Thalidomide & its Thalidomide & its analogues: analogues: Importance in Importance in Pharmacology Pharmacology

Dr. Harmanjit SinghDepartment of Pharmacology, GMC, Patiala

History History Developed by German pharmaceutical

company Grünenthal in Stolberg

Introduced as a Sedative drug in the late 1950s Was found to act as an effective tranquilizer

and painkiller and was proclaimed a "wonder drug" for insomnia, coughs, colds and headaches.

Found to be an effective antiemetic which had an inhibitory effect on morning sickness, and so thousands of pregnant women took the drug to relieve their symptoms

Thalidomide – the sleeping Thalidomide – the sleeping pillpill

Hailed as a "wonder drug" that provided a "safe, sound sleep".

However the drug was also found to cure morning sickness in pregnant women

Was available as OTC drug

Chemistry of thalidomideChemistry of thalidomide

Thalidomide, a-(N-phthalimido) glutarimide, Consists of ringed structure with an asymmetric

carbon in the glutarimide ring.

Exists as an equal mixture of S-(-) and R-(+) enantiomers.

These enantiomers rapidly get interconverted under physiological conditions

Thalidomide is sparingly soluble in water and ethanol, which to date had prevented its availability as an intravenous formulation

R(+) acts as sedative

S(-) potently inhibits the release of TNF-α.

It is the teratogenic form of Thalidomide

Pharmacokinetics Pharmacokinetics

Absorption and EliminationAbsorbed in GIT, not affected by food consumption

Metabolized through a nonenzymatic pathway, undergoing spontaneous hydrolysis in the blood and tissues

Found to be present in semen, not clear if it is in breast milk

Eliminated from the body in about 5-7 hours (not through feces) (only a very small amount is metabolized by cytochrome P-450)

ACTIONS OF THALIDOMIDE.

1.Inhibits leukocyte chemotaxis into site of inflammation

2. A potent sedative and increases the duration of REM sleep 3. Reduces phagocytosis by polymorphonuclear leukocytes

4. Enhances mononuclear cell production of cytokines like IL-2, , IL-10 and inhibits IL-6 & IL-12 production

5. Increases mean plasma levels of IL-2 receptors

6. Reduces TNF-a production by decreasing the half-life of related mRNA

7. Inhibits FGF-2 mediated angiogenesis, Possesses potent teratogenic actions

The Thalidomide Disaster The Thalidomide Disaster In the late 1950s and early 1960s, more than 10,000

children in 46 countries were born with deformities such as phocomelia as a consequence of thalidomide use

The Australian obstetrician William McBride and the German pediatrician Widukind Lenz suspected a link between birth defects and the drug

They were later awarded a number of honors for this contribution

In the United Kingdom the drug was licensed in 1958. Of the approximately 2,000 babies born with defects, 466 survived. The drug was withdrawn in 1961.

In US , Dr. Frances Kelsey, Ph.D., M.D., (born 24 July 1914) a Pharmacologist, most famous as the reviewer for the U.S. FDA, refused to authorize thalidomide for market from the Richardson-Merrell company because of lack of studies regarding its toxicity profile (peripheral neuropathy)

Reduced impact of thalidomide in US patients. Never approved for sale in the United States, but

millions of tablets had been distributed to physicians during a clinical testing program.

It was impossible to know how many pregnant women were given this drug to help alleviate morning sickness or as a sedative

DAMAGE

10,000-12,000 thalidomide babies46 affected countries 40% of victims died within a year of birth Today, there are approximately 5000 thalidomide survivors.

Symptom PatternSymptom Pattern

Phocomelia i.e. abnormal limbs

Amelia i.e. missing limbs

Other Teratogenic Effects

Abnormal number of digits

Missing/malformed eye(s) and ear(s)

Anal atresia

Brain damage/autism

spinal cord defects

Cleft lip or palate

Heart, Kidney ,GIT and Genital defects

MECHANISM OF MECHANISM OF TERATOGENICITYTERATOGENICITY

MECHANISM OF MECHANISM OF TERATOGENICITYTERATOGENICITYThalidomide intercalates into DNA (the thalidomide

molecule, which has a flat structure, can slide into gaps between the subunits of the DNA molecule.

Thalidomide does not intercalate at random into the DNA but intercalates at guanine sites.

Thalidomide, which is composed of three attached rings, two of which look in overall structure almost identical to guanine and adenine,

Attaches more strongly to guanine than adenine.

Mech. Of teratogenicity

Interfere with the production of certain proteins necessary for limb development such as the integrin subunit beta 3

Without this critical cell-surface adhesion protein, angiogenesis could be inhibited and truncation of the limb could result.

Interferes with angiogenesis by Inhibiting the growth of new vessels in a growing limb bud, would deprive the proliferating cells of critical nutrients, leading to a decrease in proliferation and a subsequent reduction in overall limb size.

Thalidomide TodayThalidomide Today“What was once the most feared drug in

pharmaceutical armory could become one of its most valuable.”

Gained FDA approval & Reintroduced in market in 1998 for ENL

Gained FDA approval for MDS associated with 5q syndrome in 2005 & for Multiple Myeloma in 2006

Now under consideration for various cancers and other conditions

Various off label uses

Thalidomide analogues Thalidomide analogues The exploration of the antiangiogenic and immunomodulatory

activities of thalidomide has led to the study and creation of thalidomide analogues.

Structural analogues of thalidomide have been developed in an attempt to enhance therapeutic efficacy while minimizing toxicity, particularly teratogenicity and peripheral neuropathy

Two groups of compounds have been identified by Celgene Corporation that exhibit distinctive spectra of biological activity, termed SelCIDs and immunomodulatory drugs (IMiDs), respectively , with enhanced TNF- inhibitory activity compared with thalidomide

CAUTION: All are assigned pregnancy category X….contraindicated because of structural resemblance to thalidomide

IMiDs – NOVEL THALIDOMIDE IMiDs – NOVEL THALIDOMIDE ANALOGUES AS ANTICANCER ANALOGUES AS ANTICANCER AGENTSAGENTSThe search for thalidomide analogues with increased

immunomodulatory activity and an improved safety profile led to the testing of amino-phthaloyl-substituted thalidomide analogues.

These 4-amino analogues, in which an amino group is added to the fourth carbon of the phthaloyl ring of thalidomide, brought about the class termed“IMiDs”.

Various N substituted and tetrafluorinated compounds have been investigated for therapeutic efficacy in several neoplasms.

Bioactivities follow the parent drug thalidomide closely, but with some increase in potency

In 2005, Celgene received FDA approval for lenalidomide

(Revlimid) for MDS as the first commercially useful derivative.

2000 times more potent than Thalidomide

FDA approved for MM in conjunction with Dexamethasone & Bortezomib

Lenalidomide is only available in a restricted distribution setting to avoid its use during pregnancy

Pomalidomide (Actimid): 20,000 times more potent than thalidomide: currently in clinical trials for various cancers,

ENMD- 0095 is another potent analogue currently undergoing clinical trials

IMiDs as ImmunomodulatorsIMiDs as Immunomodulators

Potent inhibition of TNF-alpha .This inhibition is due to increased degradation of TNF-alpha mRNA by IMiDs

Inhibit TNF-alpha more potently, as well as inhibiting LPS induced monocyte IL1-beta and IL12 production, and increase the production of IL-10.

Partial inhibitory effect on IL-6.

Stimulation of IFN-γ secretion

Induction of NK cell activity and number. This helps in lysis of Tumor cells

IMiDs as Pro-apoptotic agentsIMiDs as Pro-apoptotic agents

Inhibited the proliferation of chemoresistant multiple myeloma cells by 20% to 50%.

The anti-proliferative mechanism of action is thought to be by

- inhibition of IL-6 production.

- Arrest of cell growth at the G1 phase and trigger activation of caspase-8, enhance cell sensitivity to Fas-induced apoptosis

- Downregulate nuclear factor (NF)-κB activity as well as the expression of apoptosis inhibitory protein

IMiDs as Angiogenesis inhibitors

Antiangiogenic activities of the IMiDs,secondary to the inhibition of secretion of two angiogenic cytokines, VEGF and FGF

100-fold increased antiangiogenic potency as compared to thalidomide

Also inhibit endothelial cell migration and adhesion perhaps due to downregulation of endothelial cell integrins

Significant in the MM, where treatment with thalidomide and IMiDs inhibited the upregulation of VEGF and IL-6.

SelCIDs (Selective cytokine inhibitory drugs) The SelCIDs are potent inhibitors of Phosphodiesterase

Type 4

Evaluated in animal models of asthma, found to be potent anti-inflammatory agents with minimal A/E.

Superior in cellular activity to other PDE4 inhibitors & significantly, are without the emetic effects typically associated with PDE4 inhibitors

Potently inhibit TNF-alpha

Little or no effect on T-cell activation

possess antitumor activity .

SelCIDs

Significantly enhanced antiangiogenic activity compared with thalidomide.

Decrease the vascularity and inhibit the growth of tumors

The studies indicate that SelCIDs represent a novel group of angiogenesis inhibitors with potential as cancer therapeutic agents

Two SelCIDs : CDC-801 and CDC-998 are presently being evaluated in clinical trials for Crohn’s disease, Hematological cancers and other conditions

CDC-998 is 100-fold more potent than CDC-801 against PDE4, without any serious A/E

Adverse effects of Thalidomide & its Adverse effects of Thalidomide & its analogues analogues Teratogenesis : “species – specific” teratogenesis”Non-teratogenic in animal models of rats, mice, hamster &

chick embryos. Teratogenic in rabbit & Humans are also highly sensitive

(maximum risk at 34-50 days of gestation). CNS effects: sedation, tremors, Peripheral (Sensory)

Neuropathy Hypersensitivity: skin rashes, urticaria, eosinophilia Haematological: neutropenia GIT: Constipation Venous Thromboembolism: more risk when

combined with dexamethasone for MM(Black Box Warning by FDA)

↓ PROPHYLAXIS SHOULD BE GIVEN

Uses of Thalidomide & its Uses of Thalidomide & its analogues analogues

FDA approved :ENL Multiple Myeloma : Myelodysplastic syndrome Promising uses Prostate cancer Aphthous ulcers (in HIV) Anti-neoplastic effects : AIDS related Kaposi’s

sarcoma Potential usesAutoimmune conditions GVHD RA & Ankylosing Spondylitis Inflammatory bowel disease SLE & Bechet’s disease

Cachexia and weight loss

HIV associated Tuberculosis Cancer cachexia Heart failure Dermatological

conditions Discoid lupus

erythematosus Actinic prurigo Prurigo nodularis pyoderma

gangrenosum

ENL (ENL (Erythema Nodosum Erythema Nodosum LeprosumLeprosum) ) A cutaneous manifestation of leprosy, characterized

by painful vasculitic rash, fever, muscle pain, joint pain, malaise, lymphadenopathy, insomnia, weight loss & peripheral neuritis

In 1964 Jacob Sheskin, Professor at the Hebrew University of Jerusalem  administered thalidomide & successfully treated a critically ill patient with ENL

Approved by the US-FDA on July,16, 1998 for the treatment, prevention and suppression of ENL

Also WHO recommended thalidomide for use in ENL

Various studies have shown a 92% response rate with thalidomide

6 weeks 200 mg1 week 200 mg

Its antipyretic & steroid sparing effect is an added advantage for its use in ENL. The effectiveness of thalidomide is due to its inhibition of TNF-α.

Changes body’s immunological and inflammatory response to bacteria

Heals lesions and skin ulcerations

Before

Multiple MyelomaMultiple MyelomaThalidomide appears to inhibit the disease progression

in MM by several mechanisms,:

Inhibition of the production of IL-6, which is a growth factor for the proliferation of myeloma cells.

Activation of apoptotic pathways through caspase 8-mediated cell death.

Inhibit angiogenesis through inhibition of growth factors

Activation of T cells to produce IL-2, thereby altering the amount and function of NK cells, thus augmenting the activity of NK-dependent cytotoxicity

Thal + Dexamethasone / lenalidomide + dexa+ bortezomib

Demonstrated Mechanisms of Action of Demonstrated Mechanisms of Action of Thalidomide/IMiDs in MMThalidomide/IMiDs in MM

Myelodysplasia

Preliminary studies showed that lenalidomide at 10 or 25 mg/day or 10 mg/day for 21 days with a 7-day treatment free period produced significant responses in patients with low and intermediate risk MDS characterized by 5q syndrome .

29% achieved a complete morphologic remission In addition, transfusion requirement decreased in 76% of

patients while 67% became red-cell- transfusion-independent.

This lead to approval of lenalidomide for the treatment of MDS

PROSTATE CANCER

The involvement of angiogenesis in prostate cancer has been demonstrated by increased microvessel density, which has been shown as a predictor of tumor stage

Encouraging early studies using thalidomide in prostate cancer led to several studies utilizing thalidomide alone or in combination with chemotherapy in androgen-independent prostate cancer (AIPC)

Patients treated with thalidomide showed reduction in the serum prostate specific antigen (PSA) of ≥ 50%.

(a) IN TREATING AIDS RELATED APHTHOUS ULCERSAphthous ulcers is a common problem patients with

HIV Often extremely painful, necrotic lesions Involving

hypopharynx and esophagus, these ulcers lead to decrease in nutritional intake and subsequent wasting. In such conditions, thalidomide treatment has been found to exert beneficial effects

(b) IN AIDS RELATED WASTING SYNDROMEDuring late stage of AIDS, wasting syndrome occurs

either associated with opportunistic infections or as chronic progressive weight loss.

As thalidomide selectively inhibits the production of TNF-a , it is proposed that it has a role in treating wasting syndrome.

(e) IN RHEUMATOID ARTHRITISThe process of bone and cartilage destruction related to

rheumatoid arthritis is considered to involve T-cells cytokines such as TNF-a, interleukin-1 and metalloproteinases.

Hence, thalidomide, by its action on the cytokine production may have a role in the treatment on rheumatoid arthritis.

(f) In ankylosing spondylitis Thalidomide has been reported to markedly improve the

symptoms of ankylosing spondylitis, like motor disability and spinal pain.

However, its beneficial effects were found to subside after the cessation of treatment

(g) In Crohn's disease and Behcet's syndrome

Clinical trials related to efficacy of thalidomide in treatment of the refractory cases of other autoimmune diseases like Crohn's disease and Behcet's syndrome are also being conducted

It has a steroid sparing effect in these conditions.

(h)In cachexia associated with cancer and CHF :

There is probable role for inflammatory cytokines such as TNFα (nicknamed cachexin ), and  IL-6, as well as Proteolysis Inducing Factor (PIF). Thalidomide inhibits these cytokines and is useful for the treatment of cachexia

Other Potential Uses Other Potential Uses

Hodgkin Lymphoma Non Hodgkin Lymphoma Glioma Pancreatic Cancer Hepatocellular carcinoma Ovarian Cancer Macular DegenerationsGVHD AIDS related Kaposi’s Sarcoma Bronchial Asthma: SelCIDs Various Skin Disorders

Precautions and ConcernsPrecautions and Concerns

Required pregnancy test in most casesEducation about the drug is requiredDrug may enter semen and men could affect

female partners

To avoid this thalidomide’s marketing and use is restricted through the mandatory System for Thalidomide Education and Prescribing Safety (STEPS) program.

This unique system of monitoring oversees the

prescribing, dispensing, and dosing of thalidomide.

S.T.E.P.SSystem for Thalidomide Education and Prescribing

Safety Developed by the Celgene Corporation An attempt to minimize the number of women exposed to

this drug during pregnancy, Thalidomide can only be prescribed by physicians who are

registered in the STEPS program, and both male and female patients must comply with mandatory contraceptive measures, patient registration, and patient surveys.

Three-step program that must be followed with all patients who are potential candidates for the drug:

- (1) patients must receive education regarding the potential benefits and side effects of thalidomide

- (2) contraceptive counseling must be provided, including emergency contraception measures, and women of childbearing potential must be given pregnancy tests

S.T.EP.SS.T.EP.S

- 3. patients must complete an informed consent form and participate in an ongoing mandatory and confidential survey.

No > 4-week supply of the drug can be prescribed at any one time, with no automatic refills

in fact, during the first 4 weeks of treatment, it is recommended that females receive only a 1-week supply until the results of weekly pregnancy tests become available.

Women must also use two reliable forms of contraception while taking the drug.

Summary Summary Thalidomide is a double-edged weapon. The 1961 tragedy remains as a bitter lesson in our

minds and serves as a reminder to exercise extreme caution and vigilance when using any new drug.

Still believed that licensed thalidomide will mean more thalidomide babies

Although approval of Drug presents controversy, if used judiciously, it can work miracles in many recalcitrant conditions

Newer analogues are more effective but still contraindication during pregnancy exists

Programs like S.T.E.P. S ensure more safe and effective use of this drug

THANK YOU