Proof-of-concept and Randomized, Placebo-controlled Trials of an FcRn Inhibitor, Batoclimab, for Thyroid Eye Disease

Abstract

Context: Inhibition of the neonatal fragment crystallizable receptor (FcRn) reduces pathogenic thyrotropin receptor antibodies (TSH-R-Ab) that drive pathology in thyroid eye disease (TED).

Objective: We report the first clinical studies of an FcRn inhibitor, batoclimab, in TED.

Design: Proof-of-concept (POC) and randomized, double-blind placebo-controlled trials.

Setting: Multicenter.

Participants: Patients with moderate-to-severe, active TED.

Intervention: In the POC trial, patients received weekly subcutaneous injections of batoclimab 680 mg for 2 weeks, followed by 340 mg for 4 weeks. In the double-blind trial, patients were randomized 2:2:1:2 to weekly batoclimab (680 mg, 340 mg, 255 mg) or placebo for 12 weeks.

Main outcome: Change from baseline in serum anti-TSH-R-Ab and total IgG (POC); 12-week proptosis response (randomized trial).

Results: The randomized trial was terminated because of an unanticipated increase in serum cholesterol; therefore, data from 65 of the planned 77 patients were analyzed. Both trials showed marked decreases in pathogenic anti-TSH-R-Ab and total IgG serum levels (P < .001) with batoclimab. In the randomized trial, there was no statistically significant difference with batoclimab vs placebo in proptosis response at 12 weeks, although significant differences were observed at several earlier timepoints. In addition, orbital muscle volume decreased (P < .03) at 12 weeks, whereas quality of life (appearance subscale) improved (P < .03) at 19 weeks in the 680-mg group. Batoclimab was generally well tolerated, with albumin reductions and increases in lipids that reversed upon discontinuation.

Conclusions: These results provide insight into the efficacy and safety of batoclimab and support its further investigation as a potential therapy for TED.

Keywords: FcRn; batoclimab; immunoglobulin G; neonatal fragment crystallizable receptor; thyroid eye disease; thyrotropin receptor autoantibodies.

Figure 1.

Batoclimab mechanism of action. (A) In the absence of batoclimab, FcRn binds to the anti-TSH-R-Ab, inhibiting their degradation and returning them into the circulation. (B) With batoclimab, FcRn is blocked from binding to anti-TSH-R-Ab. (C) Anti-TSH-R-Ab are transported to the lysosome for degradation, decreasing their levels in the circulation. TSH-R, thyrotropin receptor.

Figure 2.

CONSORT diagram. (A) POC. (B) Randomized trial*. ITT, intent to treat, defined as patients who received ≥1 dose and had ≥1 post-baseline visit. POC, proof-of-concept. *One patient missed a total of 3 doses because of COVID-19 infection. Additionally, 2 patients had their 12-week postbaseline visit as a video appointment because of COVID-restrictions and did not have clinical assessments completed at that visit. The 7-week follow-up period was completed by 44 (67.7%) patients. ^†Patients could not attend clinic visits.

Figure 3.

Serological results from POC. (A) Change in total IgG. (B) Change in total anti-TSH-R antibodies. (C) Change in stimulatory anti-TSH-R antibodies. POC, proof-of-concept; TSH-R, TSH receptor. Arrows indicate week of treatment. *P < .05 for change from baseline (t test). ^†P ≤ .005 for change from baseline (t test).

Figure 4.

Serological results in the randomized trial (ITT population). (A) Change in total IgG. (B) Change in total anti-TSH-R antibodies. (C) Change in stimulatory anti-TSH-R antibodies. ITT, intent-to-treat, defined as patients who received ≥1 dose and had ≥1 postbaseline visit; LSM, least-square mean; TSH-R, TSH receptor. Arrows indicate week of treatment. *P < .05 vs placebo. ^†P < .01 vs placebo. ^‡P < .001 vs placebo.

Figure 5.

Proptosis and CAS responders in the randomized trial (ITT population). (A) Proptosis responders. (B) CAS responders. CAS, clinical activity score of TED. ITT, intent-to-treat, defined as patients who received ≥1 dose and had ≥1 postbaseline visit. *P < .05 vs placebo.

Figure 6.

Changes in orbital muscle volume at 12 weeks postbaseline (ITT population). (A) Mean change. (B) Mean percent change. ITT, intent-to-treat, defined as patients who received ≥1 dose and had ≥1 post-baseline visit. *P < .03 vs placebo.

Figure 7.

Changes in laboratory parameters in the randomized trial. (A) Change in serum albumin. (B) Change in LDL-C. LDL-C, low-density lipoprotein cholesterol; LLN, lower limit of normal; ULN, upper limit of normal. Arrows indicate week of treatment. Values above bars are percent (SD) change from baseline in patients who had values measured both at baseline and at the timepoint of interest. *In the batoclimab 680-mg group, 5/18 (27.8%) patients had LDL-C levels ≥160 mg/dL at baseline; at 12 weeks postbaseline, 2/18 (11.1%) had LDL-C levels ≥160 to <190 mg/dL and 6/18 (33.3%) had levels ≥190 mg/dL. In the 340-mg group, 1/19 (5.3%) and 2/19 (10.5%) patients had LDL-C levels of ≥160 to <190 mg/dL and ≥190 mg/dL, respectively, at baseline; at 12 weeks postbaseline, 4/19 (21.1%) and 3/19 (15.8%) had LDL-C levels of ≥160 to <190 mg/dL and ≥190 mg/dL, respectively. In the 255-mg group, no patients had LDL-C levels ≥160 mg/dL at baseline; at 12 weeks postbaseline, 2/10 (20.0%) had levels ≥190 mg/dL.