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A Brief Look Into: Eosinophilic Granulomatosis With Polyangiitis (EGPA)
(formerly known as Churg-Strauss Syndrome)
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Dennis Ledford, MD
Allergist/Immunologist paid consultant to GSK
DR. DENNIS LEDFORD:
Hello, my name is Dennis Ledford and I’m an allergist/immunologist in Tampa, Florida. In this video, we’ll take a brief look into eosinophilic granulomatosis with polyangiitis – a form of vasculitis also known as EGPA, and formerly called Churg-Strauss syndrome.
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GSK’s Commitment to Transparency and Education
• We believe transparent scientific dialogue is in the interest of all those working to develop new medicines, improves clinical practice, and advances care for patients
• Our goal in peer discussion, led by clinical experts, is to inform prescribers and caregivers about new clinical data and relevant clinical experience relating to our innovative medicines
• This program contains evidence-based, truthful, balanced information, and speakers may share clinical experience consistent with the FDA-approved label
GSK is committed to transparency of financial relationships with healthcare professionals.
FDA=Food and Drug Administration
DR. DENNIS LEDFORD:
First, let’s talk about GSK’s commitment to transparency and education. GSK believes in transparent scientific dialogue and peer-to-peer discussion. GSK wants to inform prescribers about its medicines by providing quality programs with evidence-based, truthful, balanced information. As previously disclosed, I am a paid consultant to GSK. If you need more information on this program, please know that you can reach out to GSK in order to continue the conversation.
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EGPA: An Overview
EGPA was renamed from Churg-Strauss syndrome in 2012 and is defined as an eosinophil-rich, necrotizing granulomatous inflammation that often involves the respiratory tract. It is characterized by vasculitis affecting small- to medium-sized vessels.1
3 Phases of EGPA2-4
Prodromal:
Severe asthma that may precede systemic disease manifestations by many years
Eosinophilic:
Peripheral blood eosinophilia
Vasculitic:
Necrotizing vasculitis and granulomas
Not all patients experience all phases, and these phases may overlap2,4
References: 1. Jennette JC, et al. Arthritis Rheum. 2013;65(1):1-11. 2. Vaglio A, et al. Allergy. 2013;68(3):261-273. 3. Baldini C, et al. Rheum Dis Clin North Am. 2010;36(3):527-543. 4. Noth I, et al. Lancet. 2003;361(9357):587-594
DR. DENNIS LEDFORD:
Let’s begin with an overview of EGPA.
EGPA was renamed from Churg-Strauss syndrome in 2012.
EGPA is an eosinophil-rich, necrotizing, granulomatous inflammation of the blood vessels and the surrounding tissue that often involves the respiratory tract as well as other organ systems. It is characterized by vasculitis affecting small- to medium-sized blood vessels in affected organs.
EGPA is a rare disease, with approximately 5,000 people living with an EGPA diagnosis in the US.
EGPA typically has three classical phases, though there are exceptions. The first phase is a prodromal stage during which patients may have severe asthma and allergic symptoms, including sinus problems. This prodrome may precede systemic disease manifestations by many years.
The second phase is a variable peripheral blood eosinophilia and eosinophilic tissue infiltration in various organs.
Finally, the vasculitic phase is associated with necrotizing vasculitis and, less commonly, granulomas in one or more affected organs.
It’s important to emphasize that not all patients will experience all three phases. These phases may overlap, and the amount of time between phases may vary per patient.
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Diagnosis and Classification of EGPA
• With no accepted diagnostic criteria for EGPA, diagnosis is based on clinical manifestations1,2
• In 1990, the American College of Rheumatology (ACR) developed criteria that classified patients diagnosed with vasculitis into a specific subset1
– These criteria are meant for classification and not diagnostic purposes
Presence of ≥4 criteria
yields a sensitivity of 85% and a specificity of 99.7% for EGPA
· Asthma
· Eosinophilia (>10% of white blood cell count)
· Mononeuropathy or polyneuropathy
· Transient pulmonary infiltrates on chest x-rays
· Biopsy showing extravascular eosinophils
· Paranasal sinus abnormality
References: 1. Masi AT, et al. Arthritis Rheum. 1990;33(8):1094-1100. 2. Vaglio A, et al. Allergy. 2013;68(3):261-273.
DR. DENNIS LEDFORD:
So how is EGPA diagnosed? Well, there are currently no universally accepted EGPA diagnostic criteria, so the diagnosis is typically made based on clinical manifestations. In 1990, the American College of Rheumatology developed classification criteria for EGPA in patients diagnosed with systemic vasculitis. While these criteria are meant for classification purposes, and not diagnostic purposes, they include: the presence of asthma, eosinophilia, mononeuropathy or polyneuropathy, transient pulmonary infiltrates on chest X-rays, biopsy showing extravascular eosinophils or eosinophilic vasculitis, and paranasal sinus abnormality.
The presence of four or more of these criteria have a sensitivity of 85% and a specificity of 99.7% for EGPA.
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Treatment of EGPA
Key Goals of Therapy
• Control the Disease and Preserve Organ and Tissue Function: One of the main goals is to induce and maintain remission and to prevent organ damage
• Reduce Drug-Related Toxicities: Corticosteroid sparing is a key goal
Reference: Groh M, et al. Eur J Intern Med. 2015;26(7):545-553.
DR. DENNIS LEDFORD:
There are two key goals in the management of EGPA.
First, we want to control the disease, and preserve organ and tissue function. So, we should be thinking about how can we induce and maintain remission, and help prevent organ damage.
Second, we want to reduce drug-related toxicities. A key goal is sparing corticosteroid use.
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NUCALA (mepolizumab):
The first and only FDA-approved treatment for adults with eosinophilic granulomatosis with polyangiitis (EGPA).
Important Safety Information
CONTRAINDICATIONS: NUCALA should not be administered to patients with a history of hypersensitivity to mepolizumab or excipients in the formulation.
NUCALA is also indicated for the:
· add-on maintenance treatment of patients 6 years and older with severe asthma with an eosinophilic phenotype. NUCALA is not indicated for the relief of acute bronchospasm or status asthmaticus.
· treatment of adult and pediatric patients aged 12 years and older with hypereosinophilic syndrome (HES) for ≥6 months without an identifiable non-hematologic secondary cause.
Additional Important Safety Information is presented later in this video
Please see additional Important Safety Information for NUCALA throughout this video.
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Please see full Prescribing Information, including Patient Information, available at NUCALAHCP.com.
DR. DENNIS LEDFORD:
With these goals in mind, let’s discuss NUCALA, mepolizumab, which is the first and only FDA-approved treatment for adults with eosinophilic granulomatosis with polyangiitis, or EGPA.
NUCALA should not be administered to patients with a history of hypersensitivity to mepolizumab or excipients in the formulation. These excipients include polysorbate 80.
You may already be familiar with NUCALA for its other indications—as an add-on treatment for patients 6 years and older with severe eosinophilic asthma; or for the treatment of hypereosinophilic syndrome, also known as HES, in adult and pediatric patients 12 years and older, with HES that has been present for 6 months or more, without an identifiable non-hematologic secondary cause. Please note that NUCALA is not indicated for the relief of acute bronchospasm or status asthmaticus.
I will present more Important Safety Information later in this video.
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NUCALA: Mechanism of Action and Pharmacodynamics
Mepolizumab is a humanized IL-5 antagonist monoclonal antibody
[image of eosinophil]
IL-5 is the major cytokine responsible for the growth and differentiation, recruitment, activation, and survival of eosinophils.
Mepolizumab binds to IL-5 and inhibits the bioactivity of IL-5 by blocking its binding to the alpha chain of the IL-5 receptor complex expressed on the eosinophil cell surface.
This inhibits IL-5 signaling and reduces the production and survival of eosinophils.
NUCALA reduced blood eosinophil level by 83% within 4 weeks.
The mechanism of action of mepolizumab in EGPA has not been definitively established.
Results are descriptive. The clinical significance of these pharmacodynamic data is unknown.
IL-5=interleukin 5.
DR. DENNIS LEDFORD:
While the mechanism of action of NUCALA in EGPA has not been definitively established, let’s review how it is thought to work.
NUCALA, or mepolizumab, is a humanized interleukin-5 antagonist, monoclonal antibody.
IL-5 is the major cytokine responsible for the growth, differentiation, recruitment, activation, and survival of eosinophils.
NUCALA binds to IL-5, and this action blocks IL-5 from binding to the IL-5 receptor, thereby inhibiting the IL-5 signaling process. This reduces the production and survival of eosinophils.
In fact, within 4 weeks, NUCALA reduced blood eosinophil levels by 83%. These results are descriptive and the clinical significance of these pharmacodynamic data is not known.
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Important Safety Information (cont’d)
WARNINGS AND PRECAUTIONS
Hypersensitivity Reactions
Hypersensitivity reactions (eg, anaphylaxis, angioedema, bronchospasm, hypotension, urticaria, rash) have occurred with NUCALA. These reactions generally occur within hours of administration but can have a delayed onset (ie, days). If a hypersensitivity reaction occurs, discontinue NUCALA.
Acute Asthma Symptoms or Deteriorating Disease
NUCALA should not be used to treat acute asthma symptoms, acute exacerbations, or acute bronchospasm.
Opportunistic Infections: Herpes Zoster
Herpes zoster infections have occurred in patients receiving NUCALA. Consider vaccination if medically appropriate.
Reduction of Corticosteroid Dosage
Do not discontinue systemic or inhaled corticosteroids abruptly upon initiation of therapy with NUCALA. Decreases in corticosteroid doses, if appropriate, should be gradual and under the direct supervision of a physician. Reduction in corticosteroid dose may be associated with systemic withdrawal symptoms and/or unmask conditions previously suppressed by systemic corticosteroid therapy.
Parasitic (Helminth) Infection
Treat patients with pre-existing helminth infections before initiating therapy with NUCALA. If patients become infected while receiving NUCALA and do not respond to anti-helminth treatment, discontinue NUCALA until infection resolves.
Please see additional Important Safety Information for NUCALA throughout this video.
DR. DENNIS LEDFORD:
Hypersensitivity reactions, including anaphylaxis, angioedema, bronchospasm, hypotension, urticaria, and rash have occurred with NUCALA. These reactions generally occur within hours of administration but can have a delayed onset. If a hypersensitivity reaction occurs, discontinue NUCALA.
NUCALA should not be used to treat acute asthma symptoms, acute exacerbations, or acute bronchospasm.
Herpes zoster infections have occurred in patients receiving NUCALA. Consider vaccination if medically appropriate.
Do not discontinue systemic or inhaled corticosteroids abruptly upon initiation of therapy with NUCALA. Decreases in corticosteroid doses, if appropriate, should be gradual and under the direct supervision of a physician. Reduction in corticosteroid dose may be associated with systemic withdrawal symptoms and/or unmask conditions previously suppressed by systemic corticosteroid therapy.
Treat patients with pre-existing helminth infections before initiating therapy with NUCALA, as eosinophils are a component of immune response to parasites. If patients become infected while receiving NUCALA and do not respond to anti-helminth treatment, discontinue NUCALA until infection resolves.
I will be presenting additional Important Safety Information later in this video.
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Efficacy and Safety Results for NUCALA
Mepolizumab Treatment in Relapsing or Refractory EGPA
(MIRRA Study)
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Please see additional Important Safety Information for NUCALA throughout this video.
DR. DENNIS LEDFORD:
Now let’s review the efficacy and safety results for NUCALA from the Mepolizumab Treatment in Relapsing or Refractory EGPA Study, also known as the MIRRA study.
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Clinical Study for EGPA—Mepolizumab Treatment in Relapsing or Refractory EGPA—MIRRA STUDY
[Table]
Phase 3, randomized, placebo-controlled, double-blind study (N=136)
Screening: Weeks -4 to 0 all patients received stable OCS dose
NUCALA 300 mg + SOC (n=68)
Placebo + SOC (n=68)
Weeks 0 to 4, patients received stable OCS dose – Starting at Week 4, OCS tapering could begin
Follow-up: Weeks 52 to 60 (last dose administered at Week 48)
300 MG OF NUCALA ADMINISTERED SUBCUTANEOUSLY AS THREE 100-MG INJECTIONS EVERY 4 WEEKS
• SOC was defined as OCS (prednisolone or prednisone) ± immunosuppressants
• At Week 4 (and thereafter): OCS dose could be tapered per physician judgment or a suggested protocol
OCS=oral corticosteroids; SOC=standard of care.
Reference: Wechsler ME, et al. N Engl J Med. 2017;376(20):1921-1932.
DR. DENNIS LEDFORD:
The MIRRA study was a phase 3, randomized, placebo-controlled, double-blind study. Prior to randomization, there was a 4-week screening period during which all patients received a stable dose of daily oral corticosteroids, or OCS.
Patients were randomized into one of two groups and received either NUCALA 300 mg administered subcutaneously as three 100-mg injections every 4 weeks, or three placebo injections, both in combination with standard of care. The trial was for a 52-week treatment period.
Standard of care was defined as oral corticosteroid therapy with or without immunosuppressants.
Treatment with OCS, but not other therapies, was gradually reduced at the investigator’s discretion, starting from Week 4 through the end of the study.
The follow-up period of the trial extended from Week 52 to Week 60.
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Clinical Study Population—MIRRA STUDY
Key inclusion criteria1
· EGPA diagnosis for ≥6 months based on the history/presence of asthma
and eosinophilia (eosinophil level >10% or absolute count >1000 cells/μL)
· Relapsing or refractory disease on a stable OCS dose ≥7.5 mg/day but
not ˃50 mg/day
· Plus at least TWO additional features of EGPA
– Histopathologic evidence of eosinophilia*
– Neuropathy†
– Pulmonary infiltrates
– Sinonasal abnormality
– Cardiomyopathy‡
– Glomerulonephritis
– Alveolar hemorrhage
– Palpable purpura
– ANCA positivity§
Key exclusion criteria2
• Patients with GPA or MPA
• Organ-threatening or life-threatening EGPA within 3 months before screening
• Certain medications that required a predetermined washout period (eg, rituximab, cyclophosphamide)
*Defined as evidence of eosinophilic vasculitis, perivascular eosinophilic infiltration, or eosinophil-rich granulomatous inflammation.
†Mono or poly (motor deficit or nerve conduction abnormality).
‡Established by means of echocardiography or MRI.
§MPO or PR3.
ANCA=antineutrophil cytoplasmic antibody; GPA=granulomatosis with polyangiitis; MPA=microscopic polyangiitis; MPO=myeloperoxidase; MRI=magnetic resonance imaging; PR3=proteinase 3.
References: 1. Wechsler ME, et al. N Engl J Med. 2017;376(20):1921-1932. 2. Supplement to: Wechsler ME, et al. N Engl J Med. 2017;376(20 suppl):1-23.
DR. DENNIS LEDFORD:
To be included in the study, patients had to meet the following inclusion criteria: Patients had to have an EGPA diagnosis for at least 6 months based on a past medical history of asthma and eosinophilia, which was characterized by an eosinophil level over 10% of total white blood cells, or an eosinophil count over 1000 cells per microliter.
Additionally, their EGPA had to be relapsing or refractory while on a stable dose of oral corticosteroids between 7.5 and 50 milligrams per day.
Lastly, patients had to exhibit at least two additional features of EGPA, including histopathologic evidence of eosinophilia, mono- or polyneuropathy, pulmonary infiltrates, and sinonasal abnormality, or the others you see here.
The study excluded patients who had granulomatosis with polyangiitis – also known as Wegener’s granulomatosis or GPA, as well as patients who had microscopic polyangiitis, or MPA.
Patients who had organ-threatening or life-threatening EGPA within the 3 months prior to the screening period were also excluded, as were patients on certain medications requiring a washout period, such as rituximab or cyclophosphamide.
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Demographics and Baseline Characteristics—MIRRA STUDY
[Table]
Baseline Characteristics1,2
Baseline Characteristics1,2
NUCALA 300 mg + SOC (n=68), Placebo + SOC (n=68)
Mean (SD) age, years, 48.7 (12.4), 48.2 (14.3)
Female, %, 62, 56
White, %, 94, 90
Mean disease duration (SD), years, 5.2 (4.4), 5.9 (4.9)
History of ANCA positivity, %, 19, 19
Relapsing disease, %, 75, 72
Refractory disease, % , 50, 59
History of ≥1 admission to the intensive therapy unit, %, 12, 19
Median OCS (prednisolone/prednisone) dose, mg/day, 12, 11
High-dose OCS (>20 mg/day), %, 16, 15
Immunosuppressive therapy*, %, 60, 46
Baseline blood eosinophil count (geometric mean), cells/μL, 177, 172
*The most common immunosuppressive therapies at baseline were azathioprine, methotrexate, and mycophenolic acid.
Reference: 1. Data on file, GSK. 2. Wechsler ME, et al. N Engl J Med. 2017;376(20):1921-1932.
DR. DENNIS LEDFORD:
Looking at the baseline characteristics, we can see the two groups are similar.
Most patients in the study were Caucasian, in their late 40s, and had EGPA for between 5 and almost 6 years.
A large percentage of patients experienced a history of at least 1 confirmed relapse in the 2 years prior, with 75% and 72% in the NUCALA group and placebo group, respectively. Patients’ median oral corticosteroid dose was 12 mg per day in the NUCALA group and 11 mg per day in the placebo group.
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Co-primary Endpoints—MIRRA STUDY
Remission
• Total accrued duration of remission over 52 weeks
• Proportion of patients in remission at both Week 36 and Week 48
Study definition of remission*
BVAS1† = 0 (No active vasculitis in any of 9 organ systems)
Prednisolone or prednisone dose ≤4 mg/day +
· GENERAL
· CUTANEOUS
· NERVOUS SYSTEM
· ENT
· CHEST
· CARDIOVASCULAR
· ABDOMINAL
· RENAL
· MUCOUS MEMBRANES/EYES
*This study definition was more stringent than the EULAR definition of remission (BVAS=0 and OCS dose ≤7.5 mg/day).2,3
†BVAS (Birmingham Vasculitis Activity Score) is a standardized, validated measure of vasculitis. Scores can range from 0 to 63, with higher scores meaning more active disease.1,4
ENT=ear, nose, and throat; EULAR=European League Against Rheumatism.
Reference: 1. Supplement to: Mukhtyar C et al. Ann Rheum Dis. 2009;68(12 suppl):1-3.
2. Wechsler ME et al. N Engl J Med. 2017;376(20):1921-1932. 3. Hellmich B et al. Ann Rheum Dis. 2007;66(5):605-617. 4. Mukhtyar C et al. Ann Rheum Dis. 2009;68(12):1827-1832.
DR. DENNIS LEDFORD:
One of the primary endpoints of the MIRRA study was to look at remission, which as I noted earlier is one of the key goals in managing EGPA. MIRRA had 2 co-primary endpoints that were total accrued duration of remission, over the 52-week treatment period, and the proportion of patients in remission at Weeks 36 and 48.
Remission was defined as an oral corticosteroid dose of less than or equal to 4 mg per day and a Birmingham Vasculitis Activity Score, or BVAS, of zero. This definition is more stringent than the EULAR definition of remission, which is a BVAS score of zero and an OCS dose less than or equal to 7.5 mg per day.
BVAS is a validated clinical tool that assesses disease activity in systemic vasculitis on a scale from 0-63. A score of zero means there is no active vasculitis in any of the nine organ systems you see on the slide.
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Longer Time in Remission With NUCALA—MIRRA STUDY
Co-primary endpoints
• Patients spent significantly more time in remission (defined as BVAS=0 and OCS* ≤4 mg/day) with NUCALA 300 mg + SOC vs placebo + SOC over the 52-week study (OR: 5.9; 95% CI: 2.7, 13.0)
• Significantly more patients were in remission (defined as BVAS=0 and OCS ≤4 mg/day) at both Week 36 and Week 48 with NUCALA vs placebo (OR: 16.7; 95% CI: 3.6, 77.6)
Remission achieved at both Week 36 and 48
32%: NUCALA 300 mg + SOC (n=22) vs 3%: Placebo + SOC (n=2)
[Bar Chart]
Percentage of patients who achieved some time in remission over 52 weeks
19%: Placebo + SOC (n=68) vs 53%: NUCALA 300 mg + SOC (n=68)
19% corresponds to n=13; 53% corresponds to n=36
Subanalysis, results are descriptive
*Prednisolone or prednisone.
CI=confidence interval; OR=odds ratio.
Reference: Wechsler ME, et al. N Engl J Med. 2017;376(20):1921-1932.
DR. DENNIS LEDFORD:
When we look at the results, the first primary endpoint was achieved in that patients on NUCALA 300 mg plus standard of care spent significantly more time in remission than patients who received placebo plus standard of care over the 52-week study.
The second primary endpoint was also met, as significantly more patients were in remission at both Week 36 and 48 with NUCALA vs placebo, at 32% vs 3%, respectively.
Thus, both co-primary endpoints were achieved.
A subanalysis showed that 53% of the patients achieved some time in remission during the treatment period, versus 19% of patients in the placebo arm. Results are descriptive.
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Fewer Relapses With NUCALA—MIRRA STUDY
Other endpoint
• NUCALA significantly reduced the annualized relapse rate by half vs placebo (rate ratio: 0.50; 95% CI: 0.36, 0.70)
[Bar Chart]
Annualized relapse rate by number of yearly relapses
2.27 Years: Placebo + SOC (n=68) vs 1.14 Years: NUCALA 300 mg + SOC (n=68)
50% reduction
Endpoint was not adjusted for multiplicity
· Relapse was defined as a worsening related to vasculitis, asthma, or sinonasal symptoms requiring an increase in dose of corticosteroids, increase in dose or addition of immunosuppressive therapy, or hospitalization.
Reference: Wechsler ME, et al. N Engl J Med. 2017;376(20):1921-1932.
DR. DENNIS LEDFORD:
Another endpoint from this study showed that NUCALA significantly reduced the annualized relapse rate versus the placebo group.
Relapse was defined as a worsening related to vasculitis, asthma or sinonasal symptoms requiring an increase in the dose of corticosteroids, an increase in dose or addition of immunosuppressants, or hospitalization.
The MIRRA study demonstrated that NUCALA significantly reduced the annualized relapse rate by 50% versus the placebo group, as shown by this other endpoint. This endpoint was not adjusted for multiplicity.
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Lower Daily OCS Dose With NUCALA—MIRRA STUDY
Secondary endpoint
• Significantly more patients receiving NUCALA achieved a lower daily OCS dose during Weeks 48 to 52 vs placebo (OR 0.20; 95% CI: 0.09, 0.41)*†
Based on this secondary endpoint, in the last 4 weeks of treatment plus SOC:
59%: NUCALA 300 mg + SOC (n=40) vs 33%: Placebo + SOC (n=23) of patients reduced OCS use to ≤7.5 mg
44%: NUCALA 300 mg + SOC (n=30) vs 7%: Placebo + SOC (n=5) of patients reduced OCS use to ≤4 mg
18%: NUCALA 300 mg + SOC (n=12) vs 3%: Placebo + SOC (n=2) of patients did not require OCS
Results are descriptive
*After Week 4, OCS (prednisolone or prednisone) dose could be tapered per physician judgment or a suggested protocol.
†Analyzed using a proportional odds model with covariates of treatment group, baseline OCS daily dose, baseline BVAS, and region.
Reference: Wechsler ME, et al. N Engl J Med. 2017;376(20):1921-1932.
DR. DENNIS LEDFORD:
A secondary endpoint also revealed that significantly more patients receiving NUCALA achieved a lower daily OCS dose during Weeks 48-52 versus placebo. If you recall, the median daily OCS dose of patients in this trial was 12 mg per day in the NUCALA group and 11 mg per day in the placebo group at baseline.
Based on the results of the secondary endpoint, in the last 4 weeks of the treatment period, 59% of patients receiving NUCALA reduced their steroid dose to 7.5 mg per day or less, 44% reduced their dose to 4 mg per day or less, and 18% were able to discontinue use of daily OCS. This was compared to 33%, 7%, and 3%, respectively, in the placebo group. These results are descriptive.
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Lower Daily OCS Dose With NUCALA—MIRRA STUDY
Other endpoint
• Difference in OCS dose over time with NUCALA*
Line graph detailing median prednisolone/prednisone daily dose in milligrams by study week for NUCALA 300 mg + SOC (n=68) vs Placebo + SOC (n=68).
These results are descriptive and not adjusted for multiplicity.
From The New England Journal of Medicine, Wechsler ME, Akuthota P, Jayne D, et al; for the EGPA Mepolizumab Study Team. Mepolizumab or placebo for eosinophilic granulomatosis with polyangiitis, Supplementary Appendix, Page 12. Copyright © 2017 Massachusetts Medical Society. Reprinted with permission from the Massachusetts Medical Society.
*NUCALA and placebo were administered in addition to SOC. After Week 4, OCS (prednisolone or prednisone) dose could be tapered per physician judgment or a suggested protocol.2
BL=baseline.
References: 1. Supplement to: Wechsler ME, et al. N Engl J Med. 2017;376(20)(suppl):1-23.
2. Wechsler ME, et al. N Engl J Med. 2017;376(20):1921-1932.
DR. DENNIS LEDFORD:
Finally, the MIRRA study showed that EGPA patients treated with NUCALA could lower daily oral corticosteroid dose over time. In the last 4 weeks of the study, the median OCS dose for the NUCALA group was 5 mg per day compared with 10 mg per day in the placebo group. These results are descriptive and are not adjusted for multiplicity.
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Important Safety Information (cont’d)
ADVERSE REACTIONS
In a 52-week clinical trial in patients with EGPA receiving 300 mg of NUCALA, no additional adverse reactions were identified to those reported in severe asthma clinical trials.
Adverse reactions with NUCALA 100 mg with ≥3% incidence and more common than placebo in patients with severe asthma (first 24 weeks of Trials 2 and 3)
[Table]
Adverse Reaction, %
NUCALA 100 mg (n=263), Placebo (n=257)
Headache, 19, 18
Injection site reaction, 8, 3
Back pain, 5, 4
Fatigue, 5, 4
Influenza, 3, 2
Urinary tract, 3, 2
Abdominal pain upper, 3, 2
Pruritus, 3, 2
Eczema, 3, <1
Muscle spasms, 3, <1
Please see additional Important Safety Information for NUCALA throughout this video.
DR. DENNIS LEDFORD:
Now that we have reviewed efficacy, I’ll walk you through the safety data.
During the 52-week study period, in EGPA patients receiving 300 mg of NUCALA, no additional adverse reactions were identified to those reported in severe asthma clinical trials.
From the severe asthma trials, in patients receiving NUCALA 100 mg every 4 weeks, the most common adverse reactions, occurring in 3% or more of patients and more common than placebo, included headache, injection site reaction, back pain, fatigue, influenza, urinary tract infection, upper abdominal pain, pruritus, eczema, and muscle spasms.
TEXT ONSCREEN & DR. DENNIS LEDFORD:
Important Safety Information (cont’d)
ADVERSE REACTIONS
In clinical trials in patients with severe asthma (100 mg of NUCALA), the most common adverse reactions (≥5%) were headache, injection site reaction, back pain, and fatigue.
In clinical trials in patients with EGPA or HES (300 mg of NUCALA), no additional adverse reactions were identified to those reported in severe asthma clinical trials.
Systemic reactions (allergic and nonallergic), including hypersensitivity, occurred in clinical trials in patients receiving NUCALA. Manifestations included rash, flushing, pruritus, headache, myalgia, fatigue, hypertension, warm sensation in trunk and neck, cold extremities, dyspnea, stridor, angioedema, and multifocal skin reaction. A majority of systemic reactions were experienced the day of dosing.
USE IN SPECIFIC POPULATIONS
A pregnancy exposure registry monitors pregnancy outcomes in women with asthma exposed to NUCALA during pregnancy. To enroll call 1-877-311-8972 or visit www.mothertobaby.org/asthma.
The data on pregnancy exposures from the clinical trials are insufficient to inform on drug-associated risk. Monoclonal antibodies, such as mepolizumab, are transported across the placenta in a linear fashion as the pregnancy progresses; therefore, potential effects on a fetus are likely to be greater during the second and third trimesters.
Please see additional Important Safety Information for NUCALA throughout this video.
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Clinical Benefit: Post Hoc Analysis
Clinical benefit composite endpoint, defined as:
Remission* (BVAS=0 and OCS ≤4 mg/day), And/Or No relapse†, And/Or ≥50% reduction from baseline in average OCS dose from Weeks 48 to 52
[Bar Chart]
Percentage of Patients Achieving Clinical Benefit
32%: Placebo + SOC (n=68) vs 78%: NUCALA 300 mg + SOC (n=68)
32% corresponds to n=22; 78% corresponds to n=53
A greater percentage of patients receiving NUCALA experienced clinical benefit vs placebo
These results are descriptive only and considered exploratory.
*Remission at any time during the study.
†Relapse defined as worsening related to vasculitis, asthma, or sinonasal symptoms requiring an increase in dose of corticosteroids or immunosuppressive therapy or hospitalization.
Reference: Steinfeld J, et al. J Allergy Clin Immunol. 2019;143(6):2170-2177.
DR. DENNIS LEDFORD:
Lastly, I would like to share with you the results of a post-hoc analysis that looked at a clinical benefit composite endpoint. This was defined as achieving remission at any time during the study per the study’s definition (daily OCS 4 mg or less AND a Birmingham Vasculitis Activity Score, or BVAS, of zero), and/or no relapse, and/or 50% or greater reduction from baseline in average daily oral corticosteroid dose during Weeks 48-52.
Results from this analysis showed a greater percentage of patients receiving NUCALA achieved this composite clinical endpoint versus placebo, at 78% versus 32%, respectively. These results are descriptive and considered exploratory.
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Dosage and Administration
· The recommended dosage of NUCALA for EGPA is 300 mg, administered as 3 separate 100-mg subcutaneous (SC) injections once monthly (every 4 weeks)
· NUCALA is administered into the thigh and/or abdomen (or upper arm, only by HCP or caregiver) at least 2 inches (5 cm) apart
[Image of In Office Lyophilized Powder]
· Lyophilized powder should be reconstituted and administered by an HCP
· Preparation of the 300-mg dose of NUCALA requires the reconstitution of 3 separate 100-mg vials
· In line with clinical practice, monitoring of patients after administration of biologic agents is recommended
[Image of At Home Autoinjector]
· At-home administration is intended for use under the guidance of an HCP after determining that at-home use is appropriate
· Provide training on the proper preparation and administration using the Instructions for Use
Inform patients that hypersensitivity reactions have occurred with NUCALA.
HCP=healthcare professional.
DR. DENNIS LEDFORD:
Now that we understand the potential benefits of NUCALA for patients with EGPA, it’s important to know how NUCALA is administered, and what options there are for patients.
When prescribing NUCALA for EGPA, the recommended dosage is 300 mg every 4 weeks, and it is administered as three separate, 100-mg subcutaneous injections.
NUCALA can be administered in the office by a healthcare professional. Each of the three
100-mg vials of lyophilized powder requires reconstitution to comprise the 300-mg dose. In line with clinical practice, patients should be monitored after administration of biologic agents.
NUCALA can also be administered at home with an Autoinjector. The Autoinjector is an option for adults who are judged to be appropriate for at-home administration and are properly trained. Make sure to review the Instructions for Use and educate your patients on the proper way to prepare and inject at home and monitor for any side effects.
You can find more information, including videos, in the Dosing and Administration section of NUCALAHCP.com.
TEXT ONSCREEN:
NUCALA–The Only FDA-Approved Treatment for EGPA
In a 52-week study, NUCALA 300 mg + SOC increased the time in remission, reduced relapses, and reduced daily OCS dose vs placebo + SOC
LONGER Remission
Patients spent significantly more time in remission (defined as BVAS=0 and OCS* ≤4 mg/day) (OR: 5.9; 95% CI: 2.7, 13.0)
FEWER Relapses
Annual relapses were reduced by half with NUCALA vs placebo (rate ratio: 0.50; 95% CI: 0.36, 0.70); relapses were defined as worsening symptoms that required increased steroid dose, or increase in dose or start of immunosuppressants, or hospitalization
LOWER OCS Dose
More patients significantly reduced their OCS dose during the last 4 weeks (OR: 0.20; 95% CI: 0.09, 0.41)
*Prednisolone or prednisone
DR. DENNIS LEDFORD:
In summary, NUCALA is the only FDA-approved treatment for EGPA.
In the MIRRA study, patients who received NUCALA 300 mg spent significantly more time in remission, had fewer relapses, characterized by a 50% reduction in their annualized relapse rate, and they achieved lower OCS doses, as shown during the last four weeks of the study.
TEXT ONSCREEN:
NUCALA Is the Only EGPA Treatment to Offer:
Once-monthly dosing (Administered every 4 weeks) + No loading dose + Fixed dose (Independent of weight)
DR. DENNIS LEDFORD:
NUCALA is the only EGPA treatment to offer your patients once-monthly dosing, no loading dose, and a fixed dose, independent of weight.
Thank you for your time. I hope you found the information in this video helpful in caring for and managing your patients with EGPA.
TEXT ONSCREEN:
Please see full Prescribing Information, including Patient information, for NUCALA at www.nucalahcp.com
TEXT ONSCREEN:
[NUCALA logo]
Trademarks are owned by or licensed to the GSK group of companies.
@2021 GSK or licensor.
MPLVID200039 March 2021
