eaking Kim Giordano, MSN, CRNP. CORLN Fall SOHN 2015 The following will be a discussion about the emerging use of Biologic medications.

Transcription

1 eaking Kim Hoffmann Giordano, MSN, CRNP, CORLN Division 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 period and affects physical, emotional, intellectual, vocational, social, or spiritual functioning Wikipedia Definition of Quality of Life: The standard of health, comfort, and happiness experienced by an individual or group Wikipedia 1

2 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:

3 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

4 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 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) 4

5 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 5

6 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 cost an individual $1,500 Remicade: Can cost up to $20,000 per infusion Humira: 1 carton (2 injections) can cost $3,500 6

7 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 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 Report: America s Biopharmaceutical Companies 7

8 It takes approx 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 a high deductible plan Biologics have made a profound impact in fields of: Rheumatology Dermatology Gastroenterology Neurology 8

9 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 3: Complete any antibiotic and be infection free at the start of treatment STEP 2: Live vaccines Should be done 1 3 months before starting treatment Examples of live vaccines: flu mist, shingles, MMR, small pox 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 9

10 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 hrs after a single dose Half life: 80 hours, 5 days Pregnancy Category B 10

11 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 11

12 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 B O Brien, K. Microbiology

13 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 13

14 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 14

15 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: 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 15

16 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 16

17 PRIMARY Lack of improvement of clinical signs during INDUCTION phase WHY? Most cases unexplained Some issues with pt compliance 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:

18 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 1 st 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 18

19 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 ~ 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 19

20 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, pt once 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 F CXR: RLL pneumonia Tx: Levaquin & pain meds 20

21 Back to work in 1 week: just pneumonia Within 10 days, spikes fever 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 21

22 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 22

23 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: 1 st 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 23

24 This talk is dedicated to my friends and teammates CCFA/Team Challenge: Delaware Valley 24