ASM8: Therapeutic Oligonucleotides
ASM8 blocks the expression of the receptors for cytokines IL-3, IL-5, and GM-CSF and CCR3 with a single drug product. The drug is composed of 1:1 mixture of two modified phophorothioate oligonucleotides. One 19-mer oligonucleotide blocks the mRNA for the c -subunit common to all 3 cytokines. The second 21-mer blocks the mRNA for CCR3 (Figure 2).
The synergistic effects of knocking down two major pathways with ASM8 has been demonstrated in in vitro studies using human cell lines and in cells obtained from monkeys and allergic humans. In vivo studies in animal models of asthma (brown Norway rats) demonstrated significant reduction in airway hyper reactivity and eosinophil recruitment after allergen challenge. Each oligonucleotide demonstrated efficacy alone, but the combination produced the best results, at lower doses in both models.
Corticosteroids are first-line therapy for patients with asthma. Steroids have systemic distribution and run the risk of side effects, especially with long-term use and high dosages. ASM8 has demonstrated <1% systemic distribution in rats, monkeys, and humans. In comparison to the corticosteroid, budesonide, the rat equivalent of ASM8 has shown better efficacy on eosinophilic inflammation, even when the steroid was administered at exponential higher doses. (Figure 3). The half-life of the oligonucleotides in the lungs and the length of efficacy of ASM8 make it a once-per-day product, which should increase patients' compliance with therapy.
ASM8 is delivered topically via a nebulizer and can also be delivered by inhalers. In validation studies, the nebulizer produced the correct particle size for good delivery into the lung tissue. Additionally, the stability of oligonucleotides in powder or in aqueous solutions makes them well-suited for the therapy of chronic respiratory diseases.
Phase I results demonstrated that ASM8 is well-tolerated in humans with no serious adverse events, no effects on respiratory symptoms, laboratory values, or pulmonary function. The plasma levels of ASM8 in the subjects indicated low systemic bioavailability, decreasing the risk of toxicity. Further, ASM8 was found in the sputum at 6 and 12 hours after administration, which confirms previous publications of persistence and metabolism of oligonucleotides within the lungs.