Ionis’ antisense oligonucleotide technology forms the backbone of three drugs to treat rare diseases. Now, the company is applying the technology to the blood cancer multiple myeloma, and it has positive results in mouse models that it says support a recently launched phase 1 trial.
Antisense oligonucleotides are specially engineered pieces of DNA that bind to messenger RNAs (mRNAs) to silence particular genes and stop the production of disease-causing proteins. In the case of multiple myeloma, that gene is IRF4, which promotes the growth and proliferation of the cancer cells.
Ionis teamed up with researchers at the University of California, San Diego (UCSD), to inhibit IRF4 using an antisense oligonucleotide. In mouse models of multiple myeloma, the drug, called ION251, significantly cut levels of multiple myeloma cells and enhanced survival, the researchers reported in the journal Cell Stem Cell.
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There are many effective treatments for multiple myeloma, but patients often become resistant to them, because self-renewing stem cells that are difficult to eradicate drive the disease. IRF4 allows those stem cells and tumor cells to thrive—a phenomenon that inspired the creation of ION251.
The UCSD and Ionis researchers tested the antisense drug for six weeks in the mouse models of multiple myeloma, administering one dose per day for a week, followed by three doses per week. More than 70% of the treated mice survived the cancer, while none of the animals in the control group lived, the team reported. In the treated mice, “we couldn't find any myeloma cells left for us to study," said Leslie Crews, Ph.D., assistant professor in the department of regenerative medicine at UCSD, in a statement.
The researchers also studied cells from multiple myeloma patients and from healthy donors. ION251 eradicated multiple myeloma stem cells but left healthy blood cells alone, they said.
Several oncology research teams are exploring new methods for attacking multiple myeloma stem cells. A team at the University of Utah’s Huntsman Cancer Institute, for example, created a CAR-T treatment that targets CD229, which is prevalent on cancer stem cells, and reported promising preclinical data last year.
As for Ionis, it is applying its antisense oligonucleotide technology to several diseases. In 2018, it teamed up with AstraZeneca to develop antisense oligonucleotides for diabetes, building on an earlier partnership focused on metabolic, cardiovascular and renal diseases. Ionis is also developing antisense oligonucleotide drugs for neurological and lung diseases.
ION251 is one of several oncology drugs in Ionis’ pipeline. UCSD’s Moores Cancer Center and other research institutions are now recruiting patients for the phase 1 trial of ION251.