Poster 0122: In a 309-patient randomized trial in hospitalized COVID-19, the CD206 (mannose receptor)-targeted dexamethasone prodrug was superior to systemic dexamethasone (HR 2.31; p<0.0001), with no systemic steroid added in the '005 arm; company proposes episodic use as an adjunct to IL-1, IL-6 and TNF biologics in sJIA, PMR and rheumatoid arthritis

101 Therapeutics Ltd. (101TX), a clinical-stage biotechnology company developing macrophage-targeted therapeutics, presented Phase II/III (Phase 2/3) clinical data and a rheumatology development rationale for 101-PGC-005 ('005; designated 101-PIF-GC-005 in the published abstract), a chemically synthesized small-molecule, CD206-targeted dexamethasone prodrug, in Poster 0122 on Sunday, November 8, at ACR Convergence 2026, the annual meeting of the American College of Rheumatology (ACR), in Orlando, Florida. This was the first presentation of '005 data at a scientific meeting. In a 309-patient randomized, active-controlled trial, a three-day course of '005 was superior to systemic dexamethasone for time to clinical improvement, and Phase I studies detected free dexamethasone only at sub-clinical trace levels, with preserved morning cortisol and ACTH. The company is developing '005 as a steroid-sparing, HPA-axis-sparing adjunct to biologic therapy for patients with residual macrophage-driven inflammation, is evaluating its potential in cytokine release syndrome and immune-related complications of cancer immunotherapy, and is seeking development and commercialization partners.

The trial (NCT05656521) was a randomized, open-label, active-controlled adaptive Phase II/III study in 309 hospitalized adults with moderate COVID-19 inflammatory disease at six GCP-compliant sites in India (155 assigned to '005; 154 to dexamethasone). Patients received '005 20 mg IV once daily for three days or dexamethasone 6 mg IV once daily for five to 10 days, each with standard of care. The Phase II cohort (n=62) established the signal and the Phase III cohort (n=247) prospectively reproduced it across a later variant and vaccination landscape. Results are reported in a publicly available medRxiv preprint that has not been peer reviewed. COVID-19 was the disease studied; efficacy in rheumatic diseases has not been established. Key results presented in Poster 0122:

• Primary endpoint, time to at least 2-point improvement on the WHO ordinal scale: HR 2.31 (95% CI 1.83–2.93; p<0.0001); median 3 vs 4 days
• RT-PCR viral clearance: HR 1.47 (95% CI 1.17–1.84; p=0.0001); median 3 vs 5 days
• Day 5 discharge: 77.4% vs 29.0%
• Steroid sparing: no '005 patient received physician-initiated systemic glucocorticoid despite protocol permission, sparing approximately 30–36 mg dexamethasone per patient
• Safety: treatment-emergent adverse events 54.8% vs 54.5%; no Grade 3 or higher events, serious adverse events, deaths or discontinuations
• Retention: zero dropouts; all 309 randomized patients included in the intention-to-treat (ITT) analysis
• Phase I pharmacokinetics and HPA axis (NCT05619770): intact prodrug circulation, Tmax ~0.5 h, terminal half-life ~1.9 h, free dexamethasone only at sub-clinical trace levels detected by a high-sensitivity assay, morning cortisol and ACTH preserved after repeated supratherapeutic dosing, no glucose signal

Why it matters for rheumatology. Biologics that block a single cytokine or pathway, such as IL-1, IL-6 or TNF, have transformed care, yet many patients still have incomplete responses, breakthrough flares, persistent inflammation or dependence on systemic glucocorticoids, a residual 'efficacy ceiling.' Residual macrophage activity and parallel immune circuits may sustain disease after a dominant cytokine is blocked. '005 is designed to act orthogonally: CD206-mediated uptake into activated macrophages, intracellular release of dexamethasone, rapid macrophage modulation and debulking, with the endogenous hypothalamic-pituitary-adrenal (HPA) axis left available to regulate other glucocorticoid receptor-positive immune cells and newly recruited macrophages. In mechanistic experiments, '005 suppressed macrophage IL-6 and TNF while preserving CXCL10-associated antiviral signaling. The company proposes episodic, short-course '005 dosing alongside existing biologics, a hypothesis that requires prospective rheumatology trials. Settings identified in the abstract and poster include systemic juvenile idiopathic arthritis (sJIA), polymyalgia rheumatica (PMR), graft-versus-host disease (GVHD), and incomplete responders to single-cytokine biologics, including in rheumatoid arthritis (RA). '005 has received FDA Rare Pediatric Disease designation for sJIA, and a U.S. randomized, placebo-controlled study of '005 added to IL-1 biologic therapy in sJIA is being planned.

One receptor across indications. CD206, the mannose receptor, is encoded by a single gene, MRC1. Its mannose-recognition and endocytic machinery is conserved across inflammatory triggers and macrophage activation states, including M1-like (pro-inflammatory) and M2-like macrophages: activation changes how much CD206 a macrophage expresses, not the receptor itself. CD206 internalizes its ligand and recycles to the cell surface, enabling repeated uptake during drug exposure. Because '005 targets this host receptor rather than a specific disease trigger or cytokine, the same molecule can be tested in any indication where disease-driving macrophages express CD206. Each indication must still confirm accessible, functionally CD206-positive macrophages, intracellular delivery, dose and schedule, safety and efficacy.

Potential use in complications of cancer immunotherapy. The same macrophage-directed approach may apply to acute cytokine syndromes and immune-reactive complications of cancer therapy, including cytokine release syndrome (CRS) and immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS) after CAR-T cell and bispecific T-cell engager therapy, and immune-related adverse events (irAEs) from immune checkpoint inhibitors, some of which, such as checkpoint inhibitor-induced inflammatory arthritis, persist long after cancer treatment ends and are increasingly managed by rheumatologists. Monocytes and macrophages are central sources of IL-6 and IL-1 in CRS. Systemic glucocorticoids, the mainstay of CRS and irAE management, reach every immune cell, including the T cells that carry out the anticancer effect, and every non-immune tissue. In the Phase 2/3 trial, glucocorticoid activity restricted to CD206-positive cells, with the HPA axis left intact to supply physiological cortisol, was superior to systemic dexamethasone. The company's hypothesis is that the same combination could control these complications without broad synthetic glucocorticoid exposure of T cells or non-immune tissues. '005 has not been studied in patients with cancer, and this use requires dedicated clinical trials.

“The Phase 2/3 trial answered a basic question: does a glucocorticoid need to reach every immune cell to work?” said Michael M. Goldberg, MD, founder and chief scientific officer of 101 Therapeutics. “Restricting dexamethasone to CD206-positive cells was superior to 6 mg of systemic dexamethasone, roughly 40 mg of prednisone, which reaches every immune cell and every tissue on a fixed, non-physiological pharmacokinetic profile. Because '005 does not suppress the HPA axis, the patient's own cortisol is still released just in time, at physiological levels, to regulate the rest of the immune system. CD206-limited synthetic glucocorticoid plus intact natural cortisol outperformed broad synthetic glucocorticoid. The only free dexamethasone we measured was sub-clinical trace levels, detectable because of the extreme sensitivity of our assay and too low to suppress the HPA axis, with no glucose signal. We believe that finding should carry over to every indication where glucocorticoids are effective, and we are seeking partners to take '005 into sJIA, other rheumatic diseases and complications of cancer immunotherapy.”

Poster 0122 (Abstract 0122), “CD206-Targeted Glucocorticoid Delivery as an Adjunct to Biologic Therapy in Macrophage-Driven Autoimmune Disease: Proof-of-Concept Clinical Evidence and a Mechanistic Rationale for Addressing the Residual Inflammatory Burden of Single-Pathway Cytokine Blockade,” was presented Sunday, November 8, during the Innate Immunity Poster A session at ACR Convergence 2026 in Orlando, Florida. A copy of the poster is available on request from michael@101therapeutics.com.

Partnering. 101 Therapeutics is seeking pharmaceutical and biotechnology partners for co-development, licensing or regional rights to '005 in rheumatology, rare inflammatory disease, oncology supportive care and host-directed infectious hyperinflammation, and is meeting with business development, search-and-evaluation and life-science investment teams and scientific collaborators through the close of ACR Convergence 2026 on November 11 and afterward. To arrange a meeting, contact michael@101therapeutics.com.

Citation: Goldberg M. Arthritis Rheumatol. 2026;78(suppl 9). Abstract 0122.

Read the published abstract: https://acrabstracts.org/abstract/cd206-targeted-glucocorticoid-delivery-as-an-adjunct-to-biologic-therapy-in-macrophage-driven-autoimmune-disease-proof-of-concept-clinical-evidence-and-a-mechanistic-rationale-for-addressing-the-resi/

Clinical preprint (not peer reviewed): Goldberg MM, et al. medRxiv 2026; doi:10.64898/2026.06.05.26354839. https://www.medrxiv.org/content/10.64898/2026.06.05.26354839v1

About 101 Therapeutics

101 Therapeutics Ltd. (101TX) is an independently funded, clinical-stage biopharmaceutical company developing macrophage-targeted therapeutics for diseases in which excessive or dysregulated macrophage activity contributes to tissue injury and persistent inflammation. Its lead investigational compound, 101-PGC-005 ('005), is a chemically synthesized small-molecule, CD206 (mannose receptor, MRC1)-targeted type 1a dexamethasone prodrug (627 Da; mannose, pH-sensitive oxime-ether linker and dexamethasone in 1:1:1 stoichiometry) designed for short-course, episodic intracellular glucocorticoid delivery. The proposed mechanism involves modulation of activated inflammatory macrophages followed by apoptosis of excess pathogenic macrophages, without preventing recruitment and activation of new macrophages that can operate under physiological hypothalamic-pituitary-adrenal (HPA) axis and cortisol regulation. Development opportunities include rheumatology indications as an adjunct to biologics, rare inflammatory diseases, acute cytokine syndromes and immune-related complications of cancer immunotherapy, and host-directed anti-infective and medical-countermeasure applications in severe infectious hyperinflammation. The company has received FDA Rare Pediatric Disease designation for systemic juvenile idiopathic arthritis (sJIA), a designation relevant to potential Priority Review Voucher eligibility subject to statutory requirements; a study in sJIA is being planned. These applications remain investigational and require indication-specific studies. Patent publications include WO2022034582A1 and WO2023144815A1. 101 Therapeutics was founded by its Chief Scientific Officer, Michael M. Goldberg, MD, who as Chairman and CEO of Emisphere Technologies led development of the SNAC (salcaprozate sodium) oral absorption technology used in Novo Nordisk's oral semaglutide products, Rybelsus^® and Ozempic^® tablets for type 2 diabetes and the Wegovy^® pill for chronic weight management.

Investigational status and forward-looking statements

101-PGC-005 is investigational and has not been approved for any indication. The clinical study cited above involved COVID-19; clinical efficacy and safety in rheumatic diseases and in complications of cancer therapy have not been established. Mechanistic hypotheses, potential complementary use with biologics, and future development plans are forward-looking and subject to further testing, regulatory review, and other uncertainties. Reference to ACR Convergence identifies the presentation venue and does not imply endorsement by the American College of Rheumatology.

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At #ACR26, 101-PGC-005, a CD206-targeted, steroid-sparing glucocorticoid, beat 6 mg dexamethasone in a 309-patient Phase 2/3 trial (HR 2.31; p<0.0001), with no steroid added in the ‘005 arm. Seeking partners in rheumatology and CRS.