Revival of Thalidomide

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


1954 1956 1961 1965 1991 1994 1998 2000 Today



sedative




Shown to inhibit TNFα expression


1954 1956 1961 1965 1991 1994 1998 2000 Today



sedative





Anti-angiogenic properties shown


1954 1956 1961 1965 1991 1994 1998 2000 Today



sedative






FDA approves for ENL

Reports of effectiveness in

Multiple myeloma


1954 1956 1961 1965 1991 1994 1998 2000 Today



sedative






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

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Revival of Thalidomide