Pegaptanib

Last updated
Pegaptanib sodium
Pegaptanib sodium skeletal.svg
Clinical data
Trade names Macugen
AHFS/Drugs.com Monograph
MedlinePlus a607057
Routes of
administration 		Intravitreal injection
ATC code
Legal status
Legal status
Pharmacokinetic data
Elimination half-life 10 days
Identifiers
  • RNA, ((2'-deoxy-2'-fluoro)C-Gm-Gm-A-A-(2'-deoxy-2'-fluoro)U-(2'-deoxy-2'-fluoro)C-Am-Gm-(2'-deoxy-2'-fluoro)U-Gm-Am-Am-(2'-deoxy-2'-fluoro)U-Gm-(2'-deoxy-2'-fluoro)C-(2'-deoxy-2'-fluoro)U-(2'-deoxy-2'fluoro)U-Am-(2'-deoxy-2'-fluoro)U-Am-(2'-deoxy-2'-fluoro)C-Am-(2'-deoxy-2'-fluoro)U-(2'deoxy-2'-fluoro)C-(2'-deoxy-2'-fluoro)C-Gm-(3'→3')-dT), 5'-ester with α,α'-[4,12-dioxo-6[[[5-(phosphoonoxy)pentyl]amino]carbonyl]-3,13-dioxa-5,11-diaza-1,15-pentadecanediyl]bis[ω-methoxypoly(oxy-1,2-ethanediyl)], sodium salt [1]
CAS Number
DrugBank
ChemSpider
  • none
UNII
CompTox Dashboard (EPA)
Chemical and physical data
Formula C294H342F13N107Na28O188P28[C2H4O](m+n) (m+n≈900)
Molar mass ~50 kg/mol
   (verify)

Pegaptanib [2] sodium injection (brand name Macugen) is an anti-angiogenic medicine for the treatment of neovascular (wet) age-related macular degeneration (AMD). [3] It was discovered by NeXstar Pharmaceuticals (which merged with Gilead Sciences in 1999) and licensed in 2000 to EyeTech Pharmaceuticals, now OSI Pharmaceuticals, for late stage development and marketing in the United States. Gilead Sciences continues to receive royalties from the drugs licensing. [4] Outside the US pegaptanib is marketed by Pfizer. Approval was granted by the U.S. Food and Drug Administration (FDA) in December 2004. [5]

Contents

Mechanism of action

Pegaptanib is a pegylated anti-vascular endothelial growth factor (VEGF) aptamer, a single strand of nucleic acid that binds with specificity to a particular target. Pegaptanib specifically binds to the 165 isoform of VEGF, a protein that plays a critical role in angiogenesis (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 an antagonist to VEGF, which when injected into the eye blocks the actions of VEGF. This then reduces the growth of the blood vessels located within the eye and works to control the leakage and swelling. [3]

Means of administration

Pegaptanib is administered in a 0.3 mg dose once every six weeks by intravitreal injection. An intravitreal injection is one that is administered directly into the eye, more specifically, into the vitreous humour, or the jelly-like fluid within the eye. Pegaptanib has to be administered to the designated patient by an ophthalmologist 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. [3]

Preclinical trials

Pegaptanib underwent several preclinical studies in order to determine its safety and efficacy before moving into clinical trials.

Animal toxicology studies

Toxicology studies were conducted in rhesus monkeys, guinea pigs, rats, mice, and rabbits. [6] 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 and no immune response was taken against the API[ clarification needed ]. Aside from the intravitreal administration of the pegaptanib, it was also found that subcutaneous and intravenous routes of administration were also effective at maintaining the desired blood plasma concentration. [6] 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) microspheres, which encapsulated the drug, the minimum dosing frequency was 6 weeks to maintain the desired pharmacological effect. [6] 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. [6]

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 subfoveal choroidal neovascularization (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 (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. [6]

Phase III

After the success of the Phase I and Phase II trials, the FDA granted fast track designation for the Phase III clinical trials. [6] In these trials, pegaptanib was studied in two identical controlled, double-blind 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 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. [5]

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. [5]

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.

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. [5]

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:

Regulatory approval information

Pegaptanib (pegaptanib sodium injection) has been approved in: United States (2004) [7] Europe (2005) [3] Brazil (2005) [7] Canada (2006) [6]


Pending: Australia (Filed in 2006)

Side effects

Common side effects of pegaptanib include: [3]

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 (a monoclonal antibody, Novartis) being developed and sold, [8] and the off-label use of the cheaper Bevacizumab. [9]

Related Research Articles

<span class="mw-page-title-main">Macular degeneration</span> Medical condition associated with vision loss

Macular degeneration, also known as age-related macular degeneration, 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. Over time, however, some people experience a gradual worsening of vision that may affect one or both eyes. While it does not result in complete blindness, loss of central vision can make it hard to recognize faces, drive, read, or perform other activities of daily life. Visual hallucinations may also occur.

Bevacizumab, sold under the brand name Avastin among others, is a 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 used for colon cancer, lung cancer, glioblastoma, and renal-cell carcinoma. In many of these diseases it is used as a first-line therapy. For age-related macular degeneration it is given by injection into the eye (intravitreal).

<span class="mw-page-title-main">Anecortave acetate</span> Chemical compound

Anecortave (rINN) is a novel angiogenesis inhibitor used in the treatment of the exudative (wet) form of age-related macular degeneration. Although similar in chemical structure to the corticosteroid hydrocortisone acetate, it possesses no glucocorticoid activity. If it is approved, it will be marketed by Alcon as anecortave acetate for depot suspension under the trade name Retaane. No development has been reported since 2010.

<span class="mw-page-title-main">Intravitreal administration</span>

Intravitreal 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 introduced in 1911 when Ohm gave an injection of air into the vitreous humor to repair a detached retina. In the mid-1940s, intravitreal injections became a standard way to administer drugs to treat endophthalmitis and cytomegalovirus retinitis.

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 macular degeneration, diabetic retinopathy, and macular edema due to branch retinal vein occlusion or central retinal vein occlusion.

<span class="mw-page-title-main">Choroidal neovascularization</span> Creation of new blood vessels in the choroid layer of the eye

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 commonly exacerbated by extreme myopia, malignant myopic degeneration, or age-related developments.

Aflibercept, sold under the brand names Eylea among others, is a medication used to treat wet macular degeneration and metastatic colorectal cancer. It was developed by Regeneron Pharmaceuticals and is approved in the United States and the European Union.

<span class="mw-page-title-main">Macular telangiectasia</span> Disease of the retina affecting central vision

Macular telangiectasia is a condition of the retina, the light-sensing tissue at the back of the eye that causes gradual deterioration of central vision, interfering with tasks such as reading and driving.

<span class="mw-page-title-main">Squalamine</span> Chemical compound

Squalamine is a steroid-polyamine conjugate compound with broad spectrum antimicrobial activity and anti-angiogenic activity. It was studied as a potential cancer drug and as a potential treatment for wet macular degeneration but as of 2018 had not succeeded in Phase III trials for any use.

Retinal gene therapy holds a promise in treating different forms of non-inherited and inherited blindness.

<span class="mw-page-title-main">Branch retinal vein occlusion</span> Medical condition

Branch retinal vein occlusion is a common retinal vascular disease of the elderly. It is caused by the occlusion of one of the branches of central retinal vein.

Punctate inner choroiditis (PIC) is an inflammatory choroiditis which occurs mainly in young women. Symptoms include blurred vision and scotomata. Yellow lesions are mainly present in the posterior pole and are between 100 and 300 micrometres in size. PIC is one of the so-called White Dot Syndromes. PIC has only been recognised as a distinct condition as recently as 1984 when Watzke identified 10 patients who appeared to make up a distinct group within the White Dot Syndromes.

Aganirsen is a 25 mer DNA antisense oligonucleotide therapeutic inhibiting insulin receptor substrate-1 (IRS-1), which is being investigated as a topical treatment for ocular neovascularization. Aganirsen is a candidate for the treatment of ocular neovascularization in patients with front of the eye (cornea) or back of the eye (retinal) diseases, including progressive corneal neovascularization in patients with infectious keratitis and wet age related macular degeneration (AMD).

Joan Whitten Miller is a Canadian-American ophthalmologist and scientist who has made notable contributions to the treatment and understanding of eye disorders. She is credited for developing photodynamic therapy (PDT) with verteporfin (Visudyne), the first pharmacologic therapy for retinal disease. She also co-discovered the role of vascular endothelial growth factor (VEGF) in eye disease and demonstrated the therapeutic potential of VEGF inhibitors, forming the scientific basis of anti-VEGF therapy for age-related macular degeneration (AMD), diabetic retinopathy, and related conditions.

Anti–vascular endothelial growth factor therapy, also known as anti-VEGF therapy or medication, is the use of medications that block vascular endothelial growth factor. This is done in the treatment of certain cancers and in age-related macular degeneration. They can involve monoclonal antibodies such as bevacizumab, antibody derivatives such as ranibizumab (Lucentis), or orally-available small molecules that inhibit the tyrosine kinases stimulated by VEGF: sunitinib, sorafenib, axitinib, and pazopanib.

Brolucizumab sold under trade name Beovu among others, is a humanized single-chain antibody fragment for the treatment of neovascular (wet) age-related macular degeneration (AMD).

<span class="mw-page-title-main">Faricimab</span> Medication for macular degeneration

Faricimab, sold under the brand name Vabysmo, is a monoclonal antibody used for the treatment of neovascular age-related macular degeneration (nAMD) and diabetic macular edema (DME). Faricimab is the first bispecific monoclonal antibody to target both vascular endothelial growth factor (VEGF) and angiopoietin 2 (Ang-2). By targeting these pathways, faricimab stabilizes blood vessels in the retina. It is given by intravitreal injection by an ophthalmologist.

<span class="mw-page-title-main">Intravitreal injection</span> Method of administration of drugs into the eye by injection with a fine needle

Intravitreal injection is the method of administration of drugs into the eye by injection with a fine needle. The medication will be directly applied into the vitreous humor. It is used to treat various eye diseases, such as age-related macular degeneration (AMD), diabetic retinopathy, and infections inside the eye such as endophthalmitis. As compared to topical administration, this method is beneficial for a more localized delivery of medications to the targeted site, as the needle can directly pass through the anatomical eye barrier and dynamic barrier. It could also minimize adverse drug effects on other body tissues via the systemic circulation, which could be a possible risk for intravenous injection of medications. Although there are risks of infections or other complications, with suitable precautions throughout the injection process, chances for these complications could be lowered.

Conbercept, sold under the commercial name Lumitin, is a novel vascular endothelial growth factor (VEGF) inhibitor used to treat neovascular age-related macular degeneration (AMD) and diabetic macular edema (DME). The anti-VEGF was approved for the treatment of neovascular AMD by the China State FDA (CFDA) in December 2013. As of December 2020, conbercept is undergoing phase III clinical trials through the U.S. Food and Drug Administration’s PANDA-1 and PANDA-2 development programs.

Pegcetacoplan, sold under the brand name Empaveli, among others, is a medication used to treat paroxysmal nocturnal hemoglobinuria and geographic atrophy of the retina. Pegcetacoplan is a complement inhibitor.

References

  1. ↑ Drug Information: Pegaptanib Sodium Injection Archived 2013-12-14 at the Wayback Machine
  2. ↑ "Pegaptanib". go.drugbank.com. Retrieved 2023-10-24.
  3. 1 2 3 4 5 "Macugen (pegaptanib)" (PDF). European Medicines Agency: 1–3. 2010. Retrieved 2013-12-08.
  4. ↑ "Larry Gold and Craig Tuerk (NeXstar Pharmaceuticals, Boulder, USA)". European Patent Office. 2011-02-16. Retrieved 2013-12-08.
  5. 1 2 3 4 "Highlights of Prescribing Information (Macugen)". Food and Drug Administration: 3–12. July 2007.
  6. 1 2 3 4 5 6 7 Vinores SA (2006). "Pegaptanib in the treatment of wet, age-related macular degeneration". International Journal of Nanomedicine. 1 (3): 263–8. PMC   2426796 . PMID   17717967.
  7. 1 2 "Eyetech Announces Approval of Macugen(R) in Brazil for the Treatment of Neovascular (Wet) Age-Related Macular Degeneration". Evaluate. 2005. Retrieved 2013-12-08.
  8. ↑ "Macugen product information". Evaluate. 2011. Retrieved 2013-12-08.
  9. ↑ Arevalo JF, Fromow-Guerra J, Sanchez JG, Maia M, Berrocal MH, Wu L, et al. (2008). "Primary intravitreal bevacizumab for subfoveal choroidal neovascularization in age-related macular degeneration: results of the Pan-American Collaborative Retina Study Group at 12 months follow-up". Retina. 28 (10): 1387–94. doi:10.1097/IAE.0b013e3181884ff4. PMID   18827735. S2CID   8694305.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.