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TRANSCRIPT
Kim Giordano, MSN, CRNP. CORLN Fall SOHN 2015
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Kim Hoffmann Giordano, MSN, CRNP, CORLNDivision of Otolaryngology
The Children’s Hospital of Philadelphia
The following will be a discussion about the emerging use of “Biologic” medications.
Highlighting on the basics of the “Biological Revolution” & how these complex compounds that are changing the quality of lives for patients with autoimmune diseases.
• Definition of Health:
• A state of complete physical, mental and social well‐being and not merely the absence of disease or infirmity World Health Organization
• Definition of Chronic Illness:
• Any disorder that persists over a long periodand affects physical, emotional, intellectual,vocational, social, or spiritual functioningWikipedia
• Definition of Quality of Life:
• The standard of health, comfort, and happiness experienced by an individual or groupWikipedia
Kim Giordano, MSN, CRNP. CORLN Fall SOHN 2015
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The last decade has seen a revolution in the treatment of patients of chronic immuno‐inflammatory diseases
These include disease processes such as:
Rheumatoid Arthritis
Psoriasis
Plaque Psoriasis
Psoriatic Arthritis
Inflammatory Bowel Diseases
Crohn’s Disease
Ulcerative Colitis
Approximately 20 years ago, it started with an appreciation of the possible role of TNF–α in the pathogenesis of auto‐immune disease
This lead to an understanding that provided the basis for the development and use of genetically engineered biopharmaceuticals specifically targeting TNF–α in patients with chronic inflammatory disorders
Bendtzen, K. Immunotherapy: 2012
Kim Giordano, MSN, CRNP. CORLN Fall SOHN 2015
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Anti‐TNF inhibitor is a pharmaceutical drug that suppresses response to Tumor Necrosis Factor (TNF), which is part of the inflammatory response
TNF is a cytokine of the immune system characterized by modulating cell death, proliferation, and inflammation
TNF is involved in clinical problems associated with autoimmune and immune mediated disorders
AKA
TNF inhibitors
Anti‐TNFs
TNF‐alpha antagonists
TNF blockers
Specifically refer to engineered macromolecular products
Protein‐based and nucleic acid‐based drugs which distinguish them from other products like blood components or vaccines
Extracted from biological sources
Chhina, M. FDA Basics. 2013
Kim Giordano, MSN, CRNP. CORLN Fall SOHN 2015
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Sugars, proteins or nucleic acids or complex combinations of the these substances
May be living entities: Cells and tissues
Isolated from a variety of sources:
Human, animal or microorganism
Produced by biotechnology methods/techniques
Gene‐based & cellular biologics are the forefront of biomedical research
Chhina, M. FDA Basics. 2013
Drugs derived from living cells target specific parts of the immune system & can affect the entire immune system.
Used more restrictively for a class of therapeutics that are produced by means of biological processes involving recombinant DNA
Personalized medicine revolution
The ultimate GMOs”
1. Substances that are nearly identical to the body’s own signaling proteins
• Example:
• Biosynthetic human insulin (Humalin‐1982)
Kim Giordano, MSN, CRNP. CORLN Fall SOHN 2015
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Similar to human immune system to fight off bacteria/viruses
“Custom designed GMOs” made specifically to counteract/block any given substance in the body
Examples:
• Infliximab (Remicade‐1998)
• Adalimumab (Humira‐2002)
• Certolizumab pegol (Cimzia‐2008)
Based on a naturally occurring receptor linked to the immunoglobulin frame
• Receptor provides the construct with detailed specificity
• Example:
• Etanercept (Enbrel‐1998)
Aspirin Molecule Monoclonal Antibody Molecule
Kim Giordano, MSN, CRNP. CORLN Fall SOHN 2015
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Very expensive drug treatments!
Costs can vary among insurance companies
Depending on which Biologic, out‐of‐pocket expenses can add up to hundreds or thousands of dollars
Examples:
Enbryl: 1 carton (4 injections) can costan individual $1,500
Remicade: Can cost up to $20,000 per infusion
Humira: 1 carton (2 injections) can cost $3,500
Kim Giordano, MSN, CRNP. CORLN Fall SOHN 2015
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Many biopharmaceutical companies offer patient financial assistance programs
Enbryl Financial Assistance
Provides up to $8,000/pt /12 month period, including co‐pays/co‐insurance and deductible
Remicade: “RemiStart” Rebate Program
Eligible commercially insured pt pays $5/infusion for out‐of‐pocket costs
Humira: AbbieVie Assistance
Qualified pts can receive monthly meds potentially free
Booming business with R&D of new medicines
World’s largest drug companies made net profit of $711.4 billion from 2003‐2011
Companies include:
Abbott, Johnson & Johnson, Janssen Biotech, AbbieVie, Amgen, Takeda
Brown, T. Medscape 2014
Over the past decade, biologics have accounted for 1/3 of new medicine approvals
Currently over 907 medicines and vaccines in development
338 separate mAbs in development
By 2013, 33 mAbs were approved by U.S.
2013 Report: America’s Biopharmaceutical Companies
Kim Giordano, MSN, CRNP. CORLN Fall SOHN 2015
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It takes approx. 10‐15 yrs to bring a new medicine thorough discovery & clinical trials to patients
Average cost for R&D is $1.2 billion
U.S. accounts for 80% of R&D in health care biotechnology
2013 Report: America’s Biopharmaceutical Companies
Being chronically ill is EXPENSIVE
Big Pharma is making BILLIONS
Big Pharma wants patients to use their meds
Be your own advocate/patient advocate and research assistance programs.
Assess insurance policies
May be more of an advantage to have a commercial HMO than ahigh deductible plan
Biologics have made a profound impact in fields of:
Rheumatology
Dermatology
Gastroenterology
Neurology
Kim Giordano, MSN, CRNP. CORLN Fall SOHN 2015
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Biological therapies are designated for patients who have failed or have had inadequate response to conventional medical management of disease processes
Typically NOT a first line medication option
STEP 1:
CXR/TB testing
Biologics will compromise immune system and TB can lay dormant for years
STEP 2:
Live vaccines
Should be done 1‐3 months before starting treatment
Examples of live vaccines: flu mist, shingles, MMR, small pox
STEP 3:
Complete any antibiotic and be infection free at the start of treatment
Symptoms of infusion reactions include flu‐like illness, fever, chills, nausea and headache
Injection site reactions
As with any drugs that suppress the immune system, biologic therapy poses some increased to infections and other diseases
Kim Giordano, MSN, CRNP. CORLN Fall SOHN 2015
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Class: Anti‐psoriatic, TNF inhibitor
FDA approved 1998
Mechanism of action
Recombinant human receptor fusion protein
Binds and inactivates TNF
Prevents synovial inflammation
Onset: Between 24‐96 hrs after a single dose
Half life: 80 hours, 5 days
Pregnancy Category B
Kim Giordano, MSN, CRNP. CORLN Fall SOHN 2015
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Injection solution
Prefilled syringes: 25mg/ml & 50 mg/ml
Prefilled auto‐injector pens: 50 mg/ml
Juvenile Rheumatoid Arthritis
Adult and Pediatric dosage
Not to be given under the age of 2 yrs
> 2 yrs < 63 kg: 0.8 mg/kg SC weekly
Not to exceed 50 mg weekly
> 63 kg: 50 mg SC weekly
Adult Rheumatoid Arthritis /Psoriatic Arthritis
50 mg SC q/wk or 25 mg SC 2x/wk given on same day or 3 days apart
May be given with or without methotrexate
Ankylosing Spondylosis
50 mg SC weekly or 25 mg SC 2x/wk
Plaque Psoriasis
50 mg SC 2x/wk x 3 months then 50 mg weekly for maintenance
Increased risk for serious infection resulting in hospitalization or death
Patients > 65 at greater risk
Serious, sometimes fatal infections include reactivation of latent TB & hepatitis B, invasive fungal infections, & bacterial infections
Malignancy
Lymphoma and other malignancies, some fatal
Kim Giordano, MSN, CRNP. CORLN Fall SOHN 2015
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Upper respiratory tract infections(38%)***
Injection site reaction (37%)
URI (29%)
Headache (17%)
Rhinitis (12%)***
Nausea (9%)
Pharyngitis (7%)***
Heme:
Thrombocytopenia, aplastic anemia, leukopenia
Hepatobiliary disorders:
Autoimmune hepatitis, elevated transaminase
Class: Monoclonal antibody
FDA approved 1998
Mechanism of action:
Recombinant humanized monoclonal anti‐TNF‐α
Chimeric: 75% Human/25% Mouse mAb
Prevents synovial and intestinal inflammation
Onset: Approximately 2 weeks
Half life: 7‐40 days* (varies in literature)
Pregnancy Category Class BO’Brien, K. Microbiology 2010
Kim Giordano, MSN, CRNP. CORLN Fall SOHN 2015
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Administration: IV Infusion
Adults and Children (6‐17 yrs)
Dosage
RA: 3 mg/kg IV at 0, 2, 6 weeks and q 8 weeks
Crohn’s/UC /Psoriasis /Plaque Psoriasis:
5 mg/kg IV at 0, 2, 6 weeks and q 8 weeks
***If incomplete response is noted, dose may be increased to 10 mg/kg or increase frequency to every 4 weeks
Depends on institution
May be premediated with Benadryl, acetaminophen and steroids to avoid infusion reactions
IV infusion over 2‐4 hrs
Monitor patient for acute infusion reactions
Do not infuse with any other agents
Kim Giordano, MSN, CRNP. CORLN Fall SOHN 2015
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Serious infections, sometimes fatal
Serious, sometimes fatal blood disorders
Lymphoma and solid tissue cancers
Liver injury/hepatotoxicity
Reactivation of hepatitis B
Reactivation of tuberculosis
Lethal hepato‐splenic T‐cell lymphoma*
Drug induced SLE (Lupus‐like syndrome)
Demyelinating CNS disorders
Development of antinuclear antibodies (50%)
Infection (36%)
URI (32%) *****
Nausea (21%)
Infusion reaction (20%)
Other respiratory infections (12‐14%)****
Sinusitis, cough, pharyngitis, bronchitis
Rhinitis (8%)*****
Lupus‐like syndrome (<5%)
Serious infections and malignancies including melanoma and non melanoma skin cancer
Kim Giordano, MSN, CRNP. CORLN Fall SOHN 2015
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Class: Monoclonal antibody
FDA approved 2002
RA/PA/AS/UC/CD/PP/JIA
Mechanism of action:
Fully humanized anti‐TNF‐α
Makes it suitable for long‐term use
Onset: Rapid ‐ 2 weeks
Half Life: 10‐20 days
Pregnancy Class B
Administer: SC injection every other wk
Auto‐inject Pen: 40 mg/0.8 ml
Prefilled Syringe: 40 mg/0.8 ml; 20 mg/0.4 ml; 10 mg/0.4 ml
Adult and Children: > 4 yrs
Dosage varies for specific disease processes
Induction phase:
Day 1: 4 injections
Day 15: 2 injections
Maintenance:
Day 29: 1 injection every other wk
Kim Giordano, MSN, CRNP. CORLN Fall SOHN 2015
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Serious infections, sometimes fatal
Lymphoma and solid tissue cancers
Non melanoma skin cancer
Hepatic injury
Reactivation of tuberculosis
Fatal hepato‐splenic T‐cell lymphoma*
Demyelinating CNS disorders
Cardiac failure
URI +++
Sinusitis+++
Flu Syndrome
Nausea
Abdominal Pain
Headache
Rash
Injection Site Reactions
Kim Giordano, MSN, CRNP. CORLN Fall SOHN 2015
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PRIMARY
• Lack of improvement of clinical signs during INDUCTION phase
• WHY?
Most cases unexplained
Some issues with ptcompliance in self‐admin of drugs
Often trial with increased doses/intervals
SECONDARY
• In contrast, pts initially respond to tx and eventually lose response
• WHY?
• Complex reasons
• Pt‐related factors
• Immunogenicity
• Anti‐drug antibodies
Potential hazard of all biologic agents that are engineered molecular targeted therapies
Many repeated injections/infusions may trigger antidrug antibodies
Antibodies in TNFs are exogenous proteins and are “foreign” to human immune system
Anti‐drug antibodies decrease efficacy, cause response failure &/or lead to discontinuation of therapy
Rosman, Z, Shoenfield, Y, et al: Biologic update: 2013
Kim Giordano, MSN, CRNP. CORLN Fall SOHN 2015
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Case Study
47 yo female with hx of UC x 20 yrs
Steroid dependent and no longer responding to oral/topical medications
Never been able to achieve long‐term UC remission
Disease is progressing to involve entire colon
Symptoms are more debilitating with an increase in extra‐colonic disease manifestations
Biologic #1: Remicade
2009: Remicade is started
CXR and TB testing completed
Induction started and pt was pre‐medicated with Benadryl, acetaminophen and Decadron
Pt reported feeling good after 1st
infusion but slight pain in left thumb after infusion, dismisses symptom
#1: Remicade
Remicade induction: 0, 2, 6 weeks
Pt reports feeling better at week 3 and then had break through symptoms at week 5
Maintenance infusions titrated to q 4 weeks
Pt in clinical remission
“Renewed sense of health & quality of life”
“Forgot what healthy felt like…”
Continues with thumb pain after each infusion but dismisses it as an odd reaction
Kim Giordano, MSN, CRNP. CORLN Fall SOHN 2015
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7 months on Remicade
2 weeks after infusion reports sudden hives on H&N
Symptoms progress
Migrating excruciating joint pain/swelling, fever, fatigue, malaise
Labwork: Elevated ANA and elevated liver enzymes
Dx: Drug‐induced Lupus & hepatotoxicity
Remicade is discontinued
Remicade HALF LIFE is ~ 20‐40 days
2011: After 6 months, pt begins Humira
Auto‐injector pens – Induction phase
Maintenance dose SC q 2 weeks
Symptoms better but persistent after 2 months
Dose was increased to weekly with good relief
Pt resumes active life style, feels “healthy again”
Symptoms better but persistent after 2 months
Dose was increased to weekly with good relief
Kim Giordano, MSN, CRNP. CORLN Fall SOHN 2015
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2 years later, pt experiencing increased symptoms and ultimately acknowledges Humira is no longer keeping symptoms under control.
Humira is discontinued due to secondary failure response
No adverse effects were noted
11/2012: 51 yo female begins new treatment
Induction phase: Self‐injection auto‐fill syringes
Maintenance dose: 2 syringes q month
After several weeks, symptoms improve, ptonce again reporting “ feeling healthy”
Resumes very active life style and enjoying high “quality of life”
6/2013: Pt reportedly doing well. Very active, running daily & finishes half marathon.
7/6/2013: Fatigue, malaise, weight loss, low grade temp and sudden onset shortness of breath
ER admission for acute SOB
Temp 102.1 F
CXR: RLL pneumonia
Tx: Levaquin & pain meds
Kim Giordano, MSN, CRNP. CORLN Fall SOHN 2015
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Back to work in 1 week: “just pneumonia”
Within 10 days, spikes fever 101.5 F, increased SOB, fatigue
PCP Rx: Zithromax
CXR unchanged: RLL pneumonia
CT scan: Round, dense 6 cm x 4 cm mass in right lower lobe
Critical Care/Pulmonology/ID/GI consult
Differential Diagnosis:
Lymphoma
Malignancy
Latent TB
Opportunistic infection
Pulmonary abscess
Kim Giordano, MSN, CRNP. CORLN Fall SOHN 2015
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Bronchoscopy/Lung biopsy
Pt sent home on oral ABX pending biopsy results
Bactrim
Zithromax
Biopsy results
No malignancy identified
No organism identified to interim ABX tx
Biphasic fever & extreme fatigue persists for 12 weeks
July 1 ‐ September 30, 2013
Persistent symptoms
Fever, extreme fatigue, weight loss, productive cough, poor sleep, loss of appetite
10/1/2013: Pt returns to work after 12 weeks
Not quite back to baseline, but much improved
Takes approx. 6 months to recover from pulmonary infection, but unable to resume active lifestyle
Clinically in remission from Cimzia tx
Kim Giordano, MSN, CRNP. CORLN Fall SOHN 2015
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2015: Severe UC symptoms return
5/2015: Starts ENTYVIO
A new anti‐TNF‐α approved for IBD in Fall, 2014
Induction: 0, 2, 6 weeks IV infusion over 30 mins
Maintenance: q 8 weeks IV Infusion
9/3/15: 1st maintenance infusion
So far, so good…
Biologic medications are here to stay!
Important for all health care providers to be aware of what they are and their potential side effects
MUST be aware of ORL adverse effects
The FUTURE:
Generic forms of biologics are in development and will be marketed as “Biosimilars”