Plasma-cell depletion therapy for severe Graves' disease

Graves' disease (autoimmune thyroid overactivity) affects around 3% of women over their life-time and gives symptoms such as heart palpitations, heat intolerance, unintended weight loss, enlarged thyroid, red and swollen eyelids, protuberant eyeballs and double vision. These symptoms are caused by an abnormal immune response leading to a circulating antibody (known as TRAb) that stimulates the thyroid gland and causes inflammation and growth of the tissues around the eyes. While many patients can be successfully treated with anti-thyroid drugs, these do not improve the eye problems. A sizeable minority of patients have severe Graves' disease, with more intense thyroid overactivity and worse eye inflammation, which is associated with blood TRAb levels that are ten times higher than normal. These people are not cured by medication and frequently have disabling eye disease and occasionally loss of vision. Currently these severe Graves' disease patients have their thyroid gland removed surgically, followed by several eye operations to correct the visual function and appearance of the eyes. These are expensive operations and overall, only 50% of NHS patients feel that the outcomes of such treatment are satisfactory. Better treatments are sorely needed.

The TRAb antibodies that drive the thyroid and eye symptoms are produced by a type of white blood cell called a plasma cell, whose sole purpose is to make large quantities of antibodies. This project will find out whether a new treatment called daratumumab that has been developed to treat plasma cell cancer, could also be used to target the benign plasma cells in patients with severe Graves' disease. By removing plasma cells in Graves' disease, we would expect a reduction in the disease-causing TRAb antibody concentration and a rapid improvement in the thyroid overactivity and eye symptoms.

This study will perform a 2-stage clinical trial of daratumumab in 30 patients with severe Graves' disease. Because daratumumab has not been used in Graves' disease before, the first part of our study will administer 4 different doses to small groups of participants to see which of the doses works best and has least side-effects. Then we will use these optimal daratumumab doses and a placebo to treat larger groups of patients. The daratumumab is given twice by intravenous infusion to each participant, and the thyroid and eye state of each person will be followed for 6 months afterwards. Our study could change the lives of many people with severe Graves' disease, who in the future might be able to have treatment with infusions of daratumumab, rather than several surgical operations. In addition, our study might open a door whereby daratumumab might be used to treat several other autoimmune conditions where abnormal antibodies also drive the disease process.

Patients with severe Graves' disease, defined by severe hyperthyroidism, large goitre and inflammatory eye disease, have unmet clinical need and a poor response to conventional treatments. Many patients are ultimately managed by surgical thyroidectomy, with bilateral orbital decompression surgery followed by strabismus and eyelid surgeries. This aggressive autoimmune disease is caused by high concentrations of directly pathogenic TSH-receptor stimulating antibodies (TRAb), which are secreted from terminally differentiated B lymphocytes known as plasma cells. Daratumumab is a recently licenced anti-CD38 monoclonal antibody that selectively depletes plasma cells and thus has the potential to directly target the pathogenic TRAb-secreting cell type in Graves' disease. This adaptive trial will investigate proof of the concept that daratumumab has disease-modifying activity in Graves' disease.

We will recruit 30 adult patients with severe Graves' disease defined by TRAb antibody concentrations above 10U/L (normal <1.0), with either severe hyperthyroidism (FT4 >50pmol/L), inflammatory thyroid eye disease (clinical activity score >3), large goitre or thyroid dermopathy. Initially, four different doses of daratumumab and placebo will be given in a randomised dose-response study (5 x n=3 groups). Following an interim analysis, the most promising dose(s) and placebo will be trialled in a further 15 patients. The primary analysis will be a comparison of the percentage reduction in serum TRAb concentration between baseline and 12 weeks in each active IMP group and the placebo group. Secondary outcomes will include changes in serum thyroid hormones (FT3, FT4); subjective and objective measures of thyroid eye disease; thyroid volume measured by ultrasound; participant safety and subjective tolerability. Our adaptive design study will determine whether daratumumab has the potential to change the natural history of this common and morbid condition.