Medicinal Chemistry

Our Chemistry Advances

Advancing antisense chemistry has been a central focus of our research efforts. Chemical modifications can improve a drug’s stability in the body, its ability to move into certain tissues and cells, its specificity and binding strength for its intended target, its side effect profile and its ability to be metabolized and eliminated from the body. Our scientists have made great advances in chemistries; building upon our first-generation technology to create antisense drugs with enhanced pharmaceutical properties, which we call our second-generation antisense drugs. We continue to advance the chemistry and design of our drugs.

Ionis’ First-generation Chemistry

Our first-generation chemistry solved many of the fundamental hurdles for creating oligonucleotide-based drugs and provided a foundation for the majority of our next-generation chemistries. First-generation antisense drugs have a sulfur chemistry modification, known as a phosphorothioate. This modification makes the drug more resistant to degradation, increases stability in the blood stream and in tissues and prevents rapid elimination of the drug from the body.  We have one first-generation drug in the pipeline, Alicaforsen.

Ionis’ Second-generation Chemistry
(called 2′-O-methoxyethyl or 2’MOE)

Our second-generation drugs incorporate our proprietary 2’-O-methoxyethyl (2’MOE) chemistry and makes the drugs RNA-like. Because RNA hybridizes more tightly to RNA than to DNA, the second-generation drugs have a greater affinity for their RNA targets and, therefore, greater potency. With increased potency, our second-generation drugs are active at lower doses, which decreases the overall cost of therapy.

Second-generation chemistry slows degradation of the drugs by protecting them from nucleases, the molecules responsible for disassembling strands of nucleotides. Slower clearance of the drug from the body allows for less frequent dosing. Our scientists continue to advance our technology and improve the properties of our drugs. Currently, clinicians are studying antisense drugs using many routes of delivery including enema, intrathecal, intravenous, subcutaneous, topical and intravitreal.

Ionis’ Second-generation Plus Chemistry
(called Generation 2+)

In the last few years we have made significant improvements in our drug discovery screening processes that have resulted in second-generation drugs with better drug properties.  We call these newer drugs our Generation 2+ drugs.  We have several Generation 2+ drugs in late-stage development, including volanesorsen and IONIS-FXIRx.  In clinical studies we have observed an increase in potency of approximately 2-fold in Generation 2+ drugs over our second-generation drugs.  In addition, we have observed lower incidences of injection-site reactions and flu-like symptoms compared to our second-generation drugs.

Ionis’ Generation 2.5 Chemistry
(called constrained ethyl or cET)

We have published data demonstrating that our Generation 2.5 drugs generally have enhanced potency over our Generation 2+ drugs and are broadly distributed throughout the body to multiple tissues including liver, kidney, lung, muscle, adipose, adrenal gland, peripheral nerves and tumor tissues. Our Generation 2.5 drugs constitute some of our recently added new drugs.  Antisense drugs that utilize Generation 2.5 chemistry are designed to provide up to a 10-fold increase in potency over Generation 2.0 drugs. In addition, Generation 2.5 chemistry expands the range of targets and tissues that are available to antisense therapy. The development of this new chemistry demonstrates Ionis’ commitment to the continued advancement of antisense chemistry to improve the potency and therapeutic index of antisense drugs. Currently, four drugs in our pipeline incorporate our Generation 2.5 chemistry. These drugs are IONIS-STAT3-2.5Rx, IONIS-AR-2.5Rx, IONIS-DMPK-2.5Rx and IONIS-RHO-2.5Rx.

Ionis’ LIgand-Conjugated Antisense (LICA) Technology

In addition to improving the chemical foundation of our drugs, we design our LICA technology to enhance the delivery of our drugs to particular tissues. This technology adds specific chemical structures or molecules, such as conjugates, onto antisense drugs to increase the efficiency of drug uptake in a particular tissue. We have demonstrated that our LICA technology can further enhance the potency of our drugs. For example, our LICA technology directed toward liver targets has produced a greater than thirty fold increase in potency in a Phase 1 study of IONIS-APO(a)-L Rx . We can combine our LICA technology with both our Generation 2+ and our Generation 2.5 drugs to increase the potency of these drugs. We designed these first LICA drugs to inhibit targets in the liver. We are also developing LICA conjugation technology that we can use to target other tissues. We expect that we can enhance some of our future drugs, including our Generation 2.5 drugs with our LICA technology.  Currently, we have eight LICA drugs in our pipeline. These drugs are IONIS-GHR-LRx, IONIS-AGT-LRx, IONIS-ANGPTL3-LRx, IONIS-APO(a)-LRx, IONIS-APOCIII-LRx, IONIS-TMPRSS6-LRx, IONIS-GSK4-LRx and IONIS-HBV-LRx. All of these drugs are designed to inhibit targets in the liver.