REVIVAL OF THALIDOMIDE

From tragedy to promise

Dr.J.Thirunavukkarasu M.D
 History 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

Widulind Lenz- pediatric

geneticist
Lancet (1961) 2, 1358
 To promise…
1998(Aug) - FDA (USA)-Approvel
ENL
Scheffler MA. Et al.Microbes infect 2002; 4; 1193-202

WHO recommendation
WHO Tech. Rep. ser. 874 7th Rep

Lenalidomide-
multiple myeloma
myelodysplastic syndrome
 USES 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
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
palliative care

1. Cancer Cachexia/anorexia
2. Chronic nausea
3. Insomnia
4. Neoplastic fever
5. Profuse sweating
6. Angiogenesis
7. Pain
How is this possible?

???
 Thalidomide Pharmacology

Pthalidimide ring-
Teretogenicity

α –N-
phthalimidoglutarimide

Glutarimide ring-
Sedation

Bartlett et al. 2004 Nature Reviews Cancer

 Kinetics….
Oral
Liver
Well distri
Urine
 Effects …
Anti-inflammatory

Immunomodulatory effects
C
Y Macrophage
NKcell, mono
T lympho

O
K
I
N
E
S
“CYTOKINES
Are molecular

Chemical
Bombs
Of
Tissue
Destruction”
(i.e. the pro-inflammatory ones)
 ‘Cytokine-balance’
Normal
Pro- Anti-
Inflammatory Inflammatory
cytokines cytokines
 RA
Chron’s disease
TB
Cancercachexia
 Thalidomide Therapeutic
Properties IL-2

Immunomodulatory properties
a. Inhibition and stimulation of cytokines
b. Co-stimulation of primary human T cells
IL-6
IL-12
c. Modification of surface cell adhesion
molecules(ICAM-1, VCAM-1)
d. Inhibits NF-kB gene-TNFα
J infect Dis 1999; 180;216-9.
 Thalidomide Therapeutic
Properties…

Non-immunomodulatory properties
a. Anti-angiogenic activity
b. Anti-proliferative and pro-apoptotic activity
c. COX inhibition
 Tumor AngiogenesisSupporting cells
Tumor Cells
proteases
PDGFR

VEGF Extracellular Matrix

PDGF

bFGF
Basement Membrane

Endothelial Cells

Angiogenesis: formation of new blood vessels from pre-existing vasculature

Angiogenesis
 Tumor 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
1994: Anti-angiogenesis properties,
Rationale for anticancer agent
• D’Amato et al. 1994 show…
VEGF
bFGF
Thalidomide IL-6

Multiple
myelom
a
Markedly reduces
neovascularization

D’Amato et al. (1994) Proc. Natl. Acad. Sci. USA, 91, 4082-4085
 COX inhibition

Cox 2

Thalidomide angiogene
s

partly reduces
neovascularization
 OLDER USES

• MORNING SICKNESS SEDATION

 DERMATOLOGICAL 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 leprosum

TYPE 2 -LEPRA • Sheskin, in 1965,

REACTION

• 1998(Aug) - FDA (USA)-

Approvel
ENL

WHO recommendation
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 WHO Tech. Rep. ser. 874 7th Rep

months

Sheskin, J. (1965) Clin. Pharmacol. Therap. 6, 303-306

• BEHCET’S DISEASE • APTHOUS ULCER

• Antiangiogenic property
ACTINIC PRURIGO SCLERODERMA
• SARCOIDOSIS • KAPOSIS SARCOMA
 Aphthous ulcer
Bechcet’s disease
 HEART FAILURE

Stephens TD,Filmore BJ-teatology 2000;61;189-95

RHEUMATOID ARTHRITIS
Successful
strategy-1

Neutralize
with
antibodies
 “CYTOKINE
BOMBER
CELLS”

ANTI-
CYTOKINE
WEAPONS
INFLIXIMAB
(Remicade)
 Recombinant human anti TNF
monoclonal antibody

Similarly to Infliximab
 Second
strategy
against
TNF- Alpha
“ATTRACT
&
DIVERT
AWAY”
 SOLUBLE
RECEPTORS
made by
RECOMBINANT
DNA
TECHNOLOGY
“Soluble Receptors
Will “mop up’
The TNF
before they
Can ATTACK the
JOINTS”
 Femur

TNF
All
“Mopped
Up”

Tibia
Etanercept
 ANAKINRA

Interlukin-1
(IL-1)
 Naturally
Occurring
IL-1 Receptor
ANTAGONIST
IL
-1
IL-1

A RECEPTOR
1 R
IL - TARGET CELL
 IL-1 R A
IL-1

Normal Balance
Recombinant
Analogue of
Naturally
Naturally
Occurring
Occurring
IL-1
IL-1 Receptor
Receptor
ANTAGONIST
ANTAGONIST
IL-1

(Naturally Occurring
IL-1 R A
IL-1 Receptor Antagonist)

R IL-1
RA (Recombinant
Analogue)
IL
-1
IL-1

A RECEPTOR
1 R
IL - TARGET CELL
- 1
IL
RA
R
 ICannot
L-1
IL
Act on the
-1
Receptor
IL-1

RECEPTOR
- 1
IL
RA
R
Receptors TARGET CELL

Already
Blocked
ANAlogue of
InterluKIN-1
Receptor
Antagonist
IBD( chron’s disease)
• 50-300mg/day

• Dec severity of
mucosal disease
 Thalidomide use in
Hematological Malignancies
• Multiple myeloma

• AL amyloidosis

• Myelofibrosis with myeloid metaplasia

• Myelodysplastic syndrome

• Acute myeloid leukemia

Thalidomide use in Solid Tumors
• Brain tumors

• Renal cell carcinoma

• Prostate cancer

• Melanoma

• Kaposi’s sarcoma
 Sites of activity of thalidomide in
the bone marrow
Thalidomide X proliferation Thalidomide

X
cell cycle arrest
or apoptosis
IL-6
MM cells Thalidomide IL-1β
Inhibition of TNFα
myeloma cell

X
adhesion to BMSC

Bone marrow
stromal cells
VEGF
bFGF
X Bone marrow
T - cells
Inhibition of blood vessels
angiogenesis
Thalidomide
Lysis of MM
Il-2
T cell activation
IFN- γ & proliferation
Release cytotoxic
Thalidomide
mediators NK cells
 First line of treatment or,
After resistance to conventional
chemotherapy

Multiple Myeloma
Thalidomide For Ovarian
Treatment

Topotecan plus
thalidomide
CONTRAINDICATION
PREGNANCY
TOXIC EPIDERMAL
NECROLYSIS
ADVERSE EFFECTS
category-X drug
 Thalidomide 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

Alpha v β3 integrin dimer

Thalidomid
e

Angiogenesis in developing limb bud

Limb growth
Outgrowth of bud
 Adverse Effects
PNS 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 Teratogenicity (Critical Window, 21-56 days after conception.

system 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
government, society and scientific
community
 S.T.E.P.S.TM (Celgene Corp.)
System for Thalidomide Education and Prescribing
Safety

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.TM requires
• 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 guidelines
Baseline pregnancy test
Complete blood count
absolute neutrophil count,
HIV RNA
Electromyography (EMG) or
nerve conduction velocity (NCV) study.
Pregnancy testing
 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 Promise

Thalidomide
Thalidomide
is synthesized
withdrawn

1954 1956 1961 1965 1991 1994 1998 2000 Today

Introduced in Report showing

Germany as effectiveness
sedative in patients with
leprosy
 From Tragedy to Promise

Thalidomide Thalidomide Shown to inhibit

is synthesized withdrawn TNFα expression

1954 1956 1961 1965 1991 1994 1998 2000 Today

Introduced in Report showing

Germany as effectiveness
sedative in patients with
leprosy
 From Tragedy to Promise

Thalidomide Thalidomide Shown to inhibit

is synthesized withdrawn TNFα expression

1954 1956 1961 1965 1991 1994 1998 2000 Today

Introduced in Report showing

Anti-angiogenic
Germany as effectiveness
properties shown
sedative in patients with
leprosy
 From Tragedy to Promise

Thalidomide Thalidomide Shown to inhibit FDA approves

is synthesized withdrawn TNFα expression for ENL

1954 1956 1961 1965 1991 1994 1998 2000 Today

Introduced in Report showing Reports of

Anti-angiogenic
Germany as effectiveness effectiveness in
properties shown
sedative in patients with Multiple myeloma
leprosy
 From Tragedy to Promise

Thalidomide Thalidomide Shown to inhibit FDA approves Fast-track

is synthesized withdrawn TNFα expression for ENL approval of IMiDs

1954 1956 1961 1965 1991 1994 1998 2000 Today

Introduced in Report showing Reports of

Anti-angiogenic
Germany as effectiveness effectiveness in
properties shown
sedative in patients with Multiple myeloma
leprosy
 2nd Generation Thalidomide:
IMiD®s
• 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)
 LENALIDOMIDE
MULTIPLE 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
 Conclusions
• 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
Conclusions…

double-edged weapon

Thalidomide must always

remain the drug of last resort

Try to make sure that a

thalidomide tragedy never
occurs again.
Thank You