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On Friday, September 19, 1997 the FDA indicated to the Celgene Corporation that thalidomide, Thalomid® has been designated as approvable (see explanation below) for the treatment of cutaneous manifestations of erythema nodosum leprosum (ENL). In this condition there are no good alternative treatments to thalidomide. ENL is a severe and painful complication for approximately half of all leprosy patients, affecting about two million people worldwide.

The Thalidomide Chronology

Introduced in the late 1950’s

• First marketed as a sedative & for morning sickness. Never marketed in the US.

Worldwide ban in 1961

• Associated with phocomelia & other congenital abnormalities.

Sheskin, 1965¹

• Found thalidomide effective in erythema nodosum leprosum. Dose of 100 mg three to four times daily.

From the ban until now

• Unapproved, illegal use. Bootleg/blackmarket supply.
• Compassionate use approval available in the US and Canada. Supplies from Carville, La. in the past, Celgene now.

1988 – WHO recommend

• WHO’s treatment of choice for severe ENL. Based on the results of a double-blind, multi-centered trial.

Late 1997 – first US approval nears

• FDA Advisory Panel September 5, 1997 recommends the approval of thalidomide for ENL.
• FDA, September 19, 1997 designates thalidomide as approvable for the treatment of cutaneous manifestations of ENL.

Future indications

• Candidates are AIDS-related cachexia or aphthous ulcers,² graft versus host disease, and recalcitrant discoid lupus erythematosus.

Future developments

• Celgene and Andrulis are involved in on-going clinical trials with thalidomide. Celgene are working on developing related compounds with useful activity and fewer side effects.

Use of thalidomide for ENL

The WHO has stated that thalidomide is a treatment of choice for severe ENL and now the FDA has decided that the benefits of treatment with thalidomide outweigh the risks involved. ENL can be life threatening and may cause permanent nerve paralysis and disfigurement. Previously available treatments for severe ENL, corticosteroids and clofazimine are not very effective. Mild ENL has been successfully treated with aspirin, indomethacin, chloroquine or colchicine.

Other uses of thalidomide

More than 20 clinical trials are underway and the drug is also supplied on an emergency use basis or investigator IND basis for over 30 conditions. Currently the dermatologic conditions include Behcet’s disease, prurigo nodularis, discoid lupus erythematosus, pyoderma gangrenosum, erythema multiforme, Jessner’s lymphatic infiltration, pompholyx, scleroderma, urticaria, bullous pemphigoid and cutaneous sarcoidosis.³

Mechanism of action

The mechanism by which thalidomide reduces the elevated levels of tumor necrosis factor-alpha (TNF-alpha) associated with ENL is yet to be understood.⁴ Thalidomide has other immunopharmacologic actions which are under investigation.⁴

Precautions

Restricted distribution Celgene designed and has submitted a restricted distribution proposal (System for Thalidomide Education and Prescribing Safety (S.T.E.P.S.) to the FDA. The objective of the S.T.E.P.S. program is to help insure that fetal exposure to thalidomide occurs with the lowest possible incidence. This comprehensive program will be directed to physicians, pharmacists, and patients, both male and female. It will require all physicians and pharmacies to register in order to prescribe or dispense Thalomid™ (thalidomide) and all patients to complete an informed consent process and participate in a mandatory and confidential surveillance registry.

Off-label use Some members of the FDA’s Advisory panel have suggested that off-label use for other illnesses be prohibited; however the distribution system is designed to cover any use of the drug.

Informed consent waivers Patients and physicians will have to sign detailed informed consent waivers.

Contraception Female patients will have to agree to use two forms of birth control, to undergo ongoing pregnancy tests and to participate in monthly surveys. Patients who have irregular menstrual periods, vaginal bleeding or missed periods may need more frequent pregnancy tests. Males will have to agree to use condoms and to complete surveys every three months. They must abstain from sexual intercourse or use a condom during intercourse while, and for one month after, taking thalidomide. It is not known if thalidomide is present in semen.⁸

A female patient must immediately stop taking thalidomide if she:

Has a late or irregular period. Stops practicing abstinence. Stops using birth control. Thinks that she is pregnant. Does become pregnant.9

Supply of thalidomide

Thalomid™ will possibly be available commercially in the first half of this year. The projected cost of a 50 mg capsule is US$6, meaning that daily treatment of ENL (100–200 mg per day) will cost approximately US$12–24. Patients will only get a 28 day supply; subsequent supply requires a new prescription.³

Adverse effects

The most common adverse effects are drowsiness, rash and constipation.

Peripheral neuropathy

Peripheral neuropathy occurs in less than 1% of ENL patients treated with thalidomide, despite long-term treatment, pre-existing neuropathies, or use in patients who are receiving other medications known to be associated with neuropathies.³ Neuropathy is more common (between 21% and 50%) in AIDS patients. The neuropathy generally occurs following chronic use over a period of months but reports following relatively short-term use also exist. In some cases, the nerve damage has proved irreversible even after treatment with the drug is discontinued. Individual susceptibilities, with possible genetic predisposition, seem to be more important than daily dose and duration of therapy.¹⁰ Patients should be examined for early signs of neuropathy at monthly intervals for the first three months.³ Symptoms of nerve damage include numbness, tingling or pain in the arms, hands, legs and feet. Patients should be warned of this side effect, and understand that they must stop thalidomide immediately if paresthesias develop.¹¹ To detect asymptomatic neuropathy, consider measuring sensory nerve action potential (SNAP) at baseline and every six months. If symptoms develop, stop thalidomide immediately and only restart therapy if the neuropathy completely resolves.³

Birth defects

At the meeting of the FDA Advisory Committee, a spokesman for the 5,000 individuals with birth defects caused by thalidomide who are still living, was saddened at the prospect of potential approval but said that the group preferred regulation to unmonitored use of black market supplies. Celgene said that there have been no birth defects reported so far among the 5,000 ENL patients who have received thalidomide, either through clinical trials or on an emergency basis.

Future Possibilities

Molecular manipulation has uncovered other thalidomide-related compounds which inhibit TNF-alpha production more efficiently than thalidomide, and cause fewer side effects in animals.⁵ Celgene’s first compound entered Phase 1 clinical study in 1997.³ The goal, a non-teratogenic compound, with equal or greater immunomodulating potential than thalidomide, offers the exciting possibility of new and relatively safe compounds which may prove effective in treating diseases at present resistant to currently available therapies. Thalidomide itself has a range of interesting and potentially useful immuno-pharmacologic actions⁴ and after further study and sensible precautions as to its use, has a clear potential as a future immunomodulator.⁴

1. Sheskin J. Thalidomide in the treatment of lepra reactions. Clin Pharm Therap 1965; 6: 303.
2. Jacobsen JM, Greenspan JS, Spritzler J et al. Thalidomide for the treatment of oral aphthous ulcers in patients with human immunodeficiency virus infection. N Engl J Med 1997; 336: 1487-1493.
3. David Stirling, Celgene. Personal communication. January, 1997.
4. Calderon P, Anzilotti M, Phelps R. Thalidomide in dermatology. New indications for an old drug. Int J Dermatol 1997; 36: 881-887.
5. Kaplan G. quoted by Blaney C., Second thoughts about thalidomide. Medical Sciences Bulletin, originally published in NCRR Reporter, November/December 1995.
6. Lumpkin M., Deputy Director FDA’s Center for Drug Evaluation speaking at a meeting of the FDA Advisory Committee, quoted in Reuters Medical News.
7. McGuire J. Personal communication. October, 1997.
8. Thalidomide: Important patient information. US FDA Center for Drug Evaluation and Research. http://www.fda.gov/cder/news/thalidomide.htm.
9. Burkholz H. Giving thalidomide a second chance. FDA Consumer Magazine 1997: September-October.
10. Ochonisky SO, Verroust J, Basuji-Garin S. et al. Arch Dermatol 1994; 130: 66-69.
11. Powell RJ, Garner-Medwin JMM. Postgrad Med J 1994; 70: 901-904.
12. Dubertret L. Personal communication. October, 1997.

Approvable Status: An approvable letter indicates that FDA is prepared to approve the application upon the satisfaction of conditions specified in the approvable letter. Such drug products may not be legally marketed until the firm has satisfied the identified deficiencies, as well as any other requirements that may be imposed by the FDA, and has been notified in writing that the application has been approved.

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