Rosanna Sutherby, PharmD

Asthma is a chronic respiratory disease that causes narrowing and inflammation of the airways that compromises breathing and, in some cases, can be fatal. Symptoms include coughing, wheezing, shortness of breath, chest tightness and chest pain. Nearly 25 million people in the United States have asthma, and 10 people die from the disease daily.

Current asthma treatment aims to prevent exacerbations (asthma attacks) and relieve symptoms when exacerbations occur. Traditional therapies include inhaled corticosteroids, long- and short-acting beta-agonist inhalers, long- and short-acting inhaled anticholinergics, leukotriene receptor antagonists and oral corticosteroids.

Most asthma cases are treatable using the currently available therapies mentioned. But about 10% of people with asthma do not respond to standard treatments and are considered to have severe asthma. The Global Initiative for Asthma (GINA) defines severe asthma as asthma that is not controlled by proper use of high-dose inhaled corticosteroids and long-acting beta-agonists or that worsens when high doses of these drugs are lowered.

Individuals with severe asthma often have persistent debilitating symptoms and require frequent use of inhalers and long-term use of oral corticosteroids. Although systemic corticosteroids can effectively treat asthma symptoms and exacerbations, their long-term use carries the risk of undesirable side effects, including osteoporosis and diabetes.

The good news is that research into the pathogenesis of asthma has led to the development of biologics that target cytokines directly involved in causing severe asthma symptoms. These cytokines include interleukin (IL)-4, IL-5 and IL-13, which are responsible for the high levels of eosinophils and immunoglobulin E (IgE) seen in some types of severe asthma.

Severe asthma is classified into three types based on patients’ response to treatment and the presence of certain biomarkers: allergic asthma, eosinophilic asthma, and noneosinophilic asthma.

Allergic asthma is triggered by exposure to allergens, such as pollen, dust and pet dander. Patients with this type of asthma typically have increased levels of IgE as a response to allergen exposure. People with eosinophilic asthma have high levels of eosinophils that trigger inflammation of the airways. Individuals who have noneosinophilic asthma have few if any eosinophils in lab results, although some may have high levels of neutrophils.

When it comes to treatment, patients with severe allergic or eosinophilic asthma tend to respond to inhaled corticosteroids and biologics that target biomarkers prevalent in these types of asthma. But inhaled corticosteroids are not effective for those with noneosinophilic asthma, and only one of the currently available biologics targets a cytokine active in this type of asthma.

The past few years have seen a surge in the development and approval of biologics to treat severe asthma. Many of them target cytokines directly involved in the pathology of severe asthma, leading to reduced use of oral corticosteroids and significant decreases in severe exacerbations. As of 2021, GINA guidelines for the management of severe asthma include biologics as add-on therapy for severe allergic and eosinophilic asthma.

The biologics the FDA has approved as a treatment for severe asthma include Cinqair (reslizumab), Dupixent (dupilumab), Fasenra (benralizumab), Nucala (mepolizumab), Tezspire (tezepelumab), and Xolair (omalizumab).

Xolair, developed by Swiss company Novartis, was the first biologic approved in the U.S. and the EU for children and adults with severe asthma. It is an anti-IgE monoclonal antibody for use in adults and children aged 6 and older with severe allergic asthma.

Fasenra, developed by British-Swedish pharmaceutical giant AstraZeneca is an IL-5 receptor antagonist. The FDA approved the drug in 2017 as add-on treatment for severe eosinophilic asthma in adults and children aged 12 and older. In 2019, the FDA approved the Fasenra Pen, a prefilled auto-injector for self-administration of the drug.

GlaxoSmithKline’s Nucala and Teva Pharmaceutical’s Cinqair are IL-5 antagonists indicated as add-on therapy for eosinophilic asthma. Nucala, FDA-approved in 2015, is indicated for use in adults and children as young as 6 years. In January of this year, the FDA approved Nucala Autoinjector and prefilled syringes for self-administration for children, two and a half years after they were approved for adults. Cinqair, approved in the U.S. in 2016, is for intravenous use only in patients aged 18 and older.

Dupixent, coproduced by Regeneron Pharmaceuticals in upstate New York and French company Sanofi, received FDA approval in 2018 as add-on therapy for moderate to severe eosinophilic asthma in patients aged 12 and older. It had been previously approved as a treatment for eczema.

In October 2021, the FDA expanded Dupixent’s indication to include children aged 6 to 11 years. In 2020, the agency approved a Dupixent prefilled pen for self-injection. Dupixent is an IL-4 inhibitor with dual inhibitory action against IL-4 and IL-13 signaling.

Tezspire, produced by Amgen and AstraZeneca, is a first-in-class thymic stromal lymphopoietin (TSLP) blocker. TSLP is an epithelial cytokine responsible for starting a cascade of inflammation in asthma. Tezspire is the first agent with FDA-approved indications for all types of severe asthma, including noneosinophilic asthma, regardless of the presence of biomarkers. The agent was FDA approved in December 2021 as add-on treatment in patients aged 12 and older with severe asthma.

Research continues to open new pathways in the treatment of severe asthma. Although biologics have done well in controlling severe eosinophilic and allergic asthma, a treatment need remains for patients with severe noneosinophilic asthma who do not respond to corticosteroids. Additionally, current biologics consist of injectable agents, many of which must be administered by a healthcare professional. A few companies are investigating new oral drugs and inhalers for use in patients with severe asthma.

Masitinib, from AB Science, a French company, is an oral tyrosine kinase inhibitor that selectively targets mast cells involved in mucus production and airway inflammation. In a phase 3 study, masitinib significantly reduced the rate of severe asthma exacerbations in patients with severe eosinophilic and noneosinophilic asthma compared with placebo.

GlaxoSmithKline is conducting a phase 3 trial investigating the safety and efficacy of depemokimab as an add-on treatment in patients 12 years and older with severe eosinophilic asthma. Depemokimab, a long-acting IL-5 inhibitor, would become the first long-acting treatment for this condition if approved by the FDA. Current IL-5 inhibitors are dosed every 4 weeks or every 8 weeks. Depemokimab is designed to be administered every 6 months. The trial is scheduled to be finished in late 2023.

AstraZeneca and British drug company Avillion are developing a combination inhaled short-acting beta-agonist (albuterol) and corticosteroid (budesonide) for use as rescue therapy. In a phase 3 trial, the albuterol/budesonide combination significantly reduced the risk of severe asthma exacerbations when used as rescue treatment versus albuterol alone in participants with moderate to severe asthma.

Ecleralimab is a TSLP inhibitor developed by Novartis as an inhaler for maintenance treatment of moderate to severe uncontrolled asthma. If approved, ecleralimab would join Tezspire as a treatment option for patients with all types of severe asthma. Ecleralimab is currently in a phase 2 study that is scheduled to be completed in 2024.

This article originally appeared on Managed Healthcare Executive.

Articles

Six are currently on the market and more are in the pipeline. 

Biologics for Severe Asthma Surge

Atopic dermatitis, also known as eczema, is a chronic inflammatory skin condition affecting up to 10% of adults and 20% of children in the United States. It is characterized by persistent severe itching and skin barrier disruptions. The cycle of itching and scratching perpetuates inflammation and damage to the skin, leading to infections and diminished quality of life. Symptoms of AD can disrupt sleep and have negative social and emotional effects.

Until recently, treatment for atopic dermatitis has been limited to topical corticosteroids and calcineurin inhibitors for mild to moderate AD, whereas systemic steroids, immunosuppressants and phototherapy were used for moderate to severe cases. The systemic treatments are effective but come with undesirable side effects.

An overactive immune response under the skin and compromised skin tissue on the surface are the source of AD symptoms. New agents target immune system pathways and cells directly involved in the pathology of the condition.

Researchers have shown that AD may be partially caused by overactivity of Janus kinases (JAKs), a group of inflammatory cytokines. The JAKs include JAK1, JAK2, JAK3 and tyrosine kinase 2. Blocking JAK signaling pathways can dampen the production of cytokines responsible for AD symptoms, and inhibiting select JAKs can help manage specific AD symptoms.

New JAK inhibitors have been used for several autoimmune diseases, and a handful are moving through the pipeline as potential treatments for AD. The JAK inhibitors are an important addition to AD treatment for people who haven’t responded to other treatments.

“They’re amazing for these (patients with more severe cases). They have a huge, huge impact on quality of life,” said Peter A. Lio, M.D., at a session on atopic dermatitis at the annual meeting of the Academy of Managed Care Pharmacy in March. Lio is a clinical assistant professor of dermatology and pediatrics at Northwestern University’s Feinberg School of Medicine and founding director of the Chicago Integrative Eczema Center.

Incyte’s Opzelura (ruxolitinib) cream is the first topical JAK inhibitor approved by the FDA as a treatment for AD. Opzelura, which received approval in September 2021, is a JAK1 and JAK2 inhibitor indicated for the short-term treatment of mild to moderate AD in patients age 12 and older.

Earlier this year, the agency approved two oral JAK1 inhibitors that address the need for systemic therapy for moderate to severe AD. Pfizer’s Cibinqo (abrocitinib) promises relief for adults with refractory moderate to severe AD and AbbVie’s Rinvoq (upadacitinib) was approved as a treatment for adults and children age 12 and older with refractory moderate to severe AD.

Olumiant (baricitinib), an oral JAK1 and JAK2 inhibitor comarketed by Eli Lilly and Incyte, was the first of its class approved in the European Union and Japan to treat moderate to severe AD in adults. In phase 3 studies, once-daily dosing of Olumiant, combined with topical corticosteroids, significantly improved signs and symptoms of AD compared with placebo and topical corticosteroids. The companies say they are on track to complete an additional phase 3 study later and are awaiting approval from the FDA.

Delgocitinib, a topical JAK inhibitor, inhibits all members of the JAK family. It is approved in Japan as a topical ointment for adults and children age 2 and older. The drug was developed by Japan Tobacco and is distributed under the brand name Corectim by Torii Pharmaceutical, a Japanese company.

Danish company Leo Pharma is conducting phase 3 trials investigating the potential use of a delgocitinib cream in adults with moderate to severe chronic hand eczema, a type of atopic dermatitis affecting the fingers and back of the hands.

Further back in the topical JAK inhibitor pipeline is a product being developed by Aclaris Therapeutics. After failing to meet end points with its first investigational topical JAK inhibitor, Aclaris is following up with topical solution ATI-1777. This JAK1 and JAK3 inhibitor showed positive results in a phase 2a trial, and the company has said it will move forward with a larger phase 2b trial for potential use in adults with AD.

Monoclonal antibodies play a significant role in alleviating AD symptoms through blockage of cytokines critical to AD pathophysiology. The cytokines interleukin (IL)-4, IL-13 and IL-31 are of particular interest. AD’s skin barrier disruptions are driven by inhibition of certain proteins essential for healthy skin barrier function. IL-4 and IL-13 play a significant role in inhibiting those proteins. IL-31 promotes activation of the itch response on nerve cells and eosinophils, a type of disease-fighting white blood cell.

In 2017 the FDA approved Dupixent (dupilumab), an IL-4 receptor antagonist developed by Regeneron and Sanofi, to treat AD in adults. Lio sees Dupixent as a turning point in AD treatment: “It has changed everything and allows us to really offer sustained control for a huge group of people who never had it before, in a really safe way,” he said at the AMCP meeting.

In May 2020 the FDA approved Dupixent for children age 6 and older, and in August 2021 the companies reported meeting all end points in a phase 3 trial evaluating the use of the monoclonal antibody in children as young as 6 months. Adbry (tralokinumab), developed by Leo Pharma, is an IL-13 antagonist approved by the FDA in December 2021. Both biologics offer systemic treatment for moderate to severe atopic dermatitis not responding to topical treatments.

In August 2021, the FDA gave Lilly’s IL-13 inhibitor, lebrikizumab, a fast track designation, which means more frequent meetings with the FDA and a rolling review, both of which are intended to shorten the time to an approval decision.

Nemolizumab, an IL-31 inhibitor from Swiss dermatology specialist Galderma, is another drug in late-stage development. By binding to IL-31 receptors, nemolizumab keeps the interleukin from potentiating the itch sensation. In phase 2 studies, there was significant reduction in itching in patients taking nemolizumab compared with those taking placebo.

Tapinarof is a topical first-in-class therapeutic aryl hydrocarbon receptor-modulating agent developed by biopharmaceutical company Dermavant Sciences. It is a nonsteroidal topical option for patients with mild AD. Tapinarof inhibits pathways involved with inflammatory cytokines that mediate AD symptoms. After positive phase 2 trial results, Dermavant started a phase 3 trial evaluating the use of tapinarof cream in patients age 2 and older with AD.

New Jersey-based Medimetriks and Japan’s Otsuka Pharmaceuticals are developing difamilast, a topical phosphodiesterase-4 (PDE-4) inhibitor for patients age 15 and older with mild to moderate AD. PDE-4 is involved in the production of proinflammatory cytokines responsible for symptoms of AD and other inflammatory disorders. In two phase 3 trials conducted in Japan, a higher proportion of patients who received difamilast ointment experienced clear to almost-clear skin compared with participants who used placebo. Otsuka announced in September 2021 that Japanese regulators had approved difamilast, which in Japan is being sold under the brand name Moizerto. Medimetriks is preparing to launch phase 3 trials in the U.S. If difamilast makes it on to the market, it would join Eucrisa (crisaborole) as the second topical PDE-4 inhibitor used for AD treatment. The FDA approved Eucrisa in 2016.

Across the globe, new drugs — injections, topical and oral — are being developed to help patients with atopic dermatitis.

An Abundance of Options for Treating Atopic Dermatitis

In 2018, Sanofi and Regeneron Pharmaceuticals were granted FDA approval for Dupixent (dupilumab) as add-on treatment for moderate to severe eosinophilic asthma. The approval was based on positive results from three pivotal randomized clinical trials evaluating the safety and efficacy of Dupixent in adults and adolescents with moderate to severe eosinophilic asthma. Results from the trials demonstrated that Dupixent significantly improved lung function and reduced severe exacerbations compared to placebo. Additionally, Dupixent reduced the average daily use of oral corticosteroids by a higher percentage than placebo (70% versus 42%).

 in April of this year retrospectively evaluated the efficacy of Dupixent in the treatment of severe asthma in a real-world setting. The study, conducted at Jikei University Hospital in Tokyo, looked at 26 adults who received Dupixent treatment for severe asthma from April 2019 through December 2021. The primary endpoints were the change in the number of annual asthma exacerbations and the reduction in the use of oral corticosteroids at the last follow-up as measured in prednisone equivalents.

Of the 26 participants, 16 had switched to Dupixent after having previously used a different biologic for severe asthma treatment.

The study found that Dupixent significantly reduced the number of annual severe asthma exacerbations by 53% and the mean dose of daily oral corticosteroid use significantly decreased by 54%. These real-world results are comparable to those observed in major randomized clinical trials. However, the Japanese study also observed that adverse events associated with high eosinophil levels were more prominent in patients who had switched from a different biologic before starting Dupixent versus those who were biologic naïve before treatment with Dupixent. One patient who changed from Nucala (mepolizumab) discontinued Dupixent treatment due to hypereosinophilia. Another patient, who had been previously using Fasenra (benralizumab), discontinued Dupixent treatment due to a relapse of chronic eosinophilic pneumonia.

Because of these findings, the study authors suggest monitoring eosinophil levels during Dupixent treatment in patients who switch from other biologics. “Compared to biologic-naïve patients, we propose that long-term careful observation for one year be necessary when patients shift biologics from anti-IL-5/IL-5R antibody to dupilumab”, the authors recommend.

This study was a small, single-center, retrospective study. Despite these limitations, the authors believe that the study population adequately reflects a real-world setting in Japan and conclude that Dupixent is effective in the real world in reducing severe asthma exacerbations and decreasing the use of oral corticosteroids in patients with severe asthma.

This article originally appeared on Managed Healthcare Executive. 

Numata T, Araya J, Miyagawa H, et al. Real-World Effectiveness of Dupilumab for Patients with Severe Asthma: A Retrospective Study. 

 2022; 15: 395–405. Published online 2022 Apr 1. doi: 10.2147/JAA.S357548

Real-world study conducted in Japan shows Dupixent (dupilumab) reduced the number of annual severe asthma exacerbations by 53%, there were also adverse events associated with high eosinophil levels in patients who had switched from a different biologic before starting Dupixent.

Dupilumab Improves Severe Asthma Symptoms, Switching May Require Eosinophil Monitoring

Patients with severe asthma are often burdened with frequent exacerbations requiring numerous visits to clinics and doctors’ offices for symptom monitoring and treatment evaluation. New severe asthma treatments, specifically biologics, have helped manage severe asthma symptoms and decrease the frequency of exacerbations. In this respect, they have helped improve patients’ quality of life. However, many patients using biologics for severe asthma must receive treatment from a healthcare professional at a clinic or doctor’s office. This may involve making a trip to a healthcare facility at least every 4 weeks for treatment administration.

Biologics currently FDA-approved to treat severe asthma are all injectables. However, four of the six approved agents are now available in formulations that can be self-administered at home with training from a healthcare provider. Genentech’s Xolair (omalizumab) is available as a prefilled syringe for subcutaneous self-injection in patients 12 years or older with severe allergic asthma. A caregiver may administer Xolair at home to children ages 6 to 11 years.

AstraZeneca’s Fasenra Pen (benralizumab) is a prefilled autoinjector for subcutaneous self-injection in patients ages 12 years or older with severe eosinophilic asthma.

Dupixent (dupilumab), made by Regeneron and Sanofi, is available as a prefilled pen and a prefilled syringe that can be self-administered subcutaneously in patients 12 years and older with moderate to severe eosinophilic asthma. Caregivers may administer Dupixent prefilled syringes to children ages 6 to 11 years.

And in January of this year, the FDA approved a prefilled autoinjector and a prefilled pen for self-injection for GlaxoSmithKline’s Nucala (mepolizumab). Both forms are approved for subcutaneous self-injection in patients 12 years or older with severe eosinophilic asthma. Caregivers may administer Nucala to children ages 6 to 11 years with approval from a healthcare professional.

 found that most patients with severe asthma preferred and felt safe self-injecting biologics at home to treat their asthma. The study, conducted in northeast Italy, surveyed 180 patients who were undergoing regular treatment for severe asthma and were using one of the following biologics: mepolizumab, omalizumab, benralizumab, or dupilumab.

After receiving self-administration instructions from a healthcare professional, 93% of participants reported that it was easy to self-administer their medication. Of these, 52% considered the process extremely easy, and 94% felt safe while self-injecting the biologic. Mild side effects were reported by 22% of patients within 2 to 3 days of self-administration. Of all participants, 97% said they would recommend self-administration of biologic treatment for severe asthma.

Xolair (omalizumab), Fasenra (benralizumab), Dupixent (dupilumab) and Nucala (mepolizumab) can now be self-administered.