Why did CAT-152 fail to improve the prognosis of glaucoma filtration surgery?

A phase 3, multicenter, double-masked, randomized, placebo-controlled trial finds that the human monoclonal antibody to TGF-ß2 (CAT-152) failed to improve the success of trabeculectomy.
 
It may have failed to show a benefit in this study because using a standard dose of antibody may not suffice for all patients since levels of TGFbeta vary in different eyes. The failure of the antibody to improve the success of trabeculectomy might mean that larger doses are needed in those patients with more TGFbeta in their aqueous. Or it may need to be given more frequently, or for a longer period of time. Cost becomes a major limiting factor for this approach.
 
While this study of a diverse population group didn’t prove the usefulness of the antibody, it did reveal other factors associated with success or failure of trabeculectomy surgery.  

• Success rates were lower in black patients, in cases where needling of the bleb was necessary, in the presence of vascular blebs, with use of superior rectus sutures and suture lysis – all of which are known to be associated with a greater tendency towards post operative fibrosis. 
   
• Patients requiring 5-FU for postsurgical management were also more likely to be treatment failures.
   
• Patients with a primary diagnosis of pigmentary glaucoma had a higher success rate than those with other diagnoses. 

However some findings need further analysis. Of the many countries participating in the study, some with lower success rates appeared to have patients with higher intraocular pressures prior to surgery.
 
The reason for the decreased success rate may have been due to the presence of more TGFbeta in the aqueous of these patients as it has been shown that in glaucoma implants, encapsulated blebs with high IOPs have higher levels of TGFbeta. The study may have been more interesting if levels of TGFbeta were measured in the aqueous of the patients at the time of surgery, and then correlated with the effect of the antibody injection. Levels of TGFbeta often remain present in the aqueous for up to three weeks post surgery, so that the antibody given after one week may not have been efficacious. Certainly giving 5-fluorouracil at day 14 was a confounding component to the study.
 
A surprising finding was that patients with high cup to disc (C/D) ratios had better outcomes than those with lower C/D ratios. Very often the patients with high C/D ratios are treated when their pressures are relatively low as very low pressures are required, and therefore it becomes easier to lower their pressures with surgery. No mention is made of the starting pressures in the high C/D patients, which could have been on the low end of the scale, perhaps 21mmHg.