Severe asthma therapy

We are seeking partners to accelerate the development of the therapy for steroid-resistant asthma through licensing or direct investment.


Key Takeaways

  • Treatment for severe, steroid-resistant asthma, which enhances steroid activity by selectively inhibiting signaling pathways downstream of TGFẞ.
  • Up to 10% of asthma patients are resistant to inhaled corticosteroids. New drugs to control corticosteroid-resistant severe asthma is a major priority.
  • Target validation has been achieved with known compound PF670462 which enhances steroid activity without evidence of autoimmune or cardiac toxicities.

Mild to moderate asthma is usually well-controlled with inhaled corticosteroids in combination with long-acting ẞ2-adrenoceptor agonists. These drugs are insufficiently effective in the 5 to 10 percent of patients with severe steroid-resistant asthma. These patients have more frequent loss of asthma control called exacerbations, often triggered by viral infection and exposure to allergens, while being treated with current therapy. This inadequate response leads to greater likelihood of hospitalisation, and reduced quality of life, and can be fatal.


To date, the development of effective treatments for this patient population has been largely unsuccessful. Anti-cytokine biological therapies have been developed as supplements to inhaled corticosteroids. However these are expensive and only have modest efficacy on exacerbations in a subset of patients with steroid-resistant asthma.


The development of drugs to treat steroid-resistant asthma is a major priority.

University of Melbourne researchers, led by Professor Alastair Stewart, have found that TGFẞ induces corticosteroid resistance in airway epithelial cells. They also found that isoforms (ε and ẟ) of the regulatory protein casein kinase 1 (CK1) are involved in the actions of TGFẞ.


Global inhibition of TGẞ is not considered safe for chronic disease: TGFẞ is essential for normal cell function, and completely blocking it is likely to result in severe autoimmune and cardiac toxicity. Targeting the casein kinase pathway would avoid these toxicities.


Further exploration with small molecule inhibitors of CK1 ẟ/ε demonstrated that these kinases mediate TGFẞ-induced fibrogenesis and corticosteroid resistance. This was also demonstrated with siRNA against CK1 ẟ/ε. This mechanism for selectively modulating TGFẞ activity provides an opportunity to develop an inhalation treatment for severe asthma.

Target validation has been achieved with known inhibitor of CK1, PF670462. PF670462 has been shown to prevent TGFẞ-induced steroid insensitivity, and reduce TGFẞ-induced expression of fibrogenic genes, in airway epithelial cells in vitro.


Efficacy has also been established in mouse models. PF670462 has been shown to reduce virally-induced inflammation, and lung damage, and restore steroid activity in virally infected allergen-challenged mice.


These findings are the basis of a patent application which claims a method of treating, or preventing, respiratory diseases by administration of a casein kinase 1 inhibitor.

Find out more

Key Contact
Katrina Sorocos
Email
katrina.sorocos@unimelb.edu.au
Phone
+61 3 8344 1919