FINAL SOHN Biologics Fall 2015sohnnurse.com/wp-content/uploads/441-Giordano-K-Biologics.pdforal/topical medications Never been able to achieve long‐term UC remission Disease is progressing

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


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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


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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


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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)


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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


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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


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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


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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


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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


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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


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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


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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


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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


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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


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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


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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


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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


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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


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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


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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


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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


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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


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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”


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This talk is dedicated to my friends and teammates CCFA/Team Challenge: Delaware Valley

Documents

FINAL SOHN Biologics Fall 2015sohnnurse.com/wp-content/uploads/441-Giordano-K-Biologics.pdforal/topical medications Never been able to achieve long‐term UC remission Disease is progressing