August 19, 2022

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New antibody drugs approved by FDA in 2021: Tezepelumab-ekko

New antibody drugs approved by FDA in 2021: Tezepelumab-ekko



 

New antibody drugs approved by FDA in 2021: Tezepelumab-ekko

 

Overview

On December 17, 2021, the US Food and Drug Administration ( FDA ) approved Tezepelumab-ekko ( trade name Tezspire ) for the first time as an additional maintenance therapy for the treatment of pediatric and adult patients with severe asthma ≥12 years of age .

Tezepelumab is a monoclonal antibody that targets thymic interstitial lymphopoietin ( TSLP ), which is an epithelial cytokine that plays a key role in asthma inflammation.

This approval is based on the efficacy and safety data of the pivotal Phase III NAVIGATOR trial. The recommended dose of Tezepelumab is 210 mg subcutaneously every 4 weeks.

 

In September 2018, the US FDA granted tezepelumab a breakthrough drug designation ( BTD ) for the treatment of severe asthma without eosinophilic phenotype .

It is worth mentioning that in the treatment of severe asthma, Tezspire is the only biological agent that has no phenotype ( such as eosinophils or allergies ) or biomarker restrictions.

Tezepelumab was jointly developed by Amgen and AstraZeneca.

 


Pharmacodynamics and pharmacokinetics

 

Tezepelumab is a monoclonal antibody blocker targeting the human IgG2 subtype of thymic interstitial lymphopoietin. It binds to human TSLP with a dissociation constant of 15.8 μM, and blocks its interaction with heterodimeric TSLP. 

TSLP is a cytokine mainly derived from epithelial cells and plays a key role in the inflammatory cascade of asthma.

 

Airway inflammation is an important part of the pathogenesis of asthma. Multiple cell types ( such as mast cells, eosinophils, neutrophils, macrophages, lymphocytes, ILC2 cells ) and mediators ( such as histamine, arachidonic acid, leukotrienes, cytokines ) are involved Airway inflammation.

Blocking TSLP with Tezepelumab can reduce inflammation-related biomarkers and cytokines, including blood eosinophils, airway submucosal eosinophils, IgE, FeNO, IL-5, and IL-13; however, Tezepelumab is The mechanism of action in asthma is not yet fully understood.

 

After a single subcutaneous administration in the dose range of 2.1 mg to 420 mg ( 0.01 to 2 times the recommended dose ), the pharmacokinetics of Tezepelumab is proportional to the dose.

With a dosing schedule of once every 4 weeks, Tezepelumab reached a stable state after 12 weeks, and the cumulative rate of Ctrough was 1.86 times.

 

After subcutaneous injection, the highest serum concentration is reached in about 3 to 10 days. According to population pharmacokinetic analysis, the absolute bioavailability is estimated to be about 77%.

There are no clinically relevant differences in the bioavailability of different injection sites ( abdomen, thigh or upper arm ).

The central and peripheral volumes of distribution of Tezepelumab are 3.9L and 2.2L, respectively. The estimated clearance rate is 0.17 L/d, and the elimination half-life is about 26 days.

 


Clinical Trials

 

The efficacy of TEZSPIRE was evaluated in two randomized, double-blind, parallel-group, placebo-controlled clinical trials ( NCT02054130 and NCT03347279 ) over a period of 52 weeks .

PATHWAY is a 52-week dose range escalation phase II clinical trial involving a total of 550 adult patients with severe asthma. NAVIGATOR is a phase III clinical trial involving 1061 patients with severe asthma.

 

The primary endpoint of PATHWAY and NAVIGATOR is the clinically significant rate of asthma exacerbation measured within 52 weeks, and clinically significant asthma exacerbation is defined as asthma exacerbation.

In PATHWAY and NAVIGATOR, compared with the placebo group, patients treated with TEZSPIRE had a significantly lower annualized rate of asthma exacerbation, and fewer exacerbations requiring emergency and/or hospitalization.

 

New antibody drugs approved by FDA in 2021: Tezepelumab-ekko

 

In NAVIGATOR, regardless of the baseline level of blood eosinophils or FeNO, patients treated with TEZSPIRE experienced less deterioration than patients treated with placebo. Similar results also appeared in PATHWAY.

 

New antibody drugs approved by FDA in 2021: Tezepelumab-ekko

 

In NAVIGATOR and PATHWAY, compared with placebo, patients treated with TEZSPIRE had a longer period of first deterioration.

 

New antibody drugs approved by FDA in 2021: Tezepelumab-ekko

 

The baseline change in forced expiratory volume in 1 second (FEV1) is the secondary endpoint of PATHWAY and NAVIGATOR.

Compared with placebo, in both trials, TEZSPIRE provided a clinically significant improvement in the mean change in FEV1 from baseline.

 

 

In NAVIGATOR, the improvement of FEV1 appeared as early as 2 weeks after the start of treatment and lasted until week 52.

 

 

The baseline changes of the Asthma Control Questionnaire 6 ( ACQ-6 ) and the standardized asthma quality of life questionnaire [ AQLQ(S)+12 ] for people 12 years and older are also secondary endpoints of NAVIGATOR and PATHWAY.

In both trials, patients treated with Tezepelumab showed more clinically significant improvements in ACQ-6 and AQLQ(S)+12 compared to placebo.

In NAVIGATOR, TEZSPIRE’s ACQ-6 response rate was 86%, placebo was 77% ( OR=1.99; 95% CI 1.43 , 2.76), TEZSPIRE’s AQLQ (S) +12 response rate was 78%, and placebo was 77% 72% ( OR=1.36; 95% CI 1.02, 1.8 2 ).

 


Adverse reactions

The most common (incidence ≥3% ) adverse reactions of Tezepelumab include pharyngitis, arthralgia, and back pain.

 


Immunogenicity

And the therapeutic protein as, Tezepelumab immunogenic. In NAVIGATOR and another clinical trial, a total of 601 patients underwent TIVDAK immunogenicity testing, and 29 patients ( 5% ) developed anti-antibodies.

Neutralizing anti-antibodies were detected in 1 patient.

 

 

References:

1. FDA Label for BLA 761244

2. clinicaltrials.gov

New antibody drugs approved by FDA in 2021: Tezepelumab-ekko

(source:internet, reference only)


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