1. Immunotherapy to treat chronic illness
Mibs & Mabs
Immunotherapy to treat chronic illness
Kelly McMonigal, Pharm.D., BCPS
Pharmacy Clinical Leader
University Of Minnesota Medical Center
10/26/12

2. Outline 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

3. Biologics Positives: Negatives: 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

4. Monoclonal Antibodies
Classes of Biologics
Target
Structure
Anti-TNF a
Humira, Remicade, Simponi, Cimzia, Enbrel
Anti-VEGF
Lucentis, Macugen, Avastin
Miscellaneous
Rituxan, Soliris, Tysabri, Xolair, Actemra, Stelara, Ilaris
Monoclonal Antibodies
Humira, Remicade, Simponi,
Cimzia, Rituxan, Soliris,
Tysabri, Xolair, Actemra,
Stelara, Ilaris, Avastin
Mab fragment
Lucentis
Soluble receptor
Enbrel

5. Mabs: Monoclonal Antibodies
Discovered in 1975
First approved by FDA in 1980s
Use limited to acute conditions at first
First Anti-TNFa in 1990s

6. Mab Alphabet soup Adalimumab Canakinumab infliximab natalizumab
Certolizumab pegol
infliximab
natalizumab
golimumab
tocilizumab
rituximab
eculizumab
bevacizumab
ranibizumab
omalizumab
ustekinumab

7. Oh, A Rodent! Antibody name by derivation By Target:
O = mouse = “omab”
A = rat = “amab”
By Target:
Tum = tumor = gemtuzumab
Vir = viral = pavilizumab
Lim = immune, daclizumab
Kin = interleuken = canakinumab
Cir = cardiovascular = abciximab

8. Antibody production B B Protein Y Y Y Y Y Y Immortal cell (myeloma) Y
Hybridoma
Purification
Humanization

9. Bioengineering techniques
More naming….
O = mouse = omab
Xi = chimera = infliximab
ZU = humanized = certolizumab
U = human = adalimumab
Bioengineering techniques
Purification
Amplification

10. Anti-TNFa 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

11. Humira® (adalimumab) 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)

12. Humira® (adalimumab) 40 mg SQ every other week
UC/C 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

13. Remicade® (infliximab)
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

14. Remicade® (infliximab)
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

15. Enbrel® (etanercept) 50 mg SQ weekly 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

16. Cimzia® (certolizumab pegol)
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

17. Simponi® (golimumab) 50 mg SQ Q4 weeks RA with MTX PA, AS not C, P
No reports of CV, MS, cytopenias, but expect similar to other Anti-TNFa
Autoinjector or syringe

18. Anti-TNFa Side Effects
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

19. Infections Bacterial Sepsis, TB, Fungal, Viral, Opportunistic
Increased risk:
Elderly
Immunosuppressed/chronic steroids
chronic respiratory infection
Combination therapy (Humira + anakinra/abatacept)
Wait to start if active infections
Hep B reactivation –
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

20. Tuberculosis New active TB or reactivation of latent TB
Disseminated or extrapulmonary disease
Test for latent TB before use; yearly
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

21. Fungal infections
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

22. Malignancies Lymphomas Non melanoma skin cancers
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

23. Inflamatory Bowel Disease
Treatment options
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)
Potency

24. Inflamatory Bowel Disease
Goals: Treat acute disease, induce remission, and maintain remission
Biologics for mod-severe active disease
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 weeks
Move to Tysabri® if anti-TNF not tolerated or non-response
Biologic maintenance therapy
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

25. Rheumatoid Arthritis 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

26. Rituxan® (rituximab) 1000 mg IV twice two weeks apart
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
Premedicate with steroid, Benadryl, Tylenol 30 minutes prior
Not recommended for use with another biologic
Lower risk of infection than some other biologics when used in non-immunosuppressed patients
Progressive Multifocal Leukoencephalopathy (PML) reported
Reactivation of Hep B
Rare anaphylactic reactions within 2 hours

27. Actemra® (tocilizumab)
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

28. Orencia® (abatacept) Induction 500-1000 mg IV at 0, 2, 4 weeks
Costimulatory blocking fusion protein
RA – monotherapy or with DMARD
Induction mg IV at 0, 2, 4 weeks
Maintenance 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

29. Psoriasis 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

30. Amevive® (alefacept) 15 mg IM weekly 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

31. Stelara® (ustekinumab)
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

32. Psoriatic Arthritis Mild: NSAIDs Mod-severe: MTX or Anti-TNFa or both
MTX x weeks, then add or switch to TNF alpha
Combo systemic traditional agents second-line
Enbrel®/Humira®/Remicade® -> Simponi® -> Stelara®

33. Age-related Macular Degeneration (AMD)
Neovascular = “wet”
<20% of AMD, but causes 90% of severe vision loss
Biologic target = Vascular Endothelial Growth Factor
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

34. Anti-VEGF Biologics Intravitreal injection Q4-6 weeks
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

35. Xolair® (Omalizumab) 150-375 mcg SQ q2-4 weeks 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
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

36. Tysabri® (natalizumab)
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

37. Progressive multifocal leukoencephalopathy (PML)
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

38. Tysabri® (natalizumab)
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

39. Soliris® (eculizumab)
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!

40. Prolia® (denosumab) 60 mg subQ Q6 months Anti-RANKL Osteoporosis
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

41. Pediatric biologics FDA approved Others used: Rituxan®, Actemra®
Enbrel® ( JIA >4yo) 0.8 mg/kg weekly
Humira® (JIA >4yo)
20 mg dose for pts 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)

42. Ilaris® (canakinumab) >4yo Arcalyst® (rilonacept) >12yo
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

43. Biologics in Pregnancy
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:
Likely digested when taken orally by infant

44. Biologic Costs21 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

45. Biologic approvals
“September 27, 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

46. Questions?

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