text: Advantages of the Vegf Inhibitor, Macugen: A More Favourable Toxicity Profile | IOVS | ARVO Journals
  Advantages of the Vegf Inhibitor, Macugen: A More Favourable Toxicity Profile
  K. Poesen; T. Janssens; D. Lambrechts; P. Carmeliet; E. M. Conway
  K. Poesen
  Centre Transgene Technology, VIB, KUL, Leuven, Belgium
  Commercial Relationships K. Poesen, Pfizer, Inc, F; T. Janssens, Pfizer, Inc, F; D. Lambrechts, Pfizer, Inc, F; P. Carmeliet, Pfizer, Inc, F; E.M. Conway, Pfizer, Inc, F.
  Investigative Ophthalmology & Visual Science May 2008, Vol.49, 3412. doi:https://doi.org/
  K. Poesen, T. Janssens, D. Lambrechts, P. Carmeliet, E. M. Conway; Advantages of the Vegf Inhibitor, Macugen: A More Favourable Toxicity Profile. Invest. Ophthalmol. Vis. Sci. 2008;49(13):3412. doi: https://doi.org/.
  Purpose: : Since anti-VEGF therapies in other diseases have recognized systemic side effects, we assessed the toxicity profile of Macugen in mouse models of human disease.
  Methods: : Mice were treated with Macugen, vehicle alone, with the potent kinase inhibitor of VEGFR-2 (SU5416), or with the VEGFR-2 neutralizing antibody (DC101). Effects on hemostatic system activation, myocardial function, tracheal vessel pruning, and motoneuron degeneration were quantified.
  Results: : Mice treated for 3 weeks with Macugen (50 mg/kg i.p., MWF) exhibited no alterations (versus vehicle alone) in hemostatic system activity or tracheal vessel pruning. In contrast, mice treated with DC101 (750 ug ip, MWF) exhibited a significant increase in plasma levels of the hemostatic marker, plasminogen activator inhibitor (PAI)-1 (p<0.001) (10.1 + 2.0, 2.6 + 0.3, 2.4 + 0.2 ng/ml for DC101, Macugen, vehicle), and a significant decrease (p<0.05) in the number of capillaries in the neonatal trachea (6.0 + 0.4, 7.4+ 0.6, 7.5 + 0.5 capillaries/mm for DC101, Macugen, vehicle). Direct measures of heart rate, ventricular pressures (systolic, diastolic, end diastolic), and pressure gradients (dP/dt max and min) were not affected by systemic administration of Macugen over a 2 week period. Since low VEGF levels are linked to neurodegeneration, we assessed the effects over a 60-day period, of systemic administration of Macugen, SU5416 or DC101 in SOD1G93A mice, which spontaneously develop an ALS-like syndrome. SU5416 induced the most significant deterioration in neurologic function measured by rotarod performance. DC101 induced an intermediate effect, while Macugen elicited the least deleterious effect (p=NS versus vehicle). SU5416 and DC101 reduced survival by 14 and 9 days, respectively, while Macugen reduced survival only by 7 days.
  Conclusions: : Although Macugen is an inhibitor of VEGF, its specific activity against the VEGF165 isoform may explain why it appears in these mouse models, to be safer than VEGFR-2 inhibitors.