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
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
American Academy of Ophthalmology Retina Panel. Preferred Practice Panel Guidelines. AgeRelated Macular Degeneration. San Francisco, CA: American Academy of Ophthalmology 2008.
Breda L. Biologics in children’s autoimmune disorders: efficacy and safety. Eur J Pediatr (2011)
170:157–167
Bruno V. The advent of monoclonal antibodies in the treatment of chronic autoimmune diseases.
Neurol Sci 2011; 31 (Suppl 3):S283–S288
Chabner BA, Longo DL. Cancer Chemotherapy and Biotherapy: Principles and Practice, 5th edition
Focosi D. Immunosuppressive monoclonal antibodies: current and next generation. Clin Microbiol
Infect 2011; 17: 1759–1768
Gentile G. Viral infections associated with the clinical use of monoclonal antibodies Clin Microbiol
Infect 2011; 17: 1769–1775
Humira [prescribing Information]. North Chicago, IL. Abbott Laboratories; 2012
Kappos L. Natalizumab treatment for multiple sclerosis: updatedrecommendations for patient
selection and monitoring. Lancet Neurol 2011; 10: 745–58
Katzung BG. Immunology. Basic & Clinical Pharmacology, Twelfth Edition. The McGraw-Hill
Companies, Inc, 2012
Kavanaugh A. Shared Experiences and Best Practices in the Management of Rheumatoid Arthritis
and Crohn’s Disease. American Journal of Medicine, Vol 124, No 4S, April 2011
Lichtenstein GR. Management of Crohn’s Diease in Adults. ACG Practice Guidelines. Am J
Gastroenterol 2009; advance online publication 1/6/09.
Lucentis® [prescribing information]. South San Francisco, CA. Genentech, Inc; 2012.
Makol A. Rheumatoid Arthritis and Pregnancy Safety Considerations in Pharmacological
Management Drugs 2011; 71 (15): 1973-1987
The Medical Letter. Drugs for Asthma. Volume 10 (114); February 2012.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
The Medical Letter. Drugs for Inflammatory Bowel Disease. Volume 10 (115); March 2012.
The Medical Letter. Drugs for Rheumatoid Arthritis. Volume 10 (117); May 2012.
Mentor A. Guidelines of care for the management of psoriasis and psoriatic arthritis. Section 6. J Am Acad Dermatol.
Published online February 9, 2011.
Meulen J. Monoclonal Antibodies in Infectious Diseases: Clinical Pipeline in 2011. Infect Dis Clin N Am 25 (2011) 789–
802
Micromedex Drug Information. Thomson Reuters company. Accessed via thomsonhc.com website on 10/11/11.
Mushtaq S. Perioperative Management of Biologic Agents Used in Treatment of Rheumatoid Arthritis. American
Journal of Therapeutics 2011; 18, 426–434
Prolia® Medication Guide. Thousand Oaks, California. Amgen Manufacturing Ltd. 9/2012. Accessed 10/21/2012.
R&D Pipeline News.“Top 30 Biologics 2011”. La Merie publishing. April 25, 2012. Accessed 9/20/12
Shim H. One target, different effects: a comparison of distinct therapeutic antibodies against the same targets
Experimental and molecular medicine. 2011; 43 (10):539-549.
Soliris® [prescribing information]. Chesire, CT. Alexion Pharmaceuticals; 2009.
Specialtypharmajournal.com. Novartis announces positive data for experimental psoriasis drug. Accessed 9/27/12.
Tolner B. Therapeutic monoclonal antibodies approved or in review in the European Union or United States. The
Antibody Society. antibodysociety.org/news/approved_mabs.php. Accessed 10/12/12
Uetwiller F. Infections associated with monoclonal antibody and fusion protein therapy in humans. mAbs 3(5): 461-466
US Food and Drug Administration. FDA News Release. FDA permits marketing of first test for risk of rare brain
infection in some people treated with Tysabri. 1/20/12. Available at www.fda.gov /NewsEvents/Newsroom
/PressAnnouncements/ucm288471.htm. Accessed 10/12/12.
Wallis RS. Biologics and Infections: Lessons from Tumor Necrosis Factor Blocking Agents. Infect Dis Clin N Am 25
(2011) 895–910.
Zhou H, Mascelli MA. Mechanisms of Monoclonal Antibody–Drug Interactions. Annu. Rev. Pharmacol. Toxicol. 2011.
51:359–72