.
I have started this page as this drug initially looked optimistic as a treatment prospect for sIBM.
What is Etanercep (Enbrel)?
Etanercept or Enbrel is a new type of medication, called a 'biologic medication' or a BRM (biologic response modifier). ENBREL is a protein similar to one your body naturally produces. It works with the immune system to help regulate the body's natural TNF balance. TNF refers to Tumor Necrosis Factor. TNF is one of the chemical messengers (proteins) that helps to regulate the inflammatory process. During a normal immune response, TNF attaches to special cells throughout the body. This, in turn, "switches on" immune cells, causing them to release chemicals that can contribute to inflammation. When people produce too much TNF, it overwhelms the immune system's ability to control inflammation leading to diseases like rheumatoid arthritis.
ENBREL reduces the anoumt of TNFalpha- it binds and deactivates some TNFalpha molecules before they can trigger inflammation. By interrupting the chain of events that leads to inflammation, ENBREL can work with your immune system to help reduce inflammatory symptoms.
ENBREL is an important scientific advance that in many people has been shown to reduce the signs and symptoms of rheumatoid arthritis (RA), polyarticular-course juvenile rheumatoid arthritis (JRA), ankylosing spondylitis (AS) and psoriatic arthritis.
Manufactured by:
Immunex Corporation
Thousand Oaks, CA 91320-1799
U.S. License Number 1132
Marketed by Amgen and Wyeth Pharmaceuticals
Researchers find etanercept helpful in small IBM study
TMA Medical Advisory Board Member Richard J. Barohn, MD, and others studied
nine IBM patients who were treated with etanercept (Enbrel) to assess whether
the drug - sometimes used with good effect in other forms of myositis - could
slow the progression of weakness in inclusion body myositis (IBM). They treated
the group of IBM patients with etanercept, a tumor necrosis factor inhibitor,
and monitored disease progression in the patients.
In a retrospective pilot study the patients, meeting accepted diagnostic criteria, received 25 mgs of etanercept two times over a time period of 11 to 23 months for an average duration of 17 months [this is likely a misprint as Enbrel is usually given as 25mg 2x week or 50mg 1x week during a course of treatment]. The strength of the elbow flexors and handgrip was assessed at the beginning of the trial and again at six and 12 months. The data from the patients in the etanercept group were compared to a control group of six IBM patients who had undergone similar testing but who had not received the drug. The etanercept was well tolerated by the group of IBM patients who received it.
Researchers noted that grip strength improved in IBM patients treated with etanercept. In untreated patients, grip strength worsened. This difference was significant at 12 months. This preliminary data suggest that etancercept may affect disease progression in IBM. The researchers concluded that longer, prospective, controlled studies are warranted.
From: The Myositis Association, Outlook, Spring 2005, page 7. Reprinted with permission. This is a poster session report of an unpublished research study - this information may lead to a publication in the future.
The tumor necrosis factor (TNF) gene lies within the human leukocyte antigen (HLA) class III region on chromosome 6p21.3. This also ties into sIBM, see: Background.
Other references:
This reference does not appear in Pubmed because it is is a letter.
Inclusion Body Myositis Unresponsive to Etanercept.
JCR: Journal of Clinical Rheumatology. 7(4):279-280, August 2001.
Singh, Ranju MD; Cuchacovich, Raquel MD; Huang, Wenqun MD; Espinoza, Luis R.
MD
Techinical Description of the drug:
Enbrel is for Subcutaneous Injection. Patients usually take Enbrel at home
by giving themselves an injection under the skin, similar to diabetes patients
who give themselves insulin injections.
ENBREL® (etanercept) is a dimeric fusion protein consisting of the extracellular
ligand-binding portion of the human 75 kilodalton (p75) tumor necrosis factor
receptor (TNFR) linked to the Fc portion of human IgG1. The Fc component of
etanercept contains the CH2 domain, the CH3 domain and hinge region, but not
the CH1 domain of IgG1. Etanercept is produced by recombinant DNA technology
in a Chinese hamster ovary (CHO) mammalian cell expression system. It consists
of 934 amino acids and has an apparent molecular weight of approximately 150
kilodaltons. ENBREL® is supplied in a single-use prefilled 1 mL syringe
as a sterile, preservative-free solution for subcutaneous injection. The solution
of ENBREL® is clear and colorless and is formulated at pH 6.3 ± 0.2.
Each ENBREL® single-use prefilled syringe contains 0.98 mL of a 50 mg/mL
solution of etanercept with 10 mg/mL sucrose, 5.8 mg/mL sodium chloride, 5.3
mg/mL L-arginine hydrochloride, 2.6 mg/mL sodium phosphate, monobasic, monohydrate,
and 0.9 mg/mL sodium phosphate, dibasic, anhydrous. Administration of one 50
mg/mL prefilled syringe of ENBREL® provides a dose equivalent to two 25
mg vials of lyophilized ENBREL®, when vials are reconstituted and administered
as recommended. ENBREL® multiple-use vial contains sterile, white, preservative-free,
lyophilized powder. Reconstitution with 1 mL of the supplied Sterile Bacteriostatic
Water for Injection (BWFI), USP (containing 0.9% benzyl alcohol) yields a multiple-use,
clear, and colorless solution with a pH of 7.4 ± 0.3 containing 25 mg
etanercept, 40 mg mannitol, 10 mg sucrose, and 1.2 mg tromethamine.
CLINICAL PHARMACOLOGY
General
Etanercept binds specifically to tumor necrosis factor (TNF) and blocks its
interaction with cell surface TNF receptors. TNF is a naturally occurring cytokine
that is involved in normal inflammatory and immune responses. It plays an important
role in the inflammatory processes of rheumatoid arthritis (RA), polyarticular-course
juvenile rheumatoid arthritis (JRA), and ankylosing spondylitis and the resulting
joint pathology. In addition, TNF plays a role in the inflammatory process of
plaque psoriasis. Elevated levels of TNF are found in involved tissues and fluids
of patients with RA, psoriatic arthritis, ankylosing spondylitis (AS), and plaque
psoriasis. Two distinct receptors for TNF (TNFRs), a 55 kilodalton protein (p55)
and a 75 kilodalton protein (p75), exist naturally as monomeric molecules on
cell surfaces and in soluble forms. Biological activity of TNF is dependent
upon binding to either cell surface TNFR. Etanercept is a dimeric soluble form
of the p75 TNF receptor that can bind to two TNF molecules. It inhibits the
activity of TNF in vitro and has been shown to affect several animal models
of inflammation, including murine collagen-induced arthritis. Etanercept inhibits
binding of both TNFalpha; and TNFbeta;
(lymphotoxin alpha [LTalpha]) to cell surface TNFRs,
rendering TNF biologically inactive. Cells expressing transmembrane TNF that
bind ENBREL® are not lysed in vitro in the presence or absence of complement.
Etanercept can also modulate biological responses that are induced or regulated
by TNF, including expression of adhesion molecules responsible for leukocyte
migration (i.e., E-selectin and to a lesser extent intercellular adhesion molecule-1
[ICAM-1]), serum levels of cytokines (e.g., IL-6), and serum levels of matrix
metalloproteinase-3 (MMP-3 or stromelysin).
Pharmacokinetics
After administration of 25 mg of ENBREL® by a single subcutaneous (SC) injection
to 25 patients with RA, a mean ± standard deviation half-life of 102
± 30 hours was observed with a clearance of 160 ± 80 mL/hr. A
maximum serum concentration (Cmax) of 1.1 ± 0.6 mcg/mL and time to Cmax
of 69 ± 34 hours was observed in these patients following a single 25
mg dose. After 6 months of twice weekly 25 mg doses in these same RA patients,
the mean Cmax was 2.4 ± 1.0 mcg/mL (N = 23). Patients exhibited a two-
to seven-fold increase in peak serum concentrations and approximately four-fold
increase in AUC0-72 hr (range 1 to 17 fold) with repeated dosing. Serum concentrations
in patients with RA have not been measured for periods of dosing that exceed
6 months. The pharmacokinetic parameters in patients with plaque psoriasis were
similar to those seen in patients with RA. In another study, serum concentration
profiles at steady state were comparable among patients with RA treated with
50 mg ENBREL® once weekly and those treated with 25 mg ENBREL® twice
weekly. The mean (± standard deviation) Cmax, Cmin, and partial AUC were
2.4 ± 1.5 mg/L, 1.2 ± 0.7 mg/L, and 297 ± 166 mg'h/L,
respectively, for patients treated with 50 mg ENBREL® once weekly (N = 21);
and 2.6 ± 1.2 mg/L, 1.4 ± 0.7 mg/L, and 316 ± 135 mg/h/L
for patients treated with 25 mg ENBREL® twice weekly (N = 16). Pharmacokinetic
parameters were not different between men and women and did not vary with age
in adult patients. No formal pharmacokinetic studies have been conducted to
examine the effects of renal or hepatic impairment on ENBREL® disposition.
Patients with JRA (ages 4 to 17 years) were administered 0.4 mg/kg of ENBREL®
twice weekly for up to 18 weeks. The mean serum concentration after repeated
SC dosing was 2.1 mcg/mL, with a range of 0.7 to 4.3 mcg/mL. Limited data suggests
that the clearance of ENBREL® is reduced slightly in children ages 4 to
8 years. Population pharmacokinetic analyses predict that administration of
0.8 mg/kg of ENBREL® once weekly will result in Cmax 11% higher, and Cmin
20% lower at steady state as compared to administration of 0.4 mg/kg of ENBREL®
twice weekly. The predicted pharmacokinetic differences between the regimens
in JRA patients are of the same magnitude as the differences observed between
twice weekly and weekly regimens in adult RA patients. The pharmacokinetics
of ENBREL® in children < 4 years of age have not been studied.
A Fat Connection:
Certain attributes of visceral fat, the adipose tissue surrounding abdominal
organs, make its accumulation more worrisome than the accumulation of subcutaneous
fat, which resides below the skin. Such concerns include an association of increased
visceral fat with the metabolic syndrome, enhanced secretion of TNFa
and other proinflammatory adipokines, and reduced secretion of antidiabetic
and anti-inflammatory adipokines relative to those secreted by other fat depots.
Three of these hormones--TNFa , resistin, and IL-6--induce
resistance to insulin, the principal hormone that regulates blood glucose levels.
TNFa is a proinflammatory cytokine that suppresses
expression of adipocyte-specific genes; resistin maintains blood glucose levels
during fasting; and IL-6 production increases in those with obesity and diabetes.
Adiponectin and visfatin are adipokines that work synergistically with insulin
to enhance glucose uptake and metabolism in muscle and to block glucose formation
(gluconeogenesis) in liver. From: Science, Vol 307, Issue 5708, 366-367, 21
January 2005.
.