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SAN FRANCISCO -- Treatment with a novel antibody biopolymer conjugate (ABC) targeting VEGF led to favorable outcomes for patients with diabetic retinopathy (DR) in a large randomized trial.

Results showed that 41.1% of patients randomized to tarcocimab tedromer had ≥2-step improvement in the Diabetic Retinopathy Severity Scale (DRSS) after 48 weeks compared with 1.4% of patients randomized to sham injections. Fewer than 1% of patients in the tarcocimab group had ≥2-step worsening of diabetic retinopathy, reported Charles Wykoff, MD, PhD, of the Blanton Eye Institute and Houston Methodist Hospital, at the American Academy of Ophthalmology meeting.

In general, the ABC was well tolerated with the most common ocular adverse event (AE) being cataract (10.2% of patients).

"Tarcocimab met the primary endpoint and reduced the development of sight-threatening complications [STCs] by 90%," said Wykoff. "Looking forward, we now have three successful phase III tarcocimab trials in RVO [retinal vein occlusion], wet AMD, and now diabetic retinopathy.

"Beyond that, an enhanced commercial formulation of tarcocimab that combined an unconjugated portion with a bioconjugated portion of the antibody has been manufactured and that may improve usability, safety, and efficacy."

Favorable results from the DR trial, combined with the positive outcomes of the and trials, revived clinical development of tarcocimab. At the American Society of Retina Specialists meeting in July, Wykoff reported findings from two negative studies of tarcocimab in diabetic macular edema (DME). At the end of his talk, Wykoff said Kodiak Sciences would discontinue development of tarcocimab.

Three months later, fueled by a wave of positive clinical trial results, Kodiak reversed course and announced that it will "reboot" the tarcocimab clinical development program.

"We now have three successful phase III pivotal studies with tarcocimab tedromer across three different retinal vascular and exudative diseases," said Kodiak CEO Victor Perlroth, MD, . "In recent discussions with the FDA ... we believe we have a clear regulatory pathway requiring one additional positive study to support a single BLA [biologics license application] submission for all three indications."

During a discussion that followed Wykoff's presentation at AAO, panelists expressed concern about the number of patients who developed cataracts while on treatment with tarcocimab. The same issue arose in the two negative trials of DME. Additionally, the therapy's role in current treatment strategies for nonproliferative DR remained unclear to James Folk, MD, of the University of Iowa in Iowa City.

"I just wonder how you approach a patient," said Folk. "You're saying I'm going to inject this now. So you develop or don't develop retinopathy that may indicate there's a risk of developing DME or PDR [proliferative diabetic retinopathy], in which case I'll treat you for that. Should I treat you now or should I treat you later, when you need it, because a lot of people won't need it for a while."

Wykoff reported primary results from the phase III GLOW trial, a pivotal study involving patients with moderately severe to severe NPDR (DRSS levels 47 and 53, respectively) and no prior exposure to anti-VEGF therapy. Eligible patients had best corrected visual acuity (BCVA) of at least 69 letters, and a hemoglobin A1c ≤12%.

Patients randomized to tarcocimab received four doses over 48 weeks, extending the dosing interval from 8 to 12 to 24 weeks. Patients randomized to sham injections followed the same treatment pattern.

The primary endpoint was ≥2-step improvement in the DRSS. Key secondary endpoints were frequency of sight-threatening complications and DRSS improvement ≥3 steps. The study population consisted of 253 patients.

Baseline characteristics included an HbA1c of 8-8.5%, type 2 diabetes in >90%, mean BCVA of about 81 letters, central subfield thickness (CST) of 265-270 µm, and phakic lens status in 80-85% of patients. About two-thirds of the patients had a DRSS score ≥53.

The results showed that almost 30 times as many patients randomized to tarcocimab met the primary endpoint of ≥2-step improvement in DRSS (P<0.0001). Additionally, 5.6% of the tarcocimab-treated patients had ≥3-step improvement versus none in the control group (P<0.0058). Substantially more patients in DRSS level 53 met the primary endpoint (51.8% vs 22.2% in level 47). Overall, 70% tarcocimab-treated patients had at least 1-step improvement in DRSS status.

In the sham arm, 3.9% of patients had ≥2-step worsening of DRSS status versus 0.7% with tarcocimab, and 2.3% of sham-treated patients had ≥3-step worsening as compared with none in the tarcocimab group.

The change in BCVA remained similar in the treatment arms during most of the study. CST decreased an average of 15.1 µm with tarcocimab versus a 7.8-µm increase in the control group. STCs (DME, PDR, or anterior-segment neovascularization) occurred in 21.0% of the control group versus 2.3% of the tarcocimab arm (P<0.0001). The most common STC was DME, which occurred in 13.7% of the sham arm versus 0.7% of the tarcocimab arm (P<0.0001).

Aside from cataract, common ocular AEs with tarcocimab were conjunctival hemorrhage (7.0%), dry eye (3.1%), vitreous floaters (2.3%), DME (1.6%), and DR (1.6%). DME was the most common ocular AE in the control group. Wykoff said cataract occurred more often in the study eye of patients treated with tarcocimab (11.7% vs 6.3% in the fellow eye). Two patients in the tarcocimab arm developed intraocular inflammation.

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