Identifying Predictors Of Long-Lasting Response To Mepolizumab In CRSwNP: Is The Disease-Modifying Role Secondary To Restored Anti-Viral Activity Or Enhanced Epithelial Regeneration?

2024-11343

The investigators propose a real-world study to assess the mechanism of action of long-lasting response to mepolizumab in patients with chronic rhinosinusitis with nasal polyposis (CRSwNP) and identify clinically useful predictors of response. Mepolizumab is a monoclonal antibody targeting IL-5 and is approved for use in asthma and CRSwNP. In clinical studies, 12 months of treatment with mepolizumab improved signs and symptoms of CRSwNP and reduced the need for surgery. While several biologic medications targeting facets of the Type 2 mechanism are currently indicated for chronic rhinosinusitis with nasal polyps mepolizumab alone appears capable of modifying the disease's biological behaviour and producing long-standing improvements after the cessation of treatment. In the mepolizumab for CRSwNP regulatory trial (SYNAPSE), a subset of patients experienced dramatic and long-lasting, which is over 48 months after cessation of administration of the investigational medicinal product (IMP) in our experience. This has been partially captured in a follow-on study to the registration trail, which showed that a subset of patients followed for 24 weeks after cessation of biologic therapy (with continued use of mometasone furoate) demonstrated persistent improvements over baseline. However, the mechanism of the long-lasting effect in a subset of patients is not well understood, and it is impossible currently to identify patients who will derive this maximal benefit. The mechanism for the prolonged improvements in CRSwNP seen in certain patients with mepolizumab remains to be established but suggests that effects beyond eosinophil trafficking are implicated. The investigators believe that mepolizumab has IL-5-mediated pleiotropic effects which contribute to disease modification with effects extending beyond eosinophil activation and trafficking. This may include the following primary or secondary effects: i) Improving epithelial barrier function ii) Altering mast cell dynamics iii) Reversing epigenetic modifications iv) Altering the immune response to better clear pathogenic bacteria or viruses.

2023-10-03

2026-12-31

2026-12-31

Recruiting

Early phase I

36

Inclusion Criteria: * Bilateral NP, as diagnosed by endoscopy or historical CT scan * At least one NP surgery\* within the last 10 years. * Severe NP symptoms consistent with a need for surgery (obstruction VAS symptom score\>5, overall, VAS symptom score \>7, endoscopic bilateral NP score ≥4 \[with a score ≥2 in each nasal cavity\]). * Ongoing treatment with INCS (via spray or intranasal liquid steroid wash/douching) for ≥4 weeks prior to screening * ≥2 of the following CRS symptoms for at least 12 weeks: * Nasal blockage/obstruction/congestion * Nasal discharge (anterior/posterior nasal drip) * Facial pain/pressure * Reduction or loss of sense of smell Exclusion Criteria: * If as a result of a medical interview, physical examination, or screening investigation the physician responsible considers the participant unfit for the study. * Cystic fibrosis * Eosinophilic granulomatosis with polyangiitis (also known as Churg Strauss syndrome), Young's, Kartagener's or dyskinetic ciliary syndromes * Antrochoanal polyps * Nasal septal deviation occluding one nostril * Acute sinusitis or upper respiratory tract infection (URTI) at screening or 2 weeks prior to screening * Ongoing rhinitis medicamentosa (rebound or chemical-induced rhinitis) * Participants who have undergone any intranasal and/or sinus surgery (for example polypectomy, balloon dilatation or nasal stent insertion) within 6 months prior to V1 * Participants where NP surgery is contraindicated in the opinion of the Investigator * Participants with a known medical history of HIV infection. * Participants with a known, pre-existing parasitic infestation within 6 months prior to Visit 1. * Participants who are currently receiving or have received within 3 months (or 5 half-lives - whatever is the longest) prior to the screening visit, radiotherapy, or investigational medications/therapies. * Participants with a 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 GSK Medical Monitor, contraindicates their participation. Aspirin-sensitive participants are acceptable. * Participants with a history of allergic reaction to anti-IL-5 or other monoclonal antibody therapy. * Use of systemic corticosteroids (including oral corticosteroids) within 4 weeks prior to screening or planned use of such medications during the double-blind period * Treatments with biological or immunosuppressive treatment (other than Xolair) treatment within 5 terminal phase half-lives of Visit 1 * Omalizumab (Xolair) treatment in the 130 days prior to Visit 1 * Commencement or change of dose of allergen immunotherapy within the previous 3 months. * Pregnancy: Women who are pregnant or lactating or are planning on becoming pregnant during the study. Contraceptive use will be required with a double barrier method or documented effective surgical sterilization. * Immunocompromised subjects from disease or medication, other than oral corticosteroids. * Women of childbearing potential (WOCBP) will be included with measures to prevent accidental exposure to IMP by using double barrier contraception and pregnancy test prior to injection.

{'studyType': 'INTERVENTIONAL', 'phases': ['PHASE4'], 'designInfo': {'allocation': 'NA', 'interventionModel': 'SINGLE_GROUP', 'interventionModelDescription': 'Patients with severe recurrent CRSwNP will receive Mepolizumab 100mg SC once every 4 weeks for 48 weeks (twelve injections, no placebo) at the hospital.', 'primaryPurpose': 'TREATMENT', 'maskingInfo': {'masking': 'NONE'}}, 'enrollmentInfo': {'count': 36, 'type': 'ESTIMATED'}}

2023-10-16