This presentation includes -classification, biological in psoriasis,TNF alpha inbitors, T cell inhibitos, IL-12/23 inhibitors (indications,containdications,guidelines, adverse effects)
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.
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
16.
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
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
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
26.
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
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
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
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