Mibs & MabsImmunotherapy to treat chronic

illness

Kelly McMonigal, Pharm.D., BCPSPharmacy Clinical LeaderUniversity Of Minnesota Medical Center10/26/12

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

STRUCTURE

Anti-TNF Humira, Remicade, Simponi,

Cimzia, Enbrel

Anti-VEGF Lucentis, Macugen, Avastin

MiscellaneousRituxan, Soliris, Tysabri,

Xolair, Actemra, Stelara, Ilaris

Monoclonal Antibodies

Humira, Remicade, Simponi,Cimzia, Rituxan, Soliris,Tysabri, Xolair, Actemra,

Stelara, Ilaris, Avastin

Mab fragmentLucentis

Soluble receptorEnbrel

TARGET

Discovered in 1975 First approved by FDA in

1980s Use limited to acute

conditions at first First Anti-TNF in 1990s

Adalimumab

infliximab

Certolizumab

pegol

golimumab

rituximab

eculizumab

ranibizu

m

abbevaciz

um

ab

natalizuma

b

omalizumab

tocilizumab

ustekinumab

Canakinumab

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

Protein

B

Immortal cell (myeloma)

Purification

BY

YY

Y

Y

Y

Y

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 weeksMaintenance 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

BenadrylDelayed 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-TNF

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:

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

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-TNF Minimizes reactivation When LTB identified during therapy – hold

TNF 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-TNF + AZA or 6MP

Non melanoma skin cancers Prolonged immunosuppression, PUVA therapy

Avoid anti-TNF if recent malignancy

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-TNF agents (C, UC) CSA (UC) Natalizumab (C)

Pote

nc

y

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 12-16 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

DMARDs + NSAID +/- Steroid = 1st line Anti-TNF

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-TNFfailure

Use another anti-TNF 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 apartRetreat 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

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 OR125 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 weeksMaintenance 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-TNF 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” <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

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-TNF 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-TNF 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. American Academy of Ophthalmology Retina Panel. Preferred Practice Panel Guidelines. Age-Related Macular Degeneration. San Francisco, CA: American Academy of Ophthalmology 2008.

2. Breda L. Biologics in children’s autoimmune disorders: efficacy and safety. Eur J Pediatr (2011) 170:157–167

3. Bruno V. The advent of monoclonal antibodies in the treatment of chronic autoimmune diseases. Neurol Sci 2011; 31 (Suppl 3):S283–S288

4. Chabner BA, Longo DL. Cancer Chemotherapy and Biotherapy: Principles and Practice, 5th edition

5. Focosi D. Immunosuppressive monoclonal antibodies: current and next generation. Clin Microbiol Infect 2011; 17: 1759–1768

6. Gentile G. Viral infections associated with the clinical use of monoclonal antibodies Clin Microbiol Infect 2011; 17: 1769–1775

7. Humira [prescribing Information]. North Chicago, IL. Abbott Laboratories; 20128. Kappos L. Natalizumab treatment for multiple sclerosis: updatedrecommendations for

patient selection and monitoring. Lancet Neurol 2011; 10: 745–589. Katzung BG. Immunology. Basic & Clinical Pharmacology, Twelfth Edition. The McGraw-

Hill Companies, Inc, 201210. 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 201111. Lichtenstein GR. Management of Crohn’s Diease in Adults. ACG Practice Guidelines. Am J

Gastroenterol 2009; advance online publication 1/6/09.12. Lucentis® [prescribing information]. South San Francisco, CA. Genentech, Inc; 2012.13. Makol A. Rheumatoid Arthritis and Pregnancy Safety Considerations in Pharmacological

Management Drugs 2011; 71 (15): 1973-198714. The Medical Letter. Drugs for Asthma. Volume 10 (114); February 2012.

14. The Medical Letter. Drugs for Inflammatory Bowel Disease. Volume 10 (115); March 2012.15. The Medical Letter. Drugs for Rheumatoid Arthritis. Volume 10 (117); May 2012. 16. Mentor A. Guidelines of care for the management of psoriasis and psoriatic arthritis. Section 6. J Am

Acad Dermatol. Published online February 9, 2011.17. Meulen J. Monoclonal Antibodies in Infectious Diseases: Clinical Pipeline in 2011. Infect Dis Clin N Am 25

(2011) 789–80218. Micromedex Drug Information. Thomson Reuters company. Accessed via thomsonhc.com website on

10/11/11. 19. Mushtaq S. Perioperative Management of Biologic Agents Used in Treatment of Rheumatoid Arthritis.

American Journal of Therapeutics 2011; 18, 426–43420. Prolia® Medication Guide. Thousand Oaks, California. Amgen Manufacturing Ltd. 9/2012. Accessed

10/21/2012.21. R&D Pipeline News.“Top 30 Biologics 2011”. La Merie publishing. April 25, 2012. Accessed 9/20/1222. Shim H. One target, different effects: a comparison of distinct therapeutic antibodies against the same

targets Experimental and molecular medicine. 2011; 43 (10):539-549.23. Soliris® [prescribing information]. Chesire, CT. Alexion Pharmaceuticals; 2009. 24. Specialtypharmajournal.com. Novartis announces positive data for experimental psoriasis drug.

Accessed 9/27/12.25. 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 10/12/1226. Uetwiller F. Infections associated with monoclonal antibody and fusion protein therapy in humans. mAbs

3(5): 461-46627. 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.

28. Wallis RS. Biologics and Infections: Lessons from Tumor Necrosis Factor Blocking Agents. Infect Dis Clin N Am 25 (2011) 895–910.

29. Zhou H, Mascelli MA. Mechanisms of Monoclonal Antibody–Drug Interactions. Annu. Rev. Pharmacol. Toxicol. 2011. 51:359–72