Transcript Ownership interest in

Biologic Medications:
Friend or foe?
How to navigate this growing part of pharmacology as an
ND PCP
Paul S. Anderson, NMD
Hawaii DocTalks
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
• ConsultDrAnderson.com
Educational consultant for:
• Imprimis Pharmaceuticals
• Canadian College of Naturopathic Medicine
• Bastyr University
• University of Bridgeport
• Vermont Association of Naturopathic Physicians
• Key2Health
• 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
• ConsultDrAnderson.com
Educational consultant:
• Imprimis Pharmaceuticals
• Canadian College of Naturopathic Medicine
• Bastyr University
• University of Bridgeport
• Vermont Association of Naturopathic Physicians
• Key2Health
• 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.
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What are they?
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S Afr Med J 2014;104(11):787-791. DOI:10.7196/SAMJ.8947
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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 19th century, were
among the first biologics.
[Next four slides – same reference]
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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."
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http://www.nature.com/nrd/journal/v4/n1/fig_tab/nrd1607_F2.html
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Recently FDA Approved ‘Mab’s
Drug
Target, Source
Aliro-c-u-mab
(Praluent®; Sanofi US and Regeneron
Pharmaceuticals, Inc.)
Cardiovascular, fully human
PCSK9 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
PCSK9) 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®; GlaxoSmithKline)
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-17A antagonist mab for psoriasis
by "k" in the most current naming system)
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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.
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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™; AstraZeneca)
for non-small cell lung cancer.
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The ‘Cepts’ – Antibody Mimicry
Cept:
“recept of”
Designed antibody fusion protein that mimics
an immunoglobulin
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Tumor Necrosis Factor (TNF) Inhibitors:
-cept / -mab drugs
Nature Reviews Rheumatology 10,612–627 (2014) doi:10.1038/nrrheum.2014.123
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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.
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Others:
Nature Reviews Rheumatology 10,612–627 (2014) doi:10.1038/nrrheum.2014.123
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http://hubpages.com/health/Biologic-immunomodulators-drugs-for-Autoimmune-diseasesRA-Systemic-Lupus-Crohns-disease-CD
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http://www.nature.com/nrd/journal/v4/n1/fig_tab/nrd1607_F2.html
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Nature Reviews Rheumatology 10,612–627 (2014) doi:10.1038/nrrheum.2014.123
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Others
(quickly)…
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EICOSANOIDS
MEMBRANE PHOSPHOLIPID
Stimulated by: Angiotensin - 2 /
Bradykinin / Epinephrine /
Thrombin
Phospholipase A2
Inhibited by: CORTICOSTEROIDS
ARACHADONATE
Inhibited by:
Lipoxygenase
LEUKOTRIENES
Cyclooxygenase
NSAID’S
PROSTAGLANDINS /
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THROMBOXANES
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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.
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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, 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).
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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
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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 1950s, 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.
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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,
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Immune Cell Lines
Thymus:
Bone Marrow:
Hemocytoblast
Lymphoid Stem Cells
Lymphoid Stem Cells
T-Cell Lines
B-Cells
NK Cells
Peripheral Tissues:
Cell Mediated Immunity
Ab
Immunity - 2016
(c) PS(Humoral)
Anderson - www.ConsultDrA.com
Immunological Surveillance
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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.
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Tacrolimus
Dosage and Administration
• Prophylaxis of Organ Rejection, Liver Transplants
Adults PO 0.1 to 0.15 mg/kg/day in 2divided daily doses every 12 h no sooner than 6h after
transplantation. IV 0.03 to 0.05mg/kg/day as continuous infusion.
• Children PO 0.15 to 0.2 mg/kg/day in 2divided daily doses every 12 h. IV 0.03 to 0.05mg/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.
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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.
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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 non-immunocompromised
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).
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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…
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The “Original” Biologic
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EICOSANOIDS
MEMBRANE PHOSPHOLIPID
Phospholipase A2
Stimulated by: Angiotensin - 2 /
Bradykinin / Epinephrine /
Thrombin
Inhibited by: CORTICOSTEROIDS
ARACHADONATE
Inhibited by:
Lipoxygenase
Cyclooxygenase
NSAID’S
PROSTAGLANDINS /
LEUKOTRIENES
THROMBOXANES
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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
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The potential good:
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http://www.niceinsight.com/articles.aspx?post=2782&title=The+Buzz+Around+Oncolog
y+%E2%80%94+Update+On+Biologics+Approvals
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http://hubpages.com/health/Biologic-immunomodulators-drugsfor-Autoimmune-diseases-RA-Systemic-Lupus-Crohns-disease-CD
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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/biologicsIII/images/figure2b.jpg
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Adverse Events of Biologic Medications
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Gottenberg JE, et al. EULAR 2015:FRI0154
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http://images.slidepl
ayer.com/21/625741
8/slides/slide_18.jpg
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Can we decrease the need or replace them?
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“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.
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Thank
You!
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