Pegaptanib sodium injection (brand name Macugen) is an
anti-angiogenic
An angiogenesis inhibitor is a substance that inhibits the growth of new blood vessels (angiogenesis). Some angiogenesis inhibitors are endogenous and a normal part of the body's control and others are obtained exogenously through pharmaceutical d ...
medicine for the treatment of neovascular (wet)
age-related macular degeneration
Macular degeneration, also known as age-related macular degeneration (AMD or ARMD), is a medical condition which may result in blurred or no vision in the center of the visual field. Early on there are often no symptoms. Some people experien ...
(AMD). It was discovered by NeXstar Pharmaceuticals (which merged with Gilead Sciences in 1999) and licensed in 2000 to EyeTech Pharmaceuticals, now
OSI Pharmaceuticals
OSI Pharmaceuticals, Inc. was an American pharmaceutical company formerly based in Long Island, New York with facilities in Colorado, New Jersey and the United Kingdom. On Sunday, May 16, 2010 OSI agreed to be acquired by Japan-based, TSE-liste ...
, for late stage development and marketing in the United States. Gilead Sciences continues to receive royalties from the drugs licensing. Outside the US pegaptanib is marketed by
Pfizer
Pfizer Inc. ( ) is an American Multinational corporation, multinational Pharmaceutical industry, pharmaceutical and biotechnology corporation headquartered at The Spiral (New York City), The Spiral in Manhattan, New York City. Founded in 184 ...
. Approval was granted by the
U.S. Food and Drug Administration
The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...
(FDA) in December 2004.
Mechanism of action
Pegaptanib is a
pegylated
PEGylation (or pegylation) is the process of both covalent and non-covalent attachment or amalgamation of polyethylene glycol (PEG, in pharmacy called macrogol) polymer chains to molecules and macrostructures, such as a drug, therapeutic protein ...
anti-
vascular endothelial growth factor
Vascular endothelial growth factor (VEGF, ), originally known as vascular permeability factor (VPF), is a signal protein produced by many cells that stimulates the formation of blood vessels. To be specific, VEGF is a sub-family of growth factors ...
(VEGF)
aptamer
Aptamers are oligomers of artificial ssDNA, RNA, Xeno nucleic acid, XNA, or peptide that ligand, bind a specific target molecule, or family of target molecules. They exhibit a range of affinities (Dissociation constant, KD in the pM to μM rang ...
, a single strand of
nucleic acid
Nucleic acids are large biomolecules that are crucial in all cells and viruses. They are composed of nucleotides, which are the monomer components: a pentose, 5-carbon sugar, a phosphate group and a nitrogenous base. The two main classes of nuclei ...
that binds with specificity to a particular target. Pegaptanib specifically binds to the 165
isoform
A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene and are the result of genetic differences. While many perform the same or similar biological roles, some isoforms have uniqu ...
of VEGF, a protein that plays a critical role in
angiogenesis
Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature mainly by processes of sprouting and ...
(the formation of new blood vessels) and increased permeability (leakage from blood vessels), two of the primary pathological processes responsible for the vision loss associated with neovascular AMD.
Pegaptanib works as a VEGF
antagonist
An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain.
Means of administration
Pegaptanib is administered in a 0.3 mg dose once every six weeks by
intravitreal
Intravitreal administration is a route of administration of a drug, or other substance, in which the substance is delivered into the vitreous humor of the eye. "Intravitreal" literally means "inside an eye". Intravitreal injections were first intr ...
injection. An intravitreal injection is one that is administered directly into the eye, more specifically, into the
vitreous humour
The vitreous body (''vitreous'' meaning "glass-like"; , ) is the clear gel that fills the space between the lens and the retina of the eyeball (the vitreous chamber) in humans and other vertebrates. It is often referred to as the vitreous hum ...
, or the jelly-like fluid within the eye. Pegaptanib has to be administered to the designated patient by an
ophthalmologist
Ophthalmology (, ) is the branch of medicine that deals with the diagnosis, treatment, and surgery of eye diseases and disorders.
An ophthalmologist is a physician who undergoes subspecialty training in medical and surgical eye care. Following a ...
in a sterile environment. Pegaptanib is marketed as a pre-filled syringe; however the syringe contains more than the recommended dose. Therefore, the eye care professionals must adjust the dose to the recommended amount before injections.
Preclinical trials
Pegaptanib underwent several
preclinical studies
In drug development, preclinical development (also termed preclinical studies or nonclinical studies) is a stage of research that begins before clinical trials (testing in humans) and during which important feasibility, iterative testing and dr ...
in order to determine its safety and efficacy before moving into clinical trials.
Animal toxicology studies
Toxicology studies were conducted in
rhesus monkey
The rhesus macaque (''Macaca mulatta''), colloquially rhesus monkey, is a species of Old World monkey. There are between six and nine recognised subspecies split between two groups, the Chinese-derived and the Indian-derived. Generally brown or g ...
s, guinea pigs, rats, mice, and rabbits. After the administration of the aptamer into rhesus monkeys, no toxic effects where exhibited. It was also noted that there was no change in
intraocular pressure
Intraocular pressure (IOP) 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 of glaucoma. Most tonometers are calibrated t ...
and no immune response was taken against the API. Aside from the intravitreal administration of the pegaptanib, it was also found that subcutaneous and
intravenous
Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutr ...
routes of administration were also effective at maintaining the desired blood plasma concentration. In rats, pegaptanib was successful at blocking VEGF-mediated vascular leakage almost entirely. The sustained release of the drug was tested in rabbits. It was found that using
poly(lactic-co-glycolic) acid
PLGA, PLG, or poly(lactic-''co''-glycolic) acid ( CAS: ) is a copolymer which is used in a host of Food and Drug Administration (FDA) approved therapeutic devices, owing to its biodegradability and biocompatibility. PLGA is synthesized by means o ...
(PLGA) microspheres, which encapsulated the drug, the minimum dosing frequency was 6 weeks to maintain the desired pharmacological effect. This dosing interval is what carried over into the clinical trials and is still maintained today.
Clinical studies
Phase I
Phase I studies began in 1998 under Eyetech Pharmaceuticals. This study was conducted in 15 patients with wet AMD. Doses ranging from 0.25 to 30 mg per eye were injected into the eye, and patients were monitored for a period of three months. The results showed that 80% of the patients had stabilization or improvement, and 26.7% were showing improvement with no signs of toxicity.
Phase II
After the success of the Phase I study, Eyetech completed a Phase II study focusing on multiple injections. In this study, 21 patients with sub
fovea
Fovea () (Latin for "pit"; plural foveae ) is a term in anatomy. It refers to a pit or depression in a structure.
Human anatomy
*Fovea centralis of the retina
* Fovea buccalis or dimple
* Fovea of the femoral head
* Trochlear fovea of the fr ...
l
choroidal neovascularization
Choroidal neovascularization (CNV) is the creation of new blood vessels in the choroid layer of the eye. Choroidal neovascularization is a common cause of neovascular degenerative maculopathy (i.e. 'wet' macular degeneration) commonly exacerbated ...
(CNV) secondary to AMD were given multiple intravitreal injections. Due to the presence of subfoveal CNV some patients were given a secondary treatment,
photodynamic therapy
Photodynamic therapy (PDT) is a form of phototherapy involving light and a photosensitizing chemical substance used in conjunction with molecular oxygen to elicit cell death ( phototoxicity).
PDT is used in treating acne, wet age-related macula ...
(PDT) for this condition. Results showed that in 87.5% of patients who received only pegaptanib, vision stabilized or improved. In patients who received PDT alone only 50.5% saw a slight improvement. However, when the two therapies were administered together, the level of improvement reached 60% or better.
Phase III
After the success of the Phase I and Phase II trials, the FDA granted
fast track
Fast Track, Fast track, or Fasttrack may refer to:
Processes and systems
* Fast track (FDA), a U.S. Food and Drug Administration expedited review program
* Fast track (trade), the authority of the U.S. President to broker trade agreements with lim ...
designation for the Phase III clinical trials. In these trials, pegaptanib was studied in two identical controlled,
double-blind
In a blind or blinded experiment, information which may influence the participants of the experiment is withheld until after the experiment is complete. Good blinding can reduce or eliminate experimental biases that arise from a participants' expec ...
randomized clinical studies that lasted for approximately two years each. For this study approximately 1200 patients with neovascular ("wet") age-related macular degeneration were randomly put into groups to receive either a
placebo
A placebo ( ) can be roughly defined as a sham medical treatment. Common placebos include inert tablets (like sugar pills), inert injections (like saline), sham surgery, and other procedures.
Placebos are used in randomized clinical trials ...
treatment or the designated 0.3 mg, 1 mg, or 3 mg of pegaptanib administered intravitreal injections every 6 weeks. Of the 1200 patients enrolled in the study approximately 892 received the varying doses of pegaptanib and approximately 298 received the placebo injection. At the end of the first year, patients continuing the study were re-randomized for the second year.
The primary efficacy endpoint for the study was denoted by the proportion of the patients who lost less than 15 letters of visual acuity from their assessed baseline over the 54-week assessment.
Results of the first year showcased promising results for pegaptanib. In groups treated with the 0.3 mg dose at the primary efficacy endpoint, experienced a statistically significant result.
*Study 1: 73% pegaptanib vs. 60% placebo
*Study 2: 67% pegaptanib vs. 53% placebo
Also, on average, pegaptanib 0.3 mg treated patients as well as the placebo patients continued to experience vision loss. However, the rate of vision decline was significantly lower than that of patients with the placebo treatment.
Moreover, it was also determined that the second year of treatment was less effective than the first year. Results of the primary efficacy endpoint are:
*Study 1: 57% pegaptanib vs. 56% placebo
*Study 2: 61% pegaptanib vs. 34% placebo
Regulatory approval information
Pegaptanib (pegaptanib sodium injection) has been approved in: United States (2004)
Europe (2005)
Brazil (2005) Canada (2006) Pending: Australia (Filed in 2006)
Side effects
Common
side effect
In medicine, a side effect is an effect of the use of a medicinal drug or other treatment, usually adverse but sometimes beneficial, that is unintended. Herbal and traditional medicines also have side effects.
A drug or procedure usually use ...
s of pegaptanib include:
*
Anterior chamber
The anterior chamber ( AC) is the aqueous humor-filled space inside the eye between the iris and the cornea's innermost surface, the endothelium. Hyphema, anterior uveitis and glaucoma are three main pathologies in this area. In hyphema, ...
inflammation
*Raised intraocular pressure
* Punctate keratitis (small marks on the surface of the eye)
*Vitreous
floater
Floaters or eye floaters are sometimes visible deposits (e.g., the shadows of tiny structures of protein or other cell debris projected onto the retina) within the eye's vitreous humour ("the vitreous"), which is normally transparent, or between ...
s (small particles or spots in the vision)
*Retinal damage (extremely adverse)
*
Endophthalmitis
Endophthalmitis, or endophthalmia, is inflammation of the interior cavity of the eye, usually caused by an infection. It is a possible complication of all intraocular surgeries, particularly cataract surgery, and can result in loss of vision or l ...
(an infection inside the eye)
*Vitreous
haemorrhage
Bleeding, hemorrhage, haemorrhage or blood loss, is blood escaping from the circulatory system from damaged blood vessels. Bleeding can occur internally, or externally either through a natural opening such as the mouth, nose, ear, urethra, vag ...
(bleeding inside of the eye)
Commercialization
The average cost of pegaptanib was approximately $5,300 per 5 syringes in the US. In 2004, when pegaptanib was approved it was a novel drug in its target and treatment for the treatment of AMD. However, the last large market sales occurred in 2010. Shortly after in 2011, sales began to decline due to the development of a more effective treatment,
ranibizumab
Ranibizumab, sold under the brand name Lucentis among others, is a monoclonal antibody fragment (Fab) created from the same parent mouse antibody as bevacizumab. It is an anti-angiogenic that is approved to treat the "wet" type of age-related ...
(a monoclonal antibody, Novartis) being developed and sold, and the off-label use of the cheaper
Bevacizumab
Bevacizumab, sold under the brand name Avastin among others, is a monoclonal antibody medication used to treat a number of types of cancers and a specific eye disease. For cancer, it is given by slow injection into a vein (intravenous) and use ...