Early Phase Administration of Anakinra as a Rescue Treatment for Inhaled Allergen Challenge-Induced Airway Inflammation

Asthma is an increasingly common chronic illness with higher rates of hospitalization for
exacerbation than many other chronic conditions. In 2009, total asthma costs in the U.S. were
estimated at $56 billion per year, and over half the overall asthma-related costs were
attributed to inpatient hospitalization. Allergen exposure and viral infection are among the
most common triggers for asthma exacerbations. Exacerbations of allergic asthma are
characterized by an early phase response (EPR), mediated by release of preformed mediators
like histamine from mast cells, and a late phase response (LPR) 3-7 hours later mediated by
chemokines and cytokines, including IL-1β, that attract leukocytes such as neutrophils and
eosinophils to the airways, increase mucus production, trigger airway smooth muscle
contraction, and result in airway constriction and airway hyper-reactivity (AHR). The LPR is
thought to be predominantly responsible for the symptoms associated with acute exacerbations
of allergic asthma.

While corticosteroids are considered a mainstay of treatment for asthma exacerbation
regardless of the trigger, there are limitations to their effectiveness in the acute setting
including the initial lag period of 4-6 hours or more before therapeutic effect and the
concern for broad immune suppression. Corticosteroids are often ineffective in treating the
neutrophilic component of airway inflammation seen with viral infection and allergen-induced
airway inflammation. Finally, mucus plugging is a known hallmark of severe and fatal asthma,
yet there is a notable lack of effective mucolytic treatments for asthma. Time to therapeutic
benefit is key in preventing patient morbidity and mortality. Currently there is an urgent
need for anti-inflammatory treatments that work quickly and effectively in acute asthma
exacerbations.

The investigators propose that IL-1 blockade can achieve these ends and perhaps complement
corticosteroid actions. Anakinra is an FDA-approved recombinant form of human IL-1 receptor
antagonist (IL-1RA), a natural anti-inflammatory cytokine that competes with agonist binding
to the IL-1 receptor, suppressing IL-1β and IL-1a signaling. IL-1 signaling mediates key
features of viral- and allergen-induced airway inflammation. Previous studies in animal and
in vitro models demonstrate that IL-1 signaling can directly impact three aspects of an
airway inflammatory response: granulocyte (neutrophil/eosinophil) recruitment; non-specific
and allergen-specific airway reactivity; and mucin production. Numerous IL-1 blocking agents
are FDA-approved for conditions where the IL-1β pathway predominates disease pathophysiology,
such as in systemic juvenile idiopathic arthritis and the cryopyrin-associated periodic
syndromes.

Anakinra is an ideal candidate to test as a rescue treatment for acute asthma exacerbation
due to its fast onset of action (reaching peak concentrations in 3-7 hours), and a short 4-6
hour half-life. A single 1mg/kg dose (up to 100mg) of anakinra or placebo will be
administered at the onset of the EPR to model anakinra use in an emergency care setting. This
dose was chosen because it is the current FDA-approved dose for rheumatoid arthritis (RA).
Notably, the investigators have previously demonstrated that a 1 mg/kg dose resulted in
significant reduction in airway granulocyte recruitment following lipopolysaccharide (LPS)
challenge in a study of healthy volunteers. The investigators' objective is to determine if a
single 1 mg/kg dose of Anakinra can mitigate key features of asthma exacerbations, namely
AHR, airway constriction, airway inflammation, and mucous secretion/clearance.

Inclusion Criteria:

- Age range 18-45 years, inclusive

- FEV1 of at least 80% of predicted and FEV1/FVC (Forced expiratory volume in one
second/forced vital capacity) ratio of at least 0.7 (without use of bronchodilator
medications for 12 hours or long acting beta agonists for 24 hours), consistent with
lung function of persons with no more than mild episodic or mild persistent asthma.

- Physician diagnosis of asthma

- Positive methacholine inhalation challenge as performed in the separate screening
protocol within the prior 12 months (defined as provocative concentration of
methacholine of 10 mg/mL or less producing a 20% fall in FEV1 (PC20 methacholine)

- Allergic sensitization to house dust mite (D. farinae) as confirmed by positive
immediate skin prick test response

- Clinical reactivity to D. farinae assessed through inhaled allergen challenge with a
decline in FEV1 of ≥20% from baseline in the early asthmatic response and ≥15% in the
late asthmatic response.

- Negative pregnancy test for females who are not s/p hysterectomy with oophorectomy or
who have not been amenorrheic for 12 months or more.

- Oxygen saturation of >94% and blood pressure within the following limits: (Systolic
between 150-90 mmHg, Diastolic between 90-60 mmHg).

- Ability to provide an induced sputum sample.

- Negative intracutaneous tuberculin skin test (PPD) defined as less than 5mm induration
for the purpose of this protocol (positive PPD contraindication to anakinra
injection). A negative tuberculosis (TB) test within the past year (either PPD or
quantiferon TB Gold) is also acceptable

Exclusion Criteria:

Clinical contraindications:

- Any chronic medical condition considered by the PI as a contraindication to
participation in the study including significant cardiovascular disease, diabetes,
chronic renal disease, chronic thyroid disease, history of chronic infections or
immunodeficiency.

- Pregnancy or nursing a baby

- History of latex allergy/sensitivity

- Allergy/sensitivity to anakinra or its formulation

- Physician directed emergency treatment for an asthma exacerbation within the preceding
12 months.

- Exacerbation of asthma more than 2x/week which could be characteristics of a person of
moderate or severe persistent asthma as outlined in the current NHLBI guidelines for
diagnosis and management of asthma.

- Daily requirements for albuterol due to asthma symptoms (cough, wheeze, chest
tightness) which would be characteristic of a person of moderate or severe persistent
asthma as outlined in the current NHLBI guidelines for diagnosis and management of
asthma (not to include prophylactic use of albuterol prior to exercise).

- Viral upper respiratory tract infection within 4 weeks of challenge.

- Any acute infection requiring antibiotics within 4 weeks of exposure or fever of
unknown origin within 4 weeks of challenge.

- Severe asthma

- Mental illness of history of drug or alcohol abuse that, in the opinion of the
investigator, would interfere with the participant's ability to comply with study
requirements.

- Cigarette smoking >1 pack per month

- Nighttime symptoms of cough or wheeze greater than 1x/week at baseline (not during a
clearly recognized viral induced asthma exacerbation) which would be characteristic of
a person of moderate or severe persistent asthma as outlined in the current NHLBI
guidelines for diagnosis and management of asthma.

- Allergy/sensitivity to study drugs or their formulations

- Known hypersensitivity to methacholine or to other parasympathomimetic agents

- History of intubation for asthma

- Unwillingness to limit coffee, tea, cola drinks, chocolate, or other foods containing
caffeine after midnight on the days that methacholine challenge testing and inhaled
allergen challenge is to be performed

- Unwillingness to use reliable contraception if sexually active (IUD, birth control
pills/patch, condoms).

- Radiation history will be collected. Any subject whose exposure history within the
past twelve months would cause them to exceed their annual limits will be excluded

Usage of the following medications:

- Use of systemic steroid therapy within the preceding 12 months for an asthma
exacerbation. All use of systemic steroids in the last year will be reviewed by a
study physician.

- Subjects who are prescribed daily inhaled corticosteroids, cromolyn, or leukotriene
inhibitors (Montelukast or Zafirlukast) will be required to discontinue these
medications at least 4 weeks prior to their screening visit.

- Use of daily theophylline within the past month.

- Daily requirement for albuterol due to asthma symptoms (cough, wheeze, chest
tightness) which would be characteristic of a person of moderate or severe persistent
asthma as outlined in the current NHLBI guidelines for diagnosis and management of
asthma. (Not to include prophylactic use of albuterol prior to exercise).

- Use of any immunosuppressant therapy within the preceding 12 months will be reviewed
by the study physician.

- Use of any immunomodulatory therapy within the preceding 12 months.

- Use of beta blocking medications

- Antihistamines in the 5 days prior to allergen challenge

- Routine use of NSAIDs, including aspirin.

Physical/laboratory indications:

- Abnormalities on lung auscultation

- Temperature >37.8 C

- Oxygen saturation of <94%

- Systolic BP>150 mmHg or <90 mmHg or diastolic BP>90 mmHg or <60 mmHg

- Absolute neutrophil count <1.4 x 109/L

Inability or unwillingness of a participant to give written informed consent