Severe Allergic Asthma Treatment

Options By: Joseph DiMasso

Overview of Presentation

• Background of severe allergic asthma

• Therapies to manage severe allergic asthma

• Therapeutic efficacy of the treatment agents

• Cost effectiveness of the treatment agents

What is severe allergic asthma?

• A hypersensitive immune reaction that leads to:

• Airway inflammation, intermittent airflow obstruction, and bronchial hyperresponsiveness (more sensitive to airway narrowing stimuli)

• Cytokines play a critical role in amplifying inflammatory response

• Those specific to allergic inflammation: IL-4,5,9, & 13

• These are derived from Th2

How is severe allergic asthma controlled?

High Dose ICS + LABA

• Step 5 & 6 recommendation:

• Control symptoms & exacerbations for most pts

• Works by treating & reducing the inflammation

Addition of a biologic• Xolair, Cinqair or Nucala:

• Provides eosinophil suppression unlike ICS + LABA

• Works by keeping the inflammation from developing in the first place

VS.

Ensure to rule out other contributing factors

The biologic treatment targets

IgE: Xolair• MOA:

• Inhibits the binding of IgE to the IgE receptor on the surface of mast cells and basophils

• This limits the degree of release of mediators of the allergic response & reduces the number of receptors on basophils in atopic patients

IL-5: Cinqair & Nucala• MOA:

• Interleukin-5 (IL-5) antagonist that reduces the production and survival of eosinophils

• This is done by blocking the binding of IL-5 to the alpha chain of the receptor complex on the eosinophil cell surface

-Blocking IL-5: Specific for reducing eosinophilic inflammation

-Blocking IgE: Helps prevent allergic reactions

*Both aim to fix the balance between Th1 & Th2

Proposed benefits of biologic agent addition• Targets the 5-10% of pts with severe asthma; costing the

healthcare system $25 billion dollars a year• Prevents the inflammation as opposed to reducing and treating

the inflammation

• Reduce the risk of long term use of oral corticosteroids such as: • Drug induced hyperglycemia • Immunosuppression; increased risk of infection• Osteoporosis; thinning of the bones• Muscle wasting & weakness• Cataracts & Glaucoma

Potential issues of biologic agent addition• Antibody formation against the drug itself (appeared to be

transient in trials) • Unknown cancer risk• No clinical studies were conducted to assess the effect of

hepatic or renal impairment on the PK of the medications • Cannot be used in pregnancy or lactation • Not studied adequately in ages over 65yrs• Long term effects are unknown • May be very costly yet ineffective for some pts

Clinical trial result measurements

• Symptom improvement: Subjectively measured by questionnaires including the SGRQ (breathlessness attacks), AQLQ (triggers & symptoms) & the ACQ-7

• Changes in FEV1: Measured in mL at the end of each trial

• Avg decrease of OCS dose: Dose reduction after 12 weeks of therapy vs. placebo

• Total exacerbation rate: Included pts that needed to double the dose of ICS to gain better control, initiate 3+ days of OCS as well as ER visits and hospitalizations

• Hospitalization rate: Included only those who had to stay in the hospital; this averaged 3.8 days

Clinical Trial Results Result (N=850) Xolair Placebo Symptom improvement

67.8% 61.0%

Change in FEV1 N/A N/AAvg decrease of OCS dose

44% decrease in need

-

Total exacerbation rate

35.6% 42.6%

Hospitalization rate 3.7% 4.0%Result (N=1,192)

Nucala Placebo

Symptom improvement

53.1% 42.2%

Change in FEV1 140mL 138mLAvg decrease of OCS dose

50% decrease in need

-Total exacerbation rate

7.2% 13.1%

Hospitalization rate N/A N/A

Result (N=963) Cinqair Placebo Symptom improvement

66.67% 57.0%

Change in FEV1 137mL 98mLAvg decrease of OCS dose

54% decrease in need

-

Total exacerbation rate

31.5% 49.5%

Hospitalization rate 3% 5%

Overview of Xolair (Omalizumab)

• Dosing is based on weight and baseline IgE level • Drawn up in a 18gauge syringe and injected with a 25

gauge syringe• No more than 150mg (1.2mL) injection at one site • Used in ages 12+

PK Parameter Value Bioavailabilty 62% Tmax 8days Clearance Via liver & bile T1/2 25days

Xolair Dosing

Xolair (Omalizumab)

The good • Minimal significant drug

interactions • Lowers the incidence of

asthma exacerbations if uncontrolled on high dose ICS + LABA • Lowers need of OCS usage • Cheapest option

The not so good• 45% pts get injection site rxns• Over 50% of at risk pts for

Helminthic infection (parasite) are affected • Worsening pulmonary

symptoms may occurs during OCS taper • Q2-4week SQ injection in

office

Overview of Nucala (Mepolizumab)

• 100mg SQ dose found to be equally effective to higher doses • Mechanically reconstituted then drawn up and injected in

one site• Much less injection site reactions when compared to Xolair • Must have baseline eosinophils >150 cells/uL• Used in ages 12+ PK Parameter Value

Bioavailabilty 80% Tmax 6days T1/2 20days Metabolism Enzymatic proteolysis

Nucala (Mepolizumab)

The good • Fixed dose of 100mg SQ q4wk• No dose adjustments needed• For pts with eosinophilic

asthma that may be insensitive to steroids

• Lowers the incidence of asthma exacerbations if uncontrolled on high dose ICS + LABA

• Lowers need of OCS usage

The not so good• Severe headaches occur in

20% of pts • Antibody development

occurred in 6% of pts; rendering it ineffective• Not included in guidelines• Q4wk SQ injection in office

Overview of Cinqair (Reslizumab)

• 3mg/kg IV infusion of 20-50min• May require multiple vials • Much less injection site reactions when compared to Xolair • Must have baseline eosinophils >400cells/uL• Used in ages 18+

PK Parameter Value Bioavailabilty N/A Tmax N/A T1/2 24days Metabolism Enzymatic proteolysis

Cinqair (Reslizumab)

The good• Minimal significant drug

interactions• For pts with eosinophilic

asthma that may be insensitive to steroids • Lowers the incidence of

asthma exacerbations if uncontrolled on high dose ICS + LABA • Lowers need of OCS usage

The not so good• 1-20% pts had elevated

creatine kinase levels • Associated with heart attack,

skeletal muscle & brain damage

• Not included in guidelines• Infusion Q4wk in office• Most expensive option

Are these cost effective treatments?

Xolair Avg Dose: 300mg IVAvg cost per year: $23,400QALY: $492,000 to 633,500Anticipated savings: Indirect costs due to less hospitalizations & OCS use

Nucala Avg Dose: 100mg SQ Avg cost per year: $32,500QALY: $386,000Anticipated savings: Indirect costs due to less hospitalizations & OCS use

CinqairAvg Dose: 240mg IV Avg cost per year: $55,000QALY: $322,000 to $491,000Anticipated savings: Indirect costs due to less hospitalizations & OCS use

How to apply QALY’s to a patient centered care approach

Medication QALY High Dose ICS + LABA $4,100Xolair $492,000 to 633,500Nucala $386,000Cinqair $322,000 to $491,000

*Anticipate a significant cost barrier with both the patient and insurance

Conclusion

• The biologic agents do lower the rate of exacerbations & the use of oral corticosteroids • While inhaled steroids work by treating and reducing the inflammation, anti-

IgE & IL-5 therapies works by keeping inflammation from developing in the first place.

• These agents are most effective in a certain subgroup of patients• More significant therapeutic outcomes in those with more severe asthma• Adherence of pts to inhalers was not addressed in any study prior to

enrollment

• But; extremely expensive & long term side effects as well as effectiveness are unknown

References

• http://www.aafa.org/page/asthma.aspx• http://www.ncbi.nlm.nih.gov/pubmed/21536936• https://www.gsksource.com/pharma/content/dam/GlaxoSmithKline/US/en/Prescri

bing_Information/Nucala/pdf/NUCALA-PI-PIL.PDF• http://www.fda.gov/Drugs/InformationOnDrugs/ucm493518.htm• http://www.ispor.org/ValueInHealth/ShowValueInHealth.aspx?issue=5D62980A-5

2D1-42F8-8BB6-D0D18B58EE8D• http://icer-review.org/wp-content/uploads/2016/03/

ICER_Mepolizumab_AAG_031416.pdf