Pegaptanib sodium

Katz B, Goldbaum M. 2006. Macugen (pegaptanib sodium), a novel ocular therapeutic that targets vascular endothelial growth factor (VEGF). Int Opthamol Clin. 46 141-154. 

Macugen Pegaptanib sodium Eyetech Pharmaceuticals/Pfizer Marketed product Exudative AMD Intravitreal injection... 

These include pegaptanib sodium (Macugen) and ranibizmnab (Lucentis).These drugs are injected invitreally at specified intervals (see Chapter 31). 

Gonzales CR,VEGE Inhibition Smdy in Ocular Neovascularization (Vl.S.l.O.N.) Clinical Trial Group. Enhanced efficacy associated with early treatment of neovascular age-related macular degeneration with pegaptanib sodium an exploratory analysis. Retina 2005 25 815. 

The FDA approved intraocular injections include miotics, triamcinolone acetonide, pegaptanib sodium, ranibizumab, formivirsen sodium, viscoelastics and viscoadherents, and an antiviral agent for intravitreal injection. There are many small and large molecules currently in clinical trials that are delivered via intravitreal injection for the treatment of a variety of retinal diseases with a large area of focus on the treatment of AMD and macular edema. 

Pharmacodynamics. The pharmacokinetics of intravitreal pegaptanib sodium has been evaluated in several preclinical models. Examination of the plasma and vitreous humor concentration data following intravitreal administration of pegaptanib... 

Pegaptanib sodium was eliminated from the eye through systemic circulation with a terminal half-life from the vitreous of three to five days in both monkeys and rabbits. The plasma terminal half-life mimicked the vitreous humor half-life, indicative of flip-flop kinetics whereby the rate-limiting step that determines the systemic pegaptanib sodium concentration is the exit of the drug from the eye. From these observations one can estimate the vitreous humor terminal half-life in patients that would approximate the plasma terminal half-life. 

A multicenter, open-label, repeat-dose Phase IIA study of pegaptanib sodium (3.0 mg/eye) was performed in patients with subfoveal CNV secondary to AMD (72). The ophthalmic criteria included best-corrected visual acuity in the study eye worse than 20/100 on the ETDRS chart, best-corrected visual acuity in the fellow eye equal to or better than 20/400, subfoveal CNV with active CNV (either classic and/or occult) of less than 12 total disc areas in size secondary to AMD, clear ocular media and adequate pupillary dilation to permit good quality stereoscopic fundus photography, and IOP of 21 mmHg or less. A cohort scheduled to receive PDT with verteporfin prior to their first dose of pegaptanib sodium had to have equal to, or more than a 50% classic component (predominantly classic lesion). 

If three or more patients experienced dose-limiting toxicity, the dose was reduced to 2 mg and then lmg, if necessary. The intended number of patients to be treated was 20 10 patients with pegaptanib sodium alone and 10 patients with both anti-YEGF therapy and PDT. Eleven sites in the United States were selected for the studies. Hundred microliters of intravitreal pegaptanib sodium (3 mg/injec-tion) was administered on three occasions at 28-day intervals. 

PDT with verteporfin was given with pegaptanib sodium only in cases with predominantly classic (> 50%) CNV. The standard requirements and procedures for PDT administration were used. PDT was required to be given 5-10 days prior to administration of pegaptanib sodium. 

Of those patients (n = 8) who completed the 3-month treatment regimen of pegaptanib sodium alone, 87.5% had stabilized or improved visual acuity and 25.0% had a three-line improvement on the ETDRS chart at three months. Eleven patients were treated with both pegaptanib sodium and PDT. In this group of patients (n = 10) who completed the three months treatment regimen, 90% had stabilized or improved vision and 60% showed a three-line improvement of visual acuity on the ETDRS chart at three months. 

In patients treated with pegaptanib sodium alone, ocular adverse events considered likely to be associated with intravitreal injection of pegaptanib sodium included vitreous floaters or haze, mild transient anterior chamber inflammation, ocular irritation, increased IOP, intraocular air, subconjunctival hemorrhage, eye pain, lid edema/ erythema, dry eye, and conjunctival injection. In patients treated with pegaptanib sodium and PDT, adverse events probably associated included ptosis (due to the contact lens), mild anterior chamber inflammation, corneal abrasion, eye pain, foreign body sensation, chemosis, subconjunctival hemorrhage, and vitreous prolapse. 

The results of this Phase IIA multiple intravitreal injection clinical study of anti-YEGF therapy expanded the favorable safety profile reported in the Phase IA single-injection study. Specifically, the Phase IIA study showed that three consecutive anti-pegaptanib sodium intravitreal injections given monthly did not cause serious ocular or systemic adverse events. The adverse events encountered appeared to be unrelated to study drug and were generally minor. In most cases they were probably related to the intravitreal injection procedure or to the PDT therapy. These results provided the basis for the Phase III pegaptanib sodium trial described below. 

A total of 1186 patients were included in efficacy analyses 7545 intravitreous injections of pegaptanib sodium and 2557 sham injections were administered. Approximately 90% of the patients in each treatment group completed the study. An average of 8.5 injections were administered per patient out of a possible total of nine injections. 

Based on the results described above, Eyetech received Food and Drug Administration approval to market pegaptanib sodium for treatment of patients with neovascu-lar AMD. This drug is the first anti-angiogenic agent to receive approval to treat AMD. 

Macugen (pegaptanib sodium injection) shows positive visual and anatomical outcomes in a Phase II trial for patients with diabetic macular edema. Eyetech Pharmaceuticals Press Release, May 3, 2004 http //www.eyetk.com/investors/press releases.asp. 

D Amico, D.J. et al, 2006. Pegaptanib sodium for neovascular age-related macular degeneration two-year safety results of the two prospective, multicenter, controlled clinical trials. Ophthalmology, 113(6), 992-1001. 

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