Title | Teprotumumab in Thyroid-Associated Ophthalmopathy: Rationale for Therapeutic Insulin-Like Growth Factor-I Receptor Inhibition |
Creator | Terry J. Smith |
Affiliation | Department of Ophthalmology and Visual Sciences, Kellogg Eye Center, and Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan |
Abstract | Thyroid-associated ophthalmopathy (TAO) is an autoimmune component of Graves' disease for which no currently available medical therapy provides reliable and safe benefit. Based on insights generated experimentally over the past several decades, the insulin-like growth factor-I receptor (IGF-IR) has been implicated in the pathogenesis of TAO. Furthermore, an IGF-IR inhibitor, teprotumumab, has emerged from 2 clinical trials as a promising treatment for active, moderate to severe TAO. This brief review intends to provide an overview of the rationale underlying the development of teprotumumab for this disease. It is possible that teprotumumab will soon take its place in our therapeutic armamentarium for active TAO. |
Subject | Antibodies, Monoclonal, Humanized / therapeutic use; Graves Ophthalmopathy / drug therapy; Graves Ophthalmopathy / immunology; Humans; Insulin-Like Growth Factor I / immunology; Receptor, IGF Type 1 / immunology |
OCR Text | Show Basic and Translational Research Section Editors: Jeffrey L. Bennett, MD, PhD Kenneth S. Shindler, MD, PhD Teprotumumab in Thyroid-Associated Ophthalmopathy: Rationale for Therapeutic Insulin-Like Growth Factor-I Receptor Inhibition Terry J. Smith, MD Abstract: Thyroid-associated ophthalmopathy (TAO) is an autoimmune component of Graves' disease for which no currently available medical therapy provides reliable and safe benefit. Based on insights generated experimentally over the past several decades, the insulin-like growth factor-I receptor (IGF-IR) has been implicated in the pathogenesis of TAO. Furthermore, an IGF-IR inhibitor, teprotumumab, has emerged from 2 clinical trials as a promising treatment for active, moderate to severe TAO. This brief review intends to provide an overview of the rationale underlying the development of teprotumumab for this disease. It is possible that teprotumumab will soon take its place in our therapeutic armamentarium for active TAO. Journal of Neuro-Ophthalmology 2020;40:74-83 doi: 10.1097/WNO.0000000000000890 © 2020 by North American Neuro-Ophthalmology Society T hyroid-associated ophthalmopathy (TAO, A.K.A. Graves' eye disease) remains a vexing and inadequately treated autoimmune condition most commonly linked to its occurrence in Graves' disease (GD) (1). TAO frequently disfigures and in its most severe forms can threaten vision (Fig. 1). Frequently missing in discussions of TAO are the emotional and social tolls that the Department Center, and Department School, Ann of Ophthalmology and Visual Sciences, Kellogg Eye Division of Metabolism, Endocrinology and Diabetes, of Internal Medicine, University of Michigan Medical Arbor, Michigan. Supported in part by National Institutes of Health grants EY08976, DK063121, EY11708, Research to Prevent Blindness, and the Bell Charitable Family Foundation. T. J. Smith has been issued US patents 6936426, 7998681, 8153121, and 8178304 covering the inhibition of IGF-I receptor as therapy for TAO. These are held by Los Angeles Biomedical Institute and UCLA School of Medicine. He is a consultant for River Vision and Horizon Therapeutics. Address correspondence to Terry J. Smith, MD, Department of Ophthalmology and Visual Sciences, Kellogg Eye Center, Brehm Tower, University of Michigan Medical School, 1000 Wall Street, Ann Arbor, MI 48105; E-mail: terrysmi@med.umich.edu 74 disease can take and its significant reduction in quality of life (2,3). To date, no medical therapy has been developed and approved for the treatment of active moderate to severe TAO. At the heart of GD and presumably also underlying, TAO is the loss of immune tolerance for the thyrotropin receptor (TSHR) (4). Stimulating anti-TSHR antibodies, known as thyroid-stimulating immunoglobulins (TSI), are generated uniquely in GD and are detected in most patients with TAO. Although TSI levels have been found to correlate generally with the clinical behavior of TAO (5-7), the precise mechanisms through which these autoantibodies and TSHR antigen-specific T cells act in orbital tissues is not yet fully elucidated. A major barrier to progress in developing specific, targeted treatments for TAO has been the absence of high-fidelity preclinical models. To be sure, recently developed mouse models seem to represent substantial improvements over their predecessors, but they remain imperfect (8). Another hurdle in solving TAO has been the wide variation in clinical presentation observed among cases and the difficulty in distinguishing TAO from other forms of orbital inflammation and remodeling. Unfortunately, we have yet to develop reliable biomarkers for identifying those individuals with GD, especially those with early TAO, who are destined to develop severe ocular manifestations. In this brief article, I have undertaken to provide the context in which our efforts to better understand active TAO have culminated in the identification of the insulin-like growth factor-I receptor (IGF-IR) as a therapeutic target of substantial potential value. Two recently conducted clinical trials have yielded encouraging results examining teprotumumab (Tepro), a monoclonal inhibitory antibody targeting IGF-IR, in patients with active, moderate to severe TAO (9). Furthermore, the drug was generally welltolerated. It is thus possible that a new therapy that interrupts specific pathways playing important roles in disease development might soon be available for use in the clinic. Smith: J Neuro-Ophthalmol 2020; 40: 74-83 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Basic and Translational Research severe TAO, whether the patient is an active cigarette smoker or merely encounters smoke passively (14,15). Furthermore, smokers are more likely to develop disease reactivation. Thus, a critical task in the care of patients with GD, regardless of whether they manifest TAO, concerns counselling the avoidance of all sources of smoke and noxious fumes. They should also be instructed to protect their eyes from wind and direct sunlight because these can exacerbate dry eyes. FIG. 1. Image of a patient manifesting thyroid-associated ophthalmopathy. The patient manifests proptosis, eyelid retraction, periorbital edema, and inflammation during the early (active) phase of the disease. IS THYROID-ASSOCIATED OPHTHALMOPATHY AN INTEGRAL COMPONENT OF GRAVES' DISEASE OR MERELY A FREQUENT COMORBIDITY? CLINICAL PRESENTATION OF THYROIDASSOCIATED OPHTHALMOPATHY The unambiguous identification of a distinct factor(s) differentially inciting thyroid centric GD and TAO has yet to be accomplished. It remains possible that this factor may be identical for both disease manifestations. The mechanistic relationship between TAO and GD hyperthyroidism remains shrouded in uncertainty. The 2 autoimmune components are closely linked clinically with most of those patients presenting with characteristic ocular abnormalities also exhibiting thyroid dysfunction during their lifetimes (1). The onset of each component of the fully expressed GD syndrome can be simultaneous or temporally discordant, so that decades can separate development of the two. It has not yet been possible to identify genetic or epigenetic variations that discriminate between TAO and GD. Several important susceptibility genes underlie GD including cytotoxic T-lymphocyte-associated protein 4 (CTLA-4 and CD152), major histocompatibility complex (MHC) class II, and TSHR (16) with no convincing evidence for a separate genetic contribution to TAO (17). GD and Hashimoto's thyroiditis share important susceptibility genes, such as HLA-DRb1-Arg74 (18) while others seem to be specific for only one of these diseases (19). Many of these genes were identified from genome-wide association studies, association, and linkage analysis where single-nucleotide polymorphisms have emerged in cohorts of varying size. The occurrence of TAO in individuals with Hashimoto's thyroiditis, albeit considerably less frequent than in GD, adds weight for common underpinnings between GD and Hashimoto's thyroiditis. In sum, it would seem that many of the upstream genetic and epigenetic variations rendering susceptibility to GD and Hashimoto's thyroiditis within the thyroid gland are also involved in development of TAO. TAO typically presents initially with mild symptoms and signs such as dry eye, increased lacrimation, periorbital swelling and discomfort, elevated ocular pressure, eyelid retraction and lag (which can both occur with thyrotoxicosis from any cause), conjunctivitis and localized irritation (10). These manifestations can remain subtle, disappear, or progress to more severe disease. If they worsen, physical signs can dominate, such as those that interfere with daily life, including substantial proptosis, strabismus, and exposure keratopathy. At its extreme, sight can be threatened by compressive optic neuropathy or a severely deteriorating anterior eye surface. The active phase of TAO, characterized by progression and change, typically lasts 2-3 years but can sometimes be brief, lasting only a few months. By contrast, it can persist for considerably longer, sometimes for several years (11). The relationship between clinical activity of TAO and the thyroid dysfunction typically associated with GD is variable. Onset of hyperthyroidism and TAO can be concurrent or one can develop decades before the other (1). A small subset of those patients with severe TAO also develops localized myxedema, typically occurring on the pretibial skin but sometimes in other anatomic locations (12). Treatment of TAO during the active phase is usually restricted to anti-inflammatory medications such as glucocorticoids, the effectiveness of which is limited, unpredictable, and unlikely to modify the disease outcome (13). Furthermore, glucocorticoids are associated with sometimes severe side effects. The active phase of TAO transitions into an inactive (stable) period when inflammation abates and disease severity remains constant (11). Once the stable phase has been reached, elective surgical remediation of the disease manifestations is begun should it become necessary. The surgeries are usually performed in stages, beginning with orbital decompression for reduction of proptosis, followed by strabismus surgery to correct diplopia, and finally eyelid repair to improve draping of the globe and improve eye coverage. Hazards of these surgical procedures include their unpredictable outcomes and potential for reactivating the disease. Tobacco smoke exposure represents a widely recognized risk factor for developing more aggressive and Smith: J Neuro-Ophthalmol 2020; 40: 74-83 CURRENT AND DEVELOPING THERAPEUTIC LANDSCAPE FOR ACTIVE THYROIDASSOCIATED OPHTHALMOPATHY Medical treatment options during the active phase of TAO depend on disease severity and symptomatology and are extremely limited. None has thus far achieved registration by 75 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Basic and Translational Research the US Food and Drug Administration (FDA) for the treatment of TAO. Opinions about what should constitute first-line management vary among practitioners in North America and seem to differ from those in Western Europe. Nonspecific immunomodulators such as glucocorticoid steroids are widely used and in some patients can be effective in reducing inflammation and local congestion. They have not proven reliably effective in reducing the principal components of ocular disease severity, such as proptosis and diplopia. Most of the clinical studies assessing the effectiveness of steroids have been inadequately powered or uncontrolled. One of the most informative trials involving systemic steroids compared 3 dosages of methylprednisolone (20). Patients receiving the highest cumulative dosage evaluated (7.47 g) experienced a significant reduction in clinical activity score (CAS) (2.7 points) but a clinically insignificant reduction in proptosis (0.6 mm). Importantly, neither steroids nor any other medical treatments have been shown to alter the ultimate outcome of TAO. That metric might be reflected by a reduction in necessary surgical interventions after abatement of disease activity. Besides steroids, biological agents developed for other diseases have been assessed in preliminary studies of TAO. Among these, rituximab, which acts through CD20 to deplete B cells, has been examined in 2 separate, controlled, prospective studies conducted at single institutions. One compared the drug to methylprednisolone (21) and found rituximab superior in reducing from baseline the clinical activity but neither agent affected proptosis. In the other trial, rituximab failed to improve either CAS or reduce proptosis compared with placebo (22). More recently, tocilizumab, an IL-6 receptor-targeting monoclonal antibody, was found to reduce disease activity in a multicenter, placebo-controlled study of 32 patients whose TAO had previously proven to be resistant to steroids (23). Most patients receiving active drug exhibited improved CAS, but a majority of those in the placebo group also had reduction in disease activity, likely the consequence of the timedependent improvement seen along Rundle's curve (11). Neither treatment group showed sustained, clinically meaningful reduction in proptosis. Another recent trial compared mycophenolate as an add-on therapy with methylprednisolone vs methylprednisolone as a single agent after 12 weeks of treatment (24). There were no significant differences between the 2 treatment groups in the primary response (rate of response at 12 weeks). Several other candidate molecules are in various stages of development, some of which target TSHR. Among them are both monoclonal antibodies (25,26) and small molecules (27-29). In addition, HLDDR3 transgenic mice receiving 2 TSHR immunodominant region peptides exhibited suppressed T-cell and antibody responses (30). A similar conceptual approach to induce immune tolerance was used in a small Phase 1 trial of 12 patients with GD (31). In that study, 10 participants received all 10 doses of intradermal administration of peptides (31). Serum-free T3 levels were lowered in a majority 76 and the treatment strategy seemed to be well-tolerated. Although the concept of restoring immune tolerance to critical pathogenic autoantigens as a potentially effective and durable therapy for autoimmune diseases such as TAO holds great promise, substantial further study will be necessary to prove its clinical benefit and tolerability. PATHOGENIC UNDERPINNINGS OF TISSUE REMODELING IN THYROIDASSOCIATED OPHTHALMOPATHY Tissue expansion, a hallmark feature of TAO, results in altered anatomical architecture and, when adequate, results in proptosis. On close inspection, the characteristic changes in tissues are distinct from most other disease processes occurring within and adjacent to the orbit. Excessive accumulation of hyaluronan (HA) is responsible for at least some of this tissue expansion. HA is an abundant, nonsulfated glycosaminoglycan lacking a core protein (32). Tissues infiltrated with elevated HA levels tend to swell as a consequence of the molecule's remarkable hydrophilicity. The other rheological properties of HA include its remarkable viscosity in solution and an enormous Stokes radius when hydrated (33). HA in the orbit is presumed to be produced largely by residential fibroblasts. These cells can be provoked into HA production in vitro by treatment with a variety of cytokines (34-36). Mast cells have been implicated as regulators of HA production by orbital fibroblasts in TAO (37,38). Besides HA production, orbital fibroblasts can differentiate into adipocytes (39). In particular, a subset of orbital fibroblasts in the TAO orbit, distinguished by their Thy-12 phenotype, that is, their absence of CD90 surface display, can differentiate into mature, lipidaccumulating cells (40,41). The activation of peroxisome proliferator activator receptor-g with agonists in orbital fibroblasts, regardless of whether or not they derive from a healthy or diseased orbit, results in the accumulation of cytoplasmic triglycerides (42). De novo adipogenesis occurring in TAO is suggested by the detection of enhanced levels of adiponectin expression in those tissues (43). Thus, evidence for 2 discrete components of tissue expansion has been generated to plausibly explain the increased volume occupied by orbital soft tissues in TAO, namely glycosaminoglycan accumulation and adipogenesis. Which of these 2 processes predominates may underlie the clinical phenotype of the disease at presentation, potentially determining many aspects of its clinical course and response to treatment. Furthermore, the divergence of TAO into fat vs muscle predominant disease could be underpinned by an idiosyncratic balance between these 2 processes. ORBITAL FIBROBLASTS AS DISEASE EFFECTORS At the core of characteristic tissue remodeling are orbital fibroblasts, which in TAO exhibit unique phenotypic Smith: J Neuro-Ophthalmol 2020; 40: 74-83 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Basic and Translational Research attributes (Fig. 2) (44). Many of their properties set them apart from fibroblasts derived from healthy orbits (45,46) and from those coming from other anatomic regions (47). Understanding these distinctive cellular characteristics was advanced with the discovery of CD34+ fibrocytes as comprising a subset of orbital fibroblasts in TAO that are absent in tissues from healthy orbits (48). These myeloid cells presumably arise from circulating bone marrow progenitors of the monocyte lineage (49). Human fibrocytes traffic through chemokine networks that differ from those found in mice and frequently rely on the CXCR4/CXCL12 pathway (50). It has yet to be established whether this ligand/receptor cognate pair or another is involved in the putative infiltration of fibrocytes in the TAO orbit. Fibrocytes can differentiate into fat cells or myofibroblasts depending on the molecular cues they receive from their microenvironment (51). They express several "thyroid-specific" proteins including thyroglobulin, thyroperoxidase, and TSHR as a consequence of the requisite actions in fibro- cytes of the autoimmune regulator (AIRE) protein, a noncanonical transcription factor (52,53). These cells also express high constitutive levels of MHC II and efficiently present antigens (54). Thus, they seem to possess the capacity for participating in immune responses occurring within the tissues they infiltrate. A subset of fibroblasts cultivated from tissues within the TAO orbit exhibits the CD34+CXCR4+Collagen I+ phenotype, indicating that they derive from fibrocytes (55); however, they express thyroid proteins, MHC II, and AIRE at considerably lower levels than do CD34+ fibrocytes derived from the peripheral circulation (52). This observation led to our suspicions that an unidentified factor produced by CD342 orbital fibroblasts might be repressing the expression of these proteins. Recent studies have demonstrated that the CD342CXCR42 fibroblasts inhabiting the TAO orbit express and release Slit2 (56), an axon-repellent glycoprotein (57). Slit2 had been identified previously as an inhibitor of fibrocyte differentiation that could modulate bleomycin-induced lung fibrosis in FIG. 2. Theoretical model of thyroid-associated ophthalmopathy (TAO) pathogenesis. CD34+ fibrocytes, monocyte-derived progenitor cells coming from the bone marrow, circulate in Graves' disease at higher levels than in healthy control individuals. Surprisingly, fibrocytes express multiple thyroid autoantigens, including the thyrotropin receptor (TSHR), thyroglobulin, thyroperoxidase and sodium-iodide symporter. They constitutively express Class II MHC and present antigens to T cells. They can differentiate into CD34+ fibroblasts, myofibroblasts, and adipocytes, depending on the extracellular signals they encounter within their tissue niche. Many of the genes expressed by fibrocytes are detected at considerably lower levels in CD34+ fibroblasts, the apparent consequence of factors coming from residential CD342 orbital fibroblasts. When activated, CD34+ fibroblasts generate several proinflammatory or anti-inflammatory cytokines, including interleukins 1b, 6, 8, 10, 12, 16, tumor necrosis factor a, and regulated on activation, normal T cell expressed and secreted (RANTES), CXCL-12 and CD40 ligand (CD154). Orbital fibroblasts also display insulin-like growth factor-I receptor (IGF-IR) on their cell surfaces, suggesting that this receptor could be targeted as a therapy for TAO. Orbital fibroblasts express all 3 mammalian hyaluronan synthase isoenzymes and UDP glucose dehydrogenase and synthesize hyaluronan, the predominant glycosaminoglycan associated with expanding orbital tissue volume in TAO. Orbital fat can also expand in this disease. Adapted from (1). Smith: J Neuro-Ophthalmol 2020; 40: 74-83 77 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Basic and Translational Research mice (58). We have demonstrated that Slit2 attenuates the expression of AIRE and in doing so reduces the expression levels of several thyroid proteins in fibrocytes (56). In addition, Slit2 blunts the induction by bTSH of IL-6 in fibrocytes (56). In aggregate, these findings strongly suggest that fibrocytes may represent a central player in the immune pathogenesis of TAO once they inhabit the orbit. Furthermore, Slit2 may govern the immune reactivity of fibrocytes and their CD34+ fibroblast derivatives in the TAO orbit. IMPLICATING INSULIN-LIKE GROWTH FACTOR-I RECEPTOR IN THE PATHOGENESIS OF THYROIDASSOCIATED OPHTHALMOPATHY Much of the traditional thinking concerning the abnormal immune responses presumed to occur in TAO initially focused on thyroglobulin as representing a shared autoantigen with the thyroid gland (59), a concept revisited more recently (60). In principle, the notion that antigens involved in thyroid autoimmunity might prove relevant to TAO continues to seem plausible and attractive. When the molecular cloning of TSHR was finally accomplished (61), initial studies began examining the expression of TSHR in tissues apart from the thyroid gland. The initial report demonstrating TSHR in orbital tissues (62) has led to subsequent studies centering around the role of TSHR in TAO. The concept advocated by many workers in the field concerns how the identical immunoglobulin G (IgGs) underlying hyperthyroidism in GD (63) might also act as the solitary trigger provoking development of TAO. The potential involvement of another autoantigen in the disease has been greeted with resistance ranging from substantial, healthy skepticism (64) to contempt (65). Despite these opposing views, some investigators have ventured beyond the TSHR and considered other plausible molecular autoimmune targets/mechanisms that might be involved in TAO. For instance, binding sites for IGF-I were identified by Weightman et al (66) on the surfaces of orbital fibroblasts. Their studies disclosed an ability of IgGs from patients with GD (GD-IgG) to displace radiolabeled IGF-I from fibroblasts. These results suggested that autoantibodies targeting the IGF-IR might be generated in GD, implicating for the first time the IGF-IR pathway in TAO. We began to actively consider that another autoantigen beside TSHR, such as IGF-IR, could potentially play important roles in the pathogenesis of TAO (67,68). This was based on the realization that TSHR and TSIs might inadequately explain all cases of the disease. The identification of infrequent cases of severe TAO in which TSI could not be detected (69,70) suggested that another autoantigen might also be involved. Our early studies revealed that GD-IgG could initiate cell signaling in orbital fibroblasts from patients with GD but not in those cells from healthy controls (67). A 78 component of GD-IgG-initiated signaling was found to involve the FRAP/mTor/Akt/p70s6k pathway and was rapamycin sensitive. Furthermore, our studies also revealed that purified GD-IgGs could displace IGF-I binding from orbital fibroblast surfaces, replicating the earlier findings of Weightman et al (66) and identifying the relevant binding sites as IGF-IR (68). GD-IgGs could induce gene-encoding chemoattractants such as "regulated on activation, normal T cell expressed and secreted" (RANTES) and IL-16 (67,68,71). The inductions were found to be initiated through the IGF-IR, since a dominant negative mutant IGF-IR markedly attenuated this signaling, as did a monoclonal IGF-IR inhibitory antibody (68). Importantly, physiologically relevant concentrations of rhTSH failed to mimic the actions of GD-IgG or rhIGF-I. The issue of whether autoantibodies directed at IGF-IR are generated at higher levels in GD and TAO has remained controversial. Reports have supported this concept (66,68,72-74) while other studies have failed to detect these antibodies at higher levels in GD than in healthy individuals or found them to be inactive in provoking tyrosine phosphorylation of IGF-IR (75,76). Corroborating the detection of anti-IGF-IR antibodies in GD has been the finding of these antibodies in mice following immunizations with anti-TSHR plasmids and manifesting a phenotype that in some ways resembles that of TAO (8). Potential overlap between the IGF-I and TSH pathways was first recognized by Ingbar and colleagues (77,78) when they demonstrated that IGF-I could enhance the actions of TSH and GD-IgG on thyroid epithelial cells. Subsequent studies from our laboratory group revealed that IGF-IR and TSHR colocalize on orbital fibroblasts and thyroid epithelial cell membranes (79). Furthermore, pull-down studies revealed that the 2 receptor proteins were physically associated. This physical relationship suggested that some functional interactions between IGF-IR and TSHR were possible. Indeed, an inhibitory monoclonal antibody, 1H7, could attenuate the activation of Erk 1/2 not only by IGF-I but also by rhTSH and GD-IgG (79). This finding strongly suggested that interdependence between the 2 receptors was possible. IGF-IR-inhibitory antibodies can block the induction of TSH-driven gene expression, such as cytokines including IL-6 (80), chemoattractants, and chemokines such as IL-16 and RANTES (68), and several other inflammatory mediators. These findings have been corroborated by more recent reports, some from the Gershengorn group who also demonstrated that there is bidirectional cross talk between the receptors mediated through b-arrestin (79,81,82). This protein aggregate can initiate multiple signals that culminate in the activation of downstream genes, including those implicated in TAO. IGF-IR has been found to be overexpressed in GD, not only by orbital fibroblasts (79), but also by B cells (83) and T cells (84). Thus, a substantial body of evidence suggested that IGF-IR and its associated proteins and signaling pathways might be involved in TAO and therefore might represent an exploitable therapeutic target. Smith: J Neuro-Ophthalmol 2020; 40: 74-83 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Basic and Translational Research EVIDENCE FOR TEPROTUMUMAB AS AN EFFECTIVE AND SAFE TREATMENT FOR ACTIVE, MODERATE TO SEVERE THYROIDASSOCIATED OPHTHALMOPATHY Teprotumumab (Tepro) is an IGF-IR inhibitor that acts as a b-arrestin-biased agonist (82). The drug was developed by Roche/Genmab as a potential treatment for several forms of cancer but failed to prove effective in multiple therapeutic trials (85). Thus, this drug became available for repurposing for potential use in TAO. Studies performed in vitro demonstrated that Tepro and several other IGF-IR inhib- itors could alter the expression of inflammatory genes and inhibit key physiological parameters in fibrocytes and orbital fibroblasts (68,86,87). On the basis of those findings, a phase 2 therapeutic trial of Tepro in active, moderate to severe TAO, was designed to study its efficacy and safety (Fig. 3) (9). The study, which enrolled patients from July 2, 2013, until September 23, 2015, was randomized, prospective, placebo-controlled, double-masked, multicentered, and included patients whose ocular manifestations began #9 months from enrollment. Eighty-eight patients were randomly assigned to receive Tepro or placebo, both of which were administered by intravenous infusion at 3 FIG. 3. Screening, randomization, response, and follow-up of patients' participation in clinical trial RV001. A. Patients entered the trial screening process who met the inclusion criteria. They were randomized to either receive placebo or active drug during the 24-week treatment phase. B. Analysis to first response. C. Time course for meeting response criteria. D. Graded responses at Week 24. A high response indicates $3 mm proptosis and clinical activity score $3 point (on a 7-point scale) reductions. Adapted from (9). Smith: J Neuro-Ophthalmol 2020; 40: 74-83 79 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Basic and Translational Research weekly intervals over 24 weeks (8 total infusions). The primary outcome, determined at Week 24, was the aggregate endpoint of reduction in proptosis ($2 mm) and CAS ($ 2 points on a 7-point scale) in the more severely affected (study) eye without similar degrees of worsening in the fellow eye. Secondary endpoints included proptosis and CAS score reductions and improvement in a Graves' ophthalmopathy quality of life questionnaire (GO-QOL), measured as continuous variables. Within the cohort receiving Tepro, 29/42 (69%) exhibited a primary response at Week 24 while 9/45 (20%) patients receiving placebo met the primary outcome (P , 0.001). The effects of Tepro were rapid; 18/42 (43%) responded at Week 6 of treatment in contrast to placebo where 2/45 met the primary outcome (P , 0.001). With regard to the secondary outcomes, Tepro was superior to placebo in improving CAS (P , 0.001), proptosis (P , 0.001), GO-QOL visual functioning subscale (P , 0.001), and subjective diplopia (P , 0.001), as assessed at Week 24 (Fig. 4). The proptosis outcome was met in 71.4% of the group receiving teprotumumab while 20% of the placebo-treated patients achieved this response (P , 0.001) (88). GO-QOL appearance subscale trended toward more improvement than placebo but failed to achieve statistical significance at any time point. Post hoc analysis of the data reveals that significantly more patients receiving Tepro achieved a CAS score of 0 or 1 than did those in the placebo group beginning at Week 6 (P , 0.005) and at every examination thereafter (P , 0.001). With regard to safety, the only drug-related adverse event observed was hyperglycemia in patients with pre-existing diabetes mellitus. Those cases were managed by medication adjustment. In each case, diabetes drug dosage requirements returned to baseline after the completion of the treatment phase. On the basis of the results from that phase 2 trial, the US FDA designated Tepro in TAO as breakthrough therapy. A follow-up, phase 3 trial was launched, with enrollment between October 24, 2017, and August 31, 2018, in which 83 patients underwent randomization into the Tepro and placebo cohorts. Topline results from that study, publicly announced by the sponsor (Horizon Therapeutics) in advance of publication, revealed that 82.9% of patients receiving Tepro vs 9.5% of those receiving placebo achieved the primary response, $2 mm reduction from baseline in FIG. 4. Secondary efficacy end points in clinical trial RV001. A. Time course of changes in proptosis from baseline. B. Time course of change from baseline in clinical activity score. C. Post hoc analysis of the fraction of patients with clinical activity score of 0 or 1 at the time-point indicated along the abscissa. D. Change in quality of life scale (GO-QOL) visual functioning subscale. E. Change in GO-QOL appearance subscale. F. Diplopia responses. Adapted from (9). 80 Smith: J Neuro-Ophthalmol 2020; 40: 74-83 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Basic and Translational Research proptosis after 24 weeks of treatment without a similar worsening of proptosis in the fellow eye (administered as had been specified in the earlier study). The results of this phase 3 trial have been published very recently (89). Horizon announced publicly on 10 July, 2019, that they have submitted a Biologics License Application for Tepro in the treatment of active TAO. CONCLUSION Despite substantial headwinds, patients with active TAO and the health care providers who treat them may soon gain access to a promising therapy for their often debilitating and life-changing disease. Tepro was repurposed from its initially intended indications to TAO based on research conducted almost entirely in vitro. The rationale for its use in this disease arose from those insights and gained from the clarification of normal and pathological physiology of the IGF-IR pathway. Based on plausible mechanisms, Tepro seems to meaningfully alter the course of this vexing condition. It has emerged from 2 multicenter, placebocontrolled, prospective trials with encouraging results and a promising safety profile. Thus, these trials and the science that underpinned them have culminated in a therapy that may shift the management paradigm of a heretofore unsatisfactorily treated disease. 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J Clin Endocrinol Metab. 2015;100:422-431. Stan MN, Garrity JA, Carranza Leon BG, Prabin T, Bradley EA, Bahn RS. Randomized controlled trial of rituximab in patients with Graves' orbitopathy. J Clin Endocrinol Metab. 2015;100:432-441. Perez-Moreiras JV, Gomez-Reino JJ, Maneiro JR, Perez-Pampin E, Romo Lopez A, Rodriguez Alvarez FM, Castillo Laguarta JM, Del Estad Cabello A, Gessa Sorroche M, Espana Gregori E, Sales-Sanz M. Efficacy of tocilizumab in patients with moderate-to-severe corticosteroid-resistant Graves orbitopathy: a randomized clinical trial. Am J Ophthalmol. 2018;195:181-190. Kahaly GJ, Riedl M, Konig J, Pitz S, Ponto K, Diana T, Kampmann E, Kolbe E, Eckstein A, Moeller LC, Fuhrer D, Salvi M, Curro N, Campi I, Covelli D, Leo M, Marino M, Menconi F, Marcocci C, Bartalena L, Perros P, Wiersinga WM; European 81 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. 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A new small-molecule antagonist inhibits Graves' disease antibody activation of the TSH receptor. J Clin Endocrinol Metab. 2011;96:548-554. Neumann S, Nir EA, Eliseeva E, Huang W, Marugan J, Xiao J, Dulcey AE, Gershengorn MC. A selective TSH receptor antagonist inhibits stimulation of thyroid function in female mice. Endocrinology. 2014;155:310-314. Latif R, Realubit RB, Karan C, Mezei M, Davies TF. TSH receptor signaling abrogation by a novel small molecule. Front Endocrinol (Lausanne). 2016;7:130. Jansson L, Vrolix K, Jahraus A, Martin KF, Wraith DC. Immunotherapy with apitopes blocks the immune response to TSH receptor in HLA-DR transgenic mice. Endocrinology. 2018;159:3446-3457. Pearce SHS, Dayan C, Wraith DC, Barrell K, Olive N, Jansson L, Walker-Smith T, Carnegie C, Martin KF, Boelaert K, Gilbert J, Higham CE, Muller I, Murray RD, Perros P, Razvi S, Vaidya B, Wernig F, Kahaly GJ. 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Insights into potential pathogenic mechanisms of thyroid-associated ophthalmopathy. J Biol Chem. 1998;273:29615-29625. Smith TJ, Parikh SJ. HMC-1 mast cells activate human orbital fibroblasts in coculture: evidence for up-regulation of prostaglandin E2 and hyaluronan synthesis. Endocrinology. 1999;140:3518-3525. Guo N, Baglole CJ, O'Loughlin CW, Feldon SE, Phipps RP. Mast cell-derived prostaglandin D2 controls hyaluronan synthesis in human orbital fibroblasts via DP1 activation: implications for thyroid eye disease. J Biol Chem. 2010;285:15794-15804. Sorisky A, Pardasani D, Gagnon A, Smith TJ. Evidence of adipocyte differentiation in human orbital fibroblasts in primary culture. J Clin Endocrinol Metab. 1996;81:3428-3431. Koumas L, Smith TJ, Phipps RP. Fibroblast subsets in the human orbit: Thy-1+ and Thy-12 subpopulations exhibit distinct phenotypes. Eur J Immunol. 2002;32:477-485. Koumas L, Smith TJ, Feldon S, Blumberg N, Phipps RP. Thy-1 expression in human fibroblast subsets defines myofibroblastic or lipofibroblastic phenotypes. Am J Pathol. 2003;163:1291-1300. 42. Smith TJ, Koumas L, Gagnon A, Bell A, Sempowski GD, Phipps RP, Sorisky A. Orbital fibroblast heterogeneity may determine the clinical presentation of thyroid-associated ophthalmopathy. J Clin Endocrinol Metab. 2002;87:385-392. 43. Kumar S, Coenen MJ, Scherer PE, Bahn RS. Evidence for enhanced adipogenesis in the orbits of patients with Graves' ophthalmopathy. J Clin Endocrinol Metab. 2004;89:930-935. 44. Smith TJ. Unique properties of orbital connective tissue underlie its involvement in Graves' disease. Minerva Endocrinol. 2003;28:213-222. 45. Smith TJ, Wang HS, Hogg MG, Henrikson RC, Keese CR, Giaever I. Prostaglandin E2 elicits a morphological change in cultured orbital fibroblasts from patients with Graves ophthalmopathy. Proc Natl Acad Sci USA. 1994;91:5094- 5098. 46. Smith TJ. Fibroblast biology in thyroid diseases. Curr Opin Endocrinol Diabetes Obes. 2002;9:393-400. 47. Smith TJ, Bahn RS, Gorman CA. Hormonal regulation of hyaluronate synthesis in cultured human fibroblasts: evidence for differences between retroocular and dermal fibroblasts. J Clin Endocrinol Metab. 1989;69:1019-1023. 48. Douglas RS, Afifiyan NF, Hwang CJ, Chong K, Haider U, Richards P, Gianoukakis AG, Smith TJ. Increased generation of fibrocytes in thyroid-associated ophthalmopathy. J Clin Endocrinol Metab. 2010;95:430-438. 49. Bucala R, Spiegel LA, Chesney J, Hogan M, Cerami A. Circulating fibrocytes define a new leukocyte subpopulation that mediates tissue repair. Mol Med. 1994;1:71-81. 50. Phillips RJ, Burdick MD, Hong K, Lutz MA, Murray LA, Xue YY, Belperio JA, Keane MP, Strieter RM. Circulating fibrocytes traffic to the lungs in response to CXCL12 and mediate fibrosis. J Clin Invest. 2004;114:438-446. 51. Hong KM, Belperio JA, Keane MP, Burdick MD, Strieter RM. Differentiation of human circulating fibrocytes as mediated by transforming growth factor-beta and peroxisome proliferatoractivated receptor gamma. J Biol Chem. 2007;282:22910- 22920. 52. Fernando R, Atkins S, Raychaudhuri N, Lu Y, Li B, Douglas RS, Smith TJ. Human fibrocytes coexpress thyroglobulin and thyrotropin receptor. Proc Natl Acad Sci USA. 2012;109:7427- 7432. 53. Fernando R, Lu Y, Atkins SJ, Mester T, Branham K, Smith TJ. Expression of thyrotropin receptor, thyroglobulin, sodium-iodide symporter, and thyroperoxidase by fibrocytes depends on AIRE. J Clin Endocrinol Metab. 2014;99:E1236-E1244. 54. Chesney J, Bacher M, Bender A, Bucala R. The peripheral blood fibrocyte is a potent antigen-presenting cell capable of priming naive T cells in situ. Proc Natl Acad Sci USA. 1997;94:6307-6312. 55. Pilling D, Fan T, Huang D, Kaul B, Gomer RH. Identification of markers that distinguish monocyte-derived fibrocytes from monocytes, macrophages, and fibroblasts. PLoS One. 2009;4:e7475. 56. Fernando R, Grisolia ABD, Lu Y, Atkins S, Smith TJ. Slit2 modulates the inflammatory phenotype of orbit-infiltrating fibrocytes in Graves' disease. J Immunol. 2018;200:3942- 3949. 57. Nguyen Ba-Charvet KT, Brose K, Marillat V, Kidd T, Goodman CS, Tessier-Lavigne M, Sotelo C, Chedotal A. Slit2-Mediated chemorepulsion and collapse of developing forebrain axons. Neuron. 1999;22:463-473. 58. Pilling D, Zheng Z, Vakil V, Gomer RH. Fibroblasts secrete Slit2 to inhibit fibrocyte differentiation and fibrosis. Proc Natl Acad Sci USA. 2014;111:18291-18296. 59. Konishi J, Herman MM, Kriss JP. Binding of thyroglobulin and thyroglobulin-antithyroglobulin immune complex to extraocular muscle membrane. Endocrinology. 1974;95:434-446. 60. Marinò M, Chiovato L, Lisi S, Altea MA, Marcocci C, Pinchera A. Role of thyroglobulin in the pathogenesis of Graves' ophthalmopathy: the hypothesis of Kriss revisited. J Endocrinol Invest. 2004;27:230-236. Smith: J Neuro-Ophthalmol 2020; 40: 74-83 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Basic and Translational Research 61. Parmentier M, Libert F, Maenhaut C, Lefort A, Gérard C, Perret J, Van Sande J, Dumont JE, Vassart G. Molecular cloning of the thyrotropin receptor. Science. 1989;246:1620-1622. 62. Feliciello A, Porcellini A, Ciullo I, Bonavolonta G, Avvedimento EV, Fenzi G. Expression of thyrotropin-receptor mRNA in healthy and Graves' disease retro-orbital tissue. Lancet. 1993;342:337-338. 63. Michalek K, Morshed SA, Latif R, Davies TF. TSH receptor autoantibodies. Autoimmun Rev. 2009;9:113-116. 64. Wiersinga WM. Autoimmunity in Graves' ophthalmopathy: the result of an unfortunate marriage between TSH receptors and IGF-1 receptors? J Clin Endocrinol Metab. 2011;96:2386-2394. 65. Rapoport B, McLachlan SM. Reflections on thyroid autoimmunity: a personal overview from the past into the future. Horm Metab Res. 2018;50:840-852. 66. Weightman DR, Perros P, Sherif IH, Kendall-Taylor P. Autoantibodies to IGF-1 binding sites in thyroid associated ophthalmopathy. Autoimmunity. 1993;16:251-257. 67. Pritchard J, Horst N, Cruikshank W, Smith TJ. Igs from patients with Graves' disease induce the expression of T cell chemoattractants in their fibroblasts. J Immunol. 2002;168:942-950. 68. Pritchard J, Han R, Horst N, Cruikshank WW, Smith TJ. Immunoglobulin activation of T cell chemoattractant expression in fibroblasts from patients with Graves' disease is mediated through the insulin-like growth factor I receptor pathway. J Immunol. 2003;170:6348-6354. 69. Wall JR, Lahooti H, El Kochairi I, Lytton SD, Champion B. Thyroid-stimulating immunoglobulins as measured in a reporter bioassay are not detected in patients with Hashimoto's thyroiditis and ophthalmopathy or isolated upper eyelid retraction. Clin Ophthalmol. 2014;8:2071-2076. 70. Tabasum A, Khan I, Taylor P, Das G, Okosieme OE. Thyroid antibody-negative euthyroid Graves' ophthalmopathy. Endocrinol Diabetes Metab Case Rep. 2016;2016:160008. 71. Sciaky D, Brazer W, Center DM, Cruikshank WW, Smith TJ. Cultured human fibroblasts express constitutive IL-16 mRNA: cytokine induction of active IL-16 protein synthesis through a caspase-3-dependent mechanism. J Immunol. 2000;164:3806-3814. 72. Smith TJ, Hoa N. Immunoglobulins from patients with Graves' disease induce hyaluronan synthesis in their orbital fibroblasts through the self-antigen, insulin-like growth factor-I receptor. J Clin Endocrinol Metab. 2004;89:5076-5080. 73. Varewijck AJ, Boelen A, Lamberts SW, Fliers E, Hofland LJ, Wiersinga WM, Janssen JA. Circulating IgGs may modulate IGFI receptor stimulating activity in a subset of patients with Graves' ophthalmopathy. J Clin Endocrinol Metab. 2013;98:769-776. 74. Marino M, Rotondo Dottore G, Ionni I, Lanzolla G, Sabini E, Ricci D, Sframeli A, Mazzi B, Menconi F, Latrofa F, Vitti P, Marcocci C, Chiovato L. Serum antibodies against the insulinlike growth factor-1 receptor (IGF-1R) in Graves' disease and Graves' orbitopathy. J Endocrinol Invest. 2018;42:471-480. 75. Minich WB, Dehina N, Welsink T, Schwiebert C, Morgenthaler NG, Köhrle J, Eckstein A, Schomburg L. Autoantibodies to the IGF1 receptor in Graves' orbitopathy. J Clin Endocrinol Metab. 2013;98:752-760. 76. Marcus-Samuels B, Krieger CC, Boutin A, Kahaly GJ, Neumann S, Gershengorn MC. Evidence that Graves' ophthalmopathy Smith: J Neuro-Ophthalmol 2020; 40: 74-83 77. 78. 79. 80. 81. 82. 83. 84. 85. 86. 87. 88. 89. immunoglobulins do not directly activate IGF-1 receptors. Thyroid. 2018;28:650-655. Tramontano D, Cushing GW, Moses AC, Ingbar SH. Insulin-like growth factor-I stimulates the growth of rat thyroid cells in culture and synergizes the stimulation of DNA synthesis induced by TSH and Graves'-IgG. Endocrinology. 1986;119:940-942. Tramontano D, Moses AC, Veneziani BM, Ingbar SH. Adenosine 3',5'-monophosphate mediates both the mitogenic effect of thyrotropin and its ability to amplify the response to insulin-like growth factor I in FRTL5 cells. Endocrinology. 1988;122:127-132. Tsui S, Naik V, Hoa N, Hwang CJ, Afifiyan NF, Sinha Hikim A, Gianoukakis AG, Douglas RS, Smith TJ. Evidence for an association between thyroid-stimulating hormone and insulinlike growth factor 1 receptors: a tale of two antigens implicated in Graves' disease. J Immunol. 2008;181:4397-4405. Raychaudhuri N, Fernando R, Smith TJ. Thyrotropin regulates IL-6 expression in CD34+ fibrocytes: clear delineation of its cAMP-independent actions. PLoS One. 2013;8:e75100. Krieger CC, Boutin A, Jang D, Morgan SJ, Banga JP, Kahaly GJ, Klubo-Gwiezdzinska J, Neumann S, Gershengorn MC. Arrestinbeta-1 physically scaffolds TSH and IGF1 receptors to enable crosstalk. Endocrinology. 2019;160:1468-1479. Smith TJ, Janssen JAMJL. Insulin-like growth factor-I receptor and thyroid-associated ophthalmopathy. Endocr Rev. 2019;40:236-267. Douglas RS, Naik V, Hwang CJ, Afifiyan NF, Gianoukakis AG, Sand D, Kamat S, Smith TJ. B cells from patients with Graves' disease aberrantly express the IGF-1 receptor: implications for disease pathogenesis. J Immunol. 2008;181:5768-5774. Douglas RS, Gianoukakis AG, Kamat S, Smith TJ. Aberrant expression of the insulin-like growth factor-1 receptor by T cells from patients with Graves' disease may carry functional consequences for disease pathogenesis. J Immunol. 2007;178:3281-3287. Qu X, Wu Z, Dong W, Zhang T, Wang L, Pang Z, Ma W, Du J. Update of IGF-1 receptor inhibitor (ganitumab, dalotuzumab, cixutumumab, teprotumumab and figitumumab) effects on cancer therapy. Oncotarget. 2017;8:29501-29518. Chen H, Mester T, Raychaudhuri N, Kauh CY, Gupta S, Smith TJ, Douglas RS. Teprotumumab, an IGF-1R blocking monoclonal antibody inhibits TSH and IGF-1 action in fibrocytes. J Clin Endocrinol Metab. 2014;99:E1635-E1640. Smith TJ. Rationale for therapeutic targeting insulin-like growth factor-1 receptor and bone marrow-derived fibrocytes in thyroidassociated ophthalmopathy. Expert Rev Ophthalmol. 2016;11:77-79. Douglas RS. Teprotumumab, an insulin-like growth factor-1 receptor antagonist antibody, in the treatment of active thyroid eye disease: a focus on proptosis. Eye (Lond). 2019;33:183- 190. Douglas RS, Kahaly GJ, Patel A, Sile S, Thompson E, Perdok R, Fleming JC, Fowler BT, Marcocci C, Marinò M, Antonelli A, Dailey R, Harris GJ, Eckstein A, Schiffman J, Tang R, Nelson C, Salvi M, Wester S, Sherman JW, Vescio T, Holt RJ, Smith TJ. Teprotumumab for the treatment of active thyroid eye disease. N Engl J Med. 2020;382:341-352. 83 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. |
Date | 2020-03 |
Language | eng |
Format | application/pdf |
Type | Text |
Publication Type | Journal Article |
Source | Journal of Neuro-Ophthalmology, March 2020, Volume 40, Issue 1 |
Collection | Neuro-Ophthalmology Virtual Education Library: Journal of Neuro-Ophthalmology Archives: https://novel.utah.edu/jno/ |
Publisher | Lippincott, Williams & Wilkins |
Holding Institution | Spencer S. Eccles Health Sciences Library, University of Utah |
Rights Management | © North American Neuro-Ophthalmology Society |
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Reference URL | https://collections.lib.utah.edu/ark:/87278/s68m30jh |