By Deborah Borfitz

September 12, 2024 | Later this year, Immunovant will be launching a late-stage clinical trial for Graves’ disease—the first in a very, very long time. The preferred treatment option currently is methimazole, approved for medical use in the U.S. in 1950, but some patients require high doses of the drug to control their hyperthyroidism, and in up to half of cases long-term remission isn’t achievable short of surgery to remove the thyroid gland or radioactive iodine to destroy the thyroid and stop it from producing hormones. 

Such is the reality for patients with Graves’ disease, an autoimmune disorder diagnosed in 100,000 people each year in the country, according to Immunovant CEO Peter Salzmann, M.D. An estimated 25% of those individuals fall in the difficult-to-treat category, both because the condition can be highly variable from one patient to the next and drug dosing is inherently tricky. 

In a phase 2 proof-of-concept study where treatment-resistant Graves’ patients were given Immunovant’s first-generation anti-FcRn agent IMVT-1401 (batoclimab), the company announced results “meaningfully exceeded 50% response rates.” The treatment approach targets the neonatal Fc receptor (FcRn), most famous for transferring antibodies from mom to fetus during pregnancy, to block the natural recycling of other antibodies inside the body, explains Salzmann. 

In people with Graves’, FcRn recycles harmful immunoglobulin G (IgG) autoantibodies. These in turn bind to and activate the thyroid-stimulating hormone (TSH) receptor that stimulates excess thyroid hormone production. 

While batoclimab succeeded in lowering the levels of IgG autoantibodies, it also reduced another blood protein that can cause some side effects, Salzmann reports, notably albumin reductions and increases in lipids that resolve after patients stop taking the drug. That issue has been addressed with the reengineered anti-FcRn candidate IMVT-1402 that will be used in the global clinical trial.  

Complicated Condition

Graves’ disease is the leading cause of hyperthyroidism with symptoms that often include shakiness, heart palpitations, anxiety, poor sleep, and irritability. The condition “impacts relationships, work performance, exercise tolerance, and daily life,” says Mark Lupo, M.D., founder and medical director of the Thyroid & Endocrine Center of Florida that sees many Graves’ disease patients. Roughly a quarter of patients have clinically significant thyroid eye disease that presents “additional potential challenges such as double vision, disfigured appearance, pain, and ocular irritation.”  

Patients with Graves’ disease often go undiagnosed for six to 12 months or more, says Lupo. In the interim, they are sometimes treated with medications for anxiety, depression, tremors, or palpitations. 

“The thyroid is innocent in Graves’ disease,” Lupo notes, which is why he is pleased with the overall shift toward first- and second-line utilization of methimazole in lieu of destroying the organ. However, patients still struggle with fluctuating thyroid function and frequent methimazole dose changes and a portion of them have “persistent elevated high TSH receptor antibodies” despite treatment. 

Although surgery and radioactive iodine remain as fallback options when patients fail on methimazole, neither are particularly ideal, he says. Thyroidectomy comes with the risk of “hypoparathyroidism and potential injury to the nerve that goes to the vocal cord, resulting in difficulties managing calcium levels and permanent voice changes.” 

Radioactive iodine, on the other hand, can potentially increase the odds of future malignancy and aggravate thyroid eye disease—the main reasons it has fallen out of favor. Additionally, Lupo says, it increases levels of TSH receptor antibodies, which is particularly important in women of reproductive age since the antibodies cross the placenta and affect a developing fetus's thyroid.  

“To have a treatment option that directly addresses the cause of Graves’ disease—the IgG TSH receptor antibodies—would be a significant paradigm shift,” says Lupo. “We could finally begin to treat the disease upstream instead of downstream, which would have a significant quality-of-life benefit impact for our patients” via improved control of hyperthyroidism and thyroid eye disease. 

One of the biggest challenges ahead is simply setting up the clinical trial infrastructure for physician practices treating Graves’ disease patients who are largely unaccustomed to conducting studies, says Salzmann, which will involve hiring staff and ensuring everyone is properly trained. “The good news is that there is a lot of enthusiasm for a new therapy.” 

“The treatment options for Graves’ disease have not changed in many decades,” says Lupo, although in the U.S. more than 90% of clinicians would recommend methimazole initially for uncomplicated cases. “We typically use methimazole for at least 12-18 months, and do not stop methimazole until the TSH receptor antibodies are negative and the thyroid function tests are normal. With that approach, the remission rate can be greater than 50%. If there is relapse, the most common current recommendation is to resume methimazole.” 

Promising Possibilities

The plan is to establish a geographically distributed trial network to enroll as many people who qualify into the phase 3 registration trial as quickly as possible, Salzmann says. As with any trial, it will seek to get a reasonably homogenous population for purposes of data interpretation so not every patient who might want to participate will be able to do so. 

Based on the experience of patients in the batoclimab program, says Salzmann, the demands of study participation will likely be viewed as a “nice tradeoff” for the repeated visits individuals would otherwise be making to their endocrinologist trying to get their drug dosing right since methimazole has a famously narrow therapeutic window. If the right patient-specific dose of the medication for hyperthyroidism isn't taken, individuals “can go from being underdosed to overdosed [hypothyroidism] very quickly,” a kind of clinical ping-pong that can be unnerving for everyone involved.   

Most of those patients will eventually go into remission, but it might take three to seven years or, for an unlucky few, even longer, he says. “Even a year or two of having highly fluctuating thyroid hormone levels is massively disruptive to people’s lives and there is not much you can do about it today, unfortunately.”  

The second-generation IMVT-1402, like batoclimab, is administered as a once-weekly subcutaneous injection. In the proof-of-concept study, some patients self-injected after initial in-clinic visits, Salzmann notes. 

“A big part of the promise of 1402 is that it will work with a lot less effort on the part of the doctor and the patient,” says Salzmann. “It’s not titrated in the same way as methimazole. You are not trying to titrate the autoantibodies to the right level; the right level is to get rid of them.” 

Currently, many patients require the expertise of an endocrinologist to fine tune their methimazole dose for the desired response, meaning the inconvenience of multiple return trips to the doctor’s office. The goal with IMVT-1402, Salzmann says, is to have a drug where after some initial period of stabilization, patients will be able to receive ongoing care from a specialist less frequently or mainly from their primary care physician. 

Common Culprit

Autoantibodies are a key factor in many autoimmune diseases besides Graves’ disease, including myasthenia gravis and thyroid eye disease, says Salzmann. “Those are three very different diseases, but they all share a root cause ... [and] the problem is almost entirely with a single autoantibody.”  

The common culprit is the recycling by the neonatal receptor FcRn. While IMVT-1402 is initially targeting Graves’ disease, Immunovant has its sights on anti-FcRn medicines for at least 10, mostly “normal size” rare conditions collectively representing an estimated 800,000 patients in the U.S. alone, Salzmann says. 

The same autoantibodies to the thyroid-stimulating hormone receptor cause metabolic Graves’ disease and thyroid eye disease, but it is unknown why some people get mostly Graves’ or eye disease while others are afflicted with both, he continues. “The good news... is removing the autoantibodies should help both conditions.” Salzmann says he anticipates that Immunovant will eventually include Graves’ disease patients with eye symptoms in its trials; initially, for practical reasons, those with more severe eye disease will be excluded.  

While batoclimab will no longer be studied in Graves’ disease, the first-generation asset was helpful in three respects, he adds. “It let us know that FcRn inhibition has a high chance of it working” where no data on the concept previously existed for the treatment of Graves’ disease. Secondly, continues Salzmann, “it allowed us to get a sense of dose response. We used two different doses in the proof-of-concept study, and it looks like you need the higher dose to get the best response for the most people.” Finally, many patients taking batoclimab needed to reduce their methimazole dose so as not to become hypothyroid, since the investigational product was also removing the harmful antibodies. During the proof-of-concept study, he says, “we learned how to taper methimazole in the context of a clinical trial.”  

Novartis had a monoclonal antibody targeting the protein receptor for CD40, the pathway involved in the generation of autoantibodies, under development for Graves’ disease a few years ago, says Salzmann. The drug candidate was never taken forward.  

Road to Success 

Immunovant, originally a division within Roivant Sciences, formed at the end of 2017 when the licensing agreement was signed, says Salzmann. IMVT-1401 and IMVT-1402 were invented by a Korean company lacking the infrastructure at that time to run a global development program. 

Roivant took over development of these assets in the U.S., Europe, and potentially the rest of the world except for Asia. Immunovant functioned as a team within Roivant until late 2018 when, considering positive results emerging from a phase 1 healthy volunteer study, it was carved out as a private company and a year later went public. 

Salzmann was recruited as CEO, officially assuming his duties in June of 2019. A physician by training, board-certified in internal medicine, he also earned an MBA before joining Eli Lilly to serve in a variety of strategic and primarily commercial roles on a global scale, he says. In his final few years with Lilly, Salzmann was heavily involved in both commercial and development work in immunology, both of which have proven invaluable to Immunovant.  

He and Lupo met two years ago at a European Thyroid Association meeting in Brussels. Lupo is now helping Immunovant in the patient-centric design of the phase 3 study. 

The IMVT-1402 registration program for Graves’ disease will involve two different clinical studies prior to regulatory submission, Salzmann says. Details will be available later this fall on ClinicalTrials.gov, along with the findings of the batoclimab proof-of-concept study. 

Immunovant just announced results from the Phase 2a trial, which found that in patients uncontrolled on antithyroid drugs at week 12, high-dose dose batoclimab achieved a 76% response rate (56% among patients not also taking methimazole). A strong correlation was seen between the degree of IgG lowering and clinical outcomes.  

People suffering from Graves’ disease, thyroid eye disease, or myasthenia gravis—or anyone who knows or treats them—should know “innovation is on the horizon,” enthuses Salzmann. Endocrinologists can also expect to be hearing more soon about the registration trial for IMVT-1402 in Graves’ disease because a major outreach effort is planned to help spread the word.