Effects of an Anti-TSLP(Anti Thymic stromal lymphopoietinantibody) on Allergen-Induced Asthmatic Responses

DR JAWAD ALI

PGR MEDICINE KRL HOSPITAL ISLAMABAD

AMG157

MEPOLIZUMAB

INHALED

ANTI

SENSE

OLIGONUCLEOTIDE

BACKGROUND

Thymic stromal lymphopoietin (TSLP) is an epithelial-cell–derived protein belonging to cytokine family that is implicated in allergic inflammation.

It is known to play an important role in the maturation of T cell populations through activation of antigen presenting cells.

BACKGROUND

TSLP signals through a hetero dimeric receptor complex composed of the thymic stromal lymphopoietin receptor CRLF2 and the IL-7R alpha chain.

After binding STAT5 phosphorylation is induced resulting in the expression of upstream transcription factors

BACKGROUND

Levels of human TSLP messenger RNA and protein are increased in the airways of patients with asthma, as compared with controls, and the magnitude of this expression correlates with the severity of disease.

targeting TSLP may inhibit multiple biologic pathways involved in asthma.

AMG 157 is a human anti-TSLP monoclonal immunoglobulin G2λ that binds human TSLP and prevents receptor interaction.

METHODS

ELIGIBLE PATIENTS

nonsmoking men and women

18 to 60 years of age

(FEV1) of 70% or more of the predicted value

all patients had no other lung disease.

No asthma-controller treatments were allowed during the study although the use of inhaled short-acting β2-agonists as rescue treatment administered fewer than 2 days per week was permitted

All other asthma medications were discontinued at least 4 weeks before enrollment.

EXCLUSION CRITERIA Patients were excluded from the study

if they had worsening of asthma,

respiratory-related visits to the emergency department within 6 weeks before study enrollment,

previous use of AMG 157

known sensitivity to any AMG 157 excipients

STUDY DESIGN proof-of-concept,

Randomized double-blind

placebo-controlled study at five centers in Canada.

Patients were randomly assigned, in a 1:1 ratio, by means of an interactive voice-response system to receive 700 mg of AMG 157 or placebo in a 1-hour intravenous infusion on study days 1, 29, and 57

STUDY ENDPOINTS

The primary end point was the late asthmatic response, as measured 3 to 7 hours after the allergen challenge.

The primary outcome measures USED maximum percentage decrease in FEV1 and the area under the curve (AUC) of the time-adjusted percent decrease in FEV1.

STUDY ENDPOINTS The secondary end points were the late response,

as measured by the minimum FEV1 and

the AUC of the time-adjusted minimum FEV1;

the early asthmatic response, as measured within

2 hours after the allergen challenge; and the

safety, side-effect profile, and immunogenicity

of AMG 157

STUDY ENDPOINTS Exploratory end points included

levels of sputum and blood eosinophils

the fraction of exhaled nitric oxide

levels of type 2helper T (Th2) cells in the blood,

the ratio of Th2 cells to type 1 helper T (Th1) cells in theblood,

total IgE levels in blood, the provocative concentration of methacholine required to

reduce the FEV1 by 20% (methacholine PC20)

LABAROTORY PROCEDURES

The allergen for inhalation was selected on the basis of SKIN PRICK TESTING

early asthmatic response (0 to 2 hours after allergen challenge)

late asthmatic response (3 to 7 hours after allergen challenge).

Venous blood was sampled for determination of levels of leukocytes, total IgE, and cytokines, and airway eosinophils were sampled from induced sputum with the use of a standard method.

STATISTICAL ANALYSIS On the basis of evidence from previous studies

IT was determined that with 15 patients in each group, the study would have a power of 80% to detect an absolute between-group difference of 10 percentage points in the maximum percent decrease in the FEV1 during the late response.

Included In the analysis for each end point all patients who received at least one dose of AMG 157 or placebo.

RESULTS

STUDY POPULATION

From October 31, 2011, to April 5, 2013,

31 patients were enrolled (16 in the AMG-157 group and 15 in the placebo group).

All the patients received at least one dose of a study drug in accordance with the randomization schedule.

A total of 28 patients (90%) completed the full intervention period, and 27 (87%) completed the study

Of the 4 patients who did not complete the study, 3 were lost to follow-up

STUDY ENDPOINTS EARLY AND LATE ASTHMATIC RESPONSES

Treatment with AMG 157, as compared with placebo, partially attenuated both the late response early response at days 42 and 84.

The maximum percentage decrease in the FEV1 during the late response was 34.0% smaller in the AMG-157 group than in the placebo group

on day 42 (P = 0.09) and 45.9% smaller (a decrease of 11.7% vs. 21.6%) on day 84 (P = 0.02).

STUDY ENDPOINTS Patients in the AMG 157 ,COMPARED WITH THOSE

IN PLACEBO had a significant

increase in the minimum FEV1 (P = 0.01) and in the AUC of the time-adjusted minimum FEV1 (P = 0.02) during the late response on day 42 and in the minimum FEV1 (P = 0.01) on day 84.

BLOOD EOSINOPHILS

On day 29, the mean baseline blood eosinophil counts decreased from 296.5±40.2 TO 121.9±14.7 per cubic millimeter in theAMG-157 group

as compared with a decrease from 281.1±57.2 per cubic millimeter to 224.1±36.5 per cubic millimeter in the placebo group

Blood eosinophil counts increased on days 43 and 85, 1 day after the allergen challenges

the levels were significantly lower in the AMG 157 group than in the placebo group (P = 0.004).

ALLERGINAMG

157/PLACEBO

SPUTUM EOSINOPHILS

Treatment with AMG 157 decreased levels of sputum eosinophils before and after allergen challenge.

on day 83. As compared with placebo, AMG 157significantly reduced sputum eosinophil levels before allergen challenge over the course of the study (P = 0.02) and significantly attenuated allergen-induced changes 24 hours after challenge (P = 0.004).

ALLERGIN AMG 157/PLACEBO

EXHALED NITRIC OXIDE

The fraction of exhaled nitric oxide was elevated in the two study groups under baseline conditions.

treatment with AMG 157 significantly decreased the fraction of exhaled nitric oxide throughout the study (P= 0.002) and significantly attenuated allergen-induced changes 24 hours after challenge (P = 0.02)

ALLERGIN CHALLENGE

AMG157CHALLENGE/PLACEBO

ADVERSE EVENTS

Treatment with AMG 157 was not associated with changes in measured laboratory values, temperature, blood pressure, pulse, or respiration.

There were NO ADVERSE EVENTS OR DEATHS .

CONCLUSION All currently available asthma treatments attenuate

components of allergen-induced airway responses. However only inhaled glucocorticoids attenuate baseline airway levels of the fraction of exhaled nitric oxide and eosinophils.

This early proof-of-concept study indicates that targeting TSLP can reduce the fraction of exhaled nitric oxide and blood and airway eosinophils

CONCLUSION treatment for 12 weeks with AMG 157 reduced the

fraction of exhaled nitric oxide and blood and sputum eosinophils in patients with allergic asthma.

This treatment also attenuated allergen-induced changes in these inflammatory measures, as well as the early and late asthmatic responses.

These results support further work on mechanisms of action and investigation of the clinical benefit of AMG 157 in patients with poorly controlled asthma.