Batoclimab Shows Rapid Effect on Key Graves’ Disease Markers

CHICAGO — The investigational monoclonal antibody batoclimab showed safety and rapid and significant improvement in key markers of Graves’ disease, with some patients who failed to improve with standard antithyroid drugs (ATDs) showing a normalization or near-normalization of markers within just weeks of batoclimab initiation.

“These data are the first clinical evidence that neonatal fragment crystallizable receptor (FcRn) inhibition may be effective for treating Graves’ hyperthyroidism,” reported the authors in late-breaking findings at the American Thyroid Association (ATA) 2024 Meeting.

“We saw a normalization of serum free thyroxine (T4) within 2 weeks of administration of the drug, and free triiodothyronine (T3) and T4 remained normal within the higher upper limit of normal until week 24,” said first author George J. Kahaly, MD, PhD, of the Johannes Gutenberg University Medical Centre, in Mainz, Germany, while presenting the findings.

Batoclimab, a monoclonal antibody targeting FcRn, is designed to reduce immunoglobulin G (IgG) levels, while decreasing the thyrotropin receptor antibody (TRAb) levels that are key culprits in Graves’ hyperthyroidism, as well as thyroid eye disease.

With its unique mechanism, the novel drug represents a potentially important option for subgroups of patients with Graves’ disease who either don’t respond to antithyroid medications such as methimazole or prefer not to take those drugs, for instance, when pregnant.

For the phase 2a, proof-of-concept, open-label study, Kahaly and colleagues enrolled 27 patients who remained hyperthyroid despite having been treated with methimazole at doses of 10 mg or more per day for at least 12 weeks.

All the patients had T4 and/or T3, as well as TRAb levels that were above the upper limit of normal at baseline.

All received batoclimab subcutaneous injections of 680 mg/wk for 12 weeks, followed by 340 mg/wk for another 12 weeks. Of the patients, 80% were female, their median age was 52 years, and their median time since Graves’ disease diagnosis was 15.7 months.

Of the patients, 25 completed the study up to week 24, while two discontinued early due to nontreatment-related reasons. Most patients (80%) had preexisting Graves’ orbitopathy.

Within just 2 weeks of treatment initiation, 15 of the 25 patients (60%) overall had achieved serum free T3 and free T4 levels below the upper limit of normal, without increasing their antithyroid therapy.

For the key endpoints, after the first 12 weeks of high-dose (680 mg) batoclimab, the number of patients with free serum T3 and T4 levels below the upper level of normal increased to 19 (76%), again, without an increase in antithyroid therapy.

Those patients included 14 (56%) who were able to go off ATDs and five (20%) who achieved normal thyroid-stimulating hormone levels.

After the second 12-week period (by week 24), in which patients received the lower-dose (340 mg) batoclimab, 17 patients (68%) had free T3 and T4 levels below the upper limit of normal without an increase in ATDs, including nine (36%) who were able to discontinue the ATD.

Furthermore, mean TRAb levels decreased from baseline by as much as 74% at week 12 and 70% at week 24, with five patients (20%) achieving seroconversion (TRAb-negative) at week 12 and three (12%) at week 24.

“As expected, there was a rapid decrease in serum IgG, of more than 60% within 2 weeks; a decrease of 80% at weeks 6 and 12, and a sustained reduction at week 24,” Kahaly said.

Of the 15 patients who were positive for thyroid peroxidase (TPO) autobody, indicative of Hashimoto’s thyroiditis disease, at baseline, TPO antibody levels declined by more than 60% at 12 weeks, with levels sustained but slightly higher at 24 weeks.

Overall, in terms of the changes from baseline, the dosages of ATDs dropped by as much as 75% at week 6, by 100% at week 12, and 87.5% at week 24.

Thyroid volume was decreased by 9 mL from baseline at 24 weeks, and proptosis was reduced by 2.5 mm at 12 weeks and 3 mm at 24 weeks, with similar improvement observed in palpebral aperture at 12 and 24 weeks.

Further evaluation also showed significant reductions in patient anxiety, as assessed by the validated ThyPRO-39 anxiety scale, with clinically meaningful declines in scores among those on ATDs, from 31.9 at baseline to 21.5 at week 12 and 20.5 at week 24, while declines among those who were off ATDs were from 39.3 at baseline to 18.9 at week 12 and 10.9 at week 24.

Batoclimab was well tolerated among the patients who completed the 24 weeks, with no new safety signals with all adverse events being mild to moderate in severity and not treatment related; no new safety signals were observed.

One serious treatment-emergent adverse event occurred, involving worsening cholelithiasis.

The results show that “subcutaneous batoclimab very rapidly normalized FT3 and FT4 in most patients,” the authors reported.

“By week 12, more than half of patients had both T3 and T4 below the upper limit of normal and were off antithyroid treatment. Batoclimab also improved extrathyroidal signs.”

Commenting on the study, Marius N. Stan, MD, a professor of medicine with the Mayo Clinic, in Rochester, Minnesota, said the study is especially important considering the slow progress of new therapies for treating Graves’ disease.

“We added antithyroid drugs in 1943 and then radioactive iodine in 1946, and we have done nothing as far as treatment since then, so we’re almost at 80 years without tackling this disease in a different way, despite the fact that it’s an autoimmune disease,” Stan told Medscape Medical News.

“So in terms of these drugs that are looking at the autoimmune pathway antibodies and trying to tackle the antibodies, I think the answer is yes — we should pursue them,” he said.

Stan noted that a challenge of treatment of Graves’ disease is that patients do sometimes fail to respond to methimazole, and furthermore, methimazole “does nothing for the concomitant problem of eye disease, so if one drug could be used to tackle both diseases, that would be [very helpful],” he said.

Batoclimab is also being investigated in the treatment of generalized myasthenia gravis and recently showed safety and efficacy in a randomized study of adults with that condition.

Kahaly received funding from and consults for Immunovant, Inc. Stan’s disclosures included relationships with Tourmaline, Genentech, Third Rock Ventures, argenx, Septerna, OrthoDi, Horizon, Immunovant, Lassen, and Sling.