OPINION
S E P T E M B E R 2 0 1 0 • W W W. R H E U M AT O L O G Y N E W S . C O M
19
COMMENTARY
Is Bias Behind the Lack of New Obesity Drugs?
n July, a Food and Drug Administra- the epidemic nature of adiposity and its
tion advisory committee voted 10-6 devastating consequences, only two
against approval of the phentermine- drugs have been approved in the United
topiramate controlled-release combina- States for long-term treatment of obesition agent for weight loss. The panel ty: orlistat and sibutramine (the latter’s
members and the agency agreed that the fate is uncertain).
Past antiobesity drug expecombination was effective.
riences often have been disasAmong the main safety controus regarding appropriatecerns reported by the panel
ness of use and safety.
were an increase in heart rate
However, these experiences
(an average of about one excannot fully account for the
tra beat per minute), potenvirtual absence of currently
tial adverse psychological efapproved weight-loss drug
fects, impaired memory and
therapies. One might reasonconcentration, metabolic aciably question whether biases
dosis, and that both phenterexist, which may include that:
mine and topiramate are
BY HAROLD
pregnancy category C drugs.
씰 Medical science has a hisB AY S , M . D .
Obesity is an epidemic. Aditorical bias against obese paposity often causes pathogentients (Vesalius 2009;15:59-70).
ic endocrine and immune responses that 씰 Many chosen for FDA advisory panels
lead to the most common metabolic dis- have limited to no clinical experience
orders in endocrine patients: diabetes, hy- with anti-obesity drug development, at
pertension, and dyslipidemia (Expert Rev. least compared with the many clinical reCardiovasc. Ther. 2008;6:343-68).
searchers who conduct the trials. This seWeight-loss drug therapies that im- lective process is presumably done to
prove metabolic disease (such as phen- avoid bias. But without impugning the
termine-topiramate CR) are, therefore, objectivity of the FDA panel, it is reaof keen interest to practicing endocri- sonable to speculate that this selection
nologists and their patients. Yet, despite process actually has the potential to in-
I
troduce bias through the unbalanced 씰 Many “experts” have concerns that the
collection of individuals with certain high demand for a newly approved antipredispositions.
obesity drug would mean not
only use, but misuse, by clin씰 Many view obesity as a
See related
icians and patients. Thus, to
lifestyle disorder. Thus, unless
story on page protect clinicians and patients
a weight-loss drug has almost
38.
from themselves through offno associated adverse experilabel use, the FDA is encourences, many feel the drug is
unsuitable for FDA approval. This aged against approval of anti-obesity
unique standard does not apply to other agents, irrespective of the potential bendiseases. For example, the same dose of efits to endocrine patients when used aptopiramate in the full dose of phenter- propriately. This protectionism bias does
mine-topiramate CR is the commonly not apply to drug treatment of other disused and approved dose for preventing eases.
migraine headaches. To say that the riskContinued on following page
to-benefit ratio of topiramate to prevent a migraine headache is acceptable,
while that of the same topiramate dose
LETTERS
to treat obesity is unacceptable, suggests
Letters in response to articles in
disease bias.
RHEUMATOLOGY NEWS and its supplements
should include your name and address,
씰 Some of the FDA advisory panel
affiliation, and conflicts of interest in
members expressed concern that, should
regard to the topic discussed. Letters
new weight-loss drugs be approved, givmay be edited for space and clarity.
en the profound need and relative lack of
Mail: Letters, RHEUMATOLOGY NEWS,
available alternatives (other than
5635 Fishers Lane, Suite 6000,
surgery), they might result in a largeRockville, MD 20852
Fax: 240-221-2541
scale use of the drug. Obese patients and
E-mail: [email protected]
their treating clinicians might find this
Comment Voice Mail: 877-524-9335
“fear” to represent a blatant, if not
bizarre bias.
ACTEMRA® (tocilizumab)
ACTEMRA® (tocilizumab)
In the all-exposure population, the rate of malignancies remained consistent (1.10 events per 100 patient-years) with the rate
observed in the 6-month controlled period [see Warnings and Precautions].
Other Adverse Reactions
Adverse reactions occurring in 2% or more of patients on 4 mg/kg or 8 mg/kg ACTEMRA plus DMARD, and at least 1% greater
than that observed in patients on placebo plus DMARD, are summarized in Table 2.
abortion/embryo-fetal death at 10 mg/kg and 50 mg/kg doses (1.25 and 6.25 times the human dose of 8 mg/kg every
4 weeks based on a mg/kg comparison).
Nonteratogenic Effects.
Testing of a murine analogue of tocilizumab in mice did not yield any evidence of harm to offspring during the pre- and postnatal
development phase when dosed at 50 mg/kg intravenously with treatment every three days from implantation until day 21 after
delivery (weaning). There was no evidence for any functional impairment of the development and behavior, learning ability, immune
competence and fertility of the offspring.
Pregnancy Registry:
To monitor the outcomes of pregnant women exposed to ACTEMRA, a pregnancy registry has been established. Physicians are
encouraged to register patients and pregnant women are encouraged to register themselves by calling 1-877-311-8972.
Nursing Mothers
It is not known whether tocilizumab is excreted in human milk or absorbed systemically after ingestion. Because many drugs are
excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from ACTEMRA, a decision
should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the
mother.
Pediatric Use
Safety and effectiveness of ACTEMRA in pediatric patients have not been established.
Geriatric Use
Of the 2644 patients who received ACTEMRA in Studies I to V, a total of 435 rheumatoid arthritis patients were 65 years of age and
older, including 50 patients 75 years and older. The frequency of serious infection among subjects treated with ACTEMRA 65 years
of age and older was higher than those under the age of 65. As there is a higher incidence in infections in the elderly population in
general, caution should be used when treating the elderly.
Hepatic Impairment
The safety and efficacy of ACTEMRA have not been studied in patients with hepatic impairment, including patients with positive
HBV and HCV serology [see Warnings and Precautions].
Renal Impairment
No dose adjustment is required in patients with mild renal impairment. ACTEMRA has not been studied in patients with moderate
to severe renal impairment.
OVERDOSAGE
There are limited data available on overdoses with ACTEMRA. One case of accidental overdose was reported in which a patient
with multiple myeloma received a dose of 40 mg/kg. No adverse drug reactions were observed. No serious adverse drug reactions
were observed in healthy volunteers who received single doses of up to 28 mg/kg, although all 5 patients at the highest dose of
28 mg/kg developed dose-limiting neutropenia.
In case of an overdose, it is recommended that the patient be monitored for signs and symptoms of adverse reactions. Patients
who develop adverse reactions should receive appropriate symptomatic treatment.
PATIENT COUNSELING INFORMATION
Patient Counseling
Patients should be advised of the potential benefits and risks of ACTEMRA. Physicians should instruct their patients to read the
Medication Guide before starting ACTEMRA therapy.
• Infections:
Inform patients that ACTEMRA may lower their resistance to infections. Instruct the patient of the importance of contacting their
doctor immediately when symptoms suggesting infection appear in order to assure rapid evaluation and appropriate treatment.
• Gastrointestinal Perforation:
Inform patients that some patients who have been treated with ACTEMRA have had serious side effects in the stomach and
intestines. Instruct the patient of the importance of contacting their doctor immediately when symptoms of severe, persistent
abdominal pain appear to assure rapid evaluation and appropriate treatment.
Table 2
Adverse Reactions Occurring in at Least 2% or More of Patients on 4 mg/kg or 8 mg/kg ACTEMRA plus DMARD
and at Least 1% Greater Than That Observed in Patients on Placebo plus DMARD
6-Month Phase III Controlled Study Population
ACTEMRA
8 mg/kg
Methotrexate
ACTEMRA
4 mg/kg +
DMARDs
ACTEMRA
8 mg/kg +
DMARDs
Placebo +
DMARDs
N = 288
(%)
7
7
7
6
6
3
3
2
2
2
1
1
N = 284
(%)
5
6
2
2
4
1
2
1
2
2
2
5
N = 774
(%)
6
4
6
4
3
2
4
4
1
3
1
2
N = 1582
(%)
8
6
5
4
3
3
3
3
2
3
2
2
N = 1170
(%)
6
4
3
3
1
2
3
1
1
2
1
1
Monotherapy
Preferred Term
Upper Respiratory Tract Infection
Nasopharyngitis
Headache
Hypertension
ALT increased
Dizziness
Bronchitis
Rash
Mouth Ulceration
Abdominal Pain Upper
Gastritis
Transaminase increased
DRUG INTERACTIONS
Other Drugs for Treatment of Rheumatoid Arthritis
Population pharmacokinetic analyses did not detect any effect of methotrexate, nonsteroidal anti-inflammatory drugs or
corticosteroids on tocilizumab clearance.
Concomitant administration of a single dose of 10 mg/kg ACTEMRA with 10-25 mg MTX once weekly had no clinically significant
effect on MTX exposure.
ACTEMRA has not been studied in combination with biological DMARDs such as TNF antagonists [see Dosage and Administration].
Interactions with CYP450 Substrates
In vivo studies with omeprazole, metabolized by CYP2C19 and CYP3A4, and simvastatin, metabolized by CYP3A4, showed up
to a 28 % and 57% decrease in exposure one week following a single dose of ACTEMRA, respectively. The effect of tocilizumab
on CYP enzymes may be clinically relevant for CYP450 substrates with narrow therapeutic index, where the dose is individually
adjusted. Upon initiation or discontinuation of ACTEMRA, in patients being treated with these types of medicinal products,
therapeutic monitoring of effect (eg, warfarin) or drug concentration (eg, cyclosporine or theophylline) should be performed
and the individual dose of the medicinal product adjusted as needed. Prescribers should exercise caution when ACTEMRA is
coadministered with CYP3A4 substrate drugs where decrease in effectiveness is undesirable, eg, oral contraceptives, lovastatin,
atorvastatin, etc. The effect of tocilizumab on CYP450 enzyme activity may persist for several weeks after stopping therapy.
Live Vaccines
Live vaccines should not be given concurrently with ACTEMRA [see Warnings and Precautions].
USE IN SPECIFIC POPULATIONS
Pregnancy
Teratogenic Effects. Pregnancy Category C. There are no adequate and well-controlled studies in pregnant women. ACTEMRA
should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
An embryo-fetal developmental toxicity study was performed in which pregnant cynomolgus monkeys were treated intravenously
with tocilizumab (daily doses of 2, 10, or 50 mg/kg from gestation day 20-50) during organogenesis. Although there was no
evidence for a teratogenic/dysmorphogenic effect at any dose, tocilizumab produced an increase in the incidence of
Genentech USA, Inc., A Member of the Roche Group
South San Francisco, California 94080-4990
Copyright © 2010 Genentech USA, Inc. All rights reserved. 10081800
OPINION
20
S E P T E M B E R 2 0 1 0 • R H E U M AT O L O G Y N E W S
COMMENTARY
A Look Down the Gout Treatment Pipeline
llopurinol should, at least for now,
remain the standard hyperuricemia treatment for gout, despite febuxostat’s approval and the ongoing development of other gout
pharmaceuticals.
The reason is
that
allopurinol—if adequately dosed—works
for most patients.
And after decades
on the market, its
safety profile is
well known; it’s
also the least expensive option.
But even with
BY ROBERT L.
adequate dosing, W O R T M A N N , M . D .
allopurinol does
not work for everyone. For some, renal
problems or previous hypersensitivity
reactions make its use problematic.
That’s where the newer options come
in. For rheumatologists and patients
alike, they mean that allopurinol is not
the end of the line anymore. Soon, there
will likely be enough options to treat
every gout patient.
We recently reviewed febuxostat, as
well as pegloticase and other drugs in the
gout pipeline (Lancet 2010 Aug. 17 [doi:
10.1016/S0140-6736(10)60665-4]). Our
conclusion: Recent developments signal
a new era in the treatment of gout.
Febuxostat (Uloric), approved by the
Food and Drug Administration in Feb-
A
Continued from previous page
씰 Many believe that obesity is not a real
“disease.” As detailed at the recent
Physiology and Pathophysiology of
Adipose Tissue State of the Science
Conference, sponsored by the American Association of Clinical Endocrinologists, increased adiposity has pathogenic potential (“adiposopathy” or
“sick fat”), which directly contributes to
metabolic disease (http://atp.aace.
com). Unfortunately, many clinicians,
patients, and even “opinion leaders”
lack the basic science knowledge of
adipose physiology and pathophysiology and how it applies to adverse clini-
ruary 2009, is already making a difference
in clinical practice. It has been the experience of rheumatologists that patients
who have had trouble with allopurinol often respond to febuxostat. The first dose
can quickly drop the serum urate level
down to 5 mg/dL
or so, without
side effects or
rash. It’s a great
drug that is here
to stay.
Like allopurinol, febuxostat is
a xanthine oxidase inhibitor,
but a more selecAND
tive one that does
CHRISTOPHER M.
not inhibit other
B U R N S, M . D.
enzymes in the
purine and pyrimidine metabolic pathways.
Febuxostat dosing is easier, too. There
are two options in the United States: 40
mg and 80 mg/day. The allopurinol dosing range is 100-800 mg/day, depending
on patient renal history and response.
Even with those advantages, febuxostat should be seen as a second-line
agent, considered mainly for patients
who are intolerant to allopurinol. Febuxostat just has too many unknowns that
are awaiting further information. For instance, it is not known if it is more effective than allopurinol. Febuxostat was
better at dropping uric acid levels in trials, but it was compared with a suboptical outcomes. This is a bias of ignorance.
Overall, the lack of approval of antiobesity drugs suggests that, for the first
time in history, medical science is on the
cusp of proclaiming a major metabolic epidemic as being untreatable with
pharmaceuticals. This is more than
bias. It is a tragic failing of those of us
entrusted to patient care.
■
DR. BAYS is chairman of the AACE
Pathogenic Adipose Tissue Task Force.
He has received research grants and has
served as an adviser or consultant for
Vivus (which is developing obesity
therapies) and other drug companies.
E DITORIAL A DVISORY B OARD
ROY D. ALTMAN, M.D., University of
California, Los Angeles
DIMITRIOS BOUMPAS, M.D., University of
Crete, Heraklion, Greece
CHRISTOPHER M. BURNS, M.D., Dartmouth
University, Lebanon, N.H.
DANIEL E. FURST, M.D., University of
California, Los Angeles
ERIC P. GALL, M.D., University of
Arizona, Tucson
NORMAN B. GAYLIS, M.D., Private
Practice, Aventura, Fla.
KAREN S. KOLBA, M.D., Private Practice,
Santa Maria, Calif.
TORE K. KVIEN, M.D., University of Oslo
THOMAS J.A. LEHMAN, M.D., The Hospital
for Special Surgery, New York
ROBERT F. SPIERA, M.D., The Hospital for
Special Surgery, New York
VIRGINIA D. STEEN, M.D., Georgetown
University, Washington.
JOHN S. SUNDY, M.D., Duke University,
Durham, N.C.
KENNETH R. WILSKE, M.D., University of
Washington, Seattle
mal allopurinol dose (300 mg), and about
50% of gout patients need a higher dose
to control hyperuricemia.
Also, febuxostat’s cardiac safety is a
concern. Cardiac events were more common in febuxostat patients during trials,
although the implications of that are
not yet clear. Takeda Pharmaceutical
Co., the drug’s maker, is investigating the
matter further.
Finally, although no hypersensitivity reactions were attributed to febuxostat during trials, the FDA had received reports of
11 as of last May, including 2 anaphylactic
reactions, 1 case of angioedema, and 2 of
Stevens-Johnson syndrome (RHEUMATOLOGY NEWS, June 2010, p. 4).
At this time, clinicians need to use
their judgment whether to push allopurinol to therapeutic levels rather than
use febuxostat.
Patients with mild or moderate renal
insufficiency might be an exception, however. Febuxostat dosage adjustments are
not needed as long as patients’ creatinine
clearance is higher than 30 mL/min, according to the review article. Allopurinol
is typically adjusted downward for diminished renal function.
Most people with renal insufficiency
do fine even on allopurinol, as long as
they are started on a low dose that is
titrated upward to therapeutic effect,
and are monitored for kidney function.
Febuxostat is making inroads in the
United States: Some 139,565 prescriptions were written for it during its first 6
months on the market, according to
health care market analytics firm SDI
Health LLC.
One should expect a more modest reception for the next gout treatment—
pegloticase (Krystexxa)—that’s likely to
be approved by the FDA. The FDA’s
arthritis advisory committee recommended approval of the pegylated uricase
in June 2009; the agency and pegloticase’s
manufacturer, Savient Pharmaceuticals
Inc., appear to be working out the final
manufacturing and prescribing details.
Pegloticase’s strength is rapid reduction of
uric acid levels, to about 1 mg/dL within
24 hours in most cases.
Its market will be among patients who
need that kind of power: those with severe
tophaceous gout whose urate loads are so
high that there is an urgent clinical need
to lower it. Having a “big gun” for those
situations would be a major advance, especially when allopurinol and febuxostat
don’t work or can’t be used.
But pegloticase is destined to remain
in the hands of subspecialists because it’s
tricky to use. The drug is a biologic that
is administered intravenously a few times
a month. In trials, at least 25% of patients
developed antibodies to it, with subsequent infusion reactions, diminished effects, and treatment withdrawals, according to our review article.
Anaphylaxis developed in 7.3% of those
who were infused every other week. The
rapid uric acid reduction also led to frequent and sometimes severe gout flares.
Safe use is possible if rising concentrations of serum urate—a sign of antibody
development and impending infusion reaction—are caught in time. But the use issues mean that pegloticase will have a limited audience. If approved, it is unlikely to
be something that is used freely.
Other drugs intended for the management of gout are in early development. But, like febuxostat and pegloticase, they may help plug gaps in current
therapy if they’re approved for gout.
Already approved for cryopyrin-associated periodic syndromes, the anti-inflammatory interleukin-1 inhibitors rilonacept
(Arcalyst) and canakinumab (Ilaris) are being studied both for acute gout and for
prophylaxis. Conceivably, they could find
a home among gout patients who have
relative contraindications to steroids or
can’t use colchicine or NSAIDs because
they have heart failure, kidney disease,
peptic ulcers, or some other problem.
The gout pipeline also contains the uricosuric RDEA594. It is thought to be
more selective than probenecid and
benzbromarone, leading to the possibility that it would be a candidate for concomitant use with other urate-lowering
treatments. However, findings from a
small phase II trial show that RDEA594
was less effective than 300 mg allopurinol in lowering serum urate.
And combination therapy is already an
option with allopurinol and probenecid.
It is too early in development to predict whether RDEA594 itself will make
it through the FDA approval gauntlet,
but a more selective uricosuric would be
a useful addition to the expanding gout
armamentarium.
■
DR. WORTMANN is professor of medicine
in the division of rheumatology at the
Dartmouth-Hitchcock Medical Center,
Lebanon, N.H. and reports that he is a
paid consultant for Takeda Pharmaceutical
Co. and Savient Pharmaceuticals Inc.
DR. BURNS is assistant professor of
medicine in the rheumatology division of
Dartmouth-Hitchcock, and reports that he
has no conflicts of interest.
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