Drug Watch: Thalidomide's
Long and Winding Road
Leslie Hanna
Historical
Perspective
In the late 1950s and early 1960s, approximately 12,000 babies
with major, disfiguring birth defects were born to mothers
who had one thing in common: they took a sedative drug called
thalidomide during pregnancy. Although the range of effects
on the fetuses and babies varied from stillbirth to brain
damage to massive internal damage, the most common adverse
effect was phocomelia, or truncated arms and legs, commonly
referred to as "seal flipper" limbs. Some babies
had little more than a head and trunk, and tiny feet with
7-8 toes attached to the hips. Thalidomide is so toxic in
utero that many women miscarried.
Thalidomide was originally developed as a sedative in the
1950s in Germany by a company called Chemie Grunenthal,
and was marketed in Europe and Canada for several years.
Because no lethal dose was established, the drug was considered
a safer alternative to barbiturate sedatives. The drug was
prescribed to pregnant women in an attempt to reduce morning
sickness and other pregnancy-related discomfort.
In 1961 the link was made between thalidomide and birth defects.
Germany acted immediately and removed the product from the
shelves. A few days later, Britain withdrew the product,
and 4 months later, in March 1962, Canada followed. Thalidomide
had not yet received approval in the U.S.
One of the most alarming elements to this story is that no
teratogenicity, or ability to cause birth defects, was seen
in the animal studies that led to the drug's approval in
Europe.
Thalidomide vanished from sight but did not go away. In fact,
although the sale of the drug was banned, the German company
continued to manufacture thalidomide, and it remained available
primarily to doctors treating people with leprosy.
Now, 35 years later, the U.S. Food and Drug Administration
(FDA) recently has granted first-time marketing approval
to thalidomide. The story of what happened over the past
35 years involves a host of diverse people and considerations.
The Interim
After the ban in 1962, thalidomide went underground. It was
found to be an effective treatment for leprosy when, in
1964, an Israeli dermatologist who gave thalidomide to patients
for its sedative effects noticed that the lesions associated
with leprosy cleared. By 1975 the drug was established as
an accepted treatment for leprosy. Even in the U.S., where
the number of leprosy patients is very small (and where
the drug had never received marketing approval), the government
permitted thalidomide to be imported for leprosy. A small
number of people received it under strict government control.
Today, the World Health Organization (WHO) states that thalidomide
is one of the drugs of choice worldwide for erythema nodosum
leprosem (ENL), a complication of leprosy. Other drugs used
include dapsone and clofazimine.
In 1991 Gilla Kaplan, a leprosy expert from Rockefeller University
in New York City, made a discovery with far-reaching implications.
Kaplan's research showed that thalidomide inhibited a cytokine
called tumor necrosis factor-alpha (TNF-alpha), which has
been linked to disease progression in various conditions,
including HIV disease.
Thalidomide and Tumor Necrosis Factor-Alpha
TNF-alpha is a cytokine, or chemical messenger that carries
information between cells and instructs them to carry out
a specified effect. Immune system blood cells called monocytes
and macrophages, when activated, produce TNF-alpha to combat
tumor formation. Increased production of TNF spurs the immune
system to attack, but chronic elevations of the cytokine
can lead to fever, hypermetabolism and anorexia (loss of
appetite).
People with HIV, particularly those with advanced HIV disease,
have been noted to have chronically elevated TNF-alpha levels.
Elevated TNF-alpha has been noted to increase HIV expression
in vitro and to reduce the efficacy of AZT in vitro. Several
complications of HIV disease such as wasting are attributed
in part to this chronic TNF-alpha elevation. For these reasons,
HIV/AIDS researchers have been interested in drugs that
inhibit TNF-alpha hyperproduction, which is why Kaplan's
1991 discovery was of great interest to the HIV/AIDS community.
Basically, Kapan found that thalidomide works by helping
to regulate the immune response in people with HIV. Subsequent
in vitro studies have shown that thalidomide suppresses
both HIV and TNF-alpha. As for tumor formation, thalidomide
inhibits a process called angiogenesis, which means the
formation of new blood vessels. Although this anti-angiogenetic
property is beneficial when it comes to lesions associated
with leprosy or tumor formation, this is the same characteristic
responsible for stunting the growth of limbs in the babies
born with defects in the 1950s and 1960s.
Kaplan's discovery had many implications for various autoimmune
conditions, including lupus, graft-versus-host (transplant)
disease and HIV/AIDS. In nonpregnant populations, thalidomide
appears safe and effective.
Soon after Kaplan's discovery was announced, buyers' clubs
in New York and San Francisco started to import thalidomide
to distribute to people with AIDS. First, FDA ignored the
illicit distributions and allowed importation. As time passed
and thalidomide continued to be one of the biggest sellers
on the underground market, FDA recognized the need to address
what the drug meant to the community. By this time, thalidomide
could be purchased through the Internet, and the television
news program "60 Minutes" had aired a story about
the recent births of new "flipper babies" in Brazil.
(Thalidomide has been available for several years in Brazil,
with little guidance or regulation. While exact numbers
are not readily available, reports of thalidomide babies
born in recent years are highly plausible.)
Key HIV/AIDS Studies
One of the reasons for thalidomide's popularity in buyers'
clubs is that evidence continued to accumulate suggesting
bona fide utility, including data from rigorous scientific
studies conducted by the federally funded AIDS Clinical
Trials Group (ACTG). The 2 main areas of HIV-related clinical
research were wasting and aphthous ulcers. Both conditions
are fairly common in people with HIV/AIDS and both are associated
with elevations of TNF-alpha, as well as other factors.
In short, thalidomide was found to be useful for both indications.
Thalidomide has also been considered for treating Kaposi's
sarcoma, HIV-related diarrhea and tuberculosis. Because
studies in rats indicated that thalidomide reduced the efficacy
of oral contraceptives, the ACTG began to require that women
in trials involving thalidomide use supplemental forms of
birth control in addition to oral contraceptives.
ACTG 267 was a Phase I, placebo-controlled, dose-escalating
trial of the safety and pharmacokinetics of thalidomide
in 36 HIV positive people, who took 50, 150 or 300 mg daily.
Results have not yet been published.
ACTG 251 was a placebo-controlled trial that found thalidomide
to be an effective therapy for recurrent oral aphthous ulcers.
In this trial, 57 people were randomized to receive 200
mg daily of thalidomide or placebo for 4 weeks. Of the 29
people who received the drug, 61% reported a complete response,
compared to 5% of the placebo group that reported a complete
response. The most common side effect was drowsiness.
A Mexican study, published in the journal AIDS in 1996, enrolled
28 HIV positive men and women with 10% weight loss, and
gave them thalidomide. This study was double-blind and placebo-controlled.
Researchers concluded that thalidomide effectively halted
weight loss; some participants even regained weight (8 of
9 taking thalidomide maintained or gained weight, compared
to 2 of 9 taking placebo who merely maintained weight).
A Celgene Phase II/III trial of thalidomide for HIV-related
weight loss reported significant weight gain in those receiving
the drug. In this study, 102 persons who had already lost
more than 10% of their normal body weight were enrolled
at 13 sites around the U.S. They received either 100 or
200 mg thalidomide daily or placebo for 8 weeks. The people
taking 100 mg had the greatest average weight gain: 4.5
pounds, compared to 0.7 pounds in the placebo group and
2.2 pounds in the 200 mg group. Researchers believe that
the lower average weight gain in the higher dose group is
likely due to the greater drop-out rate due to side effects.
This study reportedly had a hard time enrolling participants,
in part because non-sterilized, premenopausal women were
excluded. The results were announced in April 1997.
Celgene is also sponsoring an ongoing study of thalidomide
for HIV-related aphthous ulcers, similar to the ACTG trial.
This trial has 3 arms and 2 objectives: to evaluate the
efficacy of the drug for treating recurrent aphthous ulcers
and to determine what dose will prevent recurrence. Another
ongoing Celgene Phase II trial is looking at the utility
of the drug to treat HIV-related chronic diarrhea, and measuring
body weight, quality of life and changes in TNF-alpha levels
in bowel tissue. Participants receive 100 mg thalidomide
or placebo daily, at bedtime, for 28 days. Both trials are
still enrolling. For more information, call Barbara Gerhardt
at Celgene at 1-800-890-4619 or the AIDS Clinical Trials
Information Service (ACTIS) at 1-800-TRIALS-A.
Side Effects
Thalidomide side effects of note include sedation, rash and
neurotoxicity, which may contribute to peripheral neuropathy
in people with HIV. Some research has suggested that HIV
positive persons have a higher rate of adverse events, or
side effects, when taking thalidomide than HIV negative
persons. Thalidomide probably will not be recommended for
HIV positive persons with a history of peripheral neuropathy.
C.C. Harland and other researchers from St. George's Hospital
Medical School in London recommend that prospective users
of thalidomide at any dose level have nerve conduction studies
before and while taking the drug. Since the drug causes
drowsiness, taking it at bedtime may be preferable to any
other time.
Finally, increases in HIV viral load occasionally but not
consistently have been associated with thalidomide use.
Access to Thalidomide
The first application to FDA for approval of thalidomide
was made around 1960 by a small U.S. pharmaceutical company
called Richardson Merrill. At that time, a new FDA official
named Frances Kelsey, concerned about the reported side
effect of peripheral neuropathy, delayed the process. During
the period in which the application was pending, news of
the birth defects broke, so the application for approval
in the U.S. was dropped. The government subsequently permitted
heavily restricted importation of the drug for treating
ENL, as discussed above.
Today, Celgene Corporation, headquartered in Warren, NJ,
is the leading company making thalidomide (brand name Synovir).
They have studied thalidomide for various applications including
HIV-related wasting, aphthous ulcers, rheumatoid arthritis
and leprosy-related conditions. Contemporary discussions
about access to thalidomide revolve around Celgene.
According to Matt Sharp and Sally Cooper, MD, of the Healing
Alternatives Foundation buyers' club in San Francisco and
the PWA Health Group in New York City, respectively, their
clubs began advocating in 1993 for access to thalidomide
for HIV positive people with wasting. In June 1995, the
2 buyers' clubs created the "Thalidomide Underground
Compassionate Access Program." In August 1995, Celgene
announced an FDA-approved compassionate use program for
people with wasting that involved "cost-recovery,"
meaning that people with AIDS who met the criteria of the
program would pay to receive the drug ($500 for a 12-week
supply). In response to pressure from the HIV community,
Celgene modified the program by dropping the cost-recovery
aspect and supplying drug free of charge (see "Expanded
Access Today," below).
Celgene received patent approval to manufacture thalidomide
in December 1995. On March 21, 1996, Celgene announced that
FDA had granted orphan drug status to thalidomide for treating
cachexia (wasting), adding it to a list that already included
aphthous ulcers and, in AIDS and cancer patients, mycobacterial
infections and leprosy. Also in 1996, Celgene began distributing
thalidomide through an FDA-approved expanded access program
to physicians in the U.S. and Canada for use in treating
15 clinical conditions including HIV-related cachexia, or
severe wasting. In December 1996, Celgene submitted a New
Drug Application (NDA) to FDA for the use of thalidomide
in people with ENL.
An FDA advisory committee met to debate the NDA on September
4 and 5, 1997. On September 5, Celgene announced that the
FDA had recommended approval for thalidomide for ENL, based
on data from research and from 30 years of beneficial use
for the condition. On September 19, Celgene received an
official letter that said that, on the basis of the data
submitted, the drug was approvable. Celgene may begin marketing
the drug as soon as FDA approves the package insert language
and educational materials.
Expanded Access Today
There are 2 forms of expanded access programs that exist
today. First, there is a formal protocol for use in the
treatment of HIV-related wasting. Second, there is an individual
patient (IND) process that is managed by FDA. Celgene distributes
thalidomide at no cost for any indication that the doctor
and patient have agreed is appropriate, including cancer
and some dermatologic conditions. Persons with different
reasons to be interested in thalidomide will be referred
to different branches of FDA.
The first, HIV-specific program also provides drug at no
cost to people with HIV. The major criteria include that
the patient has lost at least 5% of premorbid (normal, pre-illness)
body weight, has a life expectancy of at least 6 months
and is on a stable antiretroviral regimen. No starting dose
is required, but Celgene recommends 100 mg once a day, at
bedtime, for those who have not used the drug before. However,
people may receive 50-250 mg daily. For more information,
call Barbara Gerhardt at Celgene at 1-800-890-4619.
After the drug is available and on the market for ENL, expanded
access will continue until official approval is granted
for each additional indication.
Thalidomide's Current Status
Celgene estimates that fewer than 10,000 people are likely
to take thalidomide in its first year on the market. Early
use will probably be limited because people will be cautious.
Of the subgroup of people with AIDS who will use the drugs,
perhaps10% will be women with HIV/AIDS of childbearing age.
While most agree that women considering taking the drug
can manage their sexual/reproductive affairs accordingly,
prescribing doctors and others are understandably...well,
nervous. Some women may be reluctant to use the drug as
well.
Today, Celgene is working to develop patient/physican education
materials. The materials are designed to ameliorate fears
and to educate pharmacists, doctors and potential users
of thalidomide about the uses and risks of the drug. Final
FDA product approval for marketing is expected as soon as
the educational information and packaging is completed and
FDA-approved. Later in 1998, Celgene also plans to file
a supplemental NDA with FDA for approval of thalidomide
for HIV-related wasting.
Teratogenic Drug Concerns
Research indicates that there is a distinct window of time
in early pregnancy during which thalidomide is so devastating:
34-50 days after the last menstrual period, which is when
limbs and ears "bud" from the developing fetus
and begin to grow. The short half-life of the drug in the
blood is another important piece of information. After a
period of time after discontinuation, the drug is cleared
without long-term effects. Therefore, it is highly likely
that women could have a normal pregnancy and children after
using thalidomide. In fact, many of the women who took thalidomide
and gave birth to children with severe defects subsequently,
after stopping the drug, had normal pregnancies and defect-free
children.
Women of childbearing age do take the medication Accutane
for acne, a known powerful teratogen made by Hoffmann-La
Roche. To grant access to women of childbearing potential
while minimizing fetal risk, Roche provides strict guidelines
for the use of Accutane, which include using birth control
and checking for pregnancy. It seems reasonable that Celgene,
doctors and pharmacists could educate and counsel premenopausal
women who are interested in thalidomide in the same way,
thereby placing control over the decision in the hands of
the women who stand to benefit.
Preventing a Second Wave of Birth Defects
Randy Warren is the founder and director of Thalidomide Victims
of Canada, a group of persons with thalidomide-related birth
defects. Born with stumps for arms and legs, thumb-less
hands and non-functioning feet, Warren spent the first 8
years of his life in a hospital. The group's position has
been that they would never accept a world with thalidomide
in it. However, they have modified their position, despite
their own aversion to thalidomide, recognizing that the
same drug that devastated their lives may be able to help
others.
While the group feels that thalidomide is better distributed
legally than through the black market, they remain extremely
concerned that a new wave of babies with birth defects will
be born. Warren has stated that babies with thalidomide-related
defects are "not handicapped...[they are] deformed."
Recently, Warren has been working with Celgene to ensure
that a second wave of birth defects never occurs by ensuring
that pregnant women do not take thalidomide.
For their part, Celgene also wants to make sure that a second
wave never appears: this goal is the same for all parties.
Again, Celgene is hard at work developing the materials
and programs for distribution to pharmacists, physicians
and patients. As for the most salient concern -- thalidomide's
potential to cause birth defects -- the product packaging
will include explicit instructions to not be or become pregnant
while using the drug. Celgene also plans a registry for
all prescribing pharmacists and doctors (to register themselves,
not patients). People who prescribe thalidomide and register
will receive additional educational materials. Also, patients
will sign informed consent forms with their doctors to record
that they have received counseling about the drug, prior
to using it. "All of these are not just legal concerns,
they are first and foremost ethical concerns," says
Bruce Williams, Vice President of Celgene.
At this point, Celgene has no plans to market the drug overseas,
where the ability to regulate its distribution and use would
be severely diminished. (Overseas use may ultimately occur,
due to consumer demands and the underground market.) Once
a drug is marketed, doctors may prescribe it essentially
as they see fit. For instance, thalidomide has been approved
for leprosy, not for HIV/AIDS, yet it is common knowledge
that doctors are writing prescriptions for people with AIDS.
How will doctors with AIDS patients who are female handle
thalidomide?
Conclusion
Women who may benefit from the drug should have access to
it, after being educated about the risks to fetuses and
the importance of not becoming pregnant while taking it.
The decision about whether or not to take thalidomide should
be an informed one made ultimately by the patient. Most
likely, thalidomide will appeal to people who are not responding
to or interested in taking HAART (highly active antiretroviral
therapy). Side effects including drowsiness, rash and peripheral
neuropathy may preclude a significant minority from continuing
therapy.
In conclusion, thalidomide has undergone a remarkable developmental
pathway, and today appears to be safe and beneficial for
non-pregnant persons with diverse immune system and infectious
disorders, including HIV disease.
Leslie Hanna is Associate Editor of BETA.
References
Harland CC and others. Thalidomide-induced neuropathy and
genetic differences in drug metabolism. European Journal
of Clinical Pharmacology 49(1-2): 1-6. 1995.
Haslett P and others. The emerging role of thalidomide therapy
in HIV-infected patients. Infectious Medicine 14(5):393-398,
405-406. 1997.
Jacobson JM and others. Thalidomide for the treatment of
oral aphthous ulcers in patients with human immunodeficiency
virus infection. New England Journal of Medicine
336: 1487-1493. May 22, 1997.
Klausner JD and others. The effectof of thalidomide on the
pathogenesis of human immunodeficiency virus type 1 and
M. tuberculosis infection. Journal of Acquired Immune
Deficiency Syndromes and Human Retrovirology 11: 247-257.
1996.
Reyes-Teran G and others. Effects of thalidomide on HIV-associated
wasting syndrome: a randomized, double-blind, placebo-controlled
clinical trial. AIDS 10(13): 1501-1507. 1996.
Williams B, Vice President, Celgene. Personal communication.
February 26, 1998.
Page last updated 5 May 1998
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