101 Therapeutics Presents Phase 2/3 Clinical Data for CD206-Targeted Therapy 101-PGC-005 at ACR Convergence 2026
101 Therapeutics Ltd., a clinical-stage biotechnology company focused on developing macrophage-targeted therapeutics for inflammatory and immune-mediated diseases, has presented clinical data and a development rationale for its investigational candidate 101-PGC-005 (‘005) at ACR Convergence 2026, the annual meeting of the American College of Rheumatology (ACR), held in Orlando, Florida. The presentation took place on Sunday, November 8, 2026, as Poster 0122 during the Innate Immunity Poster A session. The announcement marked the first presentation of clinical data for ‘005 at a scientific meeting.
The investigational therapy is a chemically synthesized, small-molecule, CD206-targeted dexamethasone prodrug designed to deliver glucocorticoid activity selectively to activated macrophages. The company is developing the candidate as a potential steroid-sparing treatment approach for patients with inflammatory and autoimmune diseases who continue to experience residual inflammation despite receiving biologic therapies.
The clinical findings presented at the meeting were based on a randomized, active-controlled Phase II/III clinical study involving 309 hospitalized adults with moderate COVID-19 inflammatory disease. In the study, a three-day treatment course of ‘005 demonstrated superiority over systemic dexamethasone for the primary endpoint of time to clinical improvement. The therapy also demonstrated faster viral clearance and a higher proportion of patients discharged from the hospital by Day 5.
In addition to the Phase II/III findings, Phase I pharmacokinetic and safety evaluations provided information about the candidate’s targeted delivery mechanism and its potential effects on the hypothalamic-pituitary-adrenal (HPA) axis. The studies detected free dexamethasone only at sub-clinical trace levels, while morning cortisol and adrenocorticotropic hormone (ACTH) levels remained preserved following repeated supratherapeutic dosing.
101 Therapeutics believes these findings support further investigation of ‘005 as an adjunct to existing biologic treatments, particularly in patients whose inflammatory disease remains incompletely controlled by therapies targeting individual cytokines or immune pathways.
The company is also evaluating the potential application of its macrophage-targeted approach in systemic juvenile idiopathic arthritis (sJIA), polymyalgia rheumatica (PMR), graft-versus-host disease (GVHD), and complications associated with cancer immunotherapy. However, clinical efficacy in these conditions has not yet been established, and dedicated studies will be required to determine the therapy’s safety and effectiveness in each indication.
Michael M. Goldberg, MD, Founder and Chief Scientific Officer of 101 Therapeutics, explained that the Phase II/III study addressed an important question regarding whether glucocorticoid activity needs to reach every immune cell to achieve therapeutic effects. He highlighted that restricting dexamethasone delivery to CD206-positive cells demonstrated better clinical outcomes than systemic dexamethasone in the studied COVID-19 population.
According to Goldberg, the targeted approach may offer a different way to manage inflammation by combining selective synthetic glucocorticoid activity within macrophages with the body’s natural cortisol regulation. The company believes this strategy could potentially reduce the need for broad systemic steroid exposure while maintaining anti-inflammatory activity.
Phase II/III Clinical Study Demonstrates Faster Clinical Improvement
The Phase II/III clinical study, registered under ClinicalTrials.gov identifier NCT05656521, was a randomized, open-label, active-controlled, adaptive clinical trial conducted across six Good Clinical Practice (GCP)-compliant clinical sites in India.
The study enrolled 309 hospitalized adults with moderate COVID-19 inflammatory disease. Participants were randomly assigned to receive either 101-PGC-005 or standard systemic dexamethasone alongside standard of care.
A total of 155 patients were assigned to the ‘005 treatment group, while 154 patients received the dexamethasone control regimen.
Patients in the investigational treatment group received ‘005 at a dose of 20 mg administered intravenously once daily for three consecutive days. The control group received intravenous dexamethasone at a dose of 6 mg once daily for five to 10 days.
The trial was conducted in two stages. The initial Phase II cohort included 62 participants and was designed to establish an early clinical efficacy signal. The subsequent Phase III cohort enrolled 247 participants and prospectively evaluated the findings under a later COVID-19 variant and vaccination landscape.
The primary endpoint measured the time required for patients to achieve at least a two-point improvement on the World Health Organization (WHO) ordinal scale, which is used to assess the clinical status of patients with COVID-19.
Results showed that patients receiving ‘005 achieved clinical improvement more rapidly than those treated with systemic dexamethasone.
The investigational therapy demonstrated a hazard ratio (HR) of 2.31, with a 95% confidence interval (CI) of 1.83–2.93 and a p-value of less than 0.0001. The median time to clinical improvement was three days in the ‘005 group, compared with four days in the dexamethasone group.
These results suggest that the targeted glucocorticoid delivery approach demonstrated a favorable clinical improvement profile compared with systemic dexamethasone in the specific COVID-19 population evaluated.
The company highlighted the consistency of the clinical findings across the two study cohorts, noting that the Phase III portion prospectively reproduced the initial efficacy signal despite changes in the COVID-19 variant and vaccination environment.
It is important to note that the study evaluated patients with COVID-19 inflammatory disease. The results do not establish clinical efficacy in rheumatological or other autoimmune conditions, which remain potential areas for future development.
Faster Viral Clearance and Improved Hospital Discharge Outcomes
In addition to the primary clinical improvement endpoint, the study evaluated viral clearance through reverse transcription polymerase chain reaction (RT-PCR) testing.
Patients receiving ‘005 demonstrated faster RT-PCR viral clearance than those receiving systemic dexamethasone.
The analysis reported a hazard ratio of 1.47, with a 95% confidence interval of 1.17–1.84 and a p-value of 0.0001. The median time to viral clearance was three days in the ‘005 group, compared with five days in the dexamethasone group.
The study also reported differences in hospital discharge rates by Day 5.
Approximately 77.4% of patients treated with ‘005 were discharged by Day 5, compared with 29.0% of patients receiving systemic dexamethasone.
These findings provided additional clinical observations supporting the investigational therapy’s performance in the studied population.
Another notable finding involved the use of additional systemic glucocorticoids during treatment. Although the study protocol permitted physician-initiated systemic glucocorticoid administration when clinically necessary, no patient in the ‘005 group received additional physician-initiated systemic glucocorticoids.
According to the company’s analysis, this resulted in an estimated reduction of approximately 30–36 mg of dexamethasone exposure per patient compared with the additional systemic steroid use anticipated under the relevant treatment approach.
The company considers this steroid-sparing observation important because reducing unnecessary systemic glucocorticoid exposure may help address some of the limitations associated with conventional steroid treatment.
However, the potential steroid-sparing benefits of ‘005 will need to be investigated further in disease-specific clinical studies.
Safety Findings and Patient Retention
The Phase II/III study also evaluated the safety and tolerability of ‘005 compared with systemic dexamethasone.
Treatment-emergent adverse events were reported in 54.8% of patients receiving ‘005 and 54.5% of patients in the dexamethasone group.
The company reported no Grade 3 or higher adverse events, serious adverse events, deaths, or treatment discontinuations in either group.
Patient retention was also notable, with no dropouts reported during the study. All 309 randomized participants were included in the intention-to-treat (ITT) analysis.
The complete inclusion of randomized patients in the ITT population provides an important basis for evaluating the reported clinical outcomes.
While the safety findings are encouraging, the study population and treatment duration were specific to moderate COVID-19 inflammatory disease. Larger and longer-duration studies will be necessary to establish the safety profile of ‘005 across different inflammatory and autoimmune conditions.
The company believes the observed safety and efficacy findings provide a foundation for additional clinical development, particularly in indications where macrophage-driven inflammation contributes to disease progression.
Phase I Studies Highlight Targeted Pharmacokinetics and HPA-Axis Preservation
The development strategy for 101-PGC-005 is based on its ability to deliver dexamethasone selectively into macrophages through the CD206 receptor.
Additional information supporting this mechanism came from Phase I pharmacokinetic and HPA-axis evaluations conducted under clinical study NCT05619770.
The Phase I studies examined the behavior of the intact prodrug in circulation, the appearance of free dexamethasone, and potential effects on the body’s natural glucocorticoid regulatory system.
The pharmacokinetic findings showed that the intact prodrug remained in circulation, with a time to maximum concentration (Tmax) of approximately 0.5 hours and a terminal half-life of approximately 1.9 hours.
Importantly, free dexamethasone was detected only at sub-clinical trace levels using a high-sensitivity analytical assay.
The company also reported that morning cortisol and ACTH levels were preserved following repeated supratherapeutic dosing.
These findings are relevant because conventional systemic glucocorticoids can suppress the HPA axis, which regulates the body’s natural production and release of cortisol.
Cortisol plays an important role in controlling inflammation, maintaining immune balance, and supporting several physiological functions. Prolonged or repeated systemic glucocorticoid exposure can interfere with this regulatory system and may contribute to complications associated with steroid treatment.
According to 101 Therapeutics, the limited systemic exposure to free dexamethasone observed with ‘005 may allow the body’s endogenous cortisol system to remain functional while the investigational drug delivers glucocorticoid activity into targeted macrophages.
The Phase I evaluations also reported no glucose signal.
Although these findings provide an initial understanding of the candidate’s pharmacological behavior, additional clinical research will be required to determine whether the proposed HPA-axis-sparing profile can be maintained during treatment in patients with chronic inflammatory and rheumatic diseases.
Development Rationale for Rheumatology and Residual Inflammation
101 Therapeutics is positioning ‘005 as a potential adjunctive therapy for patients with rheumatic and autoimmune diseases who experience incomplete responses to existing biologic treatments.
Biologic therapies targeting individual inflammatory cytokines have significantly changed the treatment landscape for several autoimmune conditions.
Medicines that inhibit pathways involving interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor (TNF) have helped improve disease control across multiple inflammatory disorders.
However, some patients continue to experience persistent inflammation, breakthrough disease flares, or inadequate responses despite treatment with these targeted therapies.
Others remain dependent on systemic glucocorticoids to manage residual disease activity.
The company describes this challenge as a residual inflammatory burden or an efficacy ceiling associated with single-pathway cytokine blockade.
One potential explanation is that inflammatory diseases are driven by interconnected immune mechanisms rather than a single cytokine or signaling pathway. Even when a dominant inflammatory pathway is blocked, other immune cells and parallel inflammatory circuits may continue to contribute to disease activity.
Macrophages are important components of the innate immune system and participate in inflammatory signaling, tissue responses, and immune regulation.
In certain disease settings, activated macrophages may continue producing inflammatory mediators, including IL-6 and TNF, even when patients receive biologic therapies targeting specific cytokines.
101 Therapeutics believes that selectively targeting these macrophages could provide an additional approach to controlling inflammation without broadly suppressing the entire immune system.
The company’s proposed strategy is to use short courses of ‘005 alongside existing biologic therapies to address residual macrophage-driven inflammation.
This approach remains a development hypothesis and will require prospective clinical evaluation in rheumatology populations.
CD206-Targeted Mechanism Designed for Selective Macrophage Delivery
The mechanism of 101-PGC-005 is centered on CD206, also known as the mannose receptor, which is encoded by the MRC1 gene.
CD206 is expressed on macrophages and participates in the recognition and internalization of specific molecular structures.
The receptor’s mannose-recognition and endocytic mechanisms are conserved across different inflammatory triggers and macrophage activation states.
These include M1-like macrophages, which are generally associated with pro-inflammatory activity, and M2-like macrophages, which are often associated with tissue repair and immune regulation.
According to the company’s development rationale, inflammatory activation can change the level of CD206 expressed by macrophages without fundamentally changing the receptor’s underlying structure and internalization machinery.
CD206 can bind its ligands, internalize them into the cell, and subsequently recycle to the cell surface. This process may enable repeated uptake of targeted therapeutic molecules during drug exposure.
101-PGC-005 is designed to take advantage of this receptor-mediated uptake mechanism.
Following CD206-mediated internalization, the prodrug is intended to release dexamethasone intracellularly, concentrating glucocorticoid activity within the targeted macrophage population.
The company proposes that this selective delivery could suppress inflammatory macrophage activity while avoiding unnecessary systemic exposure to synthetic glucocorticoids.
Mechanistic experiments conducted by the company showed that ‘005 suppressed macrophage production of IL-6 and TNF while preserving CXCL10-associated antiviral signaling.
These observations are relevant because CXCL10 participates in immune signaling and antiviral responses.
The company believes that preserving certain immune functions while reducing excessive macrophage-driven inflammation could offer a differentiated therapeutic approach.
However, the degree to which these mechanistic findings translate into clinical benefits across different inflammatory diseases remains to be established.
Potential Applications Across Multiple Inflammatory Diseases
Because CD206 is a host receptor expressed by macrophages, 101 Therapeutics believes the same investigational molecule could potentially be evaluated across several diseases in which macrophage activity contributes to inflammation.
Unlike therapies directed against a specific disease-associated cytokine, the company’s approach targets a cellular delivery mechanism that may be relevant across different inflammatory conditions.
The company has identified several potential development areas, including:
- Systemic juvenile idiopathic arthritis (sJIA): A rare inflammatory condition characterized by systemic inflammation and joint involvement. 101-PGC-005 has received FDA Rare Pediatric Disease designation for sJIA.
- Polymyalgia rheumatica (PMR): An inflammatory rheumatic disease associated with pain and stiffness, particularly involving the shoulders and hips.
- Rheumatoid arthritis (RA): The company is considering the potential use of ‘005 in patients who experience incomplete responses to biologic therapies targeting individual cytokines.
- Graft-versus-host disease (GVHD): An immune-mediated complication that can occur following allogeneic stem cell transplantation and involve significant inflammatory activity.
- Residual inflammation following biologic treatment: The company is exploring whether selective macrophage modulation could complement existing biologic therapies in patients with persistent inflammatory disease activity.
For sJIA, 101 Therapeutics is planning a U.S. randomized, placebo-controlled clinical study evaluating ‘005 as an adjunct to IL-1 biologic therapy.
The proposed study is expected to investigate whether targeted macrophage glucocorticoid delivery can improve inflammatory disease control when combined with an established cytokine-targeted treatment.
Further clinical development will need to establish the appropriate patient population, dosing regimen, treatment duration, safety profile, and efficacy of ‘005 in each indication.
Potential Role in Cancer Immunotherapy-Related Complications
Beyond rheumatology, 101 Therapeutics is exploring the potential application of ‘005 in inflammatory complications associated with cancer immunotherapy.
These include cytokine release syndrome (CRS), immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS), and immune-related adverse events (irAEs).
CRS and IEC-HS can occur following treatments such as chimeric antigen receptor T-cell (CAR-T) therapy and bispecific T-cell engager treatments.
These therapies activate immune cells to recognize and attack cancer cells but can also trigger excessive inflammatory responses in some patients.
Monocytes and macrophages are important contributors to inflammatory cytokine production during CRS, particularly through the release of IL-6 and IL-1.
Systemic glucocorticoids are commonly used to manage severe inflammatory complications. However, these medicines can affect multiple immune cell populations and tissues throughout the body.
One consideration in cancer immunotherapy is that broad immunosuppression may potentially interfere with the activity of immune cells responsible for attacking cancer.
101 Therapeutics believes that CD206-targeted delivery could offer a more selective approach by concentrating glucocorticoid activity in macrophages while limiting exposure of other immune cells, including T cells.
The company also sees potential applications in immune-related adverse events associated with immune checkpoint inhibitors.
Some of these complications, including checkpoint inhibitor-induced inflammatory arthritis, may persist even after cancer treatment has ended and increasingly require management by rheumatology specialists.
The company’s hypothesis is that targeted macrophage modulation could help control inflammatory complications while avoiding unnecessary broad synthetic glucocorticoid exposure.
However, ‘005 has not yet been studied in patients with cancer. Its potential application in CRS, IEC-HS, and immune-related adverse events remains investigational and will require dedicated clinical trials.
101 Therapeutics Seeks Development and Commercialization Partners
101 Therapeutics is actively seeking pharmaceutical and biotechnology partners to advance the clinical development and potential commercialization of 101-PGC-005.
The company is considering co-development arrangements, licensing agreements, and regional commercialization rights across several therapeutic areas.
Its partnering priorities include rheumatology, rare inflammatory diseases, oncology supportive care, and host-directed infectious hyperinflammation.
The company is engaging with business development teams, search-and-evaluation groups, life-science investment organizations, and scientific collaborators during ACR Convergence 2026 and beyond.
Through potential partnerships, 101 Therapeutics aims to accelerate the development of ‘005 in additional disease indications and establish the clinical evidence needed to support its broader therapeutic potential.
The company is particularly interested in collaborations that can support the planned development of ‘005 in sJIA, other rheumatic diseases, and complications associated with cancer immunotherapy.
First Scientific Presentation Highlights Development Potential
Poster 0122, titled “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 on November 8 during the Innate Immunity Poster A session at ACR Convergence 2026 in Orlando, Florida.
The presentation brought together the company’s Phase II/III clinical findings, Phase I pharmacokinetic observations, and scientific rationale for investigating selective macrophage-targeted glucocorticoid delivery.
Although the clinical efficacy findings were generated in patients with COVID-19 rather than rheumatic diseases, the company believes the results provide a foundation for evaluating the mechanism in additional inflammatory conditions.
The Phase II/III findings are reported in a publicly available medRxiv preprint that has not undergone peer review. Therefore, the reported results should be interpreted in the context of this publication status and the specific study population.
101 Therapeutics’ presentation at ACR Convergence 2026 represents an important step in introducing 101-PGC-005 to the scientific and pharmaceutical development communities.
The investigational candidate combines CD206-mediated macrophage targeting with intracellular dexamethasone delivery, with the objective of reducing inflammatory activity while limiting systemic glucocorticoid exposure and preserving endogenous HPA-axis function.
The Phase II/III COVID-19 study demonstrated faster clinical improvement and viral clearance compared with systemic dexamethasone, alongside similar treatment-emergent adverse event rates. Phase I findings also provided preliminary pharmacokinetic and hormonal observations supporting the company’s targeted delivery strategy.
Moving forward, the company’s priority is to determine whether these findings can translate into meaningful clinical benefits in rheumatology and other macrophage-driven inflammatory conditions.
The planned randomized, placebo-controlled U.S. study in sJIA, together with potential investigations in PMR, RA, GVHD, and cancer immunotherapy-related complications, represents the next stage of the development strategy.
By pursuing pharmaceutical and biotechnology partnerships, 101 Therapeutics aims to advance ‘005 through additional clinical development and explore its potential as a steroid-sparing adjunct to existing targeted treatments.
For partnership discussions, licensing opportunities, or scientific collaborations, interested organizations can contact michael@101therapeutics.com.
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.