Manufacturing and administration
How are siRNA therapies manufactured? How stable is the finished dosage form?
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.
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.
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.
How often are the therapies administered? Can a patient take the drug at home or is it administered as an outpatient procedure?
The administration frequency depends on the clinical indication and dosing requirements. This could range from once-monthly
to bimonthly administration regimens.
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
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.