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

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.