability studies beyond three years, because we haven't had an instance yet where we've fallen out of specification.

PharmTech: How often are the therapies administered? Can a patient take the drug at home or is it administered as an outpatient procedure?

Tracy (Alnylam): The administration frequency depends on the clinical indication and dosing requirements. This could range from once-monthly to bimonthly administration regimens.

Houston (MDRNA): The exact frequency for administration will depend on the indication. However, it is expected the administration schedules for oncology drug products will be similar to established regimens such as once every three weeks. Preclinical studies in models of liver and bladder cancer have confirmed that the inhibition of messenger RNA (mRNA) persists for at least two to three weeks after dose administration. For oncology indications we assume the dosing would be conducted within a clinical setting as expertise in intravenous (i.v.) (in the treatment of liver cancer, for example) or intravesicle (in the treatment of bladder cancer, for example) administration are needed, and drug administration will be a part of overall therapy and monitoring. It is possible that administration of this drug could take place in an outpatient situation because the patient would not be required to remain in the doctor's care after administration of the drug. Future drug products that allow for self-administration to treat indications other than oncology or maintenance therapies in which patients can be adequately trained are also under consideration.

Thompson (Quark): At the moment, all of our programs that are being evaluated at the clinic for siRNAs involve some sort of injection. We have two programs that target the eye because siRNAs can be administered locally through intravitreal administration, which is the standard of care for the diseases we're following such as macular degeneration. The local administration means we can put a large amount of siRNA in a small space that works for days and weeks, resulting in efficient uptake in the target cells. In our systemic program, because siRNAs naturally go to the kidney following i.v. administration, our initial clinical programs are focused on that region. When a nonformulated siRNA is administered into the bloodstream, the molecules do not bind to any plasma proteins. Because of that, they are very rapidly filtered by the kidney, and subsequently the drug is taken up by the kidney's proximal tubule cells.


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