mepolizumab, reslizumab, lebrikizumab, tralokinumab, dupilumab

The UMABS have arrived!

IMG_0184

There is a group of new medicines hitting the market that may help patients with EGPA / CSS.  Since Asthma is such a large component in many patients with CSS these are mostly targeted at the asthma market.

These are various targeted biologic therapies that are currently in late-stage development for asthma, including GlaxoSmithKline’s Nucala (mepolizumab),  ( Teva’s Cinquil (reslizumab), Roche’s lebrikizumab, AstraZeneca’s tralokinumab, and Sanofi and Regeneron’s dupilumab.

Most of the new drugs in the asthma pipeline are interleukin inhibitors targeting inflammatory pathways.  Interleukin inhibitors are immunosuppressive agents which inhibit the action of interleukins. Interleukins are a group of cytokines which are synthesized by lymphocytes, monocytes, macrophages, and certain other cells. They function especially in regulation of the immune system.

I have attempted to gather information here about these new medicines and given links to find out more information.  I have Churg Strauss Syndrome (CSS) which has been renamed eosinophilic granulomatosis with polyangiitis (EGPA).   I live in  the USA, so my research is pertaining to the US market and focusing on CSS/EGPA.  A google search could give you more information pertaining to your country.  I do not work for these drug companies, nor am I in the medical profession.  I am a patient, a researcher and a life long teacher.

Mepolizumab under brand name Nucala in the USA

Nucalaapproved by FDA in November of 2015

Description:

Mepolizumab is a humanized IL-5 antagonist monoclonal antibody. Mepolizumab is produced by recombinant DNA technology in Chinese hamster ovary cells.

US- FDA-Approved Indications:

NUCALA is an interleukin-5 antagonist monoclonal antibody (IgG1 kappa) indicated for add-on maintenance treatment of patients with severe asthma aged 12 years and older, and with an eosinophilic phenotype.

Mepolizumab is an interleukin-5 antagonist (IgG1 kappa). IL-5 is the major cytokine responsible for the growth and differentiation, recruitment, activation, and survival of eosinophils.  Mepolizumab binds to IL-5 with a dissociation constant of 100 pM, inhibiting the bioactivity of IL-5 by blocking its binding to the alpha chain of the IL-5 receptor complex expressed on the eosinophil cell surface. Inflammation is an important component in the pathogenesis of asthma. Multiple cell types (e.g. , mast cells, eosinophils, neutrophils, macrophages, lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, cytokines) are involved in inflammation. Mepolizumab, by inhibiting IL-5 signaling, reduces the production and survival of eosinophils ; however, the mechanism of mepolizumab action in asthma has not been definitively established.

This is where it can help CSS patients.  If your asthma is the eosinophilic phenotype then Mepolizumab can lower the EOS in your airway which can lead to better asthma control.   This is not to be confused with Xolair which works on IGE / allergic type asthma by lowering the IGE level in patients.  Also note how it states “add-on” not replacement.

Dosage and Administration:

Nucala is given subcutaneously, 100mg administered once every 4 weeks under a doctors supervision.

At this time Mepolizumab is considered investigational and not medically necessary for all other conditions, including but not limited to:

  • aspirin-exacerbated respiratory disease (AERD)
  • atopic dermatitis
  • eosinophilic esophagitis
  • eosinophilic granulomatosis with polyangiitis (EGPA) (Churg-Strauss syndrome)
  • nasal polyposis
  • hypereosinophilic syndromes (other than severe eosinophilic asthma)

At this time (5/11/2016) this is a kinda grey area for CSS patients.   You can in the USA get insurance approval for Mepolizumab for your EOS type asthma but NOT for CSS.  SO, usually you can (if you qualify) receive this medicine through your asthma or pulmonary doctor.

Now there are current studies going on using Mepolizumab at a dose of 300mg, every 4 weeks.  The study is due to conclude in August of 2016 then we can all await the results and see if Mepolizumab will be allowed at a higher dose for CSS patients.

Early, very non scientific, reports of CSS patients with the EOS type asthma using Mepolizumab has been very positive.  I can say that I have been able to lower my prednisone and am now off all asthma inhalers after just 4 months of Nucala / Mepolizumab.  Others have has similar results, although once your prednisone is lowered other CSS symptoms may become more prominent and this is why this is an add on medicine at the current 100mg dosage and not a total replacement medicine (in my opinion).   There are side effects, as in most of our immune suppressing medicines and it is up to the patient to really investigate these before making medicine choices.

Reslizumab under the name Cinqair

CINQAIR®

logoNOW APPROVED for use in the USA 4/26/2016.

CINQAIR® is a new anti-interleukin-5 approved as an add-on treatment for adults (18 years and older) with severe asthma and elevated eosinophil levels.

CINQAIR (reslizumab) is a humanized interleukin-5 antagonist monoclonal antibody (IgG4k).  Reslizumab is produced by recombinant DNA technology in murine myeloma non-secreting 0 (NS0) cells.

Reslizumab is an interleukin-5 antagonist (IgG4, kappa). IL-5 is the major cytokine responsible for the growth and differentiation, recruitment, activation, and survival of eosinophils. Reslizumab binds to IL-5 with a dissociation constant of 81 pM, inhibiting the bioactivity of IL-5 by blocking its binding to the alpha chain of the IL-5 receptor complex expressed on the eosinophil surface. Inflammation is an important component in the pathogenesis of asthma. Multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, cytokines) are involved in inflammation. Reslizumab, by inhibiting IL-5 signaling, reduces the production and survival of eosinophils; however,the mechanism of reslizumab action in asthma has not been definitively established.

INDICATIONS AND USAGE

CINQAIR is an interleukin-5 antagonist monoclonal antibody (IgG4 kappa) indicated for add-on maintenance treatment of patients with severe asthma aged 18 years and older, and with an eosinophilic phenotype (1).

Limitations of Use: CINQAIR is not indicated for:

• treatment of other eosinophilic conditions

• relief of acute bronchospasm or status asthmaticus

DOSAGE AND ADMINISTRATION

•  intravenous infusion only.

• Should be administered in a healthcare setting by a healthcare professional prepared to manage anaphylaxis

• Recommended dosage regimen is 3 mg/kg once every 4 weeks by intravenous infusion over 20-50 minutes

Reslizumab is also indicated for an add on in Eosinophilic Asthma so that is where CSS/EGPA patients can benefit from it.  Patients are just beginning to receive this medication in the USA so I do not have any patient remarks on it yet.

Lebrikizumab

being studies by Rorche and GeneTech not FDA approved in Phase III clinical trials

Lebrikizumab is a humanised monoclonal antibody designed to specifically block the action of interleukin-13. Roche is also conducting clinical studies of the injectable therapy in chronic obstructive pulmonary disease, atopic dermatitis and idiopathic pulmonary fibrosis.

About Lebrikizumab

Lebrikizumab is a novel humanized monoclonal antibody designed to specifically block the action of interleukin-13 (IL-13), a cytokine that is a key contributor to airway inflammation and asthma disease processes in some people. Clinical studies in asthma, chronic obstructive pulmonary disease (COPD), atopic dermatitis (AD) and idiopathic pulmonary fibrosis (IPF) are ongoing.

About Eosinophils

Eosinophils are inflammatory cells that can be present in increased numbers in the airways and blood of people with asthma (eosinophilia). Airway eosinophilia has been associated with key features of asthma. IL-13 plays an important role in attracting eosinophils from the blood to the airway, hence contributing to airway eosinophilia.

About Periostin

Periostin is a protein that has been identified as a key biomarker of inflammation in certain types of asthma. Its presence can be measured with a blood test. In people with asthma who have high levels of serum periostin, IL-13 appears to be a major contributor to their airway inflammation. An elevated serum periostin level has also been shown to be a predictor of airway eosinophilia, a prominent feature of asthma.

In February 2016 Roche reports mixed Phase III data for lebrikizumab in severe asthma.

Do your research on this one.  I am not finding a proposed marketing name in the US and the drug trials have very mixed reviews.  Interested to see how phase III trials go and what illnesses it is finally approved for.

Tralokinumab

being studied by AstraZeneca and Abbott

Interleukin (IL)-13 is a pleiotropic cytokine believed to be an important mediator in the development and maintenance of the human asthmatic phenotype through its role in key underlying mechanisms including inflammation , airway hyperresponsiveness (AHR) , fibrosis  and increased mucus production . Elevated IL-13 levels have been identified in the sputum of a proportion of subjects with asthma including those with severe disease treated with systemic corticosteroids.

Tralokinumab (CAT-354) is a human immunoglobulin (Ig)G4 monoclonal antibody which potently and specifically neutralises IL-13  and has been shown to inhibit a range of IL-13-mediated effects in pre-clinical studies. Tralokinumab is in clinical development for the treatment of asthma,

July 2015 — a study was done :

Efficacy and safety of tralokinumab in patients with severe uncontrolled asthma: a randomised, double-blind, placebo-controlled, phase 2b trial.   In this study it was found Tralokinumab does not significantly reduce asthma exacerbations.

This drug is still in the testing phases for asthma and other inflammatory illness.

 

Dupilumab

being developed by Regeneron and Sanofi

Dupilumab is a monoclonal antibody designed for the treatment of atopic diseases. It binds to the alpha subunit of the interleukin-4 receptor (IL-4Rα).[2] Through blockade of IL-4Rα, dupilumab modulates signaling of both the interleukin 4 and interleukin 13 pathway, which have been implicated in the pathophysiology of allergic disease, particularly asthma and atopic dermatitis.

Dupilumab is first systemic therapy to show positive Phase 3 results in patients with moderate-to-severe atopic dermatitis, a serious, chronic inflammatory skin disease marked by widespread rash, itching and associated psychosocial comorbidities.  U.S. regulatory submission for dupilumab planned for third quarter of 2016.

So, how does this drug enter the world of CSS you may be asking yourself.  Well, a clinical study was done, Effect of Subcutaneous Dupilumab on Nasal Polyp Burden in Patients With Chronic Sinusitis and Nasal Polyposis, which showed some positive results.  As we know many CSS/EGPA patients suffer from Nasal Polyps and Sinusitis.

In 2013 there was a study of  Dupilumab in Persistent Asthma with Elevated Eosinophil Levels with promising results.

My Conclusions on the UMABS:

I think there is great promise here to help alleviate some of the symptoms of CSS and I am very excited to see how much research is being done.  We as a CSS/EGPA community because of the rarity of our illness depend on drugs being marketing to other communities and then being studied and used off label for CSS/EGPA (this was true for Rituxan many years ago).  As always it is up to you as a patient to do your research before beginning any new drug therapy, each have their burden of side effects and as always insist on careful and continued monitoring while on and after any drug therapy.

 A really good follow-up article to read

Novel targeted therapies for eosinophilic disorders by Michael E. Wechsler, MD, MMSc, Patricia C. Fulkerson, MD, PhD, […], and Amy D. Klion, MD

From 2012 but a great Table graphic explaining Biological drugs in asthma treatment.

PDF links to handouts and prescription information (including known side effects):

Nucala

Cinqair

want to read more about CSS/EGPA?

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2 Responses to mepolizumab, reslizumab, lebrikizumab, tralokinumab, dupilumab

  1. John Pierce says:

    Exceptional piece Karen. I have been in both phase 1 (with Mike Wechsler) and phase 3 trials of mepolizumab and am currently receiving 300 mg subcu via a long term access trial subsequent to the P3 trial. I thought myself fairly well informed but the breadth of your study is enlightening.
    My personal experiance with mepolizumab has been very positive. I believe there was actually some positive immune system remodeling during the phase one trial that brought my life threatening intractable css into control. Now I’m much better with only occassional flares (none in 9 months) and hoping to taper from the last 8mg of prednisone. Just had my first 300 mg shots in april aften the Boston p3 trial.

    • karen in wonderland says:

      Thank you John. I am a quick study and I wanted to let CSS patients know that these medicines exist and may be helpful. Nucala has totally changed my life, my cough is gone and my nebulizer is packed away. It’s been wonderful to have the last three months off from all my airway issues due to CSS. I would very much like to try the 300mg shot because right now I am on Rituxan and know I can not be on both so we are keeping track of blood results and symptoms to see if I have to make a choice.

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