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Batoclimab (“IMVT-1401”)

Batoclimab (“IMVT-1401”)

Immunovant’s first investigational product, batoclimab (“IMVT-1401”), is a novel, fully human monoclonal antibody targeting the neonatal Fc receptor (FcRn). In nonclinical studies and in clinical trials conducted to date, batoclimab has been observed to reduce IgG antibody levels. High levels of pathogenic IgG antibodies drive a variety of autoimmune diseases and, as a result, we believe that this product candidate has the potential to address a variety of IgG-mediated autoimmune diseases as a self-administered subcutaneous injection.

The FcRn receptor facilitates IgG recycling. Batoclimab enhances the degradation of IgG by targeting FcRn and preventing endogenous IgG from binding. This increased catabolism of IgG may curtail the harmful immune response exhibited by auto-antibodies.

IMVT-1402

Immunovant’s second investigational product, IMVT-1402, is also a novel, fully human FcRn-targeting antibody. As with batoclimab, in nonclinical studies, IMVT-1402 has been observed to reduce IgG antibody levels and is designed to enable a subcutaneous route of administration delivered in a matter of seconds.

Mechanism of Action

FcRn is the primary protein responsible for preventing the degradation of IgG antibodies and albumin. The role of FcRn is to bind to the IgG antibodies in the endosome, and transport them to the cell surface, where they are released back into circulation.

Batoclimab and IMVT-1402 are designed to selectively bind to and inhibit FcRn, thus blocking the recycling of IgG antibodies. The figure to the right illustrates the mechanism of action for batoclimab and IMVT-1402.

Indications

Myasthenia Gravis (MG)
MG is a rare, chronic autoimmune disorder characterized by weakness and fatigue of voluntary muscles. The clinical course of MG is variable but usually progressive, and patients tend to experience fluctuating symptoms. There is an estimated prevalence of 18 cases of MG per 100,000 people in the United States. For women, disease onset typically occurs around their 20s and 30s, whereas for men it peaks in their 50s and 60s. Overall, MG affects women more frequently than men.

The disease is most often caused by autoantibodies that target the acetylcholine receptor or muscle-specific tyrosine kinase receptor at the neuromuscular junction, disrupting normal muscular function. Symptoms typically emerge in the eyes (e.g., drooping eyelids, double vision, blurred vision) and progress into the face, throat, or limbs. Some patients may experience life-threatening respiratory complications due to the weakening of muscles involved in respiration.

Thyroid Eye Disease (TED)
TED, also known as Graves’ Ophthalmopathy, is an autoimmune disorder affecting the tissues around the eyes. It is a progressive and clinically variable disease that can become debilitating, disfiguring, or sight-threatening. The incidence of TED in the United States is approximately 10 per 100,000.

TED can be caused by IgG autoantibodies that form against the thyroid-stimulating hormone receptor (TSHR). These antibodies, which also cause Graves’ disease, target the extraocular space and result in clinical manifestations of the disease. Common signs of disease include proptosis (eye bulging), tearing, periorbital edema (swelling around the eyes), dry eyes, and pain behind the eyes; in severe cases, double vision or vision loss may occur.

Chronic Inflammatory Demyelinated Polyneuropathy (CIDP)
CIDP is an autoimmune neurological disorder characterized by damage to the myelin sheaths or the nodes on nerve fibers of the peripheral nervous system. Though the clinical presentation of CIDP is diverse, it can be categorized into monophasic, relapsing-remitting, or chronic progressive disease. CIDP is a rare disease that can occur in any age group and affects men twice as much as women. Its prevalence is estimated to be approximately 9 per 100,000 people in the United States.

CIDP appears to be mediated by IgG antibodies that are directed against myelin or proteins at the node of Ranvier; however, the specific target of these antibodies is not yet established. The hallmark signs of CIDP are weakness, tingling sensations, or loss of sensation in the arms and legs that is symmetrical and gradually worsens.

Graves’ Disease
Graves’ Disease is an autoimmune disorder associated with the overproduction of thyroid hormones and is the most common cause of hyperthyroidism. Although Graves’ Disease can affect any age group or gender, it is most prevalent in women younger than 40 years of age with its prevalence estimated at 35 per 100,000 in the United States.

The disease is mediated by thyroid-stimulating IgG antibodies that cause the thyroid gland to produce an excess of thyroid hormones, resulting in systemic manifestations that affect multiple organs. Patients typically present with classic signs and symptoms of hyperthyroidism, such as heat intolerance, weight loss, anxiety, and frequent bowel movements. The disease can also manifest with ophthalmopathy (e.g., eye redness, swelling, bulging) or dermopathy. If left untreated, patients not only experience the unpleasant impact of elevated thyroid hormones, but also may develop arrhythmias, heart failure, or life-threatening thyroid storms.

Warm Autoimmune Hemolytic Anemia (WAIHA)
WAIHA is a rare blood disorder in which healthy red blood cells are prematurely destroyed, leading to anemia. Symptoms typically develop chronically over several weeks to months, but rapid progression over a span of days has also been observed. Based on published estimates, prevalence rate of about 17 per 100,000 people. About 50% of cases are idiopathic, whereas the rest are secondary to underlying malignant, autoimmune, or infectious triggers.

This type of anemia is mediated by IgG autoantibodies that form against red blood cells. The clinical presentation of WAIHA is variable, but most commonly includes nonspecific symptoms of anemia such as fatigue, weakness, skin paleness, and shortness of breath. The condition can be life-threatening if left untreated.

References

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  • Sudulagunta S.R., et al. Refractory myasthenia gravis – clinical profile, comorbidities and response to rituximab. German Medical Science, 2016
  • Davies T. and Burch H.B. Clinical features and diagnosis of Graves’ orbitopathy (ophthalmopathy), UpToDate, 2018
  • McAlinden C. An overview of thyroid eye disease. Eye and Vision, 2014
  • Mathey EK, Park SB, Hughes RAC, et al Chronic inflammatory demyelinating polyradiculoneuropathy: from pathology to phenotype Journal of Neurology, Neurosurgery & Psychiatry 2015
  • Koike H, Katsuno M. Pathophysiology of Chronic Inflammatory Demyelinating Polyneuropathy: Insights into Classification and Therapeutic Strategy. Neurol Ther. 2020 Dec;9(2):213-227. doi: 10.1007/s40120-020-00190-8. Epub 2020 May 14
  • Stern RA, et al., Jr. A survey study of neuropsychiatric complaints in patients with Graves' disease. J Neuropsychiatry Clin Neurosci. 1996 Spring;8(2):181-5. doi: 10.1176/jnp.8.2.181. PMID: 9081554
  • Girgis CM, Champion BL, Wall JR. Current concepts in Graves' disease. Ther Adv Endocrinol Metab. 2011 Jun;2(3):135-44. doi: 10.1177/2042018811408488. PMID: 23148179; PMCID: PMC3474632
  • Roumier M., et al. Characteristics and outcome of warm autoimmune hemolytic anemia in adults: new insights based on a single-center experience with 60 patients. American Journal of Hematology, 2014