This presentation includes -classification, biological in psoriasis,TNF alpha inbitors, T cell inhibitos, IL-12/23 inhibitors (indications,containdications,guidelines, adverse effects)

1. Biologicals (Part-1)

2.  Biologicals - are genetically engineered proteins
produced by living organisms to target specific points
of inflammatory cascade including antibodies against
cell surface markers,cytokines & adhesion molecules.
 Inhibit specific components of the immune system.
INTRODUCTION

3. 1, Recombinant human cytokines and Growth Factors.
e.g. Interferons & Interleukins.
2, Monoclonal antibodies
 Chimeric mAbs (-ximab) composed of foreign-derived, murine amino acids
linked to heavy and light constant regions of human origin.
 Humanized mAbs (-zumab) from non-human species whose protein
sequences have been modified to increase their similarity to antibody
produced in humans.
 Human mAbs (-umab) are entirely composed of human sequences.
3, Fusion antibody proteins
e.g. Alefacept,Etanercept.
Biologicals in dermatology

4. Nomenclature of monoclonal ABs
• Devided into 4 parts.
• Prefix + Target + Origin + Suffix.
• Suffix for all is MAB.
• Depending upon origin-XI for chimeric, U for human etc.
• Target is identified by specific letters e.g VI for virus, CI for
circulation etc.
• Prefix is also different for each monoclonal antibody.

6.  Psoriasis:
 TNF antagonist: Infliximab, Adalimumab, Etanercept,
Certolizumab ,Golizumab.
 T cell inhibitors: Alefacept, Efalizumab
 IL12/23 antagonist: Ustekinumab, Briakinumab, Secukinumab
 Others: Apremilast (PDE-4 inhibitors)
 Recently: Itolizumab (anti CD6)
Classification based on indication

7.  Autoimmune blistering disorders
 Anti CD20: Rituximab
 Anti TNF: Infliximab, Etanercept (case reports)
 Hidreadenitis suppurativa & pyoderma gangrenosum
 Anti TNF: Infliximab, Adalimumab
 IL antagonists: Ustekinumab (case reports)
 Granulomatous disease: Anti TNF
 PRP: Anti TNF
 Alopecia areata: Alefacept,Efalizumab

8.  Chronic urticaria: Omalizumab
( mab against C epsilon 3 domain of IgE)
 Atopic dermatitis
 rINF gamma
 Anti T cell , Anti TNF
 Omalizumab
 Mepolizumab ( anti IL5)
 Malignant melanoma
 INF alpha 2b.IL2
 Anti CTLA-4 mab: Ipilimumab, Tremelimumab
 BRAF inhibitors: Vemurafenib, Dabrafenib
 MEK inhibitors: Trametinib, Sorafenib

9. Biologicals in Psoriasis
TNF inhibitors & T cell antagonists

10. Patient candidate for systemic treatment
The rule of “ten”
BSA >10 (range:1-100)
and/or
PASI >10 (range: 0-72)
and
DLQI >10 (range: 0-30)
Finlay AY. Br J Dermatol 152:861-867,2005
Smith et al. Br J Dermatol 153:486-497,2005

11. Topical treatments
Phototherapy
Systemic treatments
Second line
First line
Biologics
Third line
Psoriasis treatment

12.  Treatment guidelines rank biologics as the third-line
treatment option for plaque psoriasis, after topical, photo
and systemic therapies.
 The BAD and European treatment guidelines recommend
TNF antagonists as first-line biologic therapy due to the
availability of clinical safety data across a number of
disease areas.
 Indian guidelines for biologic usage not available yet.
Current guidelines: Biologics in Psoriasis
British Association of Dermatology 2009

13.  Recalcitrant Psoriasis
 Side effects to other systemics
 Contraindications to other systemics
 Erythrodermic or Pustular Psoriasis
 Psoriatic arthritis
Patient Selection for Biological Therapy?
British Association of Dermatology 2009

14.  People whose immune systems are already significantly
compromised e.g HIV,HEP-B,C etc.
 Individuals with active infections.
 People with active tuberculosis.
 People with demyelinating diseases.
 People with congestive heart failure.
 People who have recently received a live vaccine.
Who should not take biologics?

15. Antigen
Antigen Presenting Cell
Activated T Cells
Th1 and Th 17 cytokines
(IL-2, TNF-α, IFN-Υ) & (IL-17, IL-22,
IL-23)
Inflammation of Skin
Hyperproliferation of
Keratinocytes

17.  Major cytokine produced by Th1 cells,APC’s & keratinocytes.
 Induces IL-1, IL-2 and INF-Gamma
 They occur in two distinct classes, TNF-α and TNF-β, which
are known as TNF-α and lymphotoxin-alpha (LTα),
respectively
 Present in two biologically active forms, soluble and
transmembrane TNF.
 Both forms have the capability to bind to membrane
receptors, p55 and p75.
TNF

18.  Dimeric fully human fusion protein composed of p75 cell
surface TNF receptor, fused to the Fc portion of IgG1.
 Forms an exogenous receptor for both the soluble and
transmembrane forms of TNF
 Reduces their binding to cell-bound receptors
 Interrupting TNF-mediated inflammatory responses.
ETANERCEPT

19. STRUCTURE OF
ETANERCEPT

20.  Half life- 4.8 days
 Peak level after s.c inj – 2 days
 Bioavailability of s.c Etanercept- 58%
 Metabolism is by proteolysis
 Eliminated in bile & urine
PHARMACOKINETICS

21.  Injection site reactions- 14%
 erythematous edematous patch or plaque,
 asymptomatic or tender/pruritic .
 Appears after 2nd injection.
 Treatment-warm compresses, topical steroids, oral anti-
histaminics.
 Congestive heart failure- caution advised.
 2 % pt develops anti drug antibodies but are not neutralizing.
Adverse effect

22. Supplied in 2 ways:
1,Sterile, Preservative free, lyophilised powder –
reconstituted with 1 ml of supplied bacteriostatic water.
Stored in refrigerator & not allowed to freez.
Once reconstituted, it is stable up to 14 days in refrigerator.
Each vial contains – 25 mg etanercept,10mg sucrose
40mg mannitol,1.2mg tromethamine
2, Prefilled syringe containing 50/25mg etanercept.
Before injecting allow it to return to room temperature for 15 min
to decrease inj related pain.
THERAPEUTIC GUIDELINES

23.  Dose - 50mg twice weekly s.c. for 12 weeks can
be stepped down to 50 mg once weekly and 50
mg every other week depending on clinical
response.
 Most common sites for injection- thigh,
abdomen, upper arms.
 Rotate injection site to at least 1 inch from last
site of inj.
 long-term data on efficacy are limited to 2 years.
TREATMENT IN PSOARIASIS

24. ENBREL SC inj
( 25 mg in 1 ml )
9064.2 INR (Taj)
7983.2 INR (Wyeth)
ETACEPT(cipla)
6150 INR
FORMULATION

25.  Chimeric (25% mouse and 75% human) IgG1 monoclonal
antibody specific for TNF-α.
 Neutralizes soluble TNF-alpha and blocks membrane bound
TNF-alpha.
 Half life - 7 days for (5mg/kg dose) and 9 days for (10mg/kg).
 Bioavailability in iv infusion -100%
INFLIXIMAB

27.  Infusion reactions - during infusion or upto 3hrs post
transfusion ( 20% pts )
 headache, flushing, dyspnea, injection site infiltrations, taste
perversion
 Infections- reactivation of latent TB, Hep B , histoplasmosis
 Anti drug antibodies-reduced efficasy & increased reaction.
 Congestive cardiac failure - >5mg/kg
 Hepatotoxicity - autoimmune hepatitis
ADVERSE EFFECT

28.  Each 20ml vial contains 100 mg of drug that is reconstituted
with 10 ml of sterile water and then dosed to 250ml of 0.9%
normal saline administered iv over 2 hrs.
 After preparing should be used within 3 hours
 The recommended dose of REMICADE is 5 mg/kg given as
IV infusion. Followed with similar doses at 2 and 6 wks then
every 8 wks thereafter.
 significant improvement within the first 2 weeks of treatment
and maximum benefit by week 10.
THERAPEUTICS GUIDELINE

29.  REMICADE iv
infusion(100mg)
 41039 INR (
Janssen)
FORMULATION

30.  Fully humanised IgG1 recombinant Ab that targets soluble &
transmembrane TNF-alpha.
 Prevents TNF interaction with the p55 and p75 cell surface
TNF receptors
 Bioavailability - 64%
 Half life - 14 days
 Reaches its peak conc. - 5 days
ADALIMUMAB

31.  Administered via s.c injection at a recommended dose of 80 mg
at week 0 and 40 mg at week 1, and then every other week
thereafter.
 Prefilled syringe with preservative free, sterile solution (0.8 ml)
containing 40mg of the drugHumira – inj 40 mg/0.8 ml
 $2,477.65 (Walmart)
 NA in India
THERAPEUTIC GUIDELINES

32. FDA-approved- Psoriasis , Psoriatic arthritis.
OFF-Label-
 Neutrophilic dermatoses - Aphthous stomatitis
Behcets disease
Pyoderma gangrenosum
sweet syndrome
 Bullous dermatoses - Pemphigus vulgaris
Bullous pemphigoid
Cicatricial pemphigoid
INDICATION

33.  Granulomatous dermatoses - Sarcoidosis
Granuloma annulare
 Connective tissue diseases - Dermatomyositis,scleroderma
relapsing polychondritis
SLE - INFLIXIMAB
 Others - Graft verses host disease
Hidradenitis suppuritiva
multicentric reticulohistiocytosis
PRP,SAPHO syndrome
reiter’s disease & TEN –INFLIXIMAB
• Vasculitis (case reports)

34.  Absolute –
Known hypersensitivity to drug
concurrent administration of anakinra(IL-1antagonist)
Active infections, chronic or localised infections like TB
 Relative –
family h/o demyelinating dis like multiple sclerosis
 Pregnancy category-B
CONTRAINDICATION

35. Common Adverse effects
• Malignancy risk – Lymphoma
skin cancer
• Neurological diseases – multiple sclerosis ,optic neuritis , G – B
syndrome etc.
• Infections – TB, Hep - B, invasive fungal infection etc.
• Autoimmunity – ANA ,anti-ds DNA induction.
• Hematological toxicity – rare.

36.  Baseline - CBC, LFT, RFT, Urine analysis
Tuberculin test, Chest X ray,Quantiferon gold assay
HIV, HEP-B & C
ANA, anti dsDNA(optional)
 Follow up- CBC, LFT, RFT at 3 months then 6 monthly.
 Disease severity assessment – PASI & DLQI…
 History, general & systemic examination every 3-6 monthly to
rule out heart failure,malignancy,demylination diseases.
MONITORING GUIDELINES

37.  Pegylated Fab’ fragment of a humanized anti-TNF ab.
 Pegylation extends half life (14 days)
 FDA approved for the treatment of RA and severe Crohn’s dis
but not currently approved for PsA.
 Dose- s.c 400mg at week 0, 2, 4 followed by a maintenance
dose of 200mg every 2 weeks.
 Alternatively a subcutaneous injection of 400mg every 4 weeks.
 For injection: 200 mg lyophilized powder for reconstitution in a
single use vial, with 1 mL of sterile Water for Injection
CERTOLIZUMAB PEGOL (CIMZIA)

38.  Newer Anti TNF biologic (also referred to as CNTO148)
FDA approved in April 2009
 Human IgG1κ monoclonal antibody that binds to both forms
of TNF
 It neutralizes human TNF-α resulting in decreased
circulation and binding of the cytokine to endogenous
receptors
 Used in psoriasis, alone or combined with methotrexate for
treating psoriatic arthritis
GOLIMUMAB (SIMPONI)

39.  PREPARATIONS: prefilled
syringe (with a passive
needle safety guard) or
prefilled autoinjector : 50
mg/0.5 ml
 STORAGE: stored
refrigerated at 2 to 8 C (36
to 46 F).
 DOSING: 50 mg monthly
s.c
 NA in India

40.  First FDA approval drug for moderate-to-severe
plaque psoriasis in 2003.
 It is a recombinant human fusion protein made up
of terminal portion of leucocyte function antigen 3
(LFA-3) & Fc portion of human immunoglobulin
IgG1.
 Bioavailability - 67%
 Half life -11 days
ALEFACEPT

41.  Its action by two different mechanism:
1. Competitive inhibition of co stimulatory signal
interaction between LFA-3 (present on APC ) and
CD2 (present on T –lymphocytes)
Blocks the formation and proliferation of memory
effector T cells .
2. Activates NK cells resulting granzyme mediated
apoptosis of T cells .

42.  FDA app:
Psoriasis
 Off-label:
Musculoskeletal: PSA, RA
Other immunological: AA, LP, Scleroderma
 CONTRAINDICATIONS :
Hypersensitivity to the drug
CD4+ count <250 /mm3
H/o systemic malignancy
 ADVERSE EFFECTS :
Lymphopenia (6-8 weeks after starting therapy )
Infections & malignancies- BCC & SCC
Increased liver enzymes (5-10 times than normal)
 Pregnancy cat B
Indications

43.  Administered as ( AMEVIVE) 15 mg IM inj wkly for 12 wks,
2nd course after a gap of 12 wks
 Slow acting
Lack of toxicity
Prolonged remission
NA in India

44.  Recombinant humanized IgG1 monoclonal antibody binds to
CD11a subunit in LFA-1( on T lymphocytes)
 prevents binding to ICAM-1 molecule on APC
 This leads to loss of leucocyte function –activation, adhesion &
migration.
 Bioavailability - 50%
 Half life - 6 days
EFALIZUMAB

45.  FDA approved :
Psoriasis plaque type
 OFF label :
Atopic dermatitis
Granuloma annulare
SCLE
Dermatomyositis
INDICATION
S

46.  Contraindications :
Known Hypersensitivity to drug
Platelet count < 1 lakh
H/o systemic malignancy
 Adverse effects :
Thrombocytopenia
Infections & malignancies
Increased liver enzymes
 Pregnancy cat C

47.  Available as 100mg/ml vial (RAPTIVA) for sc use .
 Administered - 0.7 mg/kg initial conditioning dose , followed
by 1mg/kg weekly dose for 12 weeks.
 rapid response ( as early as 14 d)
 more efficacious during continuous rather than intermittent
therapy .
Has been withdrawn recently due to increased risk of PML

48.  Standard systemic therapy (except methotrexate) should
be discontinued for 4 weeks prior to initiation of biologic
therapy whenever possible to minimize risk of infection.
When necessary, methotrexate co therapy may be
continued at the minimal required dose.
 When switching from one biologic therapy to another
biologic therapy, overlap should be avoided with the
recommended interval being four times the drug half-
life.
Recommendations: Transitioning from one
therapy to another

49.  Stable chronic plaque psoriasis- Etanercept or
Adalimumab 1st choice based on the favourable risk
⁄benefit profile and ease of administration.
 For patients requiring rapid disease control- Adalimumab
or Infliximab 1st choice due to the early onset of action
 For patients who do not respond to a TNF antagonist, a
second TNF antagonist may be considered.
Recommendations: How to determine the
optimal choice and sequence of therapy

50. Psoriasis-Decision Tree

51.  One large randomized controlled trial showed that etanercept
can be effective in children from age 2 to 17 years.
 Dose - 0.8mg/kg S.C. up to a maximum of 50 mg.
 There is evidence that in pediatric psoriasis, etanercept
therapy may allow tapering of other treatments
 Etanercept is approved for children 8 years and above in
Europe.
Biologics in children

52. THANK YOU