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Mibs & Mabs
Immunotherapy to treat chronic illness
Kelly McMonigal, Pharm.D., BCPS
Pharmacy Clinical Leader
University Of Minnesota Medical Center
10/26/12
Review general principles of biologic therapy
Review 19 individual therapies!
Discuss biologic place in therapy for
Crohn’s
Rheumatoid Arthritis
Psoriasis
Macular Degeneration
Multiple Sclerosis
Asthma
Positives:
•Novel MOA
•Focused target
•Potent
•Compliance help?
•Avoid absorption issues
•Few drug interactions
Negatives:
•Severe adverse effects
•IV or SQ admin
•Expensive
•Tolerance/Antibody
formation
TARGET
STRUCTURE
Anti-TNF a
Monoclonal Antibodies
Humira, Remicade, Simponi,
Cimzia, Enbrel
Anti-VEGF
Lucentis, Macugen, Avastin
Humira, Remicade, Simponi,
Cimzia, Rituxan, Soliris,
Tysabri, Xolair, Actemra,
Stelara, Ilaris, Avastin
Mab fragment
Lucentis
Miscellaneous
Rituxan, Soliris, Tysabri, Xolair,
Actemra, Stelara, Ilaris
Soluble receptor
Enbrel
Discovered in 1975
First approved by FDA in
1980s
Use limited to acute
conditions at first
First Anti-TNFa in 1990s
rituximab
ustekinumab
Antibody name by derivation
O = mouse = “omab”
A = rat = “amab”
By Target:
Tum = tumor = gemtuzumab
Vir = viral = pavilizumab
Lim = immune, daclizumab
Kin = interleuken = canakinumab
Cir = cardiovascular = abciximab
B
Y
Y
B
Y
Immortal
cell
(myeloma)
Hybridoma
Humanization
O = mouse = omab
Xi = chimera = infliximab
ZU = humanized = certolizumab
U = human = adalimumab
Bioengineering
techniques
Purification
Amplification
Humira®, Remicade®, Enbrel®,
Cimzia®, Simponi®
Bind or block pro-inflammatory cytokine Tumor Necrosis
Factor (TNF)
Cause T-cell death
Inhibit T-cell activation
Suppress downstream inflammatory chemicals
Most widely used biologics
Used for moderate to severe disease
Risk of infection/malignancy
Indications – moderate to severe
Rheumatoid arthritis (RA)
Juvenile idiopathic arthritis (JIA)
Plaque psoriasis (P)
Psoriatic arthritis (PA)
Crohn’s disease (C)
Ulcerative colitis (UC)
Ankylosing spondylitis (AS)
40 mg SQ every other week
UC/C - 160 mg x 1 then 80 mg two weeks later
Stop after 8 weeks if no remission
May increase to 40 mg weekly if decreased response
RA – 40 mg Qweek if no MTX
P - 80 mg x1, then 40 mg following week
1st dose by health care professional
Pen or prefilled syringe
Indications – RA, C/UC, PA, P, AS
Crohn’s - effective in fistulizing disease
IV infusion over 2 hours
Induction dose at 0, 2, 6 weeks
Maintenance doses Q8weeks
RA (with MTX) – 3 mg/kg
Increase up to 10 mg/kg or give q4 weeks if response lost
PA and AS - 5 mg/kg
C/UC – 5 mg/kg
Increase to 10 mg/kg if response lost
Infusion reactions – 1-2 hours of infusion
HA, dizziness, nausea flushing, fever, chills, chest pain,
cough, cyspnea, pruritis
Occur in ~10% of patients with stopping necessary in 2%
Slow/stop infusion /pretreat : steroids, Tylenol and
Benadryl
Delayed reaction at 3-14 days
similar to serum sickness : myalgias, arthralgias, fever,
rash , pruritis, HA
may need steroid treatment
Risk of reactions:
Increased interval between treatments
Induction schedule 0/2/6
Maintenance immunosuppressive
Indications – RA, PA, AS, P, JIA
Not effective in Crohn’s treatment at same dose as used
for RA
50 mg SQ weekly
P - Twice weekly for 3 months, then weekly
RA – 25 mg 2x/week or 50 mg SQ weekly
Autoinjector, prefilled syringe, Multiple use vial
Shorter t1/2 than mAbs
Quick onset of action
Quick identification of intolerance
C, RA
Potentially more infection risk than other TNF
agents
Induction 400 mg SQ at 0, 2, 4 weeks
Maintenance 400 mg SQ Q4weeks
RA – can use 200 mg every other week
Prefilled syringe or single-use vial
RA with MTX
PA, AS
not C, P
50 mg SQ Q4 weeks
No reports of CV, MS, cytopenias, but expect similar to
other Anti-TNFa
Autoinjector or syringe
Well tolerated
Injection reactions with SQ
Serious adverse events (up to 6%)
Infections, Malignancies
Neurologic reactions – Guillain-Barre, MS
New onset or worsening of CHF
Lupus-like syndrome from development of
autoantibodies – reversible
Hepatotoxicity (Remicade® warning from manufacturer )
Monitor LFTs, Hepatitis profile
Cytopenias
monitor regularly
Bacterial Sepsis, TB, Fungal, Viral, Opportunistic
Increased risk:
Wait to start if active infections
Hep B reactivation –
Elderly
Immunosuppressed/chronic steroids
chronic respiratory infection
Combination therapy (Humira + anakinra/abatacept)
Caution and frequent monitoring for carriers
D/C if reactivation occurs
Vaccines
No Live vaccines
Immunize adults for influenza, pneumococcal , hepatitis B, and
herpes zoster before starting.
Children should have immunizations up-to-date before starting
New active TB or reactivation of latent TB
Test for latent TB before use; yearly
Disseminated or extrapulmonary disease
Question exposure
Chest Xray
TB test (PPD or Quantiferon Gold)
Treat for latent TB prior to Anti-TNFa
Minimizes reactivation
When LTB identified during therapy – hold TNFa*
Remicade®/Humira® > Enbrel® for
reactivation of TB
Invasive histoplasmosis, coccidioiodomycosis,
candidiasis, aspergillosis, blastomycosis,
pneumocystosis
Antigen and antibody testing for
histoplasmosis may be negative even with
active infection
Consider empiric antifungal therapy for severe
systemic illness
Lymphomas
3-fold higher rate in some studies
Aggressive disease course
Fatal cases in children treated with TNF blockers
Most reports with adolescent males on TNF blocker for
Crohn’s
Most had anti-TNFa + AZA or 6MP
Non melanoma skin cancers
Prolonged immunosuppression, PUVA therapy
Avoid anti-TNFa if recent malignancy
Treatment options
Potency
5-aminosalicylates (UC, C)
Topical steroids (UC)
Antibiotics (C)
Budesonide (C)
Oral steroids (C, UC)
Immunomodulators- AZA, 6-MP, MTX (C, UC)
IV steroids (C, UC)
Anti-TNFa agents (C, UC)
CSA (UC)
Natalizumab (C)
Goals: Treat acute disease, induce remission, and
maintain remission
Biologics for mod-severe active disease
Biologic maintenance therapy
Humira®, Remicade® and Cimzia® (NOT Enbrel®)
Anti-TNF therapy if no response to primary therapy steroid
refractory or bad prognosis
Improvement of active disease in 2-4 weeks with maximal at
12-16 weeks
Move to Tysabri® if anti-TNF not tolerated or non-response
Scheduled is better than episodic (avoids antibody formation)
Clinical response ~60-70%, remission 40-50%
Step Up or “top down”?
Remicade®+AZA or Remicade® alone more effective than
AZA alone
DMARDs + NSAID +/- Steroid = 1st line
Anti-TNFa
Use if 1st line failure +/- MTX
Enbrel®, Remicade®, Humira® ~ equal efficacy
More effective than DMARD for joint destruction?
Work more quickly than DMARDs
If anti-TNFa failure
Use another anti-TNFa
Change biologic agent type (Rituxan®, Orencia®,
Actemra®)
Kineret® (anakinra) –lower efficacy biologics
Consider ability to do SQ injections
Anti-CD20 molecule on B-cell surface
RA – 3rd line therapy after failure of TNF. Only
approved with MTX
1000 mg IV twice two weeks apart
Retreat q6 months
Not recommended for use with another biologic
Lower risk of infection than some other biologics when used in
non-immunosuppressed patients
Premedicate with steroid, Benadryl, Tylenol 30 minutes prior
Progressive Multifocal Leukoencephalopathy (PML) reported
Reactivation of Hep B
Rare anaphylactic reactions within 2 hours
Anti- IL6
RA – 3rd line after failure of TNF agent
Clinical improvement in as little as 2 weeks
Used alone or in combo with DMARDs
4-8 mg/kg IV q4 weeks
Infusion reactions, GI symptoms, hypertension,
transient neutropenia, elevated serum transaminases,
and dyslipidemia
Severe: GI perforation, serious infections,
hypersensitivity with anaphylaxis
Costimulatory blocking fusion protein
RA – monotherapy or with DMARD
Induction 500-1000 mg IV at 0, 2, 4 weeks
Maintenance 500 -1000 mg q4 weeks OR
125 mg SQ q week
IV and SQ apparently equivalent in efficacy
Infusion over 30 min
give 1st SQ dose starting 1 day after loading dose
some omit loading dose
Not for use with other biologics
Immediate SE – HA, HTN, dizziness, anaphylaxis (rare)
Likely increases infection risk. No association with TB
Topical agents first line – used for minimal disease
Traditional systemic agents (MTX, CSA)
Phototherapy
Biologics
For failure, intolerance or comorbidities with traditional systemic
agents
Choice of biologic
No clear best first choice
Response rate for cutaneous disease = Rituxan®->Humira®->
Stelara® ->Enbrel®-> Simponi®
Often lose response over 1 year
add phototherapy or MTX
Switch to another biologic
MTX in combination? No RCT
Anti CD2 fusion protein
Psoriasis (not PA)
weaker efficacy than other biologics for psoriasis
15 mg IM weekly
12 week course of treatment
Wait at least 12 weeks before additional course
Monitoring: CD4 lymphocyte counts weekly
Hold for CD4 counts < 250 cells/L
Discontinue if < 250 x 1 month
Anti IL-12 and IL-23
Moderate to severe Psoriasis (not PA)
Faster response with less frequent dosing
Induction 45mg SQ at 0, 4 weeks
Maintenance 45 mg q12 weeks
90 mg dose if >100 kg
Injection-site reactions
Rare serious infections, malignancies and major cardiovascular events
(single report of PML)
Evaluate for TB prior
Avoid live vaccines
Angioedema and anaphylaxis – watch in patients on allergy
immunotherapy
Mild: NSAIDs
Mod-severe: MTX or Anti-TNFa or both
MTX x 12-16 weeks, then add or switch to TNF alpha
Combo systemic traditional agents second-line
Enbrel®/Humira®/Remicade® -> Simponi® ->
Stelara®
Neovascular = “wet”
Biologic target = Vascular Endothelial Growth
Factor
<20% of AMD, but causes 90% of severe vision loss
Prevent new blood vessel formation in subretinal
space
Biologics 1st line for neovascular AMD
Improved visual outcomes compared to other
therapies: Verteporfin PDT, intravitreal steroids
Biologic therapies NOT for “dry”AMD
Lucentis® (ranibizumab), Macugan® (pegaptanib)
Avastin® (bevacizumab)
Cheaper, Off label, need consent
Intravitreal injection Q4-6 weeks
May be able to give on “as needed” schedule (CATT)
Anesthesia and antibiotic before injection
watch for infection prior to administration
Severe SE:
Rare endophthalmitis, retinal detachment, anaphylaxis
Increased IOP, conjunctival hemmorrhage, eye pain,
floaters
Anti IgE antibody
Allergic asthma, for patients
>12 years old with moderate to severe persistent asthma
Not well controlled on an ICS
With sensitization to an airborn allergen
150-375 mcg SQ q2-4 weeks
Dose based on body weight and serum IgE levels
Injection site pain, bruising, rare anaphylaxis
observe for 2 hours after 1st 3 doses, then 30 min.
Pts should have EPI pen
Anti-alpha4 integrin
Multiple Sclerosis
Active relapsing-remitting form
Inadequate response to other therapy
Severe progressive form first-line
Crohn’s
After failure of Anti-TNFa
D/C at 12 weeks if no response
300 mg IV q4 weeks
1 hour infusion
Usually causes death or neurologic disability
No treatment, prevention or cure
Highest risk patients (greatest with all 3):
received Tysabri® for >2 years
on immunosuppressants before receiving Tysabri®
with antibodies to JC Virus
JC Virus antibody test available
Stratify JCV Antibody ELISA test
Administer as MONOTHERAPY
Discontinue other immunosuppressants
Taper steroids over 6 months
Avoid in HIV or leukopenia
Patients must enroll in the TOUCH program
Other SE:
Hypersensitivity reactions
Antibody development
Hepatotoxicity
Small risk of infections
Anti-C5 mAb
Treats Paroxysmal Nocturnal Hemoglobinuria
red cell transfusions in PNH
Prevents anemia, fatigue, thrombosis, and
hemoglobinemia
600 mg-1200 mg IV Q 1-4 weeks
Infusion over 35 minutes
Meningococcal infection risk, vaccinate prior
HA (up to 50%), nausea, infusion reactions
Most expensive drug in the world!
Anti-RANKL
receptor activator of nuclear factor kappa-B ligand
inhibits maturation of osteoclasts
prevents bone resorption
Osteoporosis
Males, postmenopausal females
Oncology-related
high fracture risk
60 mg subQ Q6 months
+ calcium 1000 mg/vitamin D 400 units PO daily
Hypocalcemia - screen pre-treatment
Skin problems, infections
Jaw osteonecrosis, thigh fractures
FDA approved
Enbrel® ( JIA >4yo) 0.8 mg/kg weekly
Humira® (JIA >4yo)
20 mg dose for pts 15-30 kg, 40 mg dose if > or = 30 kg
Orencia® (JIA >6yo): 10 mg/kg at weeks 0, 2, 4, then
Q4weeks
Remicade® (C> 6 yo): 5 mg/kg IV at 0, 2, 6 weeks, then
q8 weeks
Others used: Rituxan®, Actemra®
Watch:
low response to vaccines
Malignancies, esp with immunosuppression (AZA, MTX)
mAb and fusion protein against IL-1
Indications – CAPS
Familial Cold Autoinflammatory Syndrome (FCAS)
Muckle-Wells Syndrome (MWS)
Neonatal-Onset Multisystem Inflammatory Disease (NOMID)
Contraindications/SE
Dose
Canakinumab
2 mg/kg SQ q8weeks, may increase to 3 mg/kg
If > 40 kg, 150 mg q8weeks
Rilonacept 4.4 mg/kg (max 320 mg) SQ once, then
2.2 mg/kg SQ weekly
Safety data limited
Pregnancy Class B
Anti-TNFa
Case reports of VACTERL
Change therapy at conception vs use up to 30 weeks
Pregnancy Class C
Orencia®, Rituxan®, Actemra®
Change therapy prior to conception
Lactation:
Safety data limited
Likely digested when taken orally by infant
55 billion dollars in antibody sales in 2011
#1 selling biologics were Anti-TNF Antibodies
Antibodies in 4 of 10 top biologic sales classes
Antibody sales > combined other biologics
insulin, erythropoetins, coagulation factors, interferons, GCSF,
enzyme replacement
“September 27, 2012 - Novartis announced today new Phase II data
showing AIN457 (secukinumab) may significantly improve
moderate-to-severe plaque psoriasis on the hands, feet and
nails...”24
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