A Phase III Study of Subconjunctival Human Anti–Transforming Growth Factor β2 Monoclonal Antibody (CAT-152) to Prevent Scarring after First-Time Trabeculectomy


      To evaluate CAT-152 (lerdelimumab), a monoclonal antibody to transforming growth factor-β2 (TGF-β2), in preventing the progression of fibrosis in patients undergoing first-time trabeculectomy for primary open-angle (POAG) or chronic angle-closure glaucoma (CACG).


      Randomized, double-masked, multicenter, placebo-controlled trial.


      Individuals with a diagnosis of POAG, CACG, pseudoexfoliative glaucoma (PEXG), or pigmentary glaucoma (PG), with a recorded intraocular pressure (IOP) of more than 21 mmHg, visual field or optic disc changes characteristic of glaucoma, and taking the maximum tolerated dose of medication.


      Patients received unilateral trabeculectomy with either 4 subconjunctival injections of CAT-152 (100 μg in 100 μl phosphate buffer) or 4 placebo injections, administered immediately before and on completion of trabeculectomy, and on the first day and at 1 week after surgery. Patients were followed up for 12 months after surgery.

      Main Outcome Measures

      The primary outcome measure was treatment success in the study eye (unmedicated IOP of 6–16 mmHg inclusive), at the 6- and 12-month follow-up. Secondary outcome measures were the incidence of postoperative intervention with 5-fluorouracil (5-FU); incidence of surgical failure; time to surgical failure; and incidence of vascularity, microcysts, and encapsulation or demarcation of the bleb site.


      Of the 388 patients evaluated in the trial, 81% (n = 274) had either POAG or CACG, combined into a single set (POAG/CACG) analyzed by intent-to-treat (ITT) criteria. Separate ITT analyses were carried out for all participants (+PEXG/PG group), with similar results. The treatment success rate was 60% in the CAT-152 group and 68% in the placebo group (P = 0.23). No statistically significant differences emerged in the secondary end points. Patients requiring 5-FU for postsurgical management were more likely to be treatment failures (P = 0.0003). Patients with a primary diagnosis of PG (n = 49) had a higher success rate than those with other diagnoses (P = 0.0077). Administration of CAT-152 was not associated with an increased incidence of adverse events. The immunogenicity of CAT-152 was very low.


      At the dose level and regimen studied, there was no difference between CAT-152 and placebo in preventing the failure of primary trabeculectomy. The safety profile of CAT-152 was similar to that of placebo.
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        • Cairns J.E.
        Trabeculectomy: preliminary report of a surgical method of reducing intra-ocular pressure in chronic simple glaucoma without sub-conjunctival drainage of aqueous humor.
        Bibl Ophthalmol. 1970; 81: 143-153
        • AGIS Investigators
        The Advanced Glaucoma Intervention Study (AGIS): 7.
        Am J Ophthalmol. 2000; 130: 429-440
        • Addicks E.M.
        • Quigley H.A.
        • Green W.R.
        Histologic characteristics of filtering blebs in glaucomatous eyes.
        Arch Ophthalmol. 1983; 101: 795-798
        • Hitchings R.A.
        • Grierson I.
        Clinicopathological correlation in eyes with failed fistulizing surgery.
        Trans Ophthalmol Soc UK. 1983; 103: 84-88
        • Jay J.L.
        Rational choice of therapy in primary open angle glaucoma.
        Eye. 1992; 6: 243-247
        • Migdal C.
        • Gregory W.
        • Hitchings R.
        Long-term functional outcome after early surgery compared with laser and medicine in open-angle glaucoma.
        Ophthalmology. 1994; 101 (discussion 1657): 1651-1656
        • Khaw P.T.
        • Occleston N.L.
        • Schultz G.
        • et al.
        Activation and suppression of fibroblast function.
        Eye. 1994; 8: 188-195
        • Fluorouracil Filtering Surgery Study Group
        Fluorouracil Filtering Surgery Study one-year follow-up.
        Am J Ophthalmol. 1989; 108: 625-635
        • Katz G.J.
        • Higginbotham E.J.
        • Lichter P.R.
        • et al.
        Mitomycin C versus 5-fluorouracil in high-risk glaucoma filtering surgery.
        Ophthalmology. 1995; 102: 1263-1269
        • Kitazawa Y.
        • Kawase K.
        • Matsushita H.
        • et al.
        Trabeculectomy with mitomycin.
        Arch Ophthalmol. 1991; 109: 1693-1698
        • Lamping K.A.
        • Belkin J.K.
        5-Fluorouracil and mitomycin C in pseudophakic patients.
        Ophthalmology. 1995; 102: 70-75
        • Khaw P.T.
        • Doyle J.W.
        • Sherwood M.B.
        • et al.
        Effects of intraoperative 5-fluorouracil or mitomycin C on glaucoma filtration surgery in the rabbit.
        Ophthalmology. 1993; 100: 367-372
        • Crowston J.G.
        • Akbar A.N.
        • Constable P.H.
        • et al.
        Antimetabolite-induced apoptosis in Tenon’s capsule fibroblasts.
        Invest Ophthalmol Vis Sci. 1998; 39: 449-454
        • Stamper R.L.
        • McMenemy M.G.
        • Lieberman M.F.
        Hypotonus maculopathy after trabeculectomy with subconjunctival 5-fluorouracil.
        Am J Ophthalmol. 1992; 114: 544-553
        • Parrish R.
        • Minckler D.
        “Late endophthalmitis”—filtering surgery time bomb?.
        Ophthalmology. 1996; 103 ([editorial]): 1167-1168
        • Jampel H.D.
        • Pasquale L.R.
        • Dibernardo C.
        Hypotony maculopathy following trabeculectomy with mitomycin C.
        Arch Ophthalmol. 1992; 110: 1049-1050
        • Jampel H.D.
        • Roche N.
        • Stark W.J.
        Transforming growth factor-beta in human aqueous humor.
        Curr Eye Res. 1990; 9: 963-969
        • Cordeiro M.F.
        • Reichel M.B.
        • Gay J.A.
        • et al.
        Transforming growth factor-beta1, -beta2 and -beta3 in vivo: effects on normal and mitomycin-C modulated conjunctival scarring.
        Invest Ophthalmol Vis Sci. 1999; 40: 1975-1982
        • Cordeiro M.F.
        • Gay J.A.
        • Khaw P.T.
        Human anti-transforming growth factor-beta2 antibody: a new glaucoma anti-scarring agent.
        Invest Ophthalmol Vis Sci. 1999; 40: 2225-2234
        • Connor T.B.
        • Roberts A.B.
        • Sporn M.B.
        • et al.
        Correlation of fibrosis and transforming growth factor-beta type 2 levels in the eye.
        J Clin Invest. 1989; 83: 1661-1666
        • Cousins S.W.
        • McCabe M.M.
        • Danielpour D.
        Identification of transforming growth factor-beta as an immunosuppressive factor in aqueous humor.
        Invest Ophthalmol Vis Sci. 1991; 32: 2201-2211
        • Pasquale L.R.
        • Dorman-Pease M.E.
        • Lutty G.A.
        • et al.
        Immunolocalization of TGF-beta1, TGF-beta2, and TGF-beta3 in the anterior segment of the human eye.
        Invest Ophthalmol Vis Sci. 1993; 34: 23-30
        • Pfeffer B.A.
        • Flanders K.C.
        • Guerin C.J.
        • et al.
        Transforming growth factor beta2 is the predominant isoform in the neural retina, retinal pigment epithelium choroid and vitreous of the monkey eye.
        Exp Eye Res. 1994; 59: 323-333
        • Lutty G.A.
        • Merges C.
        • Threlkeld A.B.
        • et al.
        Heterogeneity in localization of isoforms of TGF-beta in human retina, vitreous and choroid.
        Invest Ophthalmol Vis Sci. 1993; 34: 477-487
        • Tripathi R.C.
        • Li J.
        • Chan W.F.
        Aqueous humor in glaucomatous eyes contains an increased level of TGFβ2.
        Exp Eye Res. 1994; 59: 723-727
        • Picht G.
        • Welge-Luessen U.
        • Grehn F.
        Transforming growth factor beta2 levels in the aqueous humor in different types of glaucoma and the relation to filtering bleb development.
        Graefes Arch Clin Exp Ophthalmol. 2001; 239: 199-207
        • Thompson J.E.
        • Vaughan T.J.
        • Williams A.J.
        • et al.
        A fully human antibody neutralising biologically active human TGF-beta2 for use in therapy.
        J Immunol Methods. 1999; 227: 17-29
        • Mead A.L.
        • Wong T.T.
        • Cordiero M.F.
        • et al.
        Evaluation of anti-TGF-beta2 antibody as a new postoperative anti-scarring agent in glaucoma surgery.
        Invest Ophthalmol Vis Sci. 2003; 44: 3394-3401
        • Siriwardena D.
        • Khaw P.T.
        • King A.J.
        • et al.
        Human antitransforming growth factor β2 monoclonal antibody: a new modulator of wound healing in trabeculectomy.
        Ophthalmology. 2002; 109: 427-431
        • WuDunn D.
        • Cantor L.B.
        • Palanca-Capistrano A.M.
        • et al.
        A prospective randomized trial comparing intraoperative 5-fluorouracil vs mitomycin C in primary trabeculectomy.
        Am J Ophthalmol. 2002; 134: 521-528
        • Akarsu C.
        • Onol M.
        • Hasanreisoglu B.
        Postoperative 5-fluorouracil versus intraoperative mitomycin C in high-risk glaucoma filtering surgery: extended follow up.
        Clin Experiment Ophthalmol. 2003; 31: 199-205
        • Morris D.A.
        • Peracha M.O.
        • Shin D.H.
        • et al.
        Risk factors for early filtration failure requiring suture release after primary glaucoma triple procedure with adjunctive mitomycin.
        Arch Ophthalmol. 1999; 117: 1149-1154
        • Fagerli M.
        • Lofors K.T.
        • Elsas T.
        Needling revision of failed filtering blebs after trabeculectomy: a retrospective study.
        Acta Ophthalmol Scand. 2003; 81: 577-582
        • Broadway D.C.
        • Bloom P.A.
        • Bunce C.
        Needle revision of failing and failed trabeculectomy blebs with adjunctive 5-fluorouracil.
        Ophthalmology. 2004; 111: 665-673
        • Jacobs S.
        • Gillis A.
        • Van Malderen L.
        Needling-revision of failed filtering blebs.
        Bull Soc Belge Ophtalmol. 2005; 297: 59-64
        • Banitt M.
        • Juzych M.S.
        • Chopra V.
        • et al.
        The effect of the timing of scleral flap suture release on the safety and long-term success of phacotrabeculectomy.
        Am J Ophthalmol. 2006; 141: 742-744
        • Edmunds B.
        • Bunce C.V.
        • Thompson J.R.
        • et al.
        Factors associated with success in first-time trabeculectomy for patients at low risk of failure with chronic open-angle glaucoma.
        Ophthalmology. 2004; 111: 97-103
        • Garrett Q.
        • Khaw P.T.
        • Blalock T.D.
        • et al.
        Involvement of CTGF in TGF-beta1-stimulation of myofibroblast differentiation and collagen matrix contraction in the presence of mechanical stress.
        Invest Ophthalmol Vis Sci. 2004; 45: 1109-1116
        • Weinblatt M.E.
        • Kremer J.M.
        • Bankhurst A.D.
        • et al.
        A trial of etanercept, a recombinant tumor necrosis factor receptor:Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate.
        N Engl J Med. 1999; 340: 253-259
        • Johnsen A.K.
        • Schiff M.H.
        • Mease P.J.
        • et al.
        Comparison of 2 doses of etanercept (50 vs 100 mg) in active rheumatoid arthritis: a randomized double blind study.
        J Rheumatol. 2006; 33: 659-664