Selective Glucocorticoid Receptor Modulators (SEGRAMs): Can They Improve the Therapeutic Index of Steroid Therapy?

Abstract

Glucocorticoids remain indispensable anti-inflammatory drugs across a wide range of inflammatory and immune-mediated diseases, but their long-term use is limited by cumulative toxicity. Attempts to develop safer steroids gave rise to selective glucocorticoid receptor agonists and modulators (SEGRAMs), initially based on the premise that anti-inflammatory efficacy might be preserved while signaling linked to adverse effects was reduced. Current glucocorticoid receptor biology no longer supports such a simple binary model. Glucocorticoid receptor output is shaped by ligand-induced conformation, DNA sequence, chromatin accessibility, cofactor recruitment, and cell-specific transcriptional context, making selective modulation a context-dependent pharmacologic phenomenon rather than a fixed molecular property. In this clinically oriented narrative review, we reassess the SEGRAMs concept from receptor biology to translational and early clinical evidence, with explicit distinction between mechanistic dissociation, translational separation of efficacy from selected toxicities, and clinically meaningful improvement in the therapeutic index. Representative compounds have shown that selective glucocorticoid receptor modulation is pharmacologically feasible and, in some settings, may separate anti-inflammatory activity from selected steroid-related liabilities. However, the available evidence also indicates that any potential advantage is disease-specific, toxicity-specific, and exposure-dependent, and that mechanistic dissociation does not by itself justify therapeutic claims, particularly in the absence of long-term comparative outcome data. The most credible future for SEGRAMs lies not in universal replacement of conventional glucocorticoids, but in their potential to improve the therapeutic index in diseases for which prolonged or repeated glucocorticoid exposure remains necessary, but in which cumulative harm from toxicity is a major treatment burden.

Introduction

Few drug classes remain as clinically indispensable – and as toxicity-limited – as glucocorticoids 1,2]. Their efficacy spans rheumatology, pulmonology, gastroenterology, nephrology, dermatology, hematology, and critical care, often with a speed and breadth of response that targeted therapies do not match [3]. Their central limitation has never been inadequate potency. Instead, it has been the inability to preserve anti-inflammatory benefit without accumulating hyperglycemia, skeletal loss, myopathy, skin fragility, weight gain, cardiovascular risk, infection, neuropsychiatric toxicity, and adrenal suppression with continued exposure [1,4,5].

This therapeutic tension gave rise to one of the central hypotheses in modern steroid pharmacology: that glucocorticoid receptor signaling might be steered rather than globally activated, allowing anti-inflammatory efficacy to be retained while toxic transcriptional programs were attenuated [6,7]. This idea generated early terms for drugs based on dissociated ligands, including selective glucocorticoid receptor agonists (SEGRAs) and selective glucocorticoid receptor modulators (SEGRMs), and later the broader term selective glucocorticoid receptor agonists and modulators (SEGRAMs) [8,9].

Two decades of mechanistic, translational, and early clinical work now allow a more exacting assessment of that idea [3,8]. The original framework was useful, but it collapsed several very different forms of success into a single label [7]. A ligand may look dissociated in a reporter assay, with reduced adverse effects in translational studies, but still fail to alter prescribing because the relevant toxicities were never meaningfully reduced [10]. Throughout this narrative review, we distinguish receptor-level dissociation from clinically meaningful therapeutic-index gain, because it has been problematic that these levels of evidence have sometimes been treated as interchangeable [6,9,11,12].

The question addressed here is therefore clinical rather than purely medicinal-chemical: can altered glucocorticoid receptor pharmacology preserve the speed and reliability of glucocorticoids while reducing the toxicities that limit prolonged use [3,8]?

Although disease-specific evidence has emerged most clearly outside mainstream adult internal medicine, the clinically most consequential question is whether selective glucocorticoid receptor modulation can reduce cumulative steroid harm in the chronic inflammatory disorders most often managed by internists, including vasculitis, inflammatory bowel disease, severe asthma, autoimmune cytopenias, and steroid-responsive nephritides [13–16].

Material and Methods

This article was undertaken as a clinically oriented narrative review addressing a practical therapeutic question: whether SEGRAMs can improve the therapeutic index of glucocorticoid therapy in settings in which steroid efficacy remains indispensable but cumulative toxicity has limited their long-term use. The review framework was predefined around 3 analytically distinct levels of evidence: mechanistic dissociation at the glucocorticoid receptor level, translational separation of anti-inflammatory efficacy from selected toxicity domains, and clinically meaningful therapeutic index gain.

Methodological Positioning of the Review

This article was designed as a structured narrative review rather than a systematic review or meta-analysis. The structured search strategy, predefined evidence domains, duplicate handling, and screening process were used to improve transparency, reduce selective omission, and define the evidentiary scope of the review. These procedures were not intended to support quantitative effect estimation, formal certainty grading, or Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-style systematic synthesis.

Because the included evidence spans receptor biology, disease-relevant preclinical models, early human pharmacology studies, randomized clinical trials, regulatory sources, and clinically oriented reviews, a single formal risk-of-bias instrument would not have provided a consistent assessment across all evidence types. Accordingly, the synthesis was interpretive and clinically oriented. Conclusions were based on mechanistic coherence, developmental maturity, comparator relevance, and clinical interpretability rather than pooled estimates or formally graded certainty of evidence.

Search Strategy and Information Sources

A structured literature search was performed in PubMed/Medical Literature Analysis and Retrieval System Online (MEDLINE), Embase, Web of Science Core Collection, and Scopus from database inception to the final search update on April 5, 2026. Searches were limited to English-language records. No study-design, species, or publication-type filters were applied at the search stage, in order to avoid excluding mechanistic, translational, or early clinical evidence relevant to the field.

The search strategy was built around the core domains most likely to define the SEGRAM literature: glucocorticoid receptor biology, selective receptor modulation, named development programs, mechanistic features of receptor output, and clinically relevant efficacy and toxicity domains. Accordingly, searches combined terms related to the glucocorticoid receptor itself (including glucocorticoid receptor and NR3C1), selective modulation terminology (including SEGRAM, SEGRA, SGRM, selective glucocorticoid receptor modulator, selective glucocorticoid receptor agonist, dissociated glucocorticoid receptor agonist, and nonsteroidal glucocorticoid receptor modulator), representative compounds and drugs (including mapracorat, fosdagrocorat, mizacorat/AZD9567, vamorolone, GRM-01, Compound A, AL-438, and Org 214007–0), mechanistic terms relevant to receptor behavior (including transrepression, transactivation, receptor conformation, chromatin, cofactor recruitment, tethering, dimerization, DNA binding, and gene regulation), and clinically relevant efficacy or toxicity domains (including therapeutic index, anti-inflammatory efficacy, dysglycemia, bone loss, growth suppression, ocular hypertension, myopathy, adrenal effects, and hypothalamic-pituitary-adrenal axis suppression). Database-specific syntax was adapted to each source, but the underlying logic was consistent across platforms: to capture both explicitly labeled SEGRAM literature and clinically relevant studies of compounds not uniformly indexed under that terminology.

To minimize omission of clinically important reports, electronic searching was supplemented by manual review of reference lists from key reviews, translational studies, and pivotal clinical reports, together with forward citation tracking for major publications and development programs.

Selection of Evidence and Scope of the Review

Eligible sources were English-language full-text reports providing mechanistic, translational, clinical, or regulatory evidence directly relevant to selective glucocorticoid receptor modulation. Eligible study designs included randomized clinical trials, non-randomized human studies, early-phase human pharmacology or translational studies, systematic reviews, meta-analyses, regulatory documents, and disease-relevant preclinical studies when these materially informed current glucocorticoid receptor biology or the developmental trajectory of a specific program.

Eligible populations and study contexts included inflammatory and immune-mediated disease settings, healthy-volunteer studies with clinically interpretable pharmacodynamic or safety readouts, and disease-relevant experimental models. Eligible interventions included candidate steroidal and nonsteroidal selective glucocorticoid receptor modulators, as well as conventional glucocorticoids used as mechanistic or clinical comparators. Outcomes of interest were defined a priori at 3 levels: receptor-proximal mechanistic outcomes, translational efficacy-to-toxicity readouts, and clinically interpretable efficacy and safety outcomes relevant to real-world glucocorticoid use. Particular weight was given to toxicity domains that influence prescribing and long-term treatment burden, especially skeletal, metabolic, muscle, ocular, growth-related, and hypothalamic-pituitary-adrenal axis effects.

Conference abstracts without full reports, duplicate publications, superseded interim analyses, narrative pieces without primary data, and isolated reporter-assay studies without disease or translational relevance were excluded from primary interpretive use. Two authors independently screened titles, abstracts, and full texts against the predefined scope of the review, with disagreements resolved by consensus.

Handling of Duplicate and Superseded Reports

When multiple publications described the same development program, overlapping cohort, sequential dataset, or interim and later analyses of the same study, they were assessed together at the program level rather than treated as independent sources of evidence. Duplicate records were removed during screening. For narrative synthesis, priority was given to the most complete, methodologically informative, and clinically interpretable report. Earlier or superseded publications were retained only when they contributed unique mechanistic or developmental information not preserved in the principal source. This approach was used to avoid double-counting while preserving the developmental logic of the field.

Screening Yield and Selection of Representative Programs

After removal of duplicates, 362 records underwent title and abstract screening, 81 full-text articles were assessed for eligibility, and 48 sources were included in the final narrative synthesis. Because the purpose of the review was interpretive rather than encyclopedic, not all included sources were given equal narrative weight. The screening yield is reported to characterize the scope of the evidence base and improve transparency, but it should not be interpreted as a PRISMA-based systematic review flow.

Programs selected for detailed discussion and for inclusion in Tables 1 and 2 were identified a priori as representative on the basis of 4 considerations: developmental maturity, relevance to the therapeutic index question, availability of clinically interpretable comparator data, and evidence sufficient to inform both anti-inflammatory efficacy and at least 1 clinically meaningful toxicity domain. Where several compounds addressed a similar mechanistic concept but differed in maturity or clinical interpretability, preference was given to the program with the clearest translational trajectory and the strongest evidence base for clinically relevant inference.

Table 1.

Representative SEGRAMs programs: translational and clinical signals relevant to therapeutic index gain.

Compound	Setting / phase	Comparator	Main efficacy signal	Main safety signal	Why it mattered / why it stalled
Mapracorat	Early proof-of-concept; ocular and preclinical inflammatory settings	Conventional glucocorticoid benchmarks	Disease-relevant anti-inflammatory activity	Reduced pressure-related liability in selected settings	Established early translational plausibility, but did not secure a convincing systemic clinical role
Fosdagrocorat	Early systemic human development	Prednisolone	Partial preservation of anti-inflammatory efficacy in a clinical (human) setting	Partial reduction of selected steroid adverse effects	Clearest early systemic proof-of-principle, but the clinical margin appeared too narrow for practice-changing impact
Mizacorat (AZD9567)	More mature translational and early clinical development	Prednisolone	Anti-inflammatory activity assessed in a more clinically interpretable, comparative framework	Intended reduction of selected systemic adverse effects relevant to chronic use	Methodologically more credible than earlier programs, but still needs clear therapeutic index differentiation
Vamorolone	Disease-specific clinical validation in chronic exposure, toxicity-sensitive care	Standard glucocorticoid therapy	Clinically meaningful benefit in a defined long-term treatment setting	Improvement in selected growth-, bone-, behavioral-, and metabolic-relevant toxicity domains	Strongest evidence that disease-specific therapeutic index gain is achievable, but not yet class-wide proof for adult internal medicine
GRM-01	Early nonsteroidal development	No clinical treatment comparison	Supports continued exploration of selective glucocorticoid receptor modulation	Too early for clinically interpretable safety conclusions	Scientifically important and hypothesis-generating, but not yet practice-informing

SEGRAMs, selective glucocorticoid receptor agonists and modulators.

Table 2.

Internal medicine settings in which a clinically meaningful safer glucocorticoid would have the greatest practical value.

Disease area	Why glucocorticoids remain indispensable	What toxicity most limits use	What a successful SEGRAM would need to improve
Vasculitis / GCA / PMR	Rapid and reliable control of vascular and systemic inflammation, especially at diagnosis and during relapse	Cumulative toxicity during long tapers: dysglycemia, osteoporosis, myopathy, weight gain, infection, adrenal suppression	Preserve induction efficacy while making prolonged tapering safer and reducing toxicity-driven taper failure
Inflammatory bowel disease	Rapid control of moderate-to-severe flares when immediate suppression is needed	Steroid dependence, repeated rescue exposure, metabolic and bone toxicity, infection, adrenal suppression	Retain flare control while lowering repeated-course burden and making bridging therapy safer
Severe asthma / eosinophilic disease	High-value rescue therapy in exacerbations; still important in recurrent or chronic systemic exposure	Repeated systemic exposure causing dysglycemia, weight gain, myopathy, bone loss, mood disturbance, adrenal suppression	Preserve rapid rescue benefit while reducing toxicity across recurrent bursts and maintenance use
Autoimmune cytopenias	Fast and predictable early control when urgent suppression of immune-mediated cell destruction is required	Toxicity with prolonged, repeated, or slow-taper treatment: metabolic effects, infection, myopathy, neuropsychiatric burden	Preserve early control while widening the safe tapering window and reducing repeated-course toxicity
Steroid-responsive nephritides	Rapid suppression of renal inflammation is often needed to prevent organ damage	Prolonged exposure causing dysglycemia, infection, muscle wasting, bone loss, fluid burden, adrenal suppression	Preserve efficacy in organ-threatening disease while reducing toxicity that limits duration and maintenance

Note: The greatest clinical value of a safer glucocorticoid is likely to emerge in diseases in which prolonged or repeated exposure makes toxicity a major determinant of treatment. SEGRAM, selective glucocorticoid receptor agonist and modulator; GCA, giant cell arteritis; PMR, polymyalgia rheumatica.

Data Synthesis

Evidence was synthesized narratively with explicit separation of mechanistic, translational, and clinical levels of inference. Greater interpretive weight was assigned to human studies, disease-relevant translational evidence, and toxicity domains likely to influence prescribing, tapering, treatment continuation, or cumulative treatment burden in routine practice. Mechanistic dissociation observed in simplified assay systems was not treated as sufficient evidence of therapeutic benefit unless supported by data indicating preserved anti-inflammatory efficacy together with attenuation of clinically meaningful toxicity signals. Because this was a structured narrative review rather than a formal systematic review or meta-analysis, no formal risk-of-bias tool, certainty-of-evidence grading, or quantitative pooling was applied. This methodological choice reflects the heterogeneity of the evidence base and the interpretive aim of the review. Conclusions were therefore based on the maturity, internal coherence, comparator relevance, and clinical interpretability of the available evidence.

Glucocorticoid Receptor Biology Relevant to SEGRAMs Design

A contemporary discussion of SEGRAMs should move beyond the view that glucocorticoid receptor signaling can be cleanly divided into 1 beneficial arm and 1 harmful arm. The receptor is structurally and functionally versatile [17,18]. In its inactive state, the glucocorticoid receptor resides in the cytoplasm within a chaperone complex [19]. Ligand binding induces conformational change, chaperone release, nuclear translocation, altered interaction with cofactors, and DNA engagement [20]. The downstream response is not a single transcriptional event. It is a family of transcriptional outcomes whose direction and magnitude depend on the ligand, cell type, chromatin landscape, accessible DNA sequence, and surrounding signaling environment [17,21].

This matters because the historical promise of dissociated glucocorticoid pharmacology rested on a simplified framework. Anti-inflammatory efficacy was linked predominantly to monomeric glucocorticoid receptor tethering and transrepression, whereas adverse effects were linked predominantly to glucocorticoid response element (GRE)-driven transactivation [6,9]. That model helped launch the field, but it does not capture the biology with enough fidelity for modern drug design [22,23]. Repression and activation are deeply entangled in physiological tissue responses.

Several of the genes induced by glucocorticoids contribute directly to anti-inflammatory efficacy [22,23]. Conversely, some adverse effects emerge not from isolated transactivation but from integrated changes in metabolism, muscle turnover, bone remodeling, salt handling, neuroendocrine regulation, and immune surveillance over time [3,24]. The same transcriptional event may be adaptive in one tissue, dispensable in another, and harmful under conditions of dose accumulation or chronic exposure [21]. Equating transactivation with toxicity is therefore no longer biologically defensible [6].

The receptor is also not adequately described by a simple monomer-benefit/dimer-toxicity framework [6]. The glucocorticoid receptor can bind canonical GREs, half-sites, composite elements, and negative response elements [25]. Glucocorticoid receptor activity is further shaped by interactions with pioneer factors, lineage-determining transcription factors, and chromatin remodelers, all of which vary across cell types [17,21]. Ligands can also alter receptor conformation, thereby influencing coactivator recruitment, residence time on DNA, and the balance between direct DNA binding and protein-protein interactions [8,18]. Selective modulation is therefore best understood as an allosteric and context-dependent phenomenon rather than a binary receptor state [9,16].

For drug development, the implication is clear. A useful SEGRAM cannot be defined solely by reduced GRE reporter activity or by a favorable ratio in a simplified in vitro assay [26,27]. It must instead produce a pattern of gene regulation that is advantageous in the tissue and disease context for which it is intended [15,28]. This represents a more demanding but more biologically realistic design goal. It reframes selective modulation as an empirically testable pharmacologic problem rather than a purely conceptual claim.

Molecular Basis of Selective Glucocorticoid Receptor Modulation

At the molecular level, selective glucocorticoid receptor modulation does not arise from a clean switch between transrepression and transactivation. It arises from differential stabilization of receptor conformations. These conformations can alter DNA occupancy, dimerization behavior, cofactor recruitment, and transcriptional crosstalk [18,21]. This receptor-level bias is then filtered through the cellular environment. Once activated, the glucocorticoid receptor operates within a regulatory landscape defined by GRE sequence variation, chromatin accessibility, epigenetic architecture, and the local availability of coactivators, corepressors, and remodeling complexes [17,21]. Glucocorticoid receptor signaling is also modified by tethering and composite interactions with inflammatory transcription factors such as NF-κB and AP-1, as well as by intersection with kinase-dependent pathways, including MAPK signaling [19,22,29,30]. These mechanisms help explain why the same ligand may produce different balances of anti-inflammatory benefit and metabolic cost across tissues and disease states. Receptor bias should therefore not be viewed as an intrinsic molecular label assigned in simplified assay systems [9,27]. It is a context-dependent pharmacologic phenotype whose clinical relevance depends on whether altered receptor output is preserved across tissues, disease states, and patterns of exposure [8,15]. For that reason, the translational relevance of a SEGRAM depends not on dissociation in abstract assay systems, but on whether a reproducible transcriptional bias translates into a measurable widening of the therapeutic window under clinically relevant conditions [8,28].

Why Conventional Glucocorticoids Remain Difficult to Improve Upon

Conventional glucocorticoids are difficult to improve upon because they remain highly effective across many inflammatory and immune-mediated conditions. In severe asthma, giant cell arteritis, vasculitis, inflammatory bowel disease, organizing pneumonia, autoimmune cytopenias, and steroid-responsive nephritides, they suppress inflammation with a speed and reliability that still define the standard against which alternatives are judged [3,16]. This has important consequences for what counts as success in the SEGRAMs field. The relevant comparator is seldom placebo. It is almost always a familiar steroid regimen that clinicians already know how to initiate, taper, intensify, and rescue with. A candidate that produces favorable mechanistic signals but does not compare adequately with this practical benchmark is unlikely to alter clinical decision-making.

The challenge is compounded by the fact that steroid toxicity is not a single endpoint. Some liabilities become clinically relevant within days, including dysglycemia, mood change, fluid retention, and electrolyte effects [1,31]. However, others emerge over months or years, including osteoporosis, growth suppression, muscle wasting, weight gain, cataract formation, and adrenal suppression [1,2,31,32]. The time course, reversibility, and clinical importance of these toxicities differ across disease and age groups [3]. Accordingly, the term “safer” is clinically meaningful only when the toxicity domain, disease context, and exposure pattern are specified [11,12]. The therapeutic window of a SEGRAM therefore cannot be treated as a universal property. It is disease-specific, exposure-specific, and often age-specific [8,15].

The real question is never whether a ligand is safer in the abstract, but whether it meaningfully improves the balance between efficacy and toxicity in a setting where conventional glucocorticoids are useful but limiting. This is the clinically relevant threshold. Evidence below this threshold may remain scientifically informative, but is unlikely to support changes in clinical practice.

From SEGRA to SEGRAM: How the Concept Changed

The original rationale for dissociated glucocorticoid receptor ligands was attractive because it was simple, testable, and pharmacologically actionable: preserve anti-inflammatory activity while limiting the transcriptional events thought to underlie steroid toxicity [6,16]. This framework gave medicinal chemistry a clear objective and helped explain the early developmental interest in dissociated ligands.

In practice, however, the terms SEGRA, SGRM, and SEGRAM have been used inconsistently [16]. In this review, “SEGRAM” is used as the broadest functional term for any ligand intended to improve the therapeutic index relative to conventional glucocorticoids. The key distinction is between receptor-level dissociation and clinically meaningful benefit.

The field has repeatedly treated these as if they were the same achievement [27,33]. However, the original model of simple dissociation as a representation of clinically meaningful benefit became untenable for 3 reasons. First, glucocorticoid receptor biology proved more context dependent than the early framework allowed [17,21]. Second, apparent selectivity often narrowed once compounds were tested in more integrated translational systems [26,28]. Third, many endpoints used to claim dissociation were easier to measure than to translate into real clinical advantage [10,27]. As a result, the central question is no longer whether a ligand behaves differently from dexamethasone in a simplified assay, but which toxicity domain it can improve, in which disease, and at what exposure [15,33]. This shift has practical implications for how evidence in the field should be evaluated. Once dissociation is treated as a molecular label rather than a therapeutic claim, the relevant question becomes whether a ligand can reduce a specific toxicity that limits glucocorticoid use while preserving meaningful anti-inflammatory efficacy [3,11,12,33].

Representative Compounds and How They Advanced the Field

For consistent clinical evaluation, each representative program can be assessed against the same practical questions: in what setting it was studied, against which comparator, what efficacy signal emerged, what toxicity domain appeared most relevant, and whether the resulting margin was large enough to alter real prescribing decisions. The main representative programs are compared within this framework in Table 1. The table summarizes key compounds, their developmental setting and comparator framework, the main efficacy and safety observations, and the principal reasons they were regarded as informative, promising, or ultimately limited in clinical translation. Collectively, these drugs illustrate both the conceptual progress and the persistent challenges in demonstrating clinically meaningful dissociation between anti-inflammatory efficacy and glucocorticoid-related toxicity. This comparison illustrates that mechanistic plausibility and partial translational separation have been observed more often than therapeutic index gains sufficient to support changes in clinical use.

Mapracorat and Early Proof-of-Concept Compounds: What They Established and Why They Stalled

Early compounds such as mapracorat were important less as near-clinical contenders than as the first disease-relevant tests of whether glucocorticoid receptor output could be steered rather than simply activated [34,35]. In ocular and preclinical inflammatory settings, mapracorat showed anti-inflammatory activity against conventional glucocorticoid benchmarks while generating signals of reduced pressure-related liability [35,36]. These findings did not establish therapeutic superiority, but they suggested that apparent dissociation could persist in disease-relevant biological systems [37].

In rabbit models of dry eye and paracentesis-induced ocular inflammation, topically administered mapracorat (BOL-303242-X) showed anti-inflammatory efficacy comparable to dexamethasone, maintaining tear volume and tear breakup time and reducing ocular inflammatory readouts, while a 6-week topical comparison showed no increase in integrated intraocular pressure or body-weight suppression with mapracorat, in contrast to dexamethasone [35].

At the same time, the trajectory of mapracorat illustrated a recurrent translational barrier in the field. A favorable mechanistic profile alone was insufficient to establish clinical value unless the observed separation was large, consistent, and clinically interpretable enough to justify a different prescribing decision [16,28,38].

Fosdagrocorat: The Clearest Early Systemic Proof-of-Principle

Among the early systemic programs, fosdagrocorat provided the most clinically observable test of the concept because it moved the argument from receptor pharmacology into human comparison against a meaningful conventional glucocorticoid benchmark [39]. Its importance was not simply that it appeared dissociated in vitro, but that it suggested, in a systemic human development program, that anti-inflammatory efficacy and selected steroid liabilities might separate in clinically interpretable ways.

The clearest evidence came from a 12-week, randomized, double-blind phase IIb trial in 323 patients with moderate-to-severe rheumatoid arthritis, in which fosdagrocorat was compared with prednisone 5 mg, prednisone 10 mg, and placebo. The primary endpoints were week-8 ACR20 response and bone-turnover biomarkers. Fosdagrocorat 10–15 mg showed efficacy similar to prednisone 10 mg while lower-dose safety signals, particularly for P1NP, were closer to prednisone 5 mg [39,40].

At the same time, fosdagrocorat clarified how demanding the translational bar really is [38]. A modest shift in the efficacy-to-toxicity balance may be scientifically important but insufficient to alter clinical practice if the margin over prednisolone is narrow, exposure-dependent, or confined to selected endpoints. Fosdagrocorat is therefore important as one of the clearest early examples of systemic translational separation in humans, while also illustrating that proof-of-principle does not necessarily establish a practice-changing margin over prednisolone.

Mizacorat (AZD9567): A More Mature Translational Strategy

Mizacorat (AZD9567) reflects a more mature stage in the evolution of the field [41,42]. The goal is no longer to propose a glucocorticoid free of clinically relevant adverse effects, but to ask a narrower and more clinically meaningful question: can sufficient anti-inflammatory efficacy be preserved while reducing the specific systemic liabilities that limit long-term glucocorticoid use?

In a randomized, double-blind phase IIa study in 21 patients with active rheumatoid arthritis, AZD9567 40 mg was compared with prednisolone 20 mg once daily for 14 days, with change in DAS28-CRP at day 15 as the primary endpoint. Efficacy was broadly similar across DAS28-CRP and secondary clinical measures, while AZD9567 showed no effect on the serum sodium: potassium ratio, supporting the claim that this treatment resulted in clinically interpretable differentiation rather than assay-level dissociation alone [41].

What distinguishes this program is not only receptor selectivity, but the effort to frame comparison in clinically interpretable terms, including benchmarking against prednisolone and greater attention to endpoints that physicians can recognize as relevant to real treatment decisions [38,42]. In that respect, mizacorat represents both a methodological and pharmacologic advance. Its eventual clinical relevance, however, will depend not on pharmacologic rationale alone, but on whether the size and consistency of the observed advantage are sufficiently large, durable, and clinically apparent enough to alter prescribing against an established prednisolone benchmark.

Vamorolone: Disease-Specific Evidence Supporting Potential Therapeutic Index Improvement

Vamorolone currently provides the most developed disease-specific clinical evidence supporting the broader concept, but it should not be misconstrued as proof that SEGRAMs have solved the central problems of steroid therapy across adult internal medicine [43]. Its significance is narrower and therefore more clearly defined: results in patients with Duchenne muscular dystrophy suggest that altered glucocorticoid receptor pharmacology can produce clinically meaningful benefit in a setting defined by chronic exposure and high sensitivity to cumulative toxicity [44,45].

The Duchenne muscular dystrophy experience is informative because it evaluates the therapeutic index question in a setting characterized by prolonged glucocorticoid exposure and high sensitivity to cumulative toxicity. In this context, even partial reductions in growth-, bone-, behavioral-, or metabolic-related liability can be clinically meaningful, provided efficacy remains adequate [43,45]. These findings indicate that vamorolone provides evidence beyond receptor-level mechanistic differentiation, supporting the possibility that disease-specific therapeutic index gain is achievable [46].

The strongest evidence comes from a 24-week randomized, double-blind, placebo- and prednisone-controlled trial in 121 steroid-naive boys aged 4 to 7 years with Duchenne muscular dystrophy, in which vamorolone met the primary motor endpoint of time-to-stand velocity versus placebo and showed less growth stunting and less adverse bone-biomarker change than prednisone, although adrenal insufficiency increased across all active-treatment groups [43,47].

For internists, the relevant lesson is not that Duchenne muscular dystrophy should define the future of the field, but that it offers a disease-specific proof-of-concept for chronic inflammatory disorders, in which repeated or prolonged glucocorticoid exposure remains necessary and cumulative harm increasingly shapes treatment decisions [14,16]. Its value is therefore validation in the context of disease and translational strategy rather than being automatically generalizable across adult internal medicine.

GRM-01 and Newer Nonsteroidal Programs

The emergence of GRM-01 and related nonsteroidal modulators indicates that the field remains scientifically active and chemically inventive [33,48]. Nonsteroidal scaffolds are attractive not simply because they are new, but because they may access receptor conformations and downstream output patterns that are not easily reached by classical steroid backbones [16,49]. These observations support continued evaluation of whether clinically meaningful differentiation may depend on chemical scaffold as well as receptor mechanism [50].

At present, however, these programs remain hypothesis-generating rather than practice-informing [48,51]. Their main value lies in testing whether the next wave of ligands can produce cleaner, more reproducible separation across clinically relevant efficacy and toxicity domains than earlier generations achieved. Until such evidence is available, strong claims about therapeutic value remain premature.

Further progress will require rigorous comparative evidence in clinically relevant efficacy and toxicity domains, particularly because earlier programs have shown that promising mechanistic or translational signals do not necessarily establish practice-changing clinical effects.

Programs with Limited Clinical Translation: Lessons for SEGRAM Development

The limited clinical translation of several SEGRAM drug-development programs is itself informative. Rather than representing simple failures of receptor pharmacology, these programs illustrate how difficult it is to translate mechanistic dissociation or favorable preclinical separation into a clinically meaningful therapeutic index advantage.

Mapracorat provided early evidence that selective glucocorticoid receptor modulation could retain anti-inflammatory activity in ocular and other disease-relevant models while generating signals of reduced selected steroid-related liabilities [34–37]. However, these data did not establish a sufficiently broad or practice-changing clinical role relative to established topical glucocorticoids. This illustrates a recurring challenge for locally administered SEGRAMs: a favorable mechanistic or preclinical profile must still translate into a clear clinical advantage over familiar and highly effective standard steroids.

Fosdagrocorat provided one of the most informative systemic proof-of-principle programs because it was tested against prednisone for rheumatoid arthritis [39,40]. Nevertheless, this program illustrates the narrow translational margin required for clinical adoption. Similar anti-inflammatory efficacy with improvement in selected biomarkers may be insufficient if the advantage over conventional glucocorticoids is modest, endpoint-specific, short-term, or not clearly linked to long-term outcomes that influence prescribing.

Earlier nonsteroidal modulators such as Org 214007–0 were also important in demonstrating pharmacologic feasibility and improved therapeutic index signals in translational systems [28]. However, they underscore that favorable preclinical separation does not necessarily predict sustained clinical differentiation. Across programs, the main translational limitations have included incomplete prediction from simplified receptor assays, difficulty establishing dose-equivalent anti-inflammatory comparisons, reliance on short-term biomarkers rather than cumulative toxicity outcomes, tissue-specific variability in glucocorticoid receptor signaling, and competition with low-cost conventional glucocorticoids that have well-established clinical efficacy.

These examples indicate that the central barrier is not simply whether selective glucocorticoid receptor modulation can be achieved, but whether it can produce a sufficiently large, durable, and clinically interpretable advantage in a defined disease context.

What Would a Clinically Meaningful Safer Steroid Actually Look Like?

The answer depends on the clinical use case, because the properties required of a rescue steroid are not the same as those required of a drug used repeatedly or over prolonged periods [3,16]. In rescue settings such as severe asthma, vasculitis, immune thrombocytopenia, ulcerative colitis flare, or acute nephritic disease, conventional glucocorticoids remain difficult to displace because clinicians rely on their speed, breadth, and predictable efficacy [33,52].

The calculation changes when exposure is prolonged or repeatedly reintroduced. In that setting, the value of a safer glucocorticoid depends less on abstract selectivity and more on whether it reduces the toxicities that accumulate over time while preserving dependable anti-inflammatory benefit [1,3]. A clinically meaningful agent would therefore need to improve the practical tolerance of continued treatment, not merely produce cleaner translational profiling. Such an advantage would require confirmation in adequately powered comparative studies with follow-up sufficient to capture cumulative toxicity domains.

Which Toxicities Matter for a Clinically Safer Glucocorticoid?

In this field, safety is not a unitary concept. The toxicities that limit glucocorticoid therapy differ in mechanism, time course, reversibility, and clinical consequence, and their relevance depends on why the drug is being used and for how long [53]. In rescue settings, clinicians may accept transient metabolic disturbance, fluid retention, or sleep disruption if inflammatory control is prompt and reliable [31]. In longer-exposure settings, the more important liabilities are those that accumulate silently and progressively shape outcomes, including hypothalamic-pituitary-adrenal-axis suppression, impaired growth, bone loss, muscle wasting, adverse body composition, insulin resistance, infection susceptibility, and organ-specific complications such as ocular hypertension, where relevant [1,2,5]. Real-world data from chronic inflammatory disease cohorts also suggest that ongoing glucocorticoid exposure may track with broader comorbidity burden, including cardiovascular disease [54].

A glucocorticoid should therefore not be considered clinically safer merely because it improves a biomarker, attenuates a preclinical signal, or performs better in a short-duration comparison. It becomes clinically safer only when it reduces the liabilities that matter in the treatment context for which it is intended [11,12].

Clinical Relevance for Internal Medicine: Where a Safer Glucocorticoid Would Matter Most

The strongest future case for SEGRAMs in internal medicine is likely to emerge not from acute rescue use, but from diseases in which glucocorticoids are repeatedly reintroduced, tapered slowly, or maintained over prolonged periods, often alongside attempts to reduce cumulative steroid exposure with steroid-sparing immunomodulatory therapy [8,15,55]. This includes systemic vasculitis, giant cell arteritis and polymyalgia rheumatica, inflammatory bowel disease, severe asthma and eosinophilic disorders, autoimmune cytopenias, and steroid-responsive nephritides [14,16,32]. In these settings, the most relevant question is not whether selective glucocorticoid receptor modulation has a favorable mechanistic profile, but whether it can reduce a clinically important component of treatment burden.

These opportunities are likely to be disease-specific rather than class-wide. In vasculitis and polymyalgia rheumatica, the dominant issue is cumulative exposure during prolonged tapering [56–58]. In inflammatory bowel disease and severe asthma, repeated rescue courses and steroid dependence are central problems [33,59,60]. In autoimmune cytopenias and nephritides, the challenge is to preserve rapid anti-inflammatory efficacy while lowering the systemic liabilities that constrain duration and dose [2,14]. The principal internal medicine settings in which such a benefit would matter most are summarized in Table 2. The table outlines the clinical reasons glucocorticoids remain indispensable in each setting, the major toxicities that constrain their use, and the specific improvements a successful SEGRAM would need to achieve to deliver meaningful therapeutic value. These indications are likely to be the most informative contexts for clinical benefit, particularly where prolonged or repeated glucocorticoid exposure makes treatment-related toxicity a major determinant of outcome and management.

Why the Field Has Advanced More Slowly Than Expected

One limitation in the development of this field has been the early reliance on an overly simplified conceptual model. The transrepression/transactivation dichotomy was a useful heuristic, but it proved too reductive to predict therapeutic performance in humans [6,7]. In some development programs, mechanistic dissociation was interpreted as implying a wider therapeutic window before this assumption had been validated in clinically relevant systems [9]. Mechanistic dissociation should therefore be considered an early level of evidence rather than sufficient evidence of therapeutic index improvement. Progress may also have been limited by suboptimal translational framing. Several programs focused primarily on whether a ligand was dissociated, whereas the clinically relevant question was which toxicity domain it might improve, in which disease, and over what duration of exposure [14,16]. Without this framing, compounds could appear promising in early studies without establishing a clearly defined clinical role.

Another persistent problem has been inadequate endpoint discipline. The field has often measured what is experimentally convenient rather than what governs treatment decisions [26]. A modest shift in a biomarker is unlikely to influence prescribing unless it maps onto a toxicity domain that meaningfully affects clinical decision-making [16,53]. In this therapeutic area, translational data alone are insufficient unless they are linked to clinically relevant endpoints. The endpoint structure has to anticipate the reasons clinicians continue, taper, switch, or stop steroids [31,61].

Competitive reality has also shaped the course of SEGRAM adoption. Conventional glucocorticoids are inexpensive, ubiquitous, familiar, and extraordinarily effective [3]. Any molecule that aims to replace them enters practice under severe comparative pressure. The best development opportunities therefore lie in diseases where cumulative exposure is itself a central part of the clinical problem [32,57].

Future Directions

The future of this field will depend less on arguments about receptor bias and more on whether specific programs can improve clinically relevant toxicity domains without sacrificing early anti-inflammatory efficacy [14,16]. The next important advance is likely to be a ligand that demonstrates improvement in a treatment-limiting toxicity domain within a defined disease setting, rather than one that appears most dissociated in a simplified assay [28]. The most informative development programs will therefore link receptor-proximal biology to translational readouts that map onto real treatment constraints [1,3,5]. These constraints include skeletal toxicity, metabolic burden, muscle catabolism, hypothalamic-pituitary-adrenal axis suppression, growth, and ocular pressure where relevant. What matters is not selectivity as an abstract pharmacologic property, but whether that selectivity produces an interpretable therapeutic advantage under the conditions in which glucocorticoids are actually used [38,42].

Future success, if demonstrated, is also likely to be disease-specific rather than universal [43,45]. Different diseases reward different pharmacologic compromises, and the most credible path forward is indication-focused glucocorticoid redesign for settings in which conventional glucocorticoids remain indispensable but cumulative exposure drives harm [32,57,62]. From this more indication-specific perspective, the future of SEGRAMs is unlikely to depend on broad replacement of prednisone. Instead, their future depends on demonstrating improved steroid therapy in settings where toxicity has become a major determinant of care.

Conclusions

SEGRAMs should now be evaluated neither on the basis of early expectations nor through premature dismissal, but by whether they deliver a measurable therapeutic index gain in a clinically relevant setting. The accumulated evidence no longer supports a binary model of beneficial transrepression and harmful transactivation; it supports a more complex view in which receptor output is context dependent and clinical value must be demonstrated rather than inferred.

The practical promise of SEGRAMs is likely to be disease-specific rather than universal, particularly in chronic or relapsing disorders in which glucocorticoids remain indispensable but cumulative toxicity increasingly shapes treatment decisions. However, durable therapeutic index improvement in these settings remains to be established in long-term comparative studies.