revival of thalidomide
TRANSCRIPT
REVIVAL OF THALIDOMIDEREVIVAL OF THALIDOMIDE
From tragedy to From tragedy to promisepromise
Dr.J.Thirunavukkarasu M.D
History of ThalidomideHistory of Thalidomide• 1954: synthesized
• 1956: introduced and marketed as a non-barbiturate sedative in Germany
– “Safest available sedative of its time”– Very effective in alleviating morning sickness – Over the counter
1957: Europe, Australia, Asia, South America, Canada (but never the USA)
Thalidomide history J Am Med Asso 1990; 263; 1474
Tragedy
Lancet (1961) 2, 1358Widulind Lenz- pediatric geneticist
To promise…To promise…1998(Aug) - FDA (USA)-Approvel
ENL
WHO recommendation
Lenalidomide-multiple myelomamyelodysplastic syndrome
Scheffler MA. Et al.Microbes infect 2002; 4; 1193-202
WHO Tech. Rep. ser. 874 7th Rep
USES OF THALIDOMIDEUSES OF THALIDOMIDE
1. NON BARBITURATE HYPNOTIC Insomnia
2. SEDATIVE Restlessness in elderly
3. ANTIEMETIC MORNING SICKNESS Hyperemesis gravidaris
4. ADJUVANT ANALGESIC PAIN
Novel uses of Thalidomide in Novel uses of Thalidomide in Specific conditions Specific conditions
1. Leprosy, Erthema Nodosum Leprosum (ENL) 2. Chronic illness syndrome e.g. Cachexia 3. Tuberculosis, Sarcoidosis 4. Aphthous ulcers in HIV syndrome and Behcet's disease. 5. Graft - versus - host disease 6. Pyoderma gangrenosum 7. Inflammatory bowel disease 8. Rheumatoid arthritis 9. Sjogren's syndrome 10. Discoid lupus erythematosis 11. Multiple myeloma 12. Advanced solid tumours eg. Renal cell carcinoma
Potential uses of thalidomide in Potential uses of thalidomide in palliative carepalliative care
1. Cancer Cachexia/anorexia 2. Chronic nausea 3. Insomnia 4. Neoplastic fever 5. Profuse sweating 6. Angiogenesis 7. Pain
How is this possible?
??????
α –N-phthalimidoglutarimide
Pthalidimide ring-Teretogenicity
Glutarimide ring-Sedation
Thalidomide PharmacologyThalidomide Pharmacology
Bartlett et al. 2004 Nature Reviews Cancer
Kinetics….
Oral Liver Well distriUrine
Effects …
Anti-inflammatory
Immunomodulatory effects
CYTOKINES
MacrophageNKcell, mono
lympho
“CYTOKINESAre molecular
ChemicalBombs
Of Tissue
Destruction”(i.e. the pro-inflammatory ones)
Pro-Inflammatory
cytokines
Anti-Inflammatory
cytokines
‘Cytokine-balance’Normal
RAChron’s disease
TBCancercachexia
Thalidomide Therapeutic Thalidomide Therapeutic PropertiesProperties
Immunomodulatory properties a. Inhibition and stimulation of cytokinesb. Co-stimulation of primary human T cellsc. Modification of surface cell adhesion
molecules(ICAM-1, VCAM-1)d. Inhibits NF-kB gene-TNFα
IL-6IL-12
IL-2
J infect Dis 1999; 180;216-9.
Thalidomide Therapeutic Thalidomide Therapeutic Properties…Properties…
Non-immunomodulatory propertiesa. Anti-angiogenic activityb. Anti-proliferative and pro-apoptotic activity c. COX inhibition
Tumor AngiogenesisTumor Angiogenesis
Angiogenesis: formation of new blood vessels from pre-existing vasculatureAngiogenesis: formation of new blood vessels from pre-existing vasculature
Tumor Cells
Endothelial Cells
Extracellular Matrix
Basement Membrane
VEGF
bFGF
PDGFR
Supporting cells
proteases
PDGF
Angiogenesis
• Removes waste from growing tumor
• Provides tumor cells with oxygen and nutrients to grow
• Inhibition of tumor angiogenesis is promising as a cancer treatment
Tumor Tumor angiogenesisangiogenesis
1994: Anti-angiogenesis properties,1994: Anti-angiogenesis properties,Rationale for anticancer agentRationale for anticancer agent
• D’Amato et al. 1994 show…
Thalidomide
Markedly reduces neovascularization
D’Amato et al. (1994) Proc. Natl. Acad. Sci. USA, 91, 4082-4085
VEGFbFGFIL-6
Multiple myelom
a
COX inhibition COX inhibition
Thalidomide
partly reduces neovascularization
Cox 2
angiogenes
OLDER USESOLDER USES
• MORNING SICKNESS SEDATION
DERMATOLOGICAL USESDERMATOLOGICAL USES
(a) Very effective: ENL, aphthous stomatitis, Behcet's disease, LE, and prurigo nodularis
(b) Moderately effective: Actinic prurigo, Langerhans cell histiocytosis, cutaneous sarcoidosis, erythema multiforme, graft- vs -host disease (GVHD), Jessner's infiltrate, and uremic pruritus
(c) Possibly effective: Kaposi's sarcoma, lichen planus, melanoma, and pyoderma gangrenosum
(d) Contraindicated: Toxic epidermal necrolysis (paradoxical increase in TNF-a activity
Erythema nodosum leprosumErythema nodosum leprosum
TYPE 2 -LEPRA REACTION
400 mg/day for patients above 35-50 kg body weight
300 mg/day, to be tapered by 100 mg every 2-4 weeks with a maintenance dose of 50-00mg for 6
months
• Sheskin, in 1965,
• 1998(Aug) - FDA (USA)-Approvel
ENL
WHO recommendation
WHO Tech. Rep. ser. 874 7th Rep
Sheskin, J. (1965) Clin. Pharmacol. Therap. 6, 303-306
• BEHCET’S DISEASE • APTHOUS ULCER
• Antiangiogenic property
ACTINIC PRURIGO ACTINIC PRURIGO SCLERODERMASCLERODERMA
• SARCOIDOSIS • KAPOSIS SARCOMA
Aphthous ulcerBechcet’s disease
HEART FAILUREHEART FAILURE
Stephens TD,Filmore BJ-teatology 2000;61;189-95
RHEUMATOID ARTHRITIS
Successfulstrategy-1
Neutralize with antibodies
ANTI-CYTOKINEWEAPONS
“CYTOKINEBOMBERCELLS”
INFLIXIMAB(Remicade)
Recombinant human anti TNF monoclonal antibody
Similarly to Infliximab
Second strategy against
TNF- Alpha
“ATTRACT &
DIVERTAWAY”
SOLUBLE RECEPTORS
made by RECOMBINANT
DNATECHNOLOGY
“Soluble Receptors Will “mop up’
The TNFbefore they
Can ATTACK theJOINTS”
Femur
Tibia
TNFAll
“Mopped
Up”
Etanercept
Interlukin-1(IL-1)
ANAKINRA
Naturally Occurring
IL-1 Receptor ANTAGONIST
TARGET CELL
IL-1RECEPTOR
IL-1
IL-1 R A
IL-1
IL-1 R A
Normal Balance
Naturally Occurring
IL-1 Receptor ANTAGONIST
RecombinantAnalogue of
IL-1
IL-1 R A (Naturally OccurringIL-1 Receptor Antagonist)
(Recombinant Analogue)
R IL-1RA
TARGET CELL
IL-1RECEPTOR
IL-1
IL-1 R A
RIL-1
RA
TARGET CELL
IL-1RECEPTOR
IL-1
RIL-1
RA
ReceptorsAlready Blocked
IL-1CannotAct on theReceptor
ANAlogue ofInterluKIN-1ReceptorAntagonist
IBD( chron’s disease)
• 50-300mg/day
• Dec severity of mucosal disease
Thalidomide use in Thalidomide use in Hematological MalignanciesHematological Malignancies
• Multiple myeloma
• AL amyloidosis
• Myelofibrosis with myeloid metaplasia
• Myelodysplastic syndrome
• Acute myeloid leukemia
Thalidomide use in Solid TumorsThalidomide use in Solid Tumors
• Brain tumors
• Renal cell carcinoma
• Prostate cancer
• Melanoma
• Kaposi’s sarcoma
Sites of activity of thalidomide in Sites of activity of thalidomide in the bone marrowthe bone marrow
Bone marrow stromal cells
MM cells
Thalidomide
X proliferation cell cycle arrest or apoptosis
Thalidomide
XInhibition of myeloma cell adhesion to BMSC
IL-1IL-1ββTNFTNFαα
IL-6IL-6X
Bone marrow blood vessels
Thalidomide
Thalidomide
XInhibition of angiogenesis
VEGF bFGF
Thalidomide
T - cells
T cell activation& proliferation
Il-2Il-2IFN-IFN- γγRelease cytotoxic
mediators
Lysis of MM
NK cells
First line of treatment or,After resistance to conventional chemotherapy
Multiple MyelomaMultiple Myeloma
Thalidomide For Ovarian Treatment
Topotecan plus thalidomide
CONTRAINDICATION
PREGNANCYPREGNANCY
TOXIC EPIDERMAL NECROLYSIS
ADVERSE EFFECTSADVERSE EFFECTS
category-X drug
Thalidomide Fetal ExposureThalidomide Fetal Exposure• Species specific
• 10 000 – 12 000 severely deformed babies born• Unknown number of aborted fetuses• Fetus malformations included:
– Amelia, complete limb absence– Phocomelia, decrease in limb development– Hypoplasia and absence of bones
• 40% thalidomide effected babies died in neonatal period from atresia of the bowel, renal dysgenesis and heart malformations
IGF-1/FGF-2 Transcription of alpha v & βunit gene
Outgrowth of bud
Angiogenesis in developing limb bud
Alpha v β3 integrin dimer
Thalidomide
Limb growth
Adverse EffectsAdverse EffectsPNS Numbness, paresthesia, pain in extremities, burning sensation
(30%)
CNS Hangover, nervousness, tremor (10%), Confusion, ear buzzing, fatigue (20-50%), Depression (5-20%), Dizziness, somnolence (>50%), Headache, fluctuation of blood pressure, bradycardia (5%)
GI Constipation (>50%), Nausea (5-20%)
Hematological Deep vein thrombosis (5-30%)
Skin Red palms, skin rash (25%), brittle fingernails, itching (20-50%)
Genital system
Teratogenicity (Critical Window, 21-56 days after conception. Effects outside this time frame unknown), menstrual irregularities, decreased libido
Endocrine Hypothyroidism and edema (5-20%)
Eleutherakis-Papaiakovou et al. (2004) Ann. Oncol. 15, 1151-1160
Challenges of thalidomide in Challenges of thalidomide in government, society and scientific government, society and scientific
communitycommunity
Celgene Corporation (Warren, New Jersey) has developed a comprehensive program to monitor the thalidomide’s prescribing, dispensing and use
GOAL: to ensure that fetal exposure to thalidomide does not occur
S.T.E.P.S.S.T.E.P.S.TMTM (Celgene Corp.) (Celgene Corp.) System for Thalidomide Education and Prescribing System for Thalidomide Education and Prescribing
SafetySafety
S.T.E.P.S.S.T.E.P.S.TMTM requiresrequires• Registration of prescribing physicians,
patients and pharmacists • Patient counseling• Informed consent • Pregnancy tests, compliance with measures
to prevent pregnancy, educational materials (including video)
• Limited prescription supply of 28 days
Monitoring guidelinesMonitoring guidelines
Baseline pregnancy test Complete blood count absolute neutrophil count, HIV RNA Electromyography (EMG) or nerve conduction velocity (NCV) study. Pregnancy testing
Interesting Facts…Interesting Facts…
• According to the FDA, recent usage patterns of Thalidomid® under the S.T.E.P.S.TM program revealed:
Almost 90% of prescription from 1998-2003 were for oncological conditions
• From 1998-2003, ~77 000 patients were prescribed Thalidomid®
• ~4000 patients were women of childbearing potential
From Tragedy to PromiseFrom Tragedy to Promise
1954 1956 1961 1965 1991 1994 1998 2000 Today
Thalidomide is synthesized
Introduced in Germany as
sedative
Thalidomide withdrawn
Report showingeffectiveness
in patients with leprosy
From Tragedy to PromiseFrom Tragedy to Promise
1954 1956 1961 1965 1991 1994 1998 2000 Today
Thalidomide is synthesized
Introduced in Germany as
sedative
Thalidomide withdrawn
Report showingeffectiveness
in patients with leprosy
Shown to inhibit TNFα expression
From Tragedy to PromiseFrom Tragedy to Promise
1954 1956 1961 1965 1991 1994 1998 2000 Today
Thalidomide is synthesized
Introduced in Germany as
sedative
Thalidomide withdrawn
Report showingeffectiveness
in patients with leprosy
Shown to inhibit TNFα expression
Anti-angiogenic properties shown
From Tragedy to PromiseFrom Tragedy to Promise
1954 1956 1961 1965 1991 1994 1998 2000 Today
Thalidomide is synthesized
Introduced in Germany as
sedative
Thalidomide withdrawn
Report showingeffectiveness
in patients with leprosy
Shown to inhibit TNFα expression
Anti-angiogenic properties shown
FDA approves for ENL
Reports of effectiveness in
Multiple myeloma
From Tragedy to PromiseFrom Tragedy to Promise
1954 1956 1961 1965 1991 1994 1998 2000 Today
Thalidomide is synthesized
Introduced in Germany as
sedative
Thalidomide withdrawn
Report showingeffectiveness
in patients with leprosy
Shown to inhibit TNFα expression
Anti-angiogenic properties shown
FDA approves for ENL
Reports of effectiveness in
Multiple myeloma
Fast-track approval of IMiDs
22ndnd Generation Thalidomide: Generation Thalidomide:IMiDIMiD®®ss
• Immunomodulatory Drugs (IMiD®s)
• Lead compound in drug discovery
• Show increased immune and anticancer properties (prevent angiogenesis and co-stimulation of T-cells)
• Lack toxicity associated with thalidomide
• Examples– Lenalidomide (REVLIMIDTM)– CC-4047 (ACTIMIDTM)
LENALIDOMIDELENALIDOMIDEMULTIPLE MYELOMA: - lenalidomide and dexamethasone is a highly active
regimen which provides survival benefits for patients with relapsed or refractory MM
MYELO DYSPLASTIC SYNDROME: - Abnormally low amount of thrombocytes as well as
neutrophils
SICKLE CELL ANEMIA: - Lenalidomide and pomalidomide
ConclusionsConclusions• Thalidomide was first marketed in the late ’50s as a sedative to
treat morning sickness
• 1961: withdrawn for teratogenic effects related to fetal exposure to thalidomide
• Thalidomide shown to have immunomodulatory and non-immunomulatory properties
• S.T.E.P.S.TM are in place to prevent fetal exposure
• Promising future as the lead compound in the development of IMiD®s
double-edged weapon Thalidomide must always remain the drug of last resort
Try to make sure that a thalidomide tragedy never occurs again.
Conclusions…Conclusions…
Thank YouThank You