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Background Analysis: US FDA Advisory Committee to Review Proposed COPD Use for GSK’s Nucala – JUL 25, 2018 (PADAC)

Announcement

The US FDA has scheduled a meeting of the Pulmonary-Allergy Drugs Advisory Committee (PADAC) for Wednesday, July 25, 2018 to discuss a supplemental biologics license application (sBLA) for Nucala (mepolizumab), by GlaxoSmithKline (GSK), for add-on treatment to inhaled corticosteroid-based maintenance treatment for the reduction of exacerbations in patients with chronic obstructive pulmonary disease (COPD) guided by blood eosinophil counts.

Indication Background

Chronic obstructive pulmonary disease (COPD) is an airway disease that includes chronic bronchitis and emphysema. It is usually caused by irritants that have damaged the lungs and airways. People who have COPD are unable to breathe normally at a level that makes the simple activities of daily life a struggle. The disease is diagnosed based on clinical symptoms, along with spirometry, chest x-rays or computed tomography (CT) scans, and arterial blood gas tests.

According to the National Institutes of Health, COPD is thought to affect 384 million people worldwide. It is currently the fourth leading cause of death in the world, and it is projected to be the third leading cause of death by 2020.

Patients with severe COPD are often prescribed triple-inhaled therapy that consists of an inhaled corticosteroid (ICS), a long-acting β2-agonist (LABA), and a long-acting muscarinic antagonist (LAMA). This therapy is recommended by the Global initiative for Chronic Obstructive Lung Disease (GOLD) for patients who experience recurrent exacerbations despite treatment with either a dual bronchodilator (preferred initial therapy) or LABA/ICS combination (alternative initial therapy).

Product Background

Mepolizumab is an anti-interleukin-5 (IL-5) antibody. IL-5 is a cytokine that promotes eosinophil growth, activation, and survival and signals the movement of eosinophils from the bone marrow into the lung. Eosinophils are believed to take part in protecting the body against infection, but in some people eosinophils cause inflammation and may be involved in the development of inflammatory diseases. Eosinophilic inflammation occurs in roughly one-fifth of COPD patients, in whom it is thought to contribute to the disease.

Eosinophilic inflammation also occurs in a subset of asthma patients. On November 4, 2015, mepolizumab was granted FDA approval for “add-on maintenance treatment of patients with severe asthma aged 12 years and older, and with an eosinophilic phenotype.” The recommended dose is 100 mg administered subcutaneously every 4 weeks. The US trade name is Nucala.

The FDA’s decision to approve mepolizumab for eosinophilic asthma partially followed the advice of the PADAC on June 11, 2015. The Committee had voted in support of approval for use in adults but against use in patients aged 12-17 years.

After the FDA approval of mepolizumab for eosinophilic asthma, GSK submitted the sBLA proposing mepolizumab for the eosinophilic COPD use. The Phase 3 clinical COPD program of mepolizumab investigated doses of 100 mg and 300 mg, given as a subcutaneous injection, every 4 weeks over 52 weeks.

On December 12, 2017, mepolizumab's indication was expanded to include “the treatment of adult patients with eosinophilic granulomatosis with polyangiitis.” Eosinophilic granulomatosis with polyangiitis was known formerly as the Churg-Strauss Syndrome. It is a systemic vasculitis (inflammation of blood vessels) often involving the respiratory tract.

Note that the indication for mepolizumab includes a limitation of use statement, “Not for relief of acute bronchospasm or status asthmaticus.”

Clinical Trials

The NDA is based primarily on the results of two phase 3 trials named MATREO and METREX (Clinicaltrials.Gov Identifiers: NCT02105961 and NCT02105948.)  Trial results were presented in NEJM in October 2017.

METREX randomized 837 patients with moderate to severe COPD to receive either the 100 mg dose of mepolizumab or placebo as an add-on to triple inhaled therapy. For the primary modified intention-to-treat population (N=462), comprising all randomized participants who received at least one dose of study treatment and had blood eosinophil counts >=150 cells/µL at screening or >=300 cells/ µL in the 12 months prior, a.k.a. the “high-stratum” population, treatment with mepolizumab demonstrated a statistically significant effect versus placebo on the primary efficacy endpoint, the mean annual rate of moderate or severe exacerbations. In particular, the rate was 1.40 per year in the mepolizumab group compared to a rate of 1.71 per year in the placebo group (rate ratio, 0.82; 95% confidence interval [CI], 0.68 to 0.98; adjusted P=0.04).

METREO randomized 674 patients with moderate to severe COPD and blood eosinophil counts >=150 cells/µL at screening or >=300 cells/ µL in the 12 months prior to receive either the 100 or 300 mg dose of mepolizumab or placebo as an add-on to triple inhaled therapy. Neither dose of mepolizumab treatment demonstrated a statistically significant effect on the primary efficacy endpoint, the mean annual rate of moderate or severe exacerbations, with a rate of 1.19 per year in the 100-mg mepolizumab group, 1.27 per year in the 300-mg mepolizumab group, and 1.49 per year in the placebo group. The rate ratios for exacerbations in the 100-mg and 300-mg mepolizumab groups versus the placebo group were 0.80 (95% CI, 0.65 to 0.98; adjusted P=0.07) and 0.86 (95% CI, 0.70 to 1.05; adjusted P=0.14), respectively. The NEJM publication notes that greater effects were seen in a subset of patients with higher blood eosinophil counts at screening. 

Regarding safety, the NEJM publication states that the safety profile of mepolizumab was similar to that of placebo in both trials.

Note that comprehensive results from the clinical development program will be presented in FDA and company briefing materials that will be posted ahead of the meeting. These materials will be summarized on the day they are posted, in our subsequent report, the Briefing Summary.

Regulatory Background

US Regulatory Background

November 7, 2017 – GSK announced the submission of the sBLA to BLA 125526

Ex-US Regulatory Background

November 7, 2017 – Along with GSK’s announcement of the US sBLA submission, the company stated that “Regulatory filings in other countries are planned during the course of 2017 and 2018.”

What’s Next?

Tarius will send a Briefing Summary after briefing materials are posted to FDA’s website (typically within 2 days of the meeting). This report will provide a summary of the FDA and the Sponsor’s briefing materials.

Tarius will send a Results Wire soon after the meeting. This report will include the voting outcomes, if applicable, and key outcomes of the discussion.

METADATA: Sponsor: GlaxoSmithKline Drug Name: mepolizumab Drug Class: anti–interleukin-5 monoclonal antibody Indication: COPD


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DISCLAIMER: The information in this document is for informational purposes only. The SAC Tracker Background Analysis contains information from publicly available sources, including FDA, sponsor, scientific, and clinical websites. Tarius A/S assumes no liability for any inaccurate or incomplete information, or for any actions taken in reliance thereon. © Tarius A/S. All rights reserved.