Biologic Medications Friend or foe How to navigate

Biologic Medications: Friend or foe? How to navigate this growing part of pharmacology as an ND PCP Paul S. Anderson, NMD Hawaii Doc. Talks Thursday 3/2/17 1: 50 - 2: 20

Dr. Paul Anderson – Financial Disclosures: Ownership interest in: • Advanced Medical Therapies Clinic Seattle, WA • Advanced Applications in Medical Practice Seminars • Consult. Dr. Anderson. com Educational consultant for: • Imprimis Pharmaceuticals • Canadian College of Naturopathic Medicine • Bastyr University • University of Bridgeport • Vermont Association of Naturopathic Physicians • Key 2 Health • Emerson Ecologics • Power to Practice • IV Nutritional Therapy Group • Sanoviv Hospital NOTE: Dr. Anderson is paid a fee to consult with the above and derives no financial gain from the sale of any product, referral or service. He is paid as an educational / medical consultant.

Dr. Anderson - Disclosures Ownership interest in: • Advanced Medical Therapies Clinic Seattle, WA • Advanced Applications in Medical Practice • Consult. Dr. Anderson. com Educational consultant: • Imprimis Pharmaceuticals • Canadian College of Naturopathic Medicine • Bastyr University • University of Bridgeport • Vermont Association of Naturopathic Physicians • Key 2 Health • Emerson Ecologics • Power to Practice • IV Nutritional Therapy Group • Sanoviv Hospital NOTE: Dr. Anderson is paid a fee to consult with the above and derives no financial gain from the sale of any product, referral or service. He is paid as an educational / medical consultant. (c) www. Consult. Dr. Anderson. com - 2017 3

What are they? (c) www. Consult. Dr. Anderson. com - 2017 4

S Afr Med J 2014; 104(11): 787 -791. DOI: 10. 7196/SAMJ. 8947 (c) www. Consult. Dr. Anderson. com - 2017 5

http: //www. medscape. com/viewarticle/867446_3 Strictly defined, a biologic is a treatment derived from an organic source. In this sense, vaccines for smallpox and rabies and antitoxins for diphtheria and tetanus, which were introduced in the 19 th century, were among the first biologics. [Next four slides – same reference] (c) www. Consult. Dr. Anderson. com - 2017 6

The 'Mabs‘ - Monoclonal Antibodies Monoclonal antibody names have four segments (and usually five syllables). The first segment is the decision of the drug developer. The next segment is the target or disease class, to which a vowel may be added to allow pronunciation. Before 2009, tumor-specific segments were used, but this practice has been discontinued because most monoclonal antibodies with oncology indications are investigated for more than one type of tumor. The third segment of the name indicates the source (eg, human, mouse) and is useful for predicting immunogenicity. The last syllable is "mab, " for "monoclonal antibody. " (c) www. Consult. Dr. Anderson. com - 2017 7

http: //www. nature. com/nrd/journal/v 4/n 1/fig_tab/nrd 1607_F 2. html (c) www. Consult. Dr. Anderson. com - 2017 8

Recently FDA Approved ‘Mab’s Drug Target, Source Aliro-c-u-mab (Praluent®; Sanofi US and Regeneron Pharmaceuticals, Inc. ) Cardiovascular, fully human PCSK 9 inhibitor mab for lowering LDL cholesterol Dara-tum-u-mab (Darzalex™; Janssen Biotech, Inc. ) Tumor, fully human ("tum" segment was replaced by "t" in the most current naming system) Mab for multiple myeloma Dinu-tu-xi-mab (Unituxin®; United Therapeutics) Tumor, chimeric Mab for pediatric patients with neuroblastoma Elo-tu-zu-mab (Empliciti™; Bristol-Myers Squibb) Tumor, humanized Immunostimulatory mab for multiple myeloma Evolo-c-u-mab (Repatha®; Amgen Inc. ) Cardiovascular, fully human PCSK 9) inhibitor mab for lowering LDL cholesterol Idaru-ci-zu-mab (Praxbind®; Boehringer Ingelheim Pharmaceuticals, Inc. ) Cardiovascular, humanized Mab to reverse the anticoagulant effects of dabigatran Mepo-li-zu-mab (Nucala®; Glaxo. Smith. Kline) Immunomodulator, humanized Interleukin-5 antagonist mab for severe asthma Neci-tum-u-mab (Portrazza™; Eli Lilly and Company) Tumor, fully human ("tum" segment was replaced by "t" in the most current naming system) EGFR antagonist for metastatic squamous nonsmall cell lung cancer Secu-kin-u-mab (Cosentyx; Novartis Pharmaceuticals) Interleukin, fully human ("kin" segment was replaced Interleukin-17 A antagonist mab for psoriasis by "k" in the most current naming system) (c) www. Consult. Dr. Anderson. com - 2017 9

The 'Mibs‘ – Cell Inhibitor / Manipulators The suffix "zomib" is the designation for protease or proteasome inhibitors. Mibs are small molecules that work inside cancer cells to slow proliferation and increase apoptosis (cell death). In 2015, the FDA approved ixazomib (Ninlaro®; Takeda Oncology) for multiple myeloma. Others mibs approved for use in the United States include bortezomib and carfilzomib. (c) www. Consult. Dr. Anderson. com - 2017 10

The 'Nibs‘ – Kinase Enzyme Inhibitors The suffix "nib" indicates a small-molecule inhibitor ("nib" is verbal shorthand for "inhibit") of kinase enzymes. More specifically, "tinib" is used for tyrosine kinase inhibitors, "anib" for angiogenesis inhibitors, and rafenib for rapidly accelerated fibrosarcoma (RAF) kinase inhibitors. The FDA approved four nibs in 2015: alectinib (Alecensa®; Genentech) for advanced non-small cell lung cancer, cobimetinib (Cotellic®; Genentech) for advanced melanoma, lenvatinib (Lenvima®; Eisai Inc. ) for advanced thyroid cancer, and osimertinib (Tagrisso™; Astra. Zeneca) for non-small cell lung cancer. (c) www. Consult. Dr. Anderson. com - 2017 11

The ‘Cepts’ – Antibody Mimicry Cept: “recept of” Designed antibody fusion protein that mimics an immunoglobulin (c) www. Consult. Dr. Anderson. com - 2017 12

Tumor Necrosis Factor (TNF) Inhibitors: -cept / -mab drugs Nature Reviews Rheumatology 10, 612– 627 (2014) doi: 10. 1038/nrrheum. 2014. 123 (c) www. Consult. Dr. Anderson. com - 2017 13

TNF Blockers • Adalimumab (HUMIRA, ("Human Monoclonal Antibody in Rheumatoid Arthritis") ) TNF inhibitor. • Like infliximab and etanercept, adalimumab binds to TNFα, preventing it from activating TNF receptors; adalimumab was constructed from a fully human monoclonal antibody. • Indications: rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, moderate to severe chronic psoriasis and juvenile idiopathic arthritis. • Cautions: prolonged treatment with adalimumab may slightly increase the risk of developing infections. (c) PS Anderson - www. Consult. Dr. A. com - 2016 14

Others: Nature Reviews Rheumatology 10, 612– 627 (2014) doi: 10. 1038/nrrheum. 2014. 123 (c) www. Consult. Dr. Anderson. com - 2017 15

http: //hubpages. com/health/Biologic-immunomodulators-drugs-for-Autoimmune-diseases. RA-Systemic-Lupus-Crohns-disease-CD (c) www. Consult. Dr. Anderson. com - 2017 16

http: //www. nature. com/nrd/journal/v 4/n 1/fig_tab/nrd 1607_F 2. html (c) www. Consult. Dr. Anderson. com - 2017 17

Nature Reviews Rheumatology 10, 612– 627 (2014) doi: 10. 1038/nrrheum. 2014. 123 (c) www. Consult. Dr. Anderson. com - 2017 18

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Others (quickly)… (c) www. Consult. Dr. Anderson. com - 2017 20

EICOSANOIDS MEMBRANE PHOSPHOLIPID Stimulated by: Angiotensin - 2 / Bradykinin / Epinephrine / Thrombin Phospholipase A 2 Inhibited by: CORTICOSTEROIDS ARACHADONATE Inhibited by: Lipoxygenase LEUKOTRIENES Cyclooxygenase NSAID’S PROSTAGLANDINS / (c) PS Anderson - www. Consult. Dr. A. com - 2016 THROMBOXANES 21

Leukotriene receptor antagonist • Pharmacology • Binds to cysteinyl leukotriene receptor 1 in the upper and lower airways to prevent leukotriene-mediated effects associated with asthma and allergic rhinitis. • Indications and Usage • Prophylaxis and chronic treatment of asthma in patients 12 mo of age and older; relief of symptoms of seasonal allergic rhinitis in patients 2 yr of age and older; relief of symptoms of perennial allergic rhinitis in patients 6 mo of age and older. • Prevention of exercise-induced bronchoconstriction (EIB) in patients 15 yr of age and older. • Unlabeled Uses • Chronic urticaria, atopic dermatitis. (c) PS Anderson - www. Consult. Dr. A. com - 2016 22

Leukotriene receptor antagonist Adverse Reactions • Cardiovascular; Cardiac complications, palpitations (postmarketing). • CNS; Headache (18%); asthenia/fatigue, dizziness (2%); abnormal dreams, depression, drowsiness, hallucinations, insomnia, paraesthesia/hypoesthesia, psychomotor hyperactivity (including agitation, aggressive behavior, irritability, restlessness, and tremor), seizures (postmarketing). • Dermatologic; Atopic dermatitis, eczema, skin infection, urticaria (at least 2%); rash (2%); vasculitic rash (postmarketing). • EENT; Conjunctivitis, ear pain, myopia, otitis, pharyngitis, rhinorrhea, sinusitis, tonsillitis (at least 2%); nasal congestion (2%); epistaxis (at least 1%). • GI; Diarrhea, dyspepsia, gastroenteritis, laryngitis, nausea, tooth infection (at least 2%); dental pain, infectious gastroenteritis (2%); pancreatitis, vomiting (postmarketing). • Hematologic-Lymphatic; Bruising, eosinophilia, increased bleeding tendency (postmarketing). • Hepatic; Cholestatic hepatitis, hepatocellular liver-injury, mixed-pattern liver injury (postmarketing). • Lab Tests; ALT/AST increased (2%); pyuria (1%). • Musculoskeletal; Arthralgia, myalgia (including muscle cramps) (postmarketing). • Respiratory; Influenza (4%); cough (3%); acute bronchitis, pneumonia, upper respiratory tract infection, wheezing (at least 2%); worsening of pulmonary symptoms (postmarketing). • Miscellaneous; Abdominal pain (3%); fever, varicella, viral infection (at least 2%); trauma (1%); edema, hypersensitivity (including anaphylaxis, hepatic eosinophilic infiltration, pruritus, and urticaria) (postmarketing). (c) PS Anderson - www. Consult. Dr. A. com - 2016 23

Leukotriene receptor antagonist • Montelukast Sodium - Singulair - Tablets 10 mg - Tablets, chewable 4 mg - Tablets, chewable 5 mg - Granules 4 mg/packet Dose in adults: 10 mg QD ALSO: • Zafirlukast (za-FIR-loo-kast) - Accolate • Zileuton Extended-Release Tablets Zyflo CR Extended-Release Tablets - Zyflo CR (c) PS Anderson - www. Consult. Dr. A. com - 2016 24

Interferon • Any of a group of proteins produced by cells in the body in response to an attack by a virus. • A cell infected by a virus releases minute amounts of interferons, which attach themselves to neighboring cells, prompting them to start producing their own protective antiviral enzymes. • The result is impairment of the growth and replication of the attacking virus. Interferon has also been shown to have some antitumor properties. • There are three known classes of interferons: alpha-, beta-, and gammainterferons. • Although they were discovered in the 1950 s, the medical use of interferons was impractical until the recombinant DNA techniques of genetic engineering made it possible to mass produce them. • Interferons used as drugs include alpha-interferon, for hepatitis B and C, human papillomavirus, hairy-cell leukemia, and Kaposi's sarcoma, and beta-interferon, for multiple sclerosis. The Columbia Encyclopedia. Copyright © 2001 -08 Columbia University Press. All rights reserved. (c) PS Anderson - www. Consult. Dr. A. com - 2016 25

Interferon BRAND NAMES: Roferon-A, Intron-A, Rebetron, Alferon-N, Peg-Intron, Avonex, Betaseron, Infergen, Actimmune, Pegasys • Classes: • Alpha, beta and gamma. • Actions: • direct the immune system's attack on viruses, bacteria, tumors and other foreign substances that may invade the body. • Used in: • Leukemia, Hepatitis B, C, Genital Warts • The beta interferons have been found useful in managing MS • Adverse Effects: • • Flu-like symptoms following each injection occur with all interferons. Depression and suicide are possible, but not common HYPOTHYROIDISM Other side effects with all interferons (may be caused by higher doses) • • • Fatigue diarrhea, nausea, vomiting, abdominal pain, anorexia joint aches, back pain and dizziness. congestion, increased heart rate, confusion, low white blood cell count, low platelet count, low red blood cell count, increase in liver enzymes, increase in triglycerides, (c) PS Anderson - www. Consult. Dr. A. com - 2016 26

Immune Cell Lines Thymus: Bone Marrow: Hemocytoblast Lymphoid Stem Cells T-Cell Lines B-Cells NK Cells Peripheral Tissues: Cell Mediated Immunity Ab (Humoral) Immunity Immunological Surveillance (c) PS Anderson - www. Consult. Dr. A. com - 2016 27

Tacrolimus • Pharmacology • Suppresses cell-mediated immune reactions and some humoral immunity, but exact mechanism is not known. The mechanism of action in atopic dermatitis is not known. • Indications and Usage • PO and IV Prophylaxis of organ rejection in patients receiving allogenic liver, kidney, or heart transplants. Used in conjunction with adrenal corticosteroids. • Topical As second-line therapy for the short-term and noncontinuous chronic treatment of moderate to severe atopic dermatitis. • Unlabeled Uses • PO and IV Prophylaxis of rejection for patients receiving bone marrow, pancreas, pancreatic island cell, and small bowel transplantation. • Topical Treatment of vitiligo in children; facial, flexural, and intertriginous psoriasis. (c) PS Anderson - www. Consult. Dr. A. com - 2016 28

Tacrolimus Dosage and Administration • Prophylaxis of Organ Rejection, Liver Transplants Adults PO 0. 1 to 0. 15 mg/kg/day in 2 divided daily doses every 12 h no sooner than 6 h after transplantation. IV 0. 03 to 0. 05 mg/kg/day as continuous infusion. • Children PO 0. 15 to 0. 2 mg/kg/day in 2 divided daily doses every 12 h. IV 0. 03 to 0. 05 mg/kg/day as continuous infusion. • Topical Dermatitis Adults Topical Apply thin layer of 0. 03% or 0. 1% to affected skin areas twice daily; rub in gently and completely; continue for 1 wk after clearing of atopic dermatitis. • Children (2 yr of age and older) Topical Apply thin layer of 0. 03% to affected skin areas twice daily; rub in gently and completely; continue for 1 wk after clearing of atopic dermatitis. General Advice • Do not use occlusive dressings with topical use. (c) PS Anderson - www. Consult. Dr. A. com - 2016 29

Pimecrolimus Dosage Form: Cream 1% • TRADE NAME: Elidel® FOR DERMATOLOGIC USE ONLY NOT FOR OPHTHALMIC USE Elidel ® (pimecrolimus) Cream 1% contains the compound pimecrolimus, the immunosuppressant 33 -epi-chloro-derivative of the macrolactam ascomycin. (c) PS Anderson - www. Consult. Dr. A. com - 2016 30

Pimecrolimus Indications and Usage for Elidel • Elidel ® (pimecrolimus) Cream 1% is indicated as secondline therapy for the short-term and non-continuous chronic treatment of mild to moderate atopic dermatitis in nonimmunocompromised adults and children 2 years of age and older, who have failed to respond adequately to other topical prescription treatments, or when those treatments are not advisable. • Elidel Cream is not indicated for use in children less than 2 years of age (see WARNINGS, boxed WARNING, and PRECAUTIONS, Pediatric Use). (c) PS Anderson - www. Consult. Dr. A. com - 2016 31

Cyclosporine • Actions • Inhibits cell-mediated immune responses • Exact mechanism(s) of immunosuppressive action not fully elucidated; appears to mainly involve inhibition of lymphocytic proliferation and function. • Produces nephrotoxic effects, which generally appear to be dose dependent and reversible • OTHER Uses: • Ophthalmic: (Dry Eye – [‘Restasis’] • Psoriasis… (c) PS Anderson - www. Consult. Dr. A. com - 2016 32

The “Original” Biologic (c) www. Consult. Dr. Anderson. com - 2017 33

EICOSANOIDS MEMBRANE PHOSPHOLIPID Phospholipase A 2 Stimulated by: Angiotensin - 2 / Bradykinin / Epinephrine / Thrombin Inhibited by: CORTICOSTEROIDS ARACHADONATE Inhibited by: Lipoxygenase Cyclooxygenase NSAID’S PROSTAGLANDINS / LEUKOTRIENES THROMBOXANES (c) www. Consult. Dr. Anderson. com - 2017 34

Relative Strength of Agents • Hydrocortisone – if considered a “ 1” then: • Cortisone – 0. 8 • Prednisone - 4 • Prednisolone - 5 • Methylprednisolone - 5 • Triamcinalone - 5 • Paramethasone - 10 • Dexamethasone - 30 • Betamethasone - 35 (c) www. Consult. Dr. Anderson. com - 2017 35

The potential good: (c) www. Consult. Dr. Anderson. com - 2017 36

http: //www. niceinsight. com/articles. aspx? post=2782&title=The+Buzz+Around+Oncolog y+%E 2%80%94+Update+On+Biologics+Approvals (c) www. Consult. Dr. Anderson. com - 2017 37

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http: //hubpages. com/health/Biologic-immunomodulators-drugs-for -Autoimmune-diseases-RA-Systemic-Lupus-Crohns-disease-CD (c) www. Consult. Dr. Anderson. com - 2017 39

The patient’s willingness to accept the potential adverse events in exchange for clinical benefits must also be considered in the choice of treatment. In a survey of patients with chronic active disease, greater risk acceptance correlated with greater symptom improvement. http: //www. clevelandclinicmeded. com/online/monograph/biologics. III/images/figure 2 b. jpg (c) www. Consult. Dr. Anderson. com - 2017 40

Adverse Events of Biologic Medications (c) www. Consult. Dr. Anderson. com - 2017 41

Gottenberg JE, et al. EULAR 2015: FRI 0154 (c) www. Consult. Dr. Anderson. com - 2017 42

http: //images. slidepl ayer. com/21/625741 8/slides/slide_18. jpg (c) www. Consult. Dr. Anderson. com - 2017 43

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Can we decrease the need or replace them? (c) www. Consult. Dr. Anderson. com - 2017 45

“Replacement” of Biologics • Interestingly there are two distinct approaches in medicine: • In autoimmune – rheumatology cases “NEVER” • In cancer secondary to biologic use “Holy shit, stop that drug now…” • If it is (or can be) done it requires very aggressive ‘whole person’ care and time. • While we are out of time in this talk, my next one on “complicated patients” will be talking about exactly what factors I use in such cases. (c) www. Consult. Dr. Anderson. com - 2017 46

Thank You! (c) www. Consult. Dr. Anderson. com - 2017 47