CHICAGO – The investigational monoclonal antibody iscalimab reduced levels of thyroid hormone and thyroid-stimulating hormone–receptor antibodies (TSHR-Ab) in some patients with Graves disease in a small study.
Of 15 patients with Graves disease, 7 patients, or 47%, saw their thyroid hormone levels normalize, and levels of TSHR-Ab normalized in 4 patients, or 27% of the cohort. In addition, mean levels of a chemokine associated with Graves disease activity dropped.
“These results suggest that iscalimab may be an effective and attractive immunomodulation strategy for Graves disease,” said George Kahaly, MD, PhD, in his presentation of the phase 2 results at the annual meeting of the American Thyroid Association (J Clin Endocrinol Metab. 2019 Sep 12. doi: 10.1210/clinem/dgz013).
Overall, patients who responded had lower levels of free triiodothyronine (FT3), free thyroxine (FT4), and TSHR-Ab and lower thyroid volume at baseline.
Iscalimab is a fully human monoclonal antibody that is active against the costimulatory protein CD40 that is present on the surface of antigen-presenting cells. Dr. Kahaly, professor of endocrinology at Johannes Gutenberg University Medical Center, Mainz, Germany, explained that in primate studies, iscalimab inhibits the T cell–dependent antibody response to an antigen, without depletion of B cells. However, iscalimab would be expected to block B-cell activation and differentiation, “leading to reduced de novo TSHR antibody production,” said Dr. Kahaly. Inhibition of T cell–dependent antibody response was seen when iscalimab was given at a dose of 3 mg/kg in healthy human study participants.
The study results presented by Dr. Kahaly were drawn from a single-arm, proof-of-concept study that enrolled 15 patients with Graves disease to 12 weeks of treatment with iscalimab. The participants were followed for an additional 24 weeks after receiving intravenous iscalimab at 10 mg/kg on study days 1, 15, 29, 57, and 85.
All participants were receiving beta blockers at enrollment; four patients had new-onset Graves disease, and the rest were experiencing a treatment relapse.
The participants were a median 49 years old, and all but two were female. One patient was Asian, and the remainder were white. They were mostly normal weight, with a mean body mass index of about 23 kg/m2.
A group of seven patients who were clear responders to iscalimab saw normalization of FT4 levels; of the eight patients considered to be nonresponders, six required rescue medication with antithyroid drugs.
For responders, the initial mean FT4 level was 33.5 pmol/L, whereas for nonresponders, it was 51.3 pmol/L (P less than .05). Similarly, mean FT3 levels were 13.6 pmol/L in responders, compared with 22 pmol/L in nonresponders (P less than .05).
Mean thyroid volume was 14.5 ml in responders, compared with 26 ml in nonresponders (P less than .005).
A subgroup of four patients within the responder group became TSHR-Ab negative, with sustained low antibody levels seen during the follow-up period. All but one of the eight nonresponders had initial TSHR-Ab levels of more than 20 U/L, whereas the seven responders began with TSHR-Ab levels of about 10 U/L or less. Mean TSHR-Ab levels at baseline were 5.6 IU/L for responders, compared with 27.3 IU/L for nonresponders (P less than .001).
Most responders also had lower initial levels of antithyroid peroxidase IgG antibodies, compared with the nonresponder group.
Levels of chemokine (motif C-X-C) ligand 13 (CXCL13) fell throughout the study period. Higher CXCL13 levels are associated with lymphocytic infiltrates seen in autoimmune thyroiditis.
Occupancy of CD40 was initially measured at week 4 of the study and it remained high until week 16, when free CD40 receptors rose rapidly for several participants in both the responder and nonresponder groups. “The iscalimab intervention resulted in complete CD40 engagement for up to 20 weeks,” wrote Dr. Kahaly and colleagues in the abstract accompanying the presentation.
In assessing CD40 target engagement, the investigators found that total soluble CD40 levels climbed during the treatment period, reaching peaks as high as 400-500 ng/mL, and then plummeted back to zero by study’s end for all participants.
A pharmacokinetic analysis revealed expected peaks of serum iscalimab after treatments, with levels dropping sharply at the end of the study period and falling to levels approaching zero by week 24 for most participants.
In terms of safety, 12 patients experienced at least one adverse event, with 3 participants reporting an episode of cystitis during the study. Fatigue, headache, insomnia, nausea, and viral upper respiratory infection were each reported by 2 patients. No injection site reactions were seen. All adverse events were mild or moderate, did not result in study withdrawal, and resolved by the end of the study period, Dr. Kahaly noted.
“These encouraging results suggest that iscalimab should be tested further to understand better its potential therapeutic benefit,” the investigators wrote.
The study was funded by Novartis, which is developing iscalimab for Graves disease, other autoimmune disorders, and as an antirejection drug for patients with kidney transplants.