Dose-response effects of TPI ASM8 in asthmatics after allergen

Allergy. 2011 Sep;66(9):1242-8. doi: 10.1111/j.1398-9995.2011.02638.x. Epub 2011 May 24.


Background: TPI ASM8 contains two modified antisense oligonucleotides (AON) targeting the beta subunit (β(c) ) of the IL-3, IL-5, GM-CSF receptors and the chemokine receptor CCR3. A previous study suggested that TPI ASM8 had broader effects than just inhibition of eosinophils in asthmatics.

Objective: We assessed whether TPI ASM8 caused a dose-dependent attenuation in the inflammatory and physiological changes after inhaled allergen challenge (AIC).

Methods: This single-center, open-label, stepwise-ascending dose study was conducted in fourteen stable, mild allergic asthmatics. Following placebo AIC, subjects underwent AIC after 4 days treatment with 1, 2, and 4 mg BID and finally 8 mg once daily (OD) of TPI ASM8, inhaled via the I-Neb™ nebuliser. Treatments were separated by 2-3-week washout periods.

Results: TPI ASM8 was safe and well tolerated at all doses. TPI ASM8 8 mg OD reduced eosinophils in sputum after AIC (by 60.9% at 7 h and 68.4% at 24 h post-AIC, P=0.016 and P=0.007, respectively). Additionally, TPI ASM8 8 mg OD significantly attenuated the early and late airway responses as shown by the reduction in the area under the curve by 45% (P=0.016) and 59%, (P=0.0015), respectively, the increase in eosinophil cationic protein (ECP) by up to 57% (P=0.021), and airway responsiveness to methacholine by more than 1 doubling dose (P=0.012). A dose-response relationship was noted, and efficacy was maintained with once per day administration.

Conclusions: TPI ASM8 attenuated a broad range of inflammatory and physiological changes after AIC, suggesting that CCR3, IL-3, and GM-CSF also are important targets for the management of asthma.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Allergens / administration & dosage
  • Allergens / immunology*
  • Anti-Asthmatic Agents / administration & dosage
  • Anti-Asthmatic Agents / adverse effects
  • Anti-Asthmatic Agents / pharmacokinetics
  • Anti-Asthmatic Agents / therapeutic use*
  • Asthma / drug therapy*
  • Asthma / genetics
  • Asthma / immunology*
  • Cytokine Receptor Common beta Subunit / genetics
  • Dose-Response Relationship, Drug
  • Female
  • Gene Expression Regulation / drug effects
  • Humans
  • Male
  • Phosphorothioate Oligonucleotides / administration & dosage
  • Phosphorothioate Oligonucleotides / adverse effects
  • Phosphorothioate Oligonucleotides / pharmacokinetics
  • Phosphorothioate Oligonucleotides / therapeutic use*
  • RNA, Messenger / genetics
  • Receptors, CCR3 / genetics
  • Respiratory Hypersensitivity / drug therapy
  • Respiratory Hypersensitivity / immunology
  • Sputum / immunology
  • Young Adult


  • Allergens
  • Anti-Asthmatic Agents
  • CCR3 protein, human
  • Cytokine Receptor Common beta Subunit
  • Phosphorothioate Oligonucleotides
  • RNA, Messenger
  • Receptors, CCR3
  • TPI ASM8