Testing set for AX-0810 in biliary atresia, cholestatic liver diseases
Therapy would reduce buildup of bile by suppressing NTCP production
AX-0810, an experimental therapy for biliary atresia and other cholestatic diseases, is expected to enter clinical testing by early next year, according to developer ProQR Therapeutics.
“As we progress our [preclinical studies to support applications for permission to start testing in people], we plan to announce translational data and more about our clinical plans for AX-0810 in the second half of the year,” Daniel A. de Boer, founder and CEO of ProQR, said in a company press release.
Cholestatic diseases are a group of disorders marked by cholestasis, or slowed or stalled bile flow. Bile is a digestive fluid that’s normally made in the liver and then shipped out to the intestines through a series of tubes called bile ducts.
When bile cannot flow properly, it builds up in the liver and spills out into the bloodstream, which results in symptoms like itching and jaundice, that is, yellowing skin and whites of the eyes. Without treatment, liver damage resulting from bile buildup can progress to liver failure or cancer. A transplant is the only therapeutic option for liver failure.
AX-0810 would treat two cholestatic disorders for which there are no approved therapies. One is biliary atresia, a rare condition that affects infants where cholestasis is caused by blocked or missing bile ducts. The other is primary sclerosing cholangitis (PSC), a chronic disorder typically diagnosed in adulthood where cholestasis results from bile duct inflammation.
The experimental therapy is intended to reduce bile buildup by suppressing the production of NTCP, a protein involved in the reuptake of bile acids coming from the intestines back to the liver for recycling.
How does AX-0810 work in cholestasis?
AX-0810 introduces a modification in the messenger RNA (mRNA) molecule of SCL10A1, the gene that codes for NTCP, to prevent the reuptake of bile acids.
mRNA is the intermediate molecule derived from DNA that guides protein production. By tweaking the code of SCL10A1’s mRNA, the therapy should suppress bile acid uptake in the liver, lowering the buildup in the liver that drives cholestatic diseases.
AX-0810 was designed using ProQR’s proprietary next-generation RNA technology called Axiomer. It involves designing RNA oligonucleotides, or small RNA molecules that target specific RNA or DNA molecules, that are modified to attract a natural RNA-editing machinery, called adenosine deaminase acting on RNA, or ADAR.
This way, the newly developed editing oligonucleotides (EONs) can promote a change in the building blocks of the target mRNA molecule that can either boost or suppress the resulting protein’s production.
Earlier this year at the annual meeting of the American Society of Cell and Gene Therapy (ASGCT), ProQR presented proof-of-concept data from this editing strategy in lab models that included nonhuman primates.
Editing SCL10A1’s mRNA with an AX-0810-like EON led to an eightfold increase in blood levels of bile salts within 72 hours, indicating an effective suppression of bile acid uptake in the liver.
Between April and June, “we took important steps toward advancing our first editing oligonucleotide programs to clinical stage, with AX-0810 targeting NTCP for cholestatic diseases,” de Boer said. “We were excited to share data at ASGCT in May, demonstrating in vivo [in living animals] proof of target engagement with meaningful changes in disease-relevant biomarkers in nonhuman primates for our NTCP program.”
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