The pharmaceutical company BASF Pharma, Ludwigshafen, Germany developed Humira (D2E7),an antibody against TNF-alpha in
collaboration with Cambridge Antibody Technology, Cambridge,U.K. BASF Pharma began enrolling volunteers for phase III clinical
trials in mid-2000. This antibody has shown the ability to reduce joint inflammation and relieve the signs of RA by
"mopping up" excess TNF-alpha. There is evidence from X-ray analysis that it can also slow down the progression of RA damage.
According to BASF Pharma,the medication lasts longer after injection,so it can be administered once per week instead of the
twice-weekly injections for Enbrel,which means it could turn out to be more convient and less expensive. Because it is a human
antibody it stimulates fewer allergic and injection site reactions. A advantage claimed over Remicade is that,inlike with
Remicade,it is not necessary to give Humira in conjunction with methotrexate,although,it can be done in combination ,in some
The combination of adalimumab with ongoing MTX therapy was demonstrated to be effective in 271 patients with RA who did
not respond completely to MTX alone. Patients in this double-blind study were randomized to receive either placebo or adalimumab
20, 40, or 80 mg every other week in addition to MTX. At the end of 24 weeks, the percentages of patients who received placebo
or adalimumab 20, 40, or 80 mg and achieved ACR20 response criteria were 15%, 48%, 66%, and 66%, respectively (all adalimumab
p < 0.0001 versus placebo). The respective values for ACR50 were 8%, 32%, 54%, and 43% (p < 0.0001 for adalimumab 40
and 80 mg versus placebo and p < 0.003 for 20-mg adalimumab versus placebo). The values for ACR70 were 5%, 10%, 27%, and
19%, respectively (p < 0.02 for the 40- and 80-mg adalimumab doses versus placebo).
Adalimumab is a fully human TNF-alpha mAb. Adalimumab has a half-life of approximately 2 weeks and is administered subcutaneously
once every other week; the proposed dose of adalimumab is 40 mg every other week. The development of inhibitors of tumor necrosis
factor (TNF) evolved from a targeted bench-to-bedside approach in which lessons learned from basic pathophysiological research
were tested in patients with debilitating chronic inflammatory diseases, in particular rheumatoid arthritis (RA). Insofar
as all prior treatments for RA evolved primarily from serendipitous observations, the TNF inhibitors represent the first rationally
based treatment, as well as the first FDA-approved recombinant proteins (biologics) for the treatment of RA.
While a T cell mediated, antigen-specific process is undoubtedly critical to the initiation of RA, sustained inflammation
is at least equally dependent on cytokine production by synovial macrophages and fibroblasts which may act on each other in
an autocrine or paracrine manner. Tumor necrosis factor-a (TNF-a) and interleukin-1 (IL-1) are the major macrophage-derived
cytokines present in the rheumatoid joint and both induce the synthesis and secretion from synovial fibroblasts of matrix-degrading
proteases, prostanoids, interleukin-6 (IL-6), interleukin-8 (IL-8) and granulocyte-macrophage colony stimulating factor (GM-CSF).
Consequently, attention has focused on inhibition of TNF-a as a way to treat RA.
Because the safety of the TNF inhibitors in humans was unknown, early trials in RA targeted patients with severe, longstanding
disease that had failed to respond adequately to conventional treatments such as methotrexate, gold salts, immunosuppressives
and others. More recently, as the safety of these agents unfolded, patients with juvenile RA and adults with early RA have
been targeted. An evolution in the selection of study outcomes has also occurred in that earlier trials focused on clinical
parameters as endpoints, while more recent trials have focused on structural (radiographic) endpoints.
Some of the clinical data that led to the FDA approval of two anti-TNF therapies for the treatment of RA will be presented.
The agents to be discussed are: a) infliximab mouse-human chimeric anti-human TNF antibody b) etanercept soluble p75 TNF receptor
coupled to Fc portion of IgG c) Relevant outcomes that are assessed in clinical trials of potential therapies for RA
include individual clinical parameters, composite scores that integrate multiple clinical parameters, and radiographic scores.
Examples of individual clinical parameters include: 1) tender joint count 2) swollen joint count 3) erythrocyte
sedimentation rate (ESR) or C-reactive protein (CRP) 4) visual analog scales for pain, function, global assessment 5)
An example of a composite score is the ACR20 score. However, the gold standard for evaluating the efficacy of a treatment
in rheumatoid arthritis is its ability to slow or halt radiographic progression of the disease that is, the treatment must
slow or halt the development of new or enlarging erosions and slow the development of new or progressive joint space narrowing.
Several scoring systems have been developed for quantifying these radiologic manifestations of RA.
Both infliximab and etanercept have been studied extensively in human subjects, and both are now FDA approved for the
treatment of RA. Initially, because of the experimental nature of these treatments, only patients with long-standing, severe
RA were evaluated and the identified outcome was clinical (but not radiologic) improvement. Although many of these patients
had failed multiple conventional treatments for RA (such as methotrexate, gold, etc.), clinical responses to the TNF inhibitors
were gratifyingly robust and rapid. More recently, patients with early disease have been targeted for study and their responses
have been similarly robust.
Even more compelling are radiographic data in both early and late disease patients which demonstrate the ability of anti-TNF
agents to slow or halt radiographic damage in the majority of patients. Clinical data provide proof of concept in humans
that TNF is indeed an important pathogenic mediator of joint damage in RA. Perhaps most intriguing about these studies is
that targeting (inhibiting) a single cytokine can profoundly alter the natural history of this disease.
TNF plays an important role in host defenses, particularly in the killing of intracellular microorganisms such as Listeria
and mycobacteria, and in inducing apoptosis of some tumor cells. Consequently, there has been some concern that long-term
inhibition of TNF could lead to an increased incidence of infection and of malignancy. In addition, as these agents are genetically
engineered proteins that will be given repeatedly over long periods for the treatment of chronic diseases, issues of immunogenicity
and injection reactions require scrutiny.
Because of the potential for an immune reaction to the mouse protein components of a chimeric antibody (Infliximab),
an alternate strategy has been to develop a fully human anti-TNF monoclonal antibody. One such antibody, known as Humira,
also known as adalumimab, was generated by phage display technology. A high affinity murine anti-TNF monoclonal antibody
was used as a template for guided selection, which involves complete replacement of the murine heavy and light chains with
human counterparts and subsequent optimization of the antigen-binding affinity. HumiraTM received FDA approval in in December,
Adalimumab (Humira) Created with phage display technology, adalimumab is the first fully human anti-TNF-alpha monoclonal
antibody (IgG1). Therefore, it has low immunogenicity and may have greater therapeutic potential than infliximab or etanercept.
This low immunogenicity may obviate the need for concomitant MTX, although such dual use has been shown to yield efficacy
benefits beyond those that might simply be additive.
The preliminary data provided to the FDA for approval purposes support a profile of clinical response that is similar
to etanercept. It has been approved both for reducing signs and symptoms of RA and inhibiting the progression of structural
damage in adults with moderately to severely active disease who have had insufficient response to one or more DMARDs.
As with the other two TNF inhibitors, the clinician should observe precautions for serious infections (including sepsis, tuberculosis,
fungal infections, and other invasive opportunistic infections), and rare cases of demyelinating disease, and malignancies
(including lymphoma), all of which have been seen with each of these agents.
Since rheumatoid arthritis itself has been associated with an increased risk of lymphoma, the significance of the observed
lymphoma cases is as yet not determined. Dose: As the latest option, adalimumab offers a much more practical, patient-friendly
dosing regimen of one subcutaneous injection of 40 mg every other week.
The exact cause of rheumatoid arthritis (RA) is not known. However, in the last decade researchers have determined that
people with RA tend to have an excess of protein called tumor necrosis factor alpha (TNF-a). TNF-a triggers inflammation as
part of the body's normal immune system response. Over production of TNF-a can lead to excessive inflammation such as that
found in patients with RA. As TNF-a builds up in the joints, it leads to joint inflammation, which can ultimately result
in joint destruction. Because of its role in the progression of RA, blocking the activity of TNF-a has become a key focus
of new RA therapies, such as HUMIRA. HUMIRA works by targeting and binding to TNF-a. This binding blocks the activity of TNF-a
which helps prevent inflammation.
HUMIRA is the first human monoclonal antibody approved for RA. HUMIRA was created using phage display technology resulting
in an antibody with human-derived heavy and light chain variable regions and human lgG1:k constant regions. This means, it
resembles antibodies normally found in the body. As HUMIRA binds and blocks the activity of TNF-a, it reduces the signs and
symptoms of RA and slows the progression of structural joint damage caused by the disease. a) Relieves the pain that you have
with rheumatoid arthritis (RA) b) Reduces the number of swollen and tender joints c) Increases your mobility
d) Slows down the rate at which your RA progresses e) Helps fight the fatigue that you experience with RA
f) Works fast - some people have experienced results in as quickly as 12 weeks after the initial dose g) Convenient
to take. You usually only need to inject HUMIRA once every two weeks. And, you can take it in the convenience of your own
home without having to visit your doctor. h) Easy to inject using a pre-measured syringe.
HUMIRA is a medicine called a TNF blocker, which is a type of protein that blocks the action of a substance your body
makes, called TNF-a. TNF-a is made by your body's immune system. People with rheumatoid arthritis (RA) have too much of it
in their bodies. The extra TNF-a in your body can attack normal healthy body tissues and cause inflammation especially in
the tissues in your bones, cartilage, and joints. HUMIRA can block the damage that too much TNF-a can cause, and it can also
lower your body's ability to fight infections. HUMIRA helps reduce the signs and symptoms of RA, such as pain and swollen
joints, and may help prevent further damage to your bones and joints. HUMIRA is used in adults with moderate to severe RA
who have had a poor response to one or more DMARDs (disease-modifying antirheumatic drugs).
HUMIRA is a biologic disease-modifying medicine that interrupts the inflammation process and helps stop the progression
of RA. The active ingredient resembles an antibody that normally occurs in your body, so it helps your body to fight RA the
way it would if it could. HUMIRA can also be taken with pain medications and other disease modifying drugs. HUMIRA is a biologic
disease-modifying antirheumatic drug, also called a DMARD. Biologic DMARDS are among the most recent RA treatments approved
by the FDA and are approved for reducing the signs and symptoms, and slowing the progression of structural damage to the joints
caused by RA.
Other biologic DMARDs include EnbrelŽ and RemicadeŽ. These DMARDs may need to be injected more frequently or require
a visit to the doctor to administer the medication. HUMIRA is the newest biologic DMARD available and was the most widely
studied TNF-a antagonist when it was submitted to the FDA.
HUMIRA can be self administered in the convenience of your own home. And, it usually only needs to be taken once every
two weeks - giving you more freedom to live your life without having to always think about taking your medication. You can
take other medicines provided your doctor has prescribed them, or has told you it's ok to take them while you're taking HUMIRA.
HUMIRA can be used alone or in combination with methotrexate or other DMARDs that are used to treat RA. It's important that
you tell your doctor about any other medicines you are taking for other conditions (for example, high blood pressure medicine)
before you start taking HUMIRA.
You should also tell your doctor about any over-the-counter drugs, herbal medicines and vitamin and mineral supplements
you're taking. You should not take HUMIRA with other TNF blockers. If you have any questions, you should ask your doctor.
Take HUMIRA by giving yourself an injection under the skin, every other week. Ask your doctor to show you or a loved one how
to inject HUMIRA. Some patients find it helpful to take HUMIRA in the morning or at bedtime. However, once you find
a time that you prefer, taking the medication at a consistent time can help you to remember to take it. It's also a good idea
to mark your calendar ahead of time with the dates that you take your treatment which may help you remember when to take it.
Always follow your doctor's instructions on when and how often to take HUMIRA.
If you forget to take HUMIRA when you're supposed to, inject the next dose right away. Then, take your next dose when
your next scheduled dose is due. This will put you back on schedule. HUMIRA needs to be stored in a refrigerator (2°C - 8°C/36-46°F)
in its original container and protected from light until it's used. HUMIRA should never be put in the freezer or frozen. Refrigerated
HUMIRA remains stable until the expiration date printed on the pre-filled syringe. If you need to take it with you, such as
when you're traveling, store it in a cool carrier with an ice pack and protect it from light.
The recommended dose of HUMIRA for adult patients with RA is 40mg (milligrams) every other week. Injected subcutaneously
(under the skin) Always follow your doctor's instructions about when and how often to take HUMIRA. Your doctor may instruct
you to take HUMIRA more frequently (every week). Unfortunately, there are no current treatments available that can cure RA.
However, HUMIRA is a disease-modifying medicine that can control and even reduce inflammation. It treats the disease and relieves
the pain by slowing or blocking joint and cartilage damage.
You'll likely notice less pain, swelling and joint stiffness, while at the same time you may also see an increased range
of movement. Patients have also reported higher energy levels. Before you start taking HUMIRA you should tell your doctor
if you're scheduled to be vaccinated for anything. Some patients will see results as quickly as 1 - 2 weeks after the initial
dose. For other patients it may take longer, up to three months. To know it's working, you'll likely notice less pain, swelling
and joint stiffness, and you may also see an increased range of movement. Patients have also reported higher energy levels.
You should always check with your healthcare provider for instructions on how to properly dispose of used needles and syringes.
You should follow any special state or local laws regarding the proper disposal of needles and syringes. Do not throw the
needle or syringe in the household trash or recycle.
Here are some tips that you may find helpful: a) You should place the used needles and syringes in a container
made specially for disposing of used syringes and needles (called a "Sharps" container), or a hard plastic container with
a screw-on cap or metal container with a plastic lid labeled "used syringes". Do not use glass or clear plastic containers.
You should always keep the container out of the reach of children. b) When the container is about two-thirds full, tape
the cap or lid down so it doesn't come off and dispose of it as instructed by your doctor, nurse or pharmacist. Do not throw
the container in the household trash or recycle. c) Used preps may be placed in the trash, unless otherwise
instructed by your doctor, nurse or pharmacist. The dose tray and cover may be recycled. The needle cover on the
pre-filled syringe contains dry natural rubber. Tell your doctor if you have any allergies to rubber or latex.
Warning signs may include a severe rash, swollen face, or difficulty breathing. If you experience any of these symptoms,
call your doctor or seek medical assistance immediately. Studies have not been done to see how HUMIRA interacts with alcohol.
Many patients experience a reaction where the injection was given. These reactions are usually mild and include redness, rash,
swelling, itching or bruising. Usually, the rash will go away within a few days. If the skin around the area where you injected
HUMIRA still hurts or is swollen, try using a towel soaked with cold water on the injection site. If you have pain, redness
or swelling around the injection site that doesn't go away within a few days or gets worse, call your doctor right away. Other
side effects are upper respiratory infections (sinus infections), headache and nausea. Any medicine can have side effects.
Like all medicines that affect your immune system, HUMIRA can cause serious side effects. The possible serious side effects
There have been rare cases where patients taking HUMIRA or other TNF-blocking agents have developed serious infections,
including tuberculosis (TB) and infections caused by bacteria or fungi. In these rare cases, some patients have died when
the bacteria that cause infections have spread throughout their body (sepsis). There have been rare cases of disorders that
affect the nervous system of people taking HUMIRA or other TNF blockers. Signs that you could be experiencing a problem affecting
your nervous system include: numbness or tingling, problems with your vision, weakness in your legs and dizziness.
There have been very rare cases of certain kinds of cancer in patients taking HUMIRA or other TNF blockers. People with
more serious RA that have had the disease for a long time may have a higher than average risk of getting a kind of cancer
that affects the lymph system, called lymphoma. If you take HUMIRA or other TNF blockers, your risk may increase. Some patients
have developed lupus-like symptoms that got better after their treatment was stopped. If you have chest pains that do not
go away, shortness of breath, joint pain or a rash on your cheeks or arms that is sensitive to the sun, call your doctor right
away. Your doctor may decide to stop your treatment.
If you develop a severe rash, swollen face or difficulty breathing while taking HUMIRA, call your doctor right away.
You should not take HUMIRA if you have an allergy to any of the ingredients in HUMIRA (adalimumab, sodium phosphate, sodium
citrate, citric acid, mannitol, and polysorbate 80). The needle cover on the pre-filled syringe contains dry natural rubber.
Tell your doctor if you have any allergies to rubber or latex. Before you start taking HUMIRA you should tell your doctor
if you have or have had any of the following: a) Any kind of infection including an infection that is in only one place
in your body (such as an open cut or sore), or an infection that is in your whole body (such as the flu). Having an infection
could put you at risk for serious side effects from HUMIRA. If you are unsure, please ask your doctor. b) A history of
infections that keep coming back or other conditions that might increase your risk of infections. c) If you've ever
had tuberculosis (TB), or if you have been in close contact with someone who's had TB. If you develop any of the symptoms
of TB (a dry cough that doesn't go away, weight loss, fever, night sweats) call your doctor right away. Your doctor will need
to examine you for TB and perform a skin test. d) If you experience any numbness or tingling or have ever had a disease
that affects your nervous system like multiple sclerosis. e) If you're scheduled to have major surgery. f)
If you're scheduled to be vaccinated for anything.
HUMIRA has not been studied in pregnant women or nursing mothers, so its not known what the effects are on
pregnant women or nursing babies. You should tell your doctor if you're pregnant, become pregnant or are thinking about becoming
pregnant. To better manage your RA, it may be helpful to eat a healthy diet, get adequate rest, and lose any excess weight.
It's also a good idea to exercise regularly which can help build strength, endurance and mobility. Many people find stress
management beneficial, too.