A Study Evaluating the Efficacy and Safety of Momelotinib in Participants With Vacuoles, E1-enzyme, X-linked, Autoinflammatory, Somatic (VEXAS) Syndrome (ATLAS)

A Randomized Phase 2/3, Double-blind, Placebo Controlled Adaptive Study Evaluating the Efficacy and Safety of Momelotinib in Participants With VEXAS Syndrome

This study will assess the efficacy and safety of momelotinib in participants with a diagnosis of VEXAS.

Study Overview

• Status: Not yet recruiting
• Conditions: VEXAS Syndrome
• Intervention / Treatment: Drug: Placebo; Drug: Momelotinib; Drug: Glucocorticoids

• Study Type: Interventional
• Enrollment (Estimated): 192
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: US GSK Clinical Trials Call Center; Phone Number: 877-379-3718; Email: GSKClinicalSupportHD@gsk.com
• Study Contact Backup: Name: EU GSK Clinical Trials Call Center; Phone Number: +44 (0) 20 89904466; Email: GSKClinicalSupportHD@gsk.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age greater than equal to (>=)18 years OR of legal age of consent in the jurisdiction in which the study is taking place, at the time of signing the Informed Consent Form.

• Confirmed diagnosis of clinical VEXAS defined by:

  1. Documented evidence of a canonical, pathogenic Ubiquitin-like modifier activating enzyme 1 (UBA1) mutation
  2. Inflammatory manifestations: current or documented past involvement within 6 months of at least one organ system
• Receiving glucocorticoid (GC) treatment (prednisone/prednisolone) for >=4 consecutive weeks for >=10 days prior to randomization.

• A female participant is eligible to participate if she is not pregnant or breastfeeding and one of the following conditions applies:

  1. Is a Participant of non-childbearing potential (PONCBP) OR
  2. Is a Participant of childbearing potential (POCBP) and using a contraceptive method that is highly effective
• Is capable of giving signed informed consent including compliance with the requirements and restrictions
• Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 to 2 at the time of screening.
• Has adequate organ function

Exclusion Criteria:

• More than 1 prior admission to an intensive care unit due to a VEXAS flare within the 6 months prior to randomization.
• History of severe corticosteroid toxicity: uncontrolled concomitant cardiovascular, nervous system, pulmonary (including obstructive pulmonary disease), renal, hepatic, endocrine (including uncontrolled diabetes mellitus), psychiatric, osteoporosis/osteomalacia, glaucoma, corneal ulcers/injuries, nausea or vomiting or gastrointestinal disease.
• High risk/very high risk Myelodysplastic syndrome (MDS), according to the Revised International Prognostic Scoring System (IPSS-R) with overall risk score >3.5.
• Peripheral blood blast counts >=10%.
• Multiple myeloma (all stages) and other active plasma cell dyscrasias requiring treatment.
• Malignancy (except disease under study including Lower-risk myelodysplastic syndrome [LR-MDS]) that has progressed or required active treatment within the past (24 months) except for basal cell or squamous cell carcinomas of the skin or in-situ carcinomas).
• Uncontrolled intercurrent illness within 12 weeks prior to initiation of momelotinib.
• Ongoing adverse reaction(s) from prior therapy that have not recovered to Grade <=1 per NCI CTCAE v6.0 or to the Baseline status preceding prior therapy
• Psychiatric illness, social situation, or any other condition that would limit informed consent and/or compliance with trial requirements or may interfere with the interpretation of study results, as judged by Investigator or Sponsor.
• Has any clinically significant gastrointestinal conditions or abnormalities that may alter absorption or swallowing
• Known contraindication or hypersensitivity to momelotinib and its metabolites, or any of their excipients.
• Presence of peripheral neuropathy >=Grade 2 per NCI CTCAE v6.0.
• Known history of disseminated mycobacterial infection.
• Known positive status for human immunodeficiency virus (HIV).
• Positive QuantiFERON (or other interferon gamma release assay) during Screening.
• Unable to receive any Pneumocystis jiroveci pneumonia (PJP) medical prophylaxis
• Known clinically significant anemia due to iron, vitamin B12 or folate deficiencies, or autoimmune or hereditary hemolytic anemia, gastrointestinal bleeding, or thalassemia.
• More than 1 prior line of VEXAS directed therapy before or after VEXAS diagnosis or other medical condition.

• Use of the following treatments within the noted time periods referenced from date of randomization:

  1. VEXAS-directed therapies (washout period) up to 5 half-lives or up 14 days if half-life is <3 days
  2. Other non-GC anti-inflammatory therapies: for non-biologics): 14 days or five half-lives, whichever is longer; for biologics): 28 days or two half-lives whichever is longer.
  3. Hematologic support therapy (e.g., ESAs, danazol, luspatercept, G-CSF): 4 weeks
  4. Cell-depleting therapies such as anti-CD20 (rituximab): 12 months
  5. Investigational agent from a class not otherwise specified: 5 half-lives or 60 days, whichever is longer
• GC use for conditions other than VEXAS, which would interfere with adherence to the fixed GC taper regimen and/or to assessment of efficacy.
• Chronic use of systemic corticosteroids for >4 years or inability to withdraw corticosteroid treatment
• Planned allogeneic HSCT for MDS or VEXAS, within 1 year.
• Any major surgery within 28 days prior to randomization.
• Prior allogeneic/autologous stem cell transplant or solid organ transplant (other than corneal).
• Presence of peripheral neuropathy >=Grade 2 per NCI CTCAE v6.0.
• Hepatitis B or C active infection, unless protocol defined criteria are met.

• Any of the following conditions within 6 months prior to randomization:

  1. Unstable angina pectoris
  2. Symptomatic congestive heart failure
  3. Uncontrolled cardiac arrhythmia
  4. QTc >450 msec or QTc >480 msec for participants with bundle branch block.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Momelotinib Dose level 1 + Glucocorticoids; Participants will receive momelotinib at dose level 1 along with glucocorticoids as a background therapy (prednisone or prednisolone). Due to adaptive design of the study, additional participants may be randomized to this arm in phase 3.	Drug: Momelotinib; Momelotinib will be administered; Other Names: GSK3070785; Drug: Glucocorticoids; Glucocorticoids (prednisone or prednisolone) will be administered
Experimental: Momelotinib Dose level 2 + Glucocorticoids; Participants will receive momelotinib at dose level 2 along with glucocorticoids as a background therapy (prednisone or prednisolone). Due to adaptive design of the study, additional participants may be randomized to this arm in phase 3	Drug: Momelotinib; Momelotinib will be administered; Other Names: GSK3070785; Drug: Glucocorticoids; Glucocorticoids (prednisone or prednisolone) will be administered
Placebo Comparator: Placebo + Glucocorticoids; Participants will receive momelotinib matched placebo along with glucocorticoids as a background therapy(prednisone or prednisolone). Due to adaptive design of the study, additional participants may be randomized to this arm in phase 3	Drug: Placebo; Placebo will be administered; Drug: Glucocorticoids; Glucocorticoids (prednisone or prednisolone) will be administered

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
ORR (Objective response rate) at Week 26	ORR is defined as the proportion of participants who have achieved complete response (CR) or partial response (PR) during the 26-week Primary Treatment Period.	At Week 26

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase 2: Percentage of participants with partial response (PR) or complete response (CR) at Week 26	Percentage of participants with PR or CR at Week 26 to support identification of the Recommended Phase 3 dose (RP3D)	At Week 26
Phase 2: Number of participants with adverse events and clinically significant changes in laboratory parameters, and vital signs to support identification of the RP3D		Up to 26 Weeks
Phase 2: Plasma concentrations of momelotinib and metabolite of momelotinib 21 (M21) to support identification of the RP3D		Up to 26 Weeks
Number of flare-free days	Flare-free days are calendar days without clinical evidence of VEXAS flare and without treatment escalation. Total number of flare-free days is defined as the cumulative number of consecutive and non-consecutive flare-free days.	Up to 26 Weeks
Duration of response (DoR)	DoR defined as the date of clinical response (CR or PR) to the date of relapse.	Up to 104 Weeks
Number of flare-free days with glucocorticoid (GC) dose <=10 mg/day	Flare-free days are calendar days without clinical evidence of VEXAS flare and without treatment escalation. Total number of flare-free days is defined as the cumulative number of consecutive and non-consecutive flare-free days.	Up to 104 Weeks
Percentage of participants achieving complete and partial biochemical response	Complete biological response is defined as complete or partial normalization of C-reactive protein.	Up to 26 Weeks
Objective response rate (ORR) at Week 52	ORR is defined as the proportion of participants who have achieved complete response or partial response	At Week 52
Number of Participants with Hematologic Improvement- Erythroid (HI-E) response per International Working Group (IWG) 2018 criteria	HI-E response is measured based on the combined incidence of: Low transfusion burden participants defined as absence of any transfusion for greater than or equal to (>=)8 consecutive weeks. High transfusion burden participants: minor response defined as reduction by >=50% of red blood cell (RBC) units for >=8 consecutive weeks. Major response defined as absence of RBC transfusions for >=8 consecutive weeks or longer up to 26 weeks.	Up to 26 Weeks
Change from Baseline in Short Form 36 (SF-36) domain and summary scores	Short-Form 36 is a health-related survey that assesses quality of life covering 8 domains: vitality; physical functioning; bodily pain; general health perceptions; physical role functioning; emotional role functioning; social role functioning; and mental health. The domain scores are weighted to a scale ranging between 0 to 100, where higher score represents better health. The Physical Component Summary (PCS) and Mental Component Summary (MCS) scores are derived from the eight domain scores. These scores are standardized to a general U.S. population average of 50, with a standard deviation of 10. For both PCS and MCS, scores range from 0 to 100, higher scores indicate a better health outcome.	Baseline and up to Week 48
Change from Baseline in European Organization for Research and Treatment of Cancer Item Library (EORTC IL) 479 score	The EORTC Item Library is a database containing >1000 individual items from more than 70 EORTC quality of life measures. A subset of 7 items from the library were selected based on symptoms experienced by participants with VEXAS syndrome. Scores range from 1 to 100 with higher scores representing a higher ("worse") level of symptoms.	Baseline and up to Week 156
Change From Baseline in Patient Reported Outcome Measurement Information System (PROMIS) Physical Function Short Form 10b	PROMIS Physical Function Short Form 10b consists of 10 questions; each with a 5-point response. PROMIS short form assesses self-reported capability of a participant rather than actual performance of physical activities. Higher scores indicate better functioning. Total possible range of scores is 10 to 50, with higher scores corresponding to a greater physical function ability.	Baseline and up to Week 156
Change from Baseline in Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-FATIGUE)	The FACIT-Fatigue is a short, 13-item questionnaire that assesses self-reported fatigue and its associated impact on daily activities over the past 7 days. A higher score indicates a better outcome (no fatigue). The total score ranges from 0 to 52, with 0 being the worst possible score and 52 being the best possible score (indicating no fatigue).	Baseline and up to Week 156
Changes from Baseline in Patient Global Impression of Severity (PGIS) scores	The PGIS is a single global question which asks participants to rate the severity of their VEXAS syndrome symptoms on a 5-point rating scale with response categories of "No symptoms", "Mild", "Moderate", "Severe", and "Very Severe." The PGIS scores ranges from 0 (absent) to 4 (very severe).	Baseline and up to Week 156
Changes in Patient Global Impression of Change (PGIC) scores	The PGIC is a single global question which asks participants to rate the change in severity of their VEXAS syndrome symptoms since starting study medication using a 5-point rating scale with response categories of "much better", "a little better", "no change", "a little worse", "much worse". The PGIC score ranges from +2 (much better) to -2 (much worse).	Baseline and up to Week 156
Changes from Baseline in European quality of life 5 dimensions 5 level version (EQ-5D-5L)	EQ-5D-5L is self-assessment questionnaire, consisting of 5 items covering 5 dimensions (mobility, self care, usual activities, pain/discomfort, and anxiety/depression). Each dimension is measured by 5-point Likert scale ranging from 1=no problems to 5=extreme problems.	Baseline and up to Week 48
Changes from Baseline in European quality of life-Visual Analogue Scale (EQ-VAS)	The EQ-VAS records the respondents self-rated health on a vertical VAS, ranging from 0 to 100, where 0 represents the worst imaginable health and 100 represents the best imaginable health.	Baseline and up to Week 48
Number of participants with adverse events (AEs) and Serious adverse events (SAEs)		Up to Week 108
Number of participants with adverse events (AEs) and Serious adverse events (SAEs) by severity		Up to Week 108
Number of participants with AEs leading to discontinuation or dose modifications		Up to Week 108
Plasma concentration of momelotinib and M21		Up to 26 Weeks
Overall Survival	Overall survival is defined as the time from randomization to the date of death due to any cause.	At Months 12, 24 and 36

Collaborators and Investigators

• Sponsor: GlaxoSmithKline
• Investigators: Study Director: GSK Clinical Trials, GlaxoSmithKline

Study record dates

Study Major Dates

• Study Start (Estimated): August 5, 2026
• Primary Completion (Estimated): December 6, 2028
• Study Completion (Estimated): June 4, 2031

Study Registration Dates

• First Submitted: April 28, 2026
• First Submitted That Met QC Criteria: April 28, 2026
• First Posted (Actual): May 6, 2026

Study Record Updates

• Last Update Posted (Actual): May 6, 2026
• Last Update Submitted That Met QC Criteria: April 28, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Adaptive; ATLAS; Momelotinib; VEXAS Syndrome; Ubiquitin-like modifier activating enzyme 1 mutation
• Additional Relevant MeSH Terms: VEXAS syndrome; Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Pharmacologic Actions; Chemical Actions and Uses; Adrenal Cortex Hormones; Glucocorticoids; N-(cyanomethyl)-4-(2-((4-(4-morpholinyl)phenyl)amino)-4-pyrimidinyl)benzamide
• Other Study ID Numbers: 223401; 2025-524416-11-00 (Other Identifier: EU CT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No