The drug, ISIS 369645, is a second-generation antisense inhibitor of the alpha subunit of the interleukin 4 receptor, (IL4R-alpha). Inhibiting the production of the IL4R-alpha inhibits the activity of two important cytokines in asthma, IL4 and IL13 that regulate inflammation, mucus overproduction and airway hyperresponsiveness.
"ISIS 369645 is the first drug from our new lung-directed inflammation program to enter development and shows how rapidly antisense technology enables the screening, validation and prioritisation of gene targets and pre-clinical profiling of potential drug candidates," said C. Frank Bennett, Isis' vice president of antisense research.
"Inhaled antisense has the potential to provide highly specific, potent and effective therapies for the treatment of asthma and other chronic pulmonary inflammatory diseases with the convenience of weekly administration," he added.
Isis has created a significant data portfolio to support ISIS 369645 as an attractive local treatment for asthma in pre-clinical studies.
Isis has shown that a mouse-optimised antisense inhibitor of IL4R-alpha potently reduces IL4R-alpha: mRNA and protein levels as well as reduce lung cytokine production and inflammation, and airway hyperresponsiveness in mouse models of asthma.
Isis have also shown that when ISIS 369645 is delivered by inhalation it is rapidly distributed to the airways achieving therapeutic drug concentrations in multiple cell types with little systemic exposure.
Isis 369645 is one of numerous drug candidates Isis is examining to target inflammatory diseases of the lung and the first to enter clinical development. The attractive profile of these second-generation antisense drugs highlights the possibilities this technology has on future drug development.
Antisense technology is a drug-discovery and development platform that involves design and use of synthetic oligonucleotides complementary to a target mRNA to inhibit production of specific disease-causing proteins. Virtually all diseases are associated with inadequate or over-production of proteins.
Traditional small molecule drugs are designed to interact with disease-causing proteins and inhibit their function. In contrast, antisense technology permits design of drugs, called antisense oligonucleotides, which intervene at the genetic level and inhibit the production of disease-associated proteins. Antisense oligonucleotide agents are developed based on genetic information.
A number of pharmaceutical and biotech companies are actively involved in second-generation antisense compound research, which have exhibited the desirable characteristics in comparison with first-generation antisense compounds.
These include fewer side effects, greater stability in the body, enabling patients to take doses less frequently, greater potency, permitting patients to take lower doses as well as greater potential for multiple routes of administration, including by injection, orally or topically.
US biotechnology company, Hybridon, have a number of antisense compounds in its pipeline, also used to treat various forms of cancer.
GEM231 is a 2nd generation antisense compound for treating solid tumor cancers. GEM231 is designed to inhibit the regulatory subunit R1alpha of Protein Kinase A, or PKA, which has been shown to be present at increased levels in the cells of many human cancers. GEM231 has been shown to have preclinical anti-tumour activity in models of various types of cancer, alone and in combination with various agents.
GEM240 is a 2nd generation antisense compound designed to inhibit mdm2. Mdm2 is a protein found in increased levels in many human cancers. Mdm2 binds to tumour suppressor protein p53, which results in reduced suppression of tumour cells by p53 and thereby contributes to the growth of cancer cells.
In animal studies, GEM240 has been shown to decrease levels of mdm2 in many types of cancer cells, including colon cancer cells, breast cancer cells and brain cancer cells, and to stabilize p53 levels in these cells.
Asthma is now one of the world's most common long-term conditions, affecting as many as 300 million people worldwide. This number could increase by a further 150 million by 2025, according to the World Health Organisation (WHO).
According to Datamonitor, the world market for asthma/COPD drugs is valued at $13.3 billion (€10.3 billion) in 2003, forecast to grow to $19 billion (€14.7 billion) by 2009. Such is the pace of the market and the rising incidences in children, annual growth rates of 10-15 per cent have been reported.