Fasenra for Treatment of Severe Eosinophilic Asthma

In November 2017, the FDA approved a new biologic for add-on treatment of severe asthma secondary to eosinophilic inflammation (i.e., eosinophilic asthma) called bevacizumab (Fasenra).

According to the NIH, a biologic agent is "a substance that is made from a living organism or its products and is used in the prevention, diagnosis, or treatment of cancer and other diseases. Biologic agents include antibodies, interleukins, and vaccines." A biologic agent can also be called either a biological agent, biological drug, or biologic.

Worldwide, about 315 million people have asthma. Of these people, between five and 10 percent have severe asthma and, if eligible, may benefit from intervention with a biologic.

How Does Fasenra Work?

To understand how Fasenra works, it’s important to examine the relationship between eosinophils, a type of white blood cell, and asthma. Typically, eosinophils protect us against parasitic worms. When inappropriately activated, however, eosinophils can damage tissues and result in asthma. Eosinophil production and function are influenced by a cytokine called interleukin-5 (IL-5).

Fasenra is a monoclonal antibody active against IL-5 receptors located on eosinophils. In a 2015 article published in Current Medical Research and Opinion, Goldman and co-authors state the following: “Benralizumab [Fasenra] induces direct, rapid, and nearly complete depletion of eosinophils through enhanced antibody-dependent cell-mediated cytotoxicity, an apoptotic process of eosinophil elimination involving natural killer cells.” Essentially, Fasenra mediates the elimination of eosinophils.

Other monoclonal antibodies against IL-5—mepolizumab (Nucala) and reslizumab (Cinqair)—bind IL-5 and thus cause eosinophil reductions through more passive and indirect means. Importantly, like Fasenra, both Nucala and Cinqair are add-on therapies.

ZONDA Clinical Trial

During the Phase III ZONDA trial, AstraZeneca researchers evaluated whether the administration of Fasenra could reduce the need for oral glucocorticoid therapy used to maintain asthma control in patients with persistent eosinophilia, or an increase in the number of eosinophils in the blood.

Importantly, long-term treatment with systemic, or oral, glucocorticoids have many negative side effects which affect the musculoskeletal, endocrine, cardiovascular, and central nervous systems. People who take oral glucocorticoids for long periods of time experience decreased quality of life. Unfortunately, between 32 and 45 percent of people with severe asthma who already take high-dose inhaled glucocorticoids and bronchodilators depend on frequent (i.e., maintenance) oral glucocorticoid therapy to control their asthma.

In the ZONDA trial, 369 patients were enrolled, and 220 of these patients were randomized into three groups. During the 28-week trial, the first experimental group received subcutaneous injections of Fasenra every four weeks, the second experimental group received subcutaneous injections of Fasenra every eight weeks, and the control group received placebo injections. Moreover, the researchers decreased oral glucocorticoid doses taken by all three groups to a minimal level needed to control asthma. The researchers also assessed annual asthma exacerbation rates, lung function, symptoms, and safety.

Here are the results of the clinical trial:

  • In both experimental groups taking Fasenra, the final median oral glucocorticoid doses were 75 percent lower than those at baseline.
  • In the placebo group, the final median oral glucocorticoid dose was 25 percent lower than those at baseline.
  • Participants taking Fasenra were more than four times as likely to experience a reduction of oral glucocorticoid dose than those receiving placebo.
  • In the experimental regimen taking Fasenra every four weeks, the annual incidence of asthma exacerbations dropped 55 percent as compared with that of the control group.
  • In the experimental regimen taking Fasenra every eight weeks, the annual incidence of asthma exacerbations dropped 70 percent as compared with that of the control group.
  • Lung function as measured using forced expiratory volume in 1 second (FEV1) was not significantly different in those taking Fasenra as compared with those taking placebo.
  • Fifty percent of patients receiving baseline doses of prednisone (i.e., oral glucocorticoids), which were less than or equal to 12.5 mg per day, were able to discontinue their use of oral glucocorticoids completely while taking Fasenra.
  • Measures assessing the asthma-related quality of life in those taking Fasenra as compared with those taking placebo were mixed. Some measures showed improvement in asthma symptoms, and others showed no change as compared with those patients taking a placebo.
  • The frequencies of adverse events were similar in those taking Fasenra and those taking a placebo, which suggests that Fasenra is likely safe.

So, what does an asthma exacerbation refer to? According to Nair and colleagues:

"An asthma exacerbation was defined as worsening of asthma that led to a temporary increase in the systemic glucocorticoid dose for at least 3 days to treat the symptoms, an emergency department visit resulting from asthma that led to treatment with a systemic glucocorticoid in addition to the patient’s regular maintenance medications, or an inpatient hospitalization because of asthma."

During the ZONDA trial, 166 patients, or 75 percent, of patients taking Fasenra experienced at least one adverse effect. Here is the breakdown of the adverse effects observed during the clinical trial:

  • Nasopharyngitis (17 percent)
  • Worsening asthma (13 percent)
  • Bronchitis (10 percent)

Of note, nasopharyngitis refers to inflammation of the nose and upper airway. The term common cold refers to nasopharyngitis. Bronchitis refers to inflammation of the lower airways or bronchial tubes in the lungs.

In total, 28 patients (13 percent) experienced what the researchers deemed “serious” adverse effects—the most common being worsening asthma. Only two patients taking Fasenra needed to discontinue the drug. These two patients actually died during the trial but of causes unrelated to the administration of Fasenra—one patient died of cardiac failure and the other died of pneumonia. (Both these patients had a number of other illnesses or comorbidities.)

The researchers concluded that in people with severe eosinophilic asthma, the maintenance dose of oral glucocorticoid therapy could be reduced in those who received Fasenra every eight weeks. Importantly, in the ZONDA trial, researchers found that the annual incidence of asthma exacerbations was actually lower in people taking Fasenra every eight weeks as compared with those taking the medication every four weeks.

Additional Clinical Trials

In two other clinical trials called SIROCCO and CALIMA, researchers also examined Fasenra efficacy. In these trials, which were published several months before the results of the ZONDA trial, the researchers found that subcutaneous injections of Fasenra every four or eight weeks reduced asthma exacerbations, improved lung function (i.e., increase FEV1 values), improved symptom control, and depleted blood eosinophils in patients with counts greater than 300 cells/microliter. Moreover, the researchers found that—although statistical tests were not evaluated—dosing Fasenra every eight weeks appeared to be more effective than administering the drug every four weeks. Importantly, administering the drug every eight weeks decreased the medication burden on the patient.

Curiously, during the ZONDA trial, 20 percent of patients taking Fasenra did not experience any reduction in oral glucocorticoid doses even though blood eosinophil counts of these patients were similar to those who had the greatest reduction in their final oral glucocorticoid doses. Nair and colleagues hypothesize that “perhaps the presence of blood eosinophilia may not identify the eosinophil as a key effector cell in some patients.”

During a subanalysis of the SIROCCO and CALIMA trials, Goldman and researchers examined whether Fasenra could reduce asthma exacerbation rates in patients regardless of eosinophil counts. The researchers found that in people with lower eosinophil counts—counts greater than or equal to 150 cells/microliter—Fasenra “reduces the burden of disease and health care costs for this difficult-to-treat population with limited treatment options.”

Similarly, previous clinical trials have shown that the other two anti–IL-5 antibodies currently on the market, Nucala and Cinqair, are effective in patients with lower eosinophil counts in the blood (i.e., greater than or equal to 150 cells/microliter).

Typically, the gold standard for the diagnosis of eosinophilic asthma involves the visualization of inflammation in bronchial airways based on the examination of a biopsy or induced sputum. These procedures, however, are difficult to perform and require special training; thus, they're not routinely employed. Instead, clinicians depend on blood eosinophil counts, which although predictive of asthma severity, are imperfect. Furthermore, eosinophil counts vary greatly depending on timing and are also sensitive to corticosteroid treatment.

According to Goldman and co-authors:

"The results of the current analyses underscore the potential limitations of defining probable responders to eosinophil depletion therapy, based on a blood eosinophil count of [300 cells/microliter] alone. More detailed characterization of the eosinophilic phenotype beyond blood eosinophil counts is needed that uses a combination of clinical characteristics (e.g., nasal polyposis), along with blood eosinophil counts. Blood eosinophil counts should be measured at several time points to address variability issues that could cause missed diagnoses for patients with eosinophilic inflammation."

Fasenra vs. the Competition

Currently, it’s unclear how Fasenra stacks up against the other biologics that target IL-5: Nucala and Cinqair. In an article titled “Benralizumab for the treatment of asthma,” Saco and co-authors write that Fasenra likely requires less frequent dosing than Nucala and Cinqair. However, the researchers also write the following regarding a comparison of the three drugs:

"Some improvements in asthma symptom scores and quality of life occur with all three biologics, but the clinical meaningfulness of these improvements is less clear .… Until quality randomized controlled trials directly compare the three, choosing among them for the treatment of eosinophilic asthma remains difficult."

AstraZeneca, which is the maker of Fasenra, plans to price the drug lower than Nucala and Cinqair, the other add-on IL-5 biologics currently on the market. Although prices of drugs vary based on several factors, according to some estimates, Nucala costs about $32,500 per year, and Cinqair costs about the same. Finally, because Fasenra can be administered less frequently than these other biologics, the price would also be lower.

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