Study of TLR-9 Agonist for Treatment of Allergic Asthma Discontinued after Disappointing Results

There are 11 different toll-like receptors (TLRs) that have been identified in humans. Of these, TLRs 1, 4, 8 and 9 have been investigated as potential targets for treatment of allergic respiratory disease. TLR-9 agonists are the chief agents currently under investigation for the treatment of asthma and allergic rhinitis.

During a session at the 2014 American Thoracic Society International Conference during which he presented results from a study of an investigational agent that is thought to inhibit T-cell-mediated airway inflammation via activation of toll-like receptor 9, Thomas Casale, MD, Professor of Internal Medicine at Morsani College of Medicine, University of South Florida, said that stability has been a problem for TLR-9 agonists in previous studies. The current study involved CYT003, a novel, first-in-class immune modulator product encapsulated in a virus-like particle for delivery developed by Cytos Biotechnology Ltd.

Results of an earlier phase 2 study of CYT003 in patients with persistent allergic asthma controlled with inhaled corticosteroids (ICS) published in the Journal of Allergy and Clinical Immunology showed that patients treated with CYT003 achieved a 50% decrease in the use of ICS by four weeks, which later tapered off.

In the current study, 365 adults (ages 18 to 65 years) with persistent moderate to severe allergic asthma, of whom 100% were using ICS and 88% were being treated with long-acting beta-adrenoceptor agonist (LABA) therapy, were enrolled in a phase 2b trial that included three active treatment groups (approximately 30 patients per group) and a placebo control group (approximately 90 patients).

Participants had scores of 1.5 or higher on the 7-item Asthma Control Questionnaire (ACQ), FEV1 scores of greater than 40% but less than 90% of predicted value, reversible airway obstruction, and positive reactions to one or more aero-allergen.

The primary endpoint was asthma control as assessed by ACQ score. Study subjects received 7 doses of CYT003 (0.3 mg, 1 mg, or 2 mg) or placebo subcutaneously at baseline and at weeks 1, 2, 4, 6, 8, and 10. There was no treatment effect seen at 12 weeks.

Additional secondary endpoints such as lung function tests (including FEV1), ACQ response rates across time, and MiniAQLQ also showed no treatment effect at 12 weeks.

Consequently, the sponsor terminated the trial and discontinued development of CYT003 for asthma. However, safety analyses are continuing until the end of the originally scheduled 12-month study period.

Casale speculated on the possible reasons for the failure of the trial:

• This was a different patient population with more severe clinical parameters than in the earlier study.
• It may have had the wrong patient population with respect to Th2 phenotypes since the initial study showed better results with the Th2-hi phenotype.
• Is the therapy as ineffective as an add-on to ICS? Casale thought the answer is probably yes.
• Was the trial design inadequately powered for a double-blind, randomized clinical trial? The answer is probably no.

With this in mind, Casale also reviewed some of the problems common to new treatments for asthma and similar diseases, noting that asthma is a very complicated disease with a wide range of immunomodulators that are potential therapeutic targets.

He said clinical trials are hampered because there is no valid animal model for asthma. Significant efficacy shown by various experimental agents in the mouse model often does not carry over into human subjects. Researchers have also not yet established the optimally effective mode of delivery for asthma treatments.

One audience member asked if the wrong primary outcome was chosen and whether the study should have instead looked at exacerbations. The questioner also asked whether the study was continued long enough to show a treatment effect.

Casale replied that the study, having been terminated early, was probably too short to show any potential effect. It was designed to be a 1-year study, overall, with a blinded observation period of 9 months.