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MACUGEN trials by Dr. Hasan Usmani
Introduction
Pegaptanib sodium (Macugen, Pfizer/OSI Eyetech) is a pegylated anti-VEGF aptamer (a single-stranded DNA or RNA molecule constructed to bind a ligand). Pegylation is a process which adds more particles to a molecule in order to make it more stable and increase its half-life; this, of course, adds to the molecular weight.
Pegaptanib binds to extracellular VEGF165 isomer this inhibiting it binding to and preventing the activation of VEGF receptors.
· Approved by the FDA for use in the United States in December 2004 · Licensed by the European Medicines Evaluating Agency, (EMEA) at a dose of 0.3mg in Feb 2006 · Launched in the UK in May 2006. · Yet to be commissioned by PCTs.
VEGF Inhibition Study In Ocular Neovascularization (VISION)
Inclusion criteria · Patients with Exudative AMD representing all angiographic subtypes (any combination of classic and occult lesion composition) · Snellen visual acuity: 6/12 to approximately 4/60 · Lesion size: up to 12 disc areas · Patients treated previously with PDT utilizing verteporfin were not excluded · Verteporfin photodynamic therapy (PDT) usage was permitted at the discretion of the investigators in patients with predominantly classic lesions.
VISION - YEAR 1
Aim · To evaluate the usefulness of Pegaptanib in treating neovascular AMD. The intention was to include a broad range of patients to reflect the spectrum of AMD encountered in clinical practice.
Method · Prospective, double-masked study, Phase 3, placebo-controlled trial · 1186 patients randomized to sham (0 mg), 0.3 mg, 1.0 mg, or 3.0 mg of drug · Intravitreal injections given every 6 weeks.
Primary endpoint · proportion of patients avoiding 3 lines / 15 letters (EDTRS) of vision loss at one year
Secondary Endpoints · Visual gain (>15 letters of vision ) · Mean change from baseline visual acuity
Results · Primary endpoint: achieved by 70% of treated (0.3mg) vs. 55% of controls. o (p<0.001) representing a 27-percent increase in responders over controls. o Risk of severe loss of vision (>30 letters):10% in treated vs. 22% in control eyes.
· Visual gain (>15 letters of vision ): achieved by 6% of treated (0.3mg) vs. 2% of controls o also achieved by 7% of 1.0 mg group and 4% of 3.0mg group
· Any gain in vision (>0 letters): 33% of treated vs. 10% of control eyes.
Combined analysis for the Primary endpoint showed that Pegptanib appeared to be efficacious at all doses tested (0.3mg, 1.0mg and 3.0mg). The FDA reviewed this data and approved the lowest dose of Pegaptanib, 0.3mg, for a broad label (all subtypes).
VISION - YEAR 2
Aim
· To evaluate the extended efficacy of Macugen · To evaluate the efficacy of one year of Macugen therapy vs. two years of Macugen therapy.
Method · 1053 patients (out of 1186) continued in the VISION study for a second year. · Patients in treatment arms re-randomized: o observation (i.e. treated for year one, observed for year two) o or continue Pegaptanib injections in the same dose group. · Patients in the sham arm were re-randomized: o to receive Pegaptanib o or continue to receive sham.
Primary Endpoint · Time until > 3 lines / 15 letters of vision was lost.
Secondary endpoints · Mean change in VA at week 102 · Proportion of eyes becoming legally blind <6/60 · Proportion of patients losing >15 letters at week 102.
Results · Overall, the proportion of patients with >15 letter loss was greater in the patients who stopped treatment after one year vs. those who continued therapy: o 7% in those who continued vs. 14% in those who discontinued. · Loss of <15 letters from baseline to week 102: o 59% treated vs. 49% controls · No rebound effect of drug discontinuation occurred.[VISION, 2006] · Dose levels above 0.3 mg did not demonstrate any additional benefit. · Eyes given Macugen for the second year average ETDRS letter loss o -9 for 0.3-mg dose vs. -17 for sham o Relative benefit of 45 % · Of patients who began treatment with worse than>20/200 acuity - better that 20/200 at two years o 34% of treated vs. 57% of sham eyes o Relative benefit of 36 percent.
Adverse effects As significant serum levels of pegaptanib are detected after intravitreal injection, [Wijngaarden, 2005] adverse side effects were recorded during the VISION trial
Although no specific local or systemic drug related toxicities were reported, however serious procedure-related adverse events were mentioned:
· Endophthalmitis: o Year 1: 12/892 (1.3%) - majority occurred before a protocol amendment ensuring that strict asceptic technique was employed o Year 2: 4/606 (0.7%) o endophthalmitis per injection in year 1: 0.16 % o endophthalmitis per injection in year 2: 0.10 % (after protocol amendment) · Traumatic lens injury: 0.7% · Retinal detachment: 0.6%
Conclusions · Intravitreal injections of 0.3mg Pegaptanib are effective in treating exudative AMD. · The therapeutic benefit is maintained regardless of lesion composition or size. · Treatment benefit is greater for two years of sustained treatment rather than one year. · However, detailed analysis of information presented to the FDA suggests that pegaptanib did not show statistically significant benefit among patients with occult disease or in lesions greater than 4 disc areas regardless of composition.[Spaide, 2004]
Further reading:
1.Fine HF,Spaide R, Exudative Age-Related Macular Degeneration: Causes and Treatment Medscape 2006(http://www.medscape.com/viewprogram/6050) Last accessed: 8/10/2007.
2. Spaide R. New treatments for AMD. Ophthalmology. 2006;113:160-161.
3. Chakravarthy U,Adamis AP, et al. VEGF Inhibition Study in Ocular Neovascularization (V.I.S.I.O.N.) Clinical Trial Group; Year 2 efficacy results of 2 randomized controlled clinical trials of pegaptanib for neovascular age-related macular degeneration. Ophthalmology. 2006;113:1508.e1-25.
3. Wijngaarden P, Coster DJ, Williams KA. Inhibitors of ocular neovascularization: promises and potential problems. JAMA. 2005;293:1509-1513.
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