Ranibizumab
Encyclopedia
Ranibizumab is a monoclonal antibody fragment (Fab) derived from the same parent mouse antibody as bevacizumab
(Avastin). It is much smaller than the parent molecule and has been affinity matured
to provide stronger binding to VEGF
-A. It is an anti-angiogenic that has been approved to treat the "wet" type of age-related macular degeneration
(ARMD), a common form of age-related vision loss
.
Some investigators believe that bevacizumab at an average cost of $42 a dose (in the U.S.) is as effective as ranibizumab at an average cost of $1,593 a dose.
Ranibizumab was developed by Genentech
and is marketed in the United States by Genentech and elsewhere by Novartis
, under the brand name Lucentis.
(VEGF-A). VEGF may trigger the growth of new vessels, which may leak blood and fluid into the eye. These leaky blood vessels may contribute to macular edema
and choroid
al neovascularization
, resulting in the wet type of ARMD.
By blocking VEGF-A in the eye, ranibizumab may prevent and reverse vision loss caused by wet macular degeneration.
of the eye) once a month. If monthly injections are not feasible, the regimen may be reduced to 1 injection every 3 months after the first 4 months.
However, dosing every 3 months is linked to a loss of approximately 5 letters (1 line) in visual acuity for the following 9 months as compared with dosing on a monthly basis. Large phase 3 clinical trials (MARINA and ANCHOR) which randomized patients with wet macular degeneration showed that 95% of ranibizumab-treated patients maintained visual acuity compared with 62% of those administered placebo (P < .01) at 1 year; moreover, up to 40% demonstrated an improvement in vision of at least 3 lines. Vision maintenance and loss were defined as a loss of less than 15 letters and a gain of 15 or more letters in visual acuity, respectively, as measured using the Early Treatment of Diabetic Retinopathy eye chart.
s, increased intraocular pressure
, and intraocular inflammation.
Although there is a theoretical risk for arterial thromboembolic events in patients receiving VEGF-inhibitors by intravitreal injection, the observed incidence rate was low (< 4%) and similar to that seen in patients randomized to placebo.
Serious adverse events related to the injection procedure occurred with an incidence rate of less than 1% and included endophthalmitis
, retinal detachment
, and traumatic cataract
s. Other serious ocular adverse events observed among ranibizumab-treated patients (incidence rate < 1%) included intraocular inflammation and blindness.
A large clinical trial was published in the New England Journal of Medicine and showed no superior effect of ranibizumab. No difference in side effects could be found.
Bevacizumab
Bevacizumab is a drug that blocks angiogenesis, the growth of new blood vessels. It is commonly used to treat various cancers, including colorectal, lung, breast, kidney, and glioblastomas....
(Avastin). It is much smaller than the parent molecule and has been affinity matured
Affinity maturation
In immunology, affinity maturation is the process by which B cells produce antibodies with increased affinity for antigen during the course of an immune response. With repeated exposures to the same antigen, a host will produce antibodies of successively greater affinities. A secondary response...
to provide stronger binding to VEGF
Vascular endothelial growth factor
Vascular endothelial growth factor is a signal protein produced by cells that stimulates vasculogenesis and angiogenesis. It is part of the system that restores the oxygen supply to tissues when blood circulation is inadequate....
-A. It is an anti-angiogenic that has been approved to treat the "wet" type of age-related macular degeneration
Macular degeneration
Age-related macular degeneration is a medical condition which usually affects older adults and results in a loss of vision in the center of the visual field because of damage to the retina. It occurs in “dry” and “wet” forms. It is a major cause of blindness and visual impairment in older adults...
(ARMD), a common form of age-related vision loss
Vision loss
Vision loss or visual loss is the absence of vision where it existed before, which can happen either acutely or chronically .-Ranges of vision loss:...
.
Some investigators believe that bevacizumab at an average cost of $42 a dose (in the U.S.) is as effective as ranibizumab at an average cost of $1,593 a dose.
Ranibizumab was developed by Genentech
Genentech
Genentech Inc., or Genetic Engineering Technology, Inc., is a biotechnology corporation, founded in 1976 by venture capitalist Robert A. Swanson and biochemist Dr. Herbert Boyer. Trailing the founding of Cetus by five years, it was an important step in the evolution of the biotechnology industry...
and is marketed in the United States by Genentech and elsewhere by Novartis
Novartis
Novartis International AG is a multinational pharmaceutical company based in Basel, Switzerland, ranking number three in sales among the world-wide industry...
, under the brand name Lucentis.
Mechanism of action
Ranibizumab binds to and inhibits a number of subtypes of vascular endothelial growth factor AVascular endothelial growth factor A
Vascular endothelial growth factor A is a protein that in humans is encoded by the VEGFA gene.- Function :This gene is a member of the platelet-derived growth factor /vascular endothelial growth factor family and encodes a protein that is often found as a disulfide linked homodimer...
(VEGF-A). VEGF may trigger the growth of new vessels, which may leak blood and fluid into the eye. These leaky blood vessels may contribute to macular edema
Macular edema
Macular edema occurs when fluid and protein deposits collect on or under the macula of the eye and causes it to thicken and swell. The swelling may distort a person's central vision, as the macula is near the center of the retina at the back of the eyeball...
and choroid
Choroid
The choroid, also known as the choroidea or choroid coat, is the vascular layer of the eye, containing connective tissue, and lying between the retina and the sclera. The human choroid is thickest at the far extreme rear of the eye , while in the outlying areas it narrows to 0.1 mm...
al neovascularization
Neovascularization
Neovascularization is the formation of functional microvascular networks with red blood cell perfusion. Neovascularization differs from angiogenesis in that angiogenesis is mainly characterized by the protrusion and outgrowth of capillary buds and sprouts from pre-existing blood vessels.In...
, resulting in the wet type of ARMD.
By blocking VEGF-A in the eye, ranibizumab may prevent and reverse vision loss caused by wet macular degeneration.
Administration
The drug is injected intravitreally (into the vitreous humourVitreous humour
The vitreous humour or vitreous humor is the clear gel that fills the space between the lens and the retina of the eyeball of humans and other vertebrates...
of the eye) once a month. If monthly injections are not feasible, the regimen may be reduced to 1 injection every 3 months after the first 4 months.
However, dosing every 3 months is linked to a loss of approximately 5 letters (1 line) in visual acuity for the following 9 months as compared with dosing on a monthly basis. Large phase 3 clinical trials (MARINA and ANCHOR) which randomized patients with wet macular degeneration showed that 95% of ranibizumab-treated patients maintained visual acuity compared with 62% of those administered placebo (P < .01) at 1 year; moreover, up to 40% demonstrated an improvement in vision of at least 3 lines. Vision maintenance and loss were defined as a loss of less than 15 letters and a gain of 15 or more letters in visual acuity, respectively, as measured using the Early Treatment of Diabetic Retinopathy eye chart.
Side effects
The most common side effects in clinical trials were conjunctival hemorrhage, eye pain, vitreous floaterFloater
Floaters are deposits of various size, shape, consistency, refractive index, and motility within the eye's vitreous humour, which is normally transparent. At young age the vitreous is perfectly transparent, but during life imperfections gradually develop. The common type of floater, which is...
s, increased intraocular pressure
Intraocular pressure
Intraocular pressure is the fluid pressure inside the eye. Tonometry is the method eye care professionals use to determine this. IOP is an important aspect in the evaluation of patients at risk from glaucoma...
, and intraocular inflammation.
Although there is a theoretical risk for arterial thromboembolic events in patients receiving VEGF-inhibitors by intravitreal injection, the observed incidence rate was low (< 4%) and similar to that seen in patients randomized to placebo.
Serious adverse events related to the injection procedure occurred with an incidence rate of less than 1% and included endophthalmitis
Endophthalmitis
Endophthalmitis is an inflammation of the internal coats of the eye. It is a dreaded complication of all intraocular surgeries, particularly cataract surgery, with possible loss of vision and the eye itself. Infectious etiology is the most common and various bacteria and fungi have been isolated as...
, retinal detachment
Retinal detachment
Retinal detachment is a disorder of the eye in which the retina peels away from its underlying layer of support tissue. Initial detachment may be localized, but without rapid treatment the entire retina may detach, leading to vision loss and blindness. It is a medical emergency.The retina is a...
, and traumatic cataract
Cataract
A cataract is a clouding that develops in the crystalline lens of the eye or in its envelope, varying in degree from slight to complete opacity and obstructing the passage of light...
s. Other serious ocular adverse events observed among ranibizumab-treated patients (incidence rate < 1%) included intraocular inflammation and blindness.
Marketing
On November 3, 2010, The New York Times reported that Genentech began offering secret rebates to about 300 ophthalmologists in an apparent inducement to get them to use more ranibizumab rather than their less expensive bevacizumab, in anticipation of the result of a comparative study trial http://www.nejm.org/doi/pdf/10.1056/NEJMoa1102673 – sponsored by the National Eye Institute – of ranibizumab and bevacizumab to assess the relative safety and effectiveness in treating ARMD. Some retina specialists consider the tactic bribery. In 2008, bevacizumab cost Medicare only $20 million for about 480,000 injections, while ranibizumab cost Medicare $537 million for only 337,000 injections. A small study showed no superior effect of ranibizumab versus bevacizumab in direct comparison.A large clinical trial was published in the New England Journal of Medicine and showed no superior effect of ranibizumab. No difference in side effects could be found.