Omalizumab to Mepolizumab Switch Study in Severe Eosinophilic Asthma Patients

A Multi-centre, Open Label, Single Arm, 32-week Treatment Study in Subjects With Severe Eosinophilic Asthma Not Optimally Controlled With Current Omalizumab Treatment Who Are Switched From Omalizumab to Mepolizumab 100mg Subcutaneous (Study Number 204471- the OSMO Study)

Mepolizumab is an anti-interleukin-5 ( IL-5) monoclonal antibody that neutralizes IL-5 and reduces eosinophil counts in both sputum and blood. Omalizumab an anti-immunoglobulin E (IgE) monoclonal antibody (mAb) is effective in the treatment of moderate to severe allergic asthma. The aim of this study is to investigate whether subjects not optimally controlled on their current omalizumab treatment, who are eligible for therapy with mepolizumab can be effectively and safely switched to treatment with mepolizumab to improve asthma control. The study will provide data on the efficacy, safety, immunogenicity, and tolerability of mepolizumab when switched directly from omalizumab without any wash-out. The learnings from this study may help guide physicians when substituting one biologic with another for the treatment of patients with severe eosinophilic asthma.

The study will be a multi-centre, open-label single arm trial. Patients with severe eosinophilic asthma who are receiving omalizumab, but are not optimally controlled will be eligible to participate. Subjects will remain on their current maintenance therapy including omalizumab throughout the run-in period for a minimum of one week and up to 4 weeks. At Visit 2 (week 0) subjects will discontinue their omalizumab treatment and be switched to mepolizumab 100 mg subcutaneous (SC) every 4 weeks for 28 weeks. The treatment period is 32 weeks, including an Exit Visit/Early Withdrawal Visit, 4 weeks following the subject's last dose of mepolizumab.

Inclusion Criteria:

• At least 12 years of age at the time of signing the informed consent. For those countries where local regulations permit enrolment of adults only, subject recruitment will be restricted to those who are >= 18 years of age.
• Asthma: A physician diagnosis of asthma for >=2 years that meets the National Heart and Lung Institute guidelines.
• Forced expiratory volume in 1 second (FEV1): Persistent airflow obstruction as indicated by: For subjects >=18 years of age at Visit 1, a pre-bronchodilator FEV1 <80% predicted recorded at Visit 1, For subjects 12-17 years of age at Visit 1, a pre-bronchodilator FEV1 <90% predicted recorded at Visit 1 or FEV1/ Forced Vital Capacity (FVC) ratio <0.8 recorded at Visit 1
• Eosinophilic asthma: Airway inflammation characterized as eosinophilic in nature as indicated by one of the following: A peripheral blood eosinophil count of >=300 cells/microliter (uL) that is related to asthma demonstrated in the past 12 months prior to Visit 1 or a peripheral blood eosinophil count of >=150 cells/uL at Visit 1 that is related to asthma.
• Inhaled Corticosteroid: A well-documented requirement for regular treatment with high-dose inhaled corticosteroid (ICS) in the 12 months prior to Visit 1 with or without maintenance oral corticosteroids (OCS). For 18 years of age and older: ICS dose must be >=880 microgram (ug)/day fluticasone propionate (FP) (ex-actuator) or equivalent daily. For ICS/ Long-Acting Beta-2-Agonists (LABA) combination preparations, the highest approved maintenance dose in the local country will meet this ICS criterion. For subjects 12-17 years of age at Visit 1: ICS dose must be >=440 ug/day fluticasone propionate (FP) (ex-actuator) or equivalent daily, For ICS/LABA combination preparations, the highest approved maintenance dose in the local country will meet this ICS criterion.
• Controller Medication: Current treatment with an additional controller medication, besides ICS, for at least 3 months or a documented failure in the past 12 months of an additional controller medication for at least 3 successive months. [e.g., LABA, leukotriene receptor antagonist (LTRA), or theophylline.]
• Asthma symptoms not optimally controlled: An ACQ-5 score of >=1.5 recorded at Visit 1.
• Omalizumab Treatment: Receiving omalizumab, based on weight and IgE levels, for at least the 4 months prior to Visit 1.
• Exacerbation history: Previously confirmed history of two or more exacerbations requiring treatment with systemic corticosteroids (intramuscular, intravenous, or oral) in the 12 months prior to Visit 1 despite the use of high-dose ICS. For subjects receiving omalizumab for >=8 months, at least one exacerbation must have occurred while on omalizumab treatment. For subjects receiving maintenance oral corticosteroids, the corticosteroid treatment for the exacerbations must have been a two-fold dose increase or greater.
• Male or eligible Female: Females: a) Non-reproductive potential defined as :Pre-menopausal females with one of the following: Documented tubal ligation, Documented hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal occlusion, Hysterectomy, Documented Bilateral Oophorectomy, Postmenopausal defined as 12 months of spontaneous amenorrhea [in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) and estradiol levels consistent with menopause (refer to laboratory reference ranges for confirmatory levels)]. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the highly effective contraception methods if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrolment. b) Reproductive potential and agrees to follow one of the options listed in the Modified List of Highly Effective Methods for Avoiding Pregnancy in Females of Reproductive Potential (FRP) from 30 days prior to the first dose of study medication and until at least five terminal half-lives or until any continuing pharmacologic effect has ended, whichever is longer, after the last dose of study medication and completion of the Exit visit/Early Withdrawal visit.The investigator is responsible for ensuring that subjects understand how to properly use these methods of contraception.
• Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the consent form and in this protocol.

Exclusion Criteria:

• Concurrent Respiratory Disease: Presence of a known pre-existing, clinically important lung condition other than asthma. This includes current infection, bronchiectasis, pulmonary fibrosis, bronchopulmonary aspergillosis, or diagnoses of emphysema or chronic bronchitis (chronic obstructive pulmonary disease other than asthma) or a history of lung cancer.
• Malignancy: A current malignancy or previous history of cancer in remission for less than 12 months prior to screening (subjects that had localized carcinoma of the skin which was resected for cure will not be excluded).
• Liver disease: Subjects must not be enrolled in the study if :At screening (Visit 1) Alanine Transaminase (ALT) >2x Upper Limit of Normal (ULN); and bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%) Current active liver or biliary disease (with the exception of Gilbert's syndrome or asymptomatic gallstones or otherwise stable chronic liver disease per investigator assessment). Stable chronic liver disease should generally be defined by the absence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, oesophageal or gastric varices, or persistent jaundice, or cirrhosis.
• Hepatitis status: Diagnosis of chronic hepatitis B, as evidenced by positive Hepatitis B surface antigen (HBsAg) at Visit 1. Chronic stable hepatitis C (e.g.,positive hepatitis C antibody test result at screening (Visit 1) or within 3 months prior to first dose of study treatment) are acceptable if subject otherwise meets entry criteria.
• Cardiovascular: Subjects who have severe or clinically significant cardiovascular disease uncontrolled with standard treatment. Including but not limited to: a) known ejection fraction of <30% or b) severe heart failure meeting New York Heart Association Class IV classification or c) hospitalised in the 12 months prior to Visit 1 for severe heart failure meeting New York Heart Association Class III or d) angina diagnosed less than 3 months prior to Visit 1 or at Visit 1
• Subjects with QT interval corrected (QTc) > 450 milliseconds (msec) or QTc > 480 msec in subjects with Bundle Branch Block at screening Visit 1.The QTc is the QT interval corrected for heart rate according to Bazett's formula (QTcB), Fridericia's formula (QTcF), and/or another method, machine-read or manually over-read. The specific formula that will be used to determine eligibility and discontinuation for an individual subject should be determined prior to initiation of the study. In other words, several different formulae cannot be used to calculate the QTc for an individual subject and then the lowest QTc value used to include or discontinue the subject from the trial.For purposes of data analysis, QTcB, QTcF, another QT correction formula, or a composite of available values of QTc will be used.
• Other Concurrent Medical Conditions: Subjects who have known, pre-existing, clinically significant endocrine, autoimmune, metabolic, neurological, renal, gastrointestinal, hepatic, haematological or any other system abnormalities that are uncontrolled with standard treatment.
• Eosinophilic Diseases: Subjects with other conditions that could lead to elevated eosinophils such as Hypereosinophilic Syndromes, including Churg-Strauss Syndrome (Eosinophilic Granulomatosis with Polyangiitis [EGPA]), or Eosinophilic Esophagitis. Subjects with a known, pre-existing parasitic infestation within 6 months prior to Visit 1 are also to be excluded.
• Immunodeficiency: A known immunodeficiency (e.g., human immunodeficiency virus [HIV]), other than that explained by the use of corticosteroids taken as therapy for asthma.
• Other Monoclonal Antibodies: Subjects who have received any monoclonal antibody (other than omalizumab) to treat inflammatory disease within 5 half-lives of Visit 1.
• Smoking history: Current smokers or former smokers with a smoking history of >=10 pack years (number of pack years = (number of cigarettes per day / 20) x number of years smoked). A former smoker is defined as a subject who quit smoking at least 6 months prior to Screening Visit 1.
• Alcohol/Substance Abuse: A history (or suspected history) of alcohol misuse or substance abuse within 2 years prior to Visit 1.
• Adherence: Subjects who have known evidence of lack of adherence to controller medications and/or ability to follow physician's recommendations.
• Hypersensitivity: Subjects with allergy/intolerance to a monoclonal antibody or biologic. History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the investigator or Medical Monitor, contraindicates their participation.
• Investigator opinion: Omalizumab treatment has provided significant clinical benefit despite experiencing 2 exacerbations in the past 12 months, and potential benefit from a switch to mepolizumab would not outweigh the potential harm after omalizumab withdrawal for the subject.
• Previous participation: Previously participated in any study with mepolizumab and received investigational product (including placebo).
• Investigational Medications: Subjects who have received treatment with an investigational drug within the past 30 days or five terminal phase half-lives of the drug whichever is longer, prior to Screening (V1) (this also includes investigational formulations of marketed products).
• Pregnancy: Subjects who are pregnant or breastfeeding. Patients should not be enrolled if they plan to become pregnant during the time of study participation.