Atopic dermatitis is a chronic rash characterized by inflammation and itching. The lifetime prevalence of atopic dermatitis is 10-20% in children and 1-3% in adults. Its prevalence has increased two- to threefold during the past three decades in industrialized countries.
Current mild to moderate atopic dermatitis treatments aim to reduce inflammation and itchiness. Combinations of antihistamines, topical corticosteroids and topical immunomodulators are the current standard of care. Corticosteroid therapy use requires caution, however, because prolonged use can cause skin atrophy and tachyphylaxis. The FDA has warned of lymphoma and other cancers associated with prolonged use of topical immunomodulators. Antihistamines do not treat the disease, but are only useful to dull the urge to scratch to relieve itching.
Recently, a clinical trial of dupilumab, a fully human monoclonal antibody that is directed against the shared alpha subunit of the IL-4 receptor and that blocks signaling from both IL-4 and IL-13, showed efficacy in moderate to severe atopic dermatitis. Dupilumab is now marketed in the United States for the treatment of moderate to severe atopic dermatitis.
We believe that an anti-IL-4RA SNA applied topically to the skin will reduce the levels of IL-4RA mRNA, and in turn IL-4RA protein, in the skin thereby preventing the inflammatory signaling through both IL-4 and IL-13. Late stage clinical trials with dupilumab have confirmed that inhibiting the function of IL-4RA leads to successful treatment of atopic dermatitis. We believe our approach of modulating IL-4RA specifically and locally will result in an improved safety profile versus topical antihistamines, corticosteroids and immunomodulators, as well as systemically administered antibodies.
Early development programs
In addition to our named pipeline programs, a variety of early stage research efforts are ongoing in areas we believe will best leverage the properties of the SNA. Potential applications of the SNA include those in neurology, ophthalmology, respiratory, and the gastrointestinal tract.
Despite delivery challenges, nucleic-acid based therapy has been successfully developed to treat a central nervous system, or CNS, disorder. Nusinersen, by Ionis Pharmaceuticals and Biogen Inc., was approved in late 2016 for the treatment of spinal muscular atrophy, or SMA, by the FDA. SMA is a genetic disorder characterized by progressive muscle wasting and loss of muscle function due to motor neuron dysfunction. SMA is characterized by reduced amount of survival of motor neuron 1, or SMN1, protein. The severity of the disease depends on the amount of a related protein, SMN2, where lesser quantities of SMN2 are correlated to more severe disease. SMN2 is similar to SMN1, but has a mutation that leads to production of truncated protein, which is normally rapidly degraded. Nusinersen is designed to mitigate the effects of this mutation by directing the production of a more stable variant of SMN2, increasing the level of SMN2 protein, and thus improving motor function. In clinical trials, SMA patients treated with nusinersen achieved and sustained meaningful improvement in motor function and survival compared to untreated patients.
To evaluate the superiority of the SNA over linear oligonucleotides in directing the production of the more stable variant of the SMN2 protein, we compared the effects of nusinersen in linear format to nusinersen in the SNA format in cells derived from SMA patients. The data demonstrate that treatment with the SNA format of nusinersen results in greater levels of the more stable full-length variant of the SMN2 mRNA and an attendant decrease in the less stable delta 7 variant of SMN2 mRNA. Importantly, the ratio of the full length to delta 7 variants is greater with the SNA format compared to the linear version of nusinersen. At the highest tested concentration, the ratio of the