Clinical trial NCT05460832
Conditions: Rheumatoid Arthritis
Keywords: Rheumatoid Arthritis (RA) MBS2320
Sponsor: Modern Biosciences Ltd
Start date: 2022-08-29; Completion date: 2024-01-03
Enrollment: 248 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Rheumatoid arthritis (RA) affects 1 percent of the population worldwide and up to 40 percent of patients don't respond to current treatments. MBS2320, the drug being tested in this trial, represents a new approach to treating RA, with the potential not only to reduce levels of inflammation but to also directly prevent bone damage. The aim of this project is to test the safety, tolerability and efficacy of MBS2320 in patients with RA in combination with an existing treatment, methotrexate.

Approximately 224 participants with moderate to severe active RA who have not responded to treatment with Methotrexate will be enrolled from around 45 to 55 sites around the world. Participants will be randomly assigned to receive 1 of 3 doses of MBS2320 (5 mg, 20 mg, or 40 mg) or placebo (a "dummy" drug).

The maximum duration of study participation for a participant will be 22 weeks, which consists of a Screening Period of up to 4 weeks, Treatment Period of 12 weeks, and a Follow-up Period of 6 weeks.

Participants on the study will be asked to attend the hospital or clinic for regular visits during which they will have planned study assessments to evaluate the effectiveness, tolerability and safety of the study drug.

Detailed description:

Arms: arm 1: None arm 2: None arm 3: None arm 4: None
Interventions: intervention 1: MBS2320 5 mg intervention 2: MBS2320 20 mg intervention 3: MBS2320 40 mg intervention 4: Placebo
Intervention descriptions: intervention 1: Oral capsule intervention 2: Oral capsule intervention 3: Oral capsule intervention 4: Oral capsule

Protocol documents:
Prot_SAP_000.pdf: 
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Protocol Synopsis 
Protocol Number: IST-06 
Title: A Randomised, Double-Blind, Placebo-Controlled, Dose-Ranging Phase 2b Study to 
Investigate the Efficacy and Safety of MBS2320 With Background Methotrexate (MTX) in 
Participants With Moderate to Severe Active Rheumatoid Arthritis (RA) Who Have Had an 
Inadequate Response to MTX Alone 
Short Title (if applicable): Dose-Ranging Phase 2b Study of MBS2320 in Participants with 
Methotrexate-Refractory RA 
Sponsor: Modern Biosciences Ltd 
2nd Floor 
3 Pancras Square 
Kings Cross 
London 
N1C 4AG 
Study Phase: 2b 
Study Sites: approximately 45 to 55 sites globally 
Indication: Rheumatoid arthritis  
Rationale: The current treatment regimen for rheumatoid arthritis (RA) consists of initial 
treatment with non-steroidal anti-inflammatory drugs (NSAIDs), low-dose glucocorticoids, 
and non-biologic disease-modifying anti-rheumatic drugs (DMARDs) such as the 
immunosuppressant, methotrexate (MTX). Second and third-line therapy is increasingly 
focused on the biologic DMARDs (bDMARDs) and targeted synthetic DMARDs 
(tsDMARDs), the most commonly used of which are anti-tumour necrosis factor (TNF) α 
agents such as adalimumab, infliximab, and etanercept and the Janus kinase (JAK) inhibitors 
such as tofacitinib, baricitinib, and upadacitinib. These agents have demonstrated their 
efficacy in reducing the signs and symptoms of disease and the inhibition of progression of 


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structural damage, but a high failure rate necessitates switching between agents. Furthermore, 
bDMARDs are associated with rare but serious side effects, including opportunistic 
infections such as tuberculosis (TB), invasive fungal infections, and malignancies such as 
lymphoma and tsDMARDs are associated with increased infections and cardiovascular 
events. In addition, neither the bDMARDs nor the tsDMARDs directly address the 
mechanism of structural damage; thus, the disability stemming from bone and joint 
destruction remains the most debilitating feature of the disease. 
There is, therefore, scope for a new DMARD with a novel mechanism of action, greater 
safety, and a mode of action that not only prevents the inflammatory component of RA, but 
also provides a directly protective effect on bone. 
MBS2320 is being developed for the once daily oral therapy of RA. Based on the 
non-clinical and clinical data generated to date, it is anticipated that MBS2320 can have a 
direct impact on structural damage in RA, in contrast to the current standard of care, and a 
reduced propensity for adverse events (AEs) arising from immunosuppression. 
Objectives and Estimands: 
Objectives 
Estimand Description (Including Endpoint) 
Primary Objective 
Primary Endpoint: Composite clinical response 
(Success/Failure) at Week 12 defined as:  
• Achieving clinical response according to the criteria 
for ACR20: 
o ≥20% improvement in 68-TJC; 
o ≥20% improvement in 66-SJC; and 
o ≥20% improvement in at least 3 of the 5 
following parameters: 
 Physician’s global assessment of disease 
activity 
 Participant’s global assessment of 
disease activity 
 Participant’s assessment of arthritis pain 
 HAQ-DI 
To evaluate the efficacy of 
MBS2320 (5 mg once daily, 
20 mg once daily, and 40 mg 
once daily) compared with 
placebo in participants with 
active RA on stable 
background MTX who have 
had an inadequate response to 
MTX alone, with confirmed 
intra-articular synovitis on 
baseline MRI. 


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Objectives 
Estimand Description (Including Endpoint) 
 hsCRP 
o Not discontinuing treatment due to tolerability 
issues or lack of efficacy; and 
o Not requiring any increase in RA medications - 
either in background medication dose (MTX) 
or any further alternative RA treatment or 
procedure. 
 
Primary Estimand 1: Difference in percentage of patients 
with moderate to severe active RA and a previous 
inadequate response to MTX alone, with confirmed 
intra-articular synovitis on baseline MRI, who would have 
a successful composite clinical response after 12 weeks of 
treatment with MBS2320 (5 mg, 20 mg, or 40 mg once 
daily) compared to placebo (each on top of stable 
background RA medication of weekly MTX). A successful 
composite clinical response is defined as achieving clinical 
response according to the criteria for ACR20 without 
discontinuing treatment due to tolerability issues or lack of 
efficacy or requiring any increase in RA medications, but 
irrespective of any interruptions required for treatment 
related reasons. 
Key Secondary Objectives 
To evaluate the efficacy of 
MBS2320 (5 mg once daily, 
20 mg once daily, and 40 mg 
once daily) compared with 
placebo on other clinical 
endpoints in participants with 
active RA on stable 
background MTX who have 
had an inadequate response to 
MTX alone, with confirmed 
intra-articular synovitis on 
baseline MRI. 
Endpoint: Change in RAMRIS scores (synovitis, bone 
oedema, and bone erosion scores, measured with MRI) 
from baseline to Week 12. 
Estimand 2A: Difference in 
mean change from baseline 
in each RAMRIS score 
(synovitis, bone oedema, 
and bone erosion scores, 
measured with MRI), in 
patients with moderate to 
severe active RA and a 
previous inadequate 
response to MTX alone, 
with confirmed intra-
articular synovitis on 
Estimand 2B: Difference 
in mean change from 
baseline in each RAMRIS 
score (synovitis, bone 
oedema, and bone erosion 
scores, measured with 
MRI), in patients with 
moderate to severe active 
RA and a previous 
inadequate response to 
MTX alone, with confirmed 
intra-articular synovitis on 


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Objectives 
Estimand Description (Including Endpoint) 
baseline MRI, assessed after 
12 weeks of treatment with 
MBS2320 (5 mg, 20 mg, or 
40 mg once daily) compared 
to placebo (each on top of 
stable background RA 
medication of weekly 
MTX), as though no 
increase in any RA 
medication and no treatment 
discontinuation or 
interruption for any reason. 
baseline MRI, assessed 
after 12 weeks of treatment 
with MBS2320 (5 mg, 20 
mg, or 40 mg once daily) 
compared to placebo (each 
on top of stable background 
RA medication of weekly 
MTX), irrespective of 
treatment discontinuation or 
interruption due to 
tolerability issues or lack of 
efficacy, and as though no 
increase in any other RA 
medication. 
 
Endpoint: Change in DAS28-hsCRP from baseline to 
Weeks 4, 8, and 12. 
Estimand 3A: Difference in 
mean change from baseline 
in DAS28-hsCRP in patients 
with moderate to severe 
active RA with a previous 
inadequate response to 
MTX alone, with confirmed 
intra-articular synovitis on 
baseline MRI, after each of 
4, 8, and 12 weeks of 
treatment with MBS2320 
(5 mg, 20 mg, or 40 mg 
once daily) compared to 
placebo (each on top of 
stable background RA 
medication of weekly 
MTX), as though no 
increase in any RA 
medication and no treatment 
Estimand 3B: Difference 
in mean change from 
baseline in DAS28-hsCRP 
in patients with moderate to 
severe active RA with a 
previous inadequate 
response to MTX alone, 
with confirmed intra-
articular synovitis on 
baseline MRI, after each of 
4, 8, and 12 weeks of 
treatment with MBS2320 
(5 mg, 20 mg, or 40 mg 
once daily) compared to 
placebo (each on top of 
stable background RA 
medication of weekly 
MTX), irrespective of 
treatment discontinuation or 
interruption due to 


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Objectives 
Estimand Description (Including Endpoint) 
discontinuation or 
interruption for any reason. 
tolerability issues or lack of 
efficacy, and as though no 
increase in any other RA 
medication. 
Endpoint: Composite clinical response (Success/Failure) 
at Weeks 4 and 8 defined as achieving clinical response 
according to the criteria for ACR20 without discontinuing 
treatment due to tolerability issues or lack of efficacy or 
requiring any increase in RA medications. 
Estimand 4: Difference in percentage of patients with 
moderate to severe active RA with a previous inadequate 
response to MTX alone, with confirmed intra-articular 
synovitis on baseline MRI, who would have a successful 
composite clinical response after each of 4 and 8 weeks of 
treatment with MBS2320 (5 mg, 20 mg, or 40 mg once 
daily) compared to placebo (each on top of stable 
background RA medication of weekly MTX). A successful 
composite clinical response is defined as achieving clinical 
response according to the criteria for ACR20 without 
discontinuing treatment due to tolerability issues or lack of 
efficacy or requiring any increase in RA medications, but 
irrespective of any interruptions required for treatment 
related reasons. 
Other Secondary Objectives 
Endpoints 
To evaluate the efficacy of 
MBS2320 (5 mg once daily, 
20 mg once daily, and 40 mg 
once daily) compared with 
placebo on other clinical 
endpoints in participants with 
active RA on stable 
background MTX who have 
had an inadequate response to 
MTX alone, with confirmed 
1. Percentage of participants achieving clinical
response according to the criteria for ACR50 at
Weeks 4, 8, and 12;
2. Percentage of participants achieving clinical
response according to the criteria for ACR70 at
Weeks 4, 8, and 12;
3. Change in hsCRP level compared to baseline at
Weeks 4, 8, and 12;
4. Change in TJC (68 joints) compared to baseline at
Weeks 4, 8, and 12;


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Objectives 
Estimand Description (Including Endpoint) 
intra-articular synovitis on 
baseline MRI. 
5. Change in SJC (66 joints) compared to baseline at 
Weeks 4, 8, and 12; 
6. Change in participant's assessment of arthritis pain 
(as measured on a 0 to 100 mm VAS) compared to 
baseline at Weeks 4, 8, and 12; 
7. Change in participant's global assessment of 
disease activity (as measured on a 0 to 100 mm 
VAS) compared to baseline at Weeks 4, 8, and 12; 
8. Change in physician's global assessment of disease 
activity (as measured on 0 to 100 mm VAS) 
compared to baseline at Weeks 4, 8, and 12; 
9. Change in participant's global impression of change 
(as measured on a 7-point scale) compared to 
baseline at Weeks 4, 8, and 12; 
10. Change in participant's global assessment of health 
(as measured on 0 to 100 mm VAS) compared to 
baseline at Weeks 4, 8, and 12; 
11. Change in EULAR RAID score compared to 
baseline at Weeks 4, 8, and 12; 
12. DAS28-hsCRP remission (i.e. DAS28-hsCRP <2.6) 
rate at Weeks 4, 8, and 12; 
13. DAS28-hsCRP low disease activity rate (i.e. 
DAS28-hsCRP <3.2) at Weeks 4, 8, and 12; 
14. EULAR response rate at Weeks 4, 8, and 12; 
15. SDAI remission (i.e. SDAI score ≤3.3) rate at 
Weeks 4, 8, and 12; 
16. CDAI remission (i.e. CDAI score ≤2.8) rate at 
Weeks 4, 8, and 12; 
17. Change in fatigue score (FACIT-F) (as measured on 
a 5-point scale) compared to baseline at Weeks 4, 8, 
and 12; 
18. Change in HAQ-DI scores compared to baseline at 
Weeks 4, 8, and 12; 
19. Change in EQ-5D scores compared to baseline at 
Weeks 4, 8, and 12; 
20. Change in CARLOS from baseline to Week 12. 


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Objectives 
Estimand Description (Including Endpoint) 
To evaluate the safety and 
tolerability of select MBS2320 
doses (5 mg once daily, 20 mg 
once daily, and 40 mg once 
daily) compared with placebo 
in participants with active RA 
on stable background MTX 
who have had an inadequate 
response to MTX alone. 
Incidence of TEAEs. 
To evaluate steady-state plasma 
concentrations of MBS2320 
and MBS2473. 
MBS2320 and MBS2473 plasma concentrations (pre-dose 
at Weeks 4 and 12) and 3 (±1) hours postdose following 
last dose at Week 12 and at the EOS.  
Exploratory Objectives 
Endpoints 
To evaluate the exploratory 
endpoints after treatment with 
MBS2320 (5 mg once daily, 
20 mg once daily, and 40 mg 
once daily) and placebo in 
participants with active RA on 
stable background MTX who 
have had an inadequate 
response to MTX alone, with 
confirmed intra-articular 
synovitis on baseline MRI. 
1. Change in exploratory biomarkers (which may
include but will not be limited to: inflammatory
cytokines, metabolites, and biomarkers of bone
turnover) compared to baseline at Week 12;
2. Change in peripheral blood leucocyte phenotype
(which may include but will not be limited to: flow
cytometry, gene expression, and/or protein levels)
compared to baseline at Weeks 4 and 12;
3. Change in ACPA levels from screening to Week 12;
4. Change in rheumatoid factor compared to baseline
at Week 12.
Other exploratory endpoints will be defined in the SAP. 
ACPA=anti-citrullinated protein antibody; ACR20=American College of Rheumatology 20% response; 
ACR50=American College of Rheumatology 50% response; ACR70=American College of Rheumatology 70% 
response; CARLOS=cartilage loss; CDAI=clinical disease activity index; DAS28=disease activity score 28 
joints; EOS=end of study; EQ-5D=EuroQoL-5 dimensions; EULAR=European League Against Rheumatism; 
FACIT-F=Functional Assessment of Chronic Illness Therapy-Fatigue; HAQ-DI=Health Assessment 
Questionnaire-Disability Index; hsCRP=high-sensitivity C-reactive protein; MRI=magnetic resonance imaging; 
MTX=methotrexate; RA=rheumatoid arthritis; RAID=Rheumatoid Arthritis Impact of Disease; 
RAMRIS=rheumatoid arthritis MRI scoring system; SAP=statistical analysis plan; SDAI=simplified disease 
activity index; SJC=swollen joint count; TEAE=treatment-emergent adverse event; TJC=tender joint count; 
VAS=visual analogue scale. 


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Diagnosis and Main Criteria for Inclusion and Exclusion: 
Inclusion Criteria 
Each participant must meet all the following criteria to be enrolled in this study: 
1. Between 18 and 75 years of age, inclusive.
2. Diagnosed with RA based on either the 1987-revised American College of
Rheumatology (ACR) classification criteria or the 2010 ACR/ European League
Against Rheumatism (EULAR) criteria for ≥3 months prior to screening.
3. Has active RA as defined by the following minimum disease activity criteria:
o
≥6 swollen joints (based on 66 joint counts) at screening and baseline visits.
o
≥6 tender joints (based on 68 joint counts) at screening and baseline visits.
o
High-sensitivity C-reactive protein (hsCRP) > upper limit of normal reference
range (ULN) at screening. One repeat assessment is acceptable for C-reactive
protein per Investigator’s discretion if all other eligibility criteria are met.
4. Considered to be inadequately responding to oral or parenteral MTX therapy for
≥3 months and <10 years prior to screening and to be tolerating a dose of 15 to 25 mg
per week for at least 56 days prior to baseline visit. Participants should also be on a
stable dose of folic acid (or equivalent) for at least 56 days prior to baseline visit.
Participants should continue with their stable doses of MTX and folic acid throughout
the study.
5. Except for MTX, must have discontinued all oral DMARDs prior to baseline visit as
specified below or for at least 5 half-lives of a drug, whichever is longer:
o
≥4 weeks prior to baseline visit for minocycline, D-penicillamine,
sulfasalazine, hydroxychloroquine, chloroquine, azathioprine, oral or
parenteral gold formulations.


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o
≥8 weeks prior to baseline visit for leflunomide (if no elimination procedure
was followed or adhere to a washout procedure i.e. 11 days washout with
cholestyramine or 30 days washout with activated charcoal) and for oral
cyclosporine.
o
≥24 weeks prior to the baseline visit for cyclophosphamide.
6. Negative test for TB by QuantiFERON-TB Gold In-Tube test. Indeterminate results
may be repeated and if negative or still indeterminate, participant may be included in
the study if they have no clinical symptoms of TB, have had no known exposure to
TB, and have had a negative chest X-ray within previous 3 months.
7. If participants are taking NSAIDs or acetaminophen for stable medical conditions,
they should be receiving these medications at a stable dose for at least 4 weeks prior
to baseline visit and the doses of the medications should be kept stable throughout the
study. If participants are taking non-steroidal anti-inflammatory drugs,
acetaminophen, tramadol, codeine, hydrocodone, and propoxyphene on a need basis,
these drugs should not be taken 24 hours prior to any study visit.
8. If participants are taking oral corticosteroids (equivalent to prednisolone ≤10 mg), or
inhaled corticosteroids, they should be receiving these medications at a stable dose
for at least 4 weeks prior to baseline visit for stable medical conditions. The doses of
the medications should be kept stable throughout the study. Oral and inhaled
corticosteroids taken as needed are allowed but may not be taken 24 hours prior to
any study visit.
9. Willing to provide written informed consent to participate in the study and to abide by
the study restrictions.
Exclusion Criteria 
Participants meeting any of the following criteria will be excluded from the study: 


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Medical Conditions: 
1. Abnormality in heart rate or blood pressure at screening that in the opinion of the 
Investigator increases the risk of participating in the study. 
2. Abnormality in the 12-lead electrocardiogram (ECG) at screening that in the opinion 
of the Investigator increases the risk of participating in the study. 
o Specific exclusion criteria are participants with QT interval corrected for heart 
rate using Fridericia's formula (QTcF) of >450 ms (males) or >460 ms (females) 
and participants with PR interval of >220 ms at screening (1 repeat assessment is 
allowed). 
3. Significant history of drug allergy, including to MBS2320 or excipients, as 
determined by the Investigator. 
4. Allergic reaction, anaphylaxis, or other reactions (eg, Stevens-Johnson syndrome, 
toxic epidermal necrolysis or leukopenia) to sulphonamides drugs. 
5. Any clinically significant neurological, gastrointestinal (GI), renal, hepatic, 
cardiovascular, psychiatric, respiratory, metabolic, endocrine, haematological, 
ophthalmic, or other major disorder which in the opinion of the Investigator would 
put the participant at risk by participating in the study (except for RA or disorders 
associated with RA that, in the Investigator’s opinion, do not constitute a risk when 
taking the investigational product (IP) and would not interfere with the study 
objectives). 
6. Any current malignancy or a history of malignancy within 5 years prior to screening, 
with the exception of adequately treated or excised non-metastatic basal cell or 
squamous cell cancer of the skin or cervical carcinoma in situ. 
7. Any other inflammatory or arthritic disease in addition to RA that may interfere with 
the study (such as fibromyalgia, polymyalgia rheumatica, giant-cell arteritis, reactive 
arthritis, systemic lupus erythematosus, psoriatic arthritis, ankylosing spondylitis). 


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8. Active infection that is clinically significant, in the Investigator’s opinion, or any 
infection requiring hospitalisation or treatment with intravenous antimicrobials 
≤60 days of screening, or any infection requiring oral antimicrobial therapy ≤2 weeks 
of the baseline visit. 
9. Clinically significant features of arthroses that could interfere with study assessments 
and objectives. 
10. History of alcoholic hepatitis or non-alcoholic steatohepatitis. 
11. History of opportunistic, chronic, or recurrent infections. 
Prior/Concomitant Therapy 
12. A live virus vaccination within the 90 days prior to baseline visit (1 year for Bacillus 
Calmette-Guerin vaccination) or intend to receive a live virus vaccination during the 
study or within 28 days after study completion. 
13. Prior exposure to any JAK inhibitor, investigational or approved, (e.g. tofacitinib, 
baricitinib, upadacitinib, filgotinib). 
14. Prior exposure to any biologic RA therapy, investigational or approved, 
(e.g. abatacept, rituximab, anakinra or tocilizumab, anti-TNFα agents [including, but 
not limited to, infliximab, adalimumab, golimumab, and biosimilars thereof]) or any 
approved or investigational monoclonal antibody or recombinant protein therapy  
15. Prosorba column treatment within 60 days prior to baseline visit. 
16. Current or expected need of other immunosuppressant medications including >10 mg 
oral prednisolone/day or equivalent corticosteroid therapy (see inclusion criterion 8). 
Use of MTX as described in Inclusion Criteria 4 is permitted. 
17. Any intravenous, intramuscular, or intra-articular corticosteroids within 30 days prior 
to baseline visit or expected to require parenteral corticosteroid through the study. 
18. High potency opiates including (but not limited to): oxycodone, oxymorphone, 
fentanyl, levorphanol, buprenorphine, methadone, hydromorphone, and morphine 
within 4 weeks prior to baseline visit. 


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19. Oral bisphosphonates within 6 months prior to baseline visit or once-a-year 
intravenous bisphosphonates within 1 year prior to baseline visit. 
20. Any prior use of denosumab. 
21. Use of strong cytochrome P450 3A4 inhibitors/inducers within 30 days or 
5 half-lives, whichever is longer, prior to baseline visit. 
22. Use of uridine 5'-diphospho-glucuronosyltransferase family 2 member B7 inhibitors 
within 30 days or 5 half-lives, whichever is longer, prior to baseline visit. 
23. Systemically administered carbonic anhydrase inhibitors within 30 days or 
5 half-lives, whichever is longer, prior to baseline visit. 
24. Any prior use of cytotoxic agents for indications other than RA (including, but not 
limited to, chlorambucil, nitrogen mustard, or other alkylating agents). 
Prior/Concurrent Clinical Study Experience 
25.  Participation in another clinical study (including attending follow-up visits) or 
receipt of any investigational drug of chemical or biologic nature within a minimum 
of 90 days or 5 half-lives of the drug (whichever is longer) prior to baseline visit. 
26. Previously received MBS2320. 
Diagnostic Assessments 
27. Chest X-ray within 90 days prior to baseline visit that shows an abnormality 
suggestive of malignancy, current infection, or old inactive TB.  
28. Screening laboratory values meeting the following criteria: 
o Serum aspartate aminotransferase or alanine aminotransferase >1.2 × ULN OR 
total bilirubin >1.5 × ULN; 
o Estimated glomerular filtration rate by simplified 4-variable Modification of Diet 
in Renal Disease formula ≤60 mL/min/1.73 m²; 
o Total white blood cell count <3,000/µL; 
o Absolute neutrophil count <1,500/µL; 


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o Platelet count <100,000/µL; 
o Absolute lymphocyte count <800/µL; 
o Haemoglobin <9 gm/dL. 
Note: One repeat assessment is acceptable (not including any laboratory findings that 
in the Investigator’s opinion are consistent with a diagnosis of RA). 
29. Positive serology results for hepatitis B surface antigen (HBsAg) or hepatitis B core 
antibody (HBcAb), hepatitis C (HCV) antibody with positive confirmatory test for 
HCV (eg polymerase chain reaction [PCR]), or human immunodeficiency virus (HIV) 
antibody at the screening visit. 
Note: Participants with a positive HBcAb and a negative HBsAg can be included in 
this study if hepatitis B surface antibody (HBsAb) is positive (considered immune 
after a natural infection). Participants with negative confirmatory test for HCV can be 
included in this clinical study. 
Other Exclusions 
30. Female who is pregnant or breastfeeding. 
31. Non-sterilized male participants who: 
o do not agree to use appropriate contraception (e.g. a condom with spermicidal 
foam/gel/film/cream) with their partners of childbearing potential or partners 
sterilised by tubal ligation. 
o do not agree to refrain from donating sperm from the time of the first dose 
until 90 days after the final dosing occasion. 
32. Female participants of childbearing potential who do not agree to use a highly 
effective method of birth control (e.g. contraceptive measure with a failure rate of 
<1% per year) in conjunction with male contraception (i.e. a condom with 
spermicidal foam/gel/film/cream) from the time of the first dose until 90 days after 
the final dosing occasion. 
33. Donated blood in the 90 days prior to screening. 


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34. Significant history of alcoholism or drug/chemical abuse within 1 year prior to 
screening, as determined by the Investigator. 
35. Surgery for RA (e.g. synovectomy, arthroplasty) within 90 days prior to baseline visit, 
previous joint replacement surgery, or surgery for RA planned during the study. 
36. History of other major surgery (requiring regional block or general anaesthesia) 
within 3 months prior to baseline or planned  surgery during the study. 
37. Prior GI surgeries or any GI procedures/conditions that may cause concerns with 
absorption of the IP. 
38. Risk factors for severe coronavirus disease 2019, which in the opinion of the 
Investigator would put the participant at risk by participating in the study. 
Study Design: 
This is a randomised, double-blind, multicentre, placebo-controlled, dose-ranging study to 
evaluate the efficacy, safety, and tolerability of MBS2320 with background MTX in 
participants with moderate to severe RA who have had an inadequate response to MTX 
alone. 
Approximately 224 participants will be enrolled in 4 cohorts (56 participants each) across 
approximately 45 to 55 sites globally. Participants will be randomly assigned in 1:1:1:1 ratio 
to receive 1 of 3 doses of MBS2320 (5 mg, 20 mg, or 40 mg) or placebo.  
The study will include 3 periods: 1) Screening Period (up to 4 weeks); 2) Treatment Period 
(12 weeks); and 3) Follow-up Period (6 weeks). 
All prospective participants will sign and date the informed consent form (ICF) prior to any 
study assessments or procedures. Potential participants will be assessed as per the eligibility 
criteria at screening. After completing all screening assessments, participants who meet all 
the inclusion criteria and none of the exclusion criteria will proceed to the Treatment Period.  
On Day 1 (Baseline Visit), participants will have to visit the study site having fasted for at 
least an 8-hour period to allow for the collection of exploratory biomarker samples in the 


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fasted state. After confirming a participant’s eligibility, they will be randomly assigned to 
receive either MBS2320 (5 mg, 20 mg, or 40 mg) or placebo. Dosing will be once daily. All 
participants will be administered their first dose of IP with food and a glass of water at the 
study site. 
Following administration of first dose of MBS2320 or placebo and before leaving the site, 
each participant will be given a card to carry at all times in case of an emergency outside the 
site. The card gives details of the study number, start and end date of the participant’s 
involvement in the study, participant details, name of the relevant study physician, and the 
address and telephone number of the site. Participants may destroy this card 4 weeks after 
they have completed the study. 
Investigational product, sufficient to last until the next visit will be dispensed to the 
participant. Participants will be instructed to self-administer the IP once daily in the morning, 
with food. If participant does not take a dose of IP within +12 hours of their regular dosing 
time, then the dose of IP should be skipped, and the participant should be instructed to take 
the IP at the next regularly scheduled time. 
Participants will have to visit the study site at Week 4 (Day 28±3 days), Week 8 
(Day 56±3 days), and Week 12 (Day 84±3 days) for study assessments. Participants will be 
instructed NOT to take their morning dose of IP at home every time they attend a study visit 
on Visits 3, 4, and 5. At Week 12 visit, the participants will arrive at the study site having 
fasted for at least an 8-hour period to allow for the collection of exploratory biomarker 
samples in the fasted state. 
The Week 12 visit will constitute the End-of-Treatment (EOT) Visit. Participants will 
complete a 6-week Follow-up Period after the last dose of IP. The Week 18 visit will 
constitute the End-of-Study (EOS) Visit.  
The maximum duration of study participation for a participant will be 22 weeks 
(approximately 154 days), which consists of a Screening Period of up to 4 weeks (28 days), 
Treatment Period of 12 weeks (84 days), and a Follow-up Period of 6 weeks (42 days). 


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The start of the study is defined as the date the first participant signs the ICF. The end of the 
study is defined as the date of the last participant’s last assessment (scheduled or 
unscheduled). 
Duration of Treatment: 12 weeks 
Efficacy Assessments: 
Swollen/Tender Joint Count 
An assessment of 66 joints for swelling and 68 joints for tenderness will be made by the 
independent Joint Assessor. Joints will be assessed and classified as swollen/not swollen and 
tender/not tender (by pressure and joint manipulation) on physical examination. Joint 
prosthesis, arthrodesis, or fused joints will not be taken into consideration for swelling or 
tenderness. Confirmation of the joints to be assessed for swelling and tenderness will be 
provided to the participating sites. 
The assessment of swollen and tender joints will also be used for the ACR clinical response 
assessment and the 28-joint count required for the DAS28-hsCRP, simplified disease activity 
index (SDAI), and clinical disease activity index (CDAI) scores. 
Participant’s Global Assessment of Disease Activity 
The participant’s overall assessment of their current disease activity will be measured on a 
visual analogue scale (VAS). The left-hand extreme of the line should be described as “very 
well” (no arthritis symptoms) and the right-hand extreme as “very poor” (maximum arthritis 
disease activity). 
Physician’s Global Assessment of Disease Activity 
The physician’s assessment of the participant’s current disease activity will be measured on a 
VAS. The left-hand extreme of the line should be described as “no arthritis activity” and the 
right-hand extreme as “extremely active arthritis”. This should be completed by the identified 
experienced Investigator. 


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Participant’s Assessment of Arthritis Pain 
The participant’s assessment of their current level of arthritis pain will be measured on a 
VAS. The left-hand extreme of the line should be described as “no pain” and the right-hand 
extreme as “worst possible pain”. 
Participant’s Global Assessment of Health 
The participant will rate their general health within the context of their RA and how they are 
doing on a VAS. The left-hand extreme of the line should be described as “very well” and the 
right-hand extreme as “extremely bad”. 
Participant’s Global Impression of Change Scale 
The participant’s assessment of the change (if any) in activity, limitations, symptoms, 
emotions, and overall quality of life (QoL) related to their condition will be assessed using a 
7-point scale, where 1 = No change (or condition has got worse) and 7 = A great deal better, 
and a considerable improvement that has made all the difference. 
European League Against Rheumatism RA Impact of Disease 
The participant’s assessment of disease impact with respect to pain, functional disability 
assessment, fatigue, sleep, physical well-being, emotional well-being, and coping will each 
be assessed using a 10-point scale, where higher values indicate worse status. 
Health Assessment Questionnaire - Disability Index 
The Stanford Health Assessment Questionnaire - Disability Index (HAQ-DI) is a 
participant-completed questionnaire specific for RA. It consists of 20 questions referring to 8 
component sets: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and 
activities. The questionnaire will be provided in validated translation into the local languages 
at the participating sites and will be scored based on the instructions from the Stanford 
University Medical Center. 


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EuroQoL 5-Dimension 
EuroQoL 5-Dimension (EQ-5D) is an instrument that evaluates the generic QoL. The EQ-5D 
consists of 1 question for each of the 5 dimensions that include mobility, self-care, usual 
activities, pain/discomfort, and anxiety/depression. The EQ-5D questionnaire also includes a 
VAS (EQ VAS), by which participants can report their perceived health status with a grade 
ranging from 0 (the worst possible health status) to 100 (the best possible health status). 
Functional Assessment of Chronic Illness Therapy-Fatigue 
The Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) scale will be used 
to assess fatigue. This is a 13-item questionnaire, in which participants are requested to score 
each question on a 0-4 scale. The FACIT-F assessment was originally developed for chronic 
illnesses and is now validated for patients with RA. 
High-Sensitivity C-Reactive Protein 
Blood samples for hsCRP analysis will be taken by venepuncture or cannulation. 
Results from the same hsCRP samples will be used for both efficacy (ACR clinical response 
and DAS28-hsCRP and SDAI scores) and PD assessments. 
Note: Participants, Investigators, and the Sponsor will be kept blinded to the results of the 
hsCRP results from randomisation to EOS. 
Magnetic Resonance Imaging 
All enrolled participants will have the magnetic resonance imaging (MRI) scans to capture 
images of their worst affected hand and wrist performed at the Week 0 (Day 1/Baseline Visit) 
and Week 12 visit. 
All images will be sent to an independent blinded central MRI reading facility for review and 
scoring. Two independent readers will assess bone erosion, bone oedema (osteitis), and 
synovitis by means of the Outcome Measures in Rheumatology Clinical Trials group 


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semi-quantitative RA-MRI scoring system (RAMRIS). Cartilage loss (CARLOS) determined 
by MRI will be assessed using a previously validated 9-point CARLOS scale. 
Safety Assessments: 
Safety variables will include assessment of concomitant medications, physical examination 
findings, ophthalmological assessments including slit-lamp examination, vital sign 
measurements (systolic and diastolic blood pressure, pulse rate, respiratory rate, and 
temperature), chest X-ray, ECG tracings, clinical laboratory test results (haematology, serum 
chemistry, urinalysis, and pregnancy test), weight, body mass index, and reporting of AEs. 
Pharmacokinetic Assessments 
Blood samples (approximately 2 mL per time point) for the determination of plasma 
concentrations of MBS2320 and MBS2473 will be taken at the following time points:  
• Pre-dose at Weeks 4 and 12, 
• 3 (±1) hours postdose following last dose at Week 12, and 
• At EOS visit.  
The actual date and time (24-hour clock time) of each sampling as well as the time and date 
of the last dose immediately prior to sampling will be recorded. 
Pharmacodynamic and Biomarker Assessments 
Anti-Citrullinated Peptide Antibody 
Blood samples for anti-citrullinated peptide antibody (ACPA) analysis will be taken at 
screening and at Week 12 (EOT) visit. 


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Rheumatoid Factor 
Blood samples for rheumatoid factor analysis will be taken at screening and at Week 12 
(EOT) visit. 
Peripheral Blood Leucocyte Phenotype 
Blood samples for evaluating peripheral blood leucocyte phenotype will be taken on Day 1 
and at Week 4 and Week 12 (EOT) visits but may be subject to change based on the ongoing 
review of the data. 
Analysis will include but will not be limited to flow cytometry and/or protein levels. 
Gene Expression 
Blood samples for gene expression analysis will be taken on Day 1 and at Week 4 and 
Week 12. 
Exploratory Biomarkers 
Blood samples for exploratory analysis will be taken on Day 1 and at Week 12 (EOT) visit 
but may be subject to change based on the ongoing review of the data. 
Exploratory analysis will include but will not be limited to inflammatory cytokines, 
metabolites, and biomarkers of bone turnover. 
Pharmacogenomic Assessments 
A blood sample for pharmacogenomics analysis will be taken on Day 1. 
Details of Applicable Monitoring Committee: 
Not applicable. 


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Investigational Product, Dosage, and Route of Administration: 
The IP will be presented in a capsule formulation containing immediate release powder of 
active drug (MBS2320) or placebo. All capsules will be identical in size and colour (opaque 
white) and contain MBS2320 at unit doses of 5 mg, 20 mg, or 40 mg, or placebo. The 
excipients used in MBS2320 comprise standard compendial pharmaceutical excipients: 
sorbitol, sodium lauryl sulphate, and magnesium stearate. On each dosing occasion, 
participants will swallow 1 capsule whole with food and a glass of water (approximately 
250 mL). Participants will be instructed to contact the Investigator in case they experience 
emesis after dosing. Any episode of emesis after dosing will be reported as an AE and is to be 
managed with anti-emetics, as advised by the Investigator. The IP dose should not be 
repeated if emesis occurs after dosing and the participant should be instructed to take the IP 
at the next regularly scheduled time. 
Sample Size: 
This study has been powered assuming that 180 participants (approximately 45 per treatment 
arm) with confirmed IA synovitis at baseline provide an ACR20 composite clinical endpoint 
at Week 12; this would provide 80% power to detect a difference between placebo (assuming 
35% response) versus MBS2320 (assuming 65% response) using a two-sided 5% 
significance level. Thus, it is anticipated that approximately 224 participants will be 
randomized which allows for a loss of 20% which may be due to unconfirmed IA synovitis, 
treatment discontinuation due to reasons unrelated to tolerability or worsening disease or for 
an unknown reason (loss to follow up without prior related intercurrent events). Note that 
participants who either discontinue treatment due to tolerability issues or require further 
treatment or increases in RA medication due to worsening disease do provide an ACR20 
composite clinical endpoint (treatment failure) even if they do not provide study data at 
Week 12. 
Statistical Methods: 
The following analysis sets will be used in the statistical analyses. 


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Enrolled Set 
The enrolled set will consist of all participants who sign the ICF. 
Safety Set 
The safety set will consist of all participants who receive at least 1 
dose of MBS2320 or placebo. All analyses using the safety set will 
group participants according to the treatment they actually receive. 
Full Analysis Set 
(FAS) 
The FAS will consist of all randomised participants whether or not 
they experienced significant protocol deviations affecting evaluation of 
the endpoints. All analyses using the FAS will group participants 
according to the randomised treatment. 
Modified Full 
Analysis Set 
(mFAS) 
The mFAS will consist of all randomised and eligible participants with 
confirmed intra-articular synovitis on baseline MRI in FAS (grouped 
according to randomised treatment). The mFAS applies analysis flags 
to censor data after certain intercurrent events: 
Flag P: Censors data after discontinuation or interruption of 
treatment for unrelated reasons (i.e. due to logistical issues or 
AEs due to an unrelated medical condition not considered to be 
due to treatment or the underlying RA disease) and resulting in 
>20% reduction in treatment administered during the 
approximately 4-week period since last visit. If treatment is 
resumed following an interruption, then subsequent data may 
be included provided at least 80% of treatment is taken during 
the previous 4-week period. This will be particularly useful for 
targeting Estimands 1 and 4. 
Flag A: Censors data after discontinuation or interruption of 
treatment for any reason or any increase in RA medications and 
will be particularly useful for targeting hypothetical estimands 
(Estimands 2A and 3A). Only interruptions resulting in >20% 
reduction in treatment administered during the approximately 
4-week period since last visit are considered relevant; for 
shorter interruptions, all resulting data are selected. If treatment 
is resumed following an interruption, then subsequent data may 
be included provided at least 80% of treatment is taken during 
the previous 4-week period. 
Flag B: Censors data after discontinuation of treatment for 
unrelated reasons or any increase in RA medications and will 
be particularly useful for targeting the ‘partially’ hypothetical 
estimands (Estimands 2B and 3B). Interruptions for unrelated 
reasons are handled in the same way as Flag P. 


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Pharmacokinetics 
(PK) Set 
The PK set will consist of all participants who receive at least 1 dose 
of MBS2320 and have at least 1 evaluable PK concentration. Analyses 
using the PK population will group participants according to treatment 
received. 
 
Statistical analysis will be performed using SAS software Version 9.4 or later. Continuous 
variables will be summarised using the mean, standard deviation, median, minimum value, 
and maximum value. Categorical variables will be summarised using frequency counts and 
percentages. Data will be listed in data listings. 
Details of the statistical analyses, methods, and data conventions will be described in the 
statistical analysis plan (SAP). All statistical tests will be 2-sided and performed using a 5% 
significance level, leading to 95% (2-sided) confidence intervals (CIs), unless indicated 
otherwise. 
Analysis of Primary Efficacy Endpoint 
Main Estimation of Primary Efficacy Estimand 1 
The primary efficacy estimand is the absolute difference between each of the 3 different 
doses of MBS2320 and placebo in the percentage of participants who would achieve 
successful composite clinical response at Week 12 (which assumes failure for those who have 
any increase in RA medications or treatment discontinuation due to lack of efficacy or 
tolerability issues). The primary efficacy estimand will be estimated using a logistic 
regression model and the delta method, with the stratification factors and treatment as factors 
using the mFAS (Flag P). Missing data will not be imputed and are assumed missing 
completely at random (MCAR). 
Sensitivity Analysis of Primary Efficacy Estimand 1 
In the sensitivity analysis of the primary efficacy estimand, multiple imputation (MI) 
assuming missingness at random (MAR) will be used to impute any missing component of 
the composite clinical response at Weeks 4, 8, and 12, and then to derive the composite 


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outcomes. The logistic model will be fitted to each multiply imputed data set and the 
estimates of difference in percentages and standard error (SE) from the delta method will be 
pooled using Rubin’s method. The overall difference of each dose relative to placebo will be 
presented with P value. 
Also, in order to further study the successful composite clinical response profile across active 
doses, an additional sensitivity analysis will be conducted for studying the dose response 
relationship among the 3 MBS2320 doses and placebo dose. A logistic model will be fitted to 
multiply imputed data sets with dose in mg as a continuous variable to assess the trend across 
dose, including placebo as zero dose (i.e. placebo=0 mg dose level and dose levels of 5 mg, 
20 mg, and 40 mg). The slope with CI and P value will be pooled using Rubin’s method. 
Analysis of Key Secondary Efficacy Endpoints 
Main Estimation of Secondary Efficacy Estimand 2A 
The first key secondary efficacy estimand (Estimand 2A) is based on the difference in mean 
change in Rheumatoid Arthritis Magnetic Resonance Imaging Score (RAMRIS) score from 
baseline to Week 12, as though no increase in any other RA medication and no treatment 
discontinuation for any reason, in patients with MBS2320 (5 mg, 20 mg, or 40 mg once 
daily) compared to placebo.  
All assessments after any of the intercurrent events will be censored. An MI model will be 
used to impute any missing (or censored) score at Week 12 assuming MAR. The RAMRIS 
score and change from baseline in RAMRIS score will be derived on each multiply imputed 
data set and analysed using analysis of covariance (ANCOVA) with fixed effect terms for 
treatment and stratification factors, and baseline RAMRIS score as covariate. Rubin’s 
method will be used to pool results so that the differences in mean change in RAMRIS score 
can be presented with 95% CI and P value. 
Estimation of Supportive Efficacy Estimand 2B 
Estimand 2B is defined as the difference in mean change in RAMRIS score from baseline to 
Week 12 in patients with MBS2320 (5 mg, 20 mg, or 40 mg once daily) compared to 


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placebo, irrespective of treatment discontinuation or interruption due to tolerability issues or 
lack of efficacy and as though no increase in any other RA medication. Data after all 
intercurrent events except discontinuation or interruption of treatment due to tolerability 
issues or lack of efficacy will be censored. Data missing for reasons unrelated to treatment 
(e.g. participant not willing to undergo MRI scan) will be imputed under the MAR 
assumption. 
A reference-based multiply imputation model will be used to impute missing data after 
discontinuation of treatment due to related reasons (tolerability issues or lack of efficacy). As 
for Estimand 2A, the change from baseline in RAMRIS score will be derived on each 
multiply imputed data set and analysed using ANCOVA, and Rubin’s method will be used to 
pool results. 
Main Estimation of Secondary Efficacy Estimand 3A  
A mixed model for repeated measures (MMRM) will be fitted to change from baseline at 
Weeks 4, 8, and 12 as the dependent variable and including fixed effects for DAS28-hsCRP 
baseline covariate, treatment, visit, treatment by visit interaction, and the stratification 
factors. An unstructured covariance will be used to model the covariances over time on 
participants. The least squares mean change from baseline in DAS28-hsCRP and differences 
relative to placebo with 95% CI and P value will presented at each time point. 
Missing data are assumed to be MAR in the MMRM, which is well suited to estimate this 
type of hypothetical estimand. 
Main Estimation of Secondary Efficacy Estimand 3B 
Similar estimation (via MMRM) as described for Estimand 3A will be conducted for 
Estimand 3B. Note that this requires participants who discontinue treatment to return at 
Week 12 for assessment. Missing data are assumed to be MAR, which is unlikely to hold in 
the case of dropouts following discontinuation of treatment. 
A sensitivity analysis will be conducted for Estimand 3B, using a reference-based MI model 
to impute missing data after discontinuation due to related reasons. The change from baseline 


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in DAS28-hsCRP will be derived on each multiply imputed data set and analysed using 
MMRM, and Rubin’s method will be used to pool results. 
Main Estimation of Secondary Efficacy Estimand 4 
The estimation of Estimand 4 is similar to that described for Estimand 1. A logistic model 
will be fitted to successful composite clinical response at each of Weeks 4 and 8 including 
the stratification factors and treatment (qualitative) as factors; missing data will not be 
imputed and assumed MCAR. 
In a sensitivity analysis, an MI model will be used to impute any missing components of the 
composite clinical response at Weeks 4, 8, and 12. Logistic model will be fitted to each 
multiply imputed data set and Rubin’s method use to pool results. The overall difference of 
each dose relative to placebo will be presented with P value, at each time point. 
Additional sensitivity analysis of the successful composite clinical response at Weeks 4, 8, 
and 12 will be performed using Logistic Generalized Linear Mixed Model with fixed effects 
for treatment, visit, treatment by visit interaction, and the stratification factors. More details 
will be provided in the SAP. 
Analyses of Other Efficacy and Exploratory Endpoints 
The other efficacy endpoints will be analysed descriptively, based on the mFAS (Flag B), 
except for ordinal endpoints (e.g. ACR50 & ACR70) which will be analysed based on mFAS 
(Flag P). Sensitivity analysis may be undertaken; details will be provided in the SAP. 
The exploratory efficacy endpoints will be analysed descriptively, based on the mFAS (with 
no flags applied) and the mFAS (Flag A). Sensitivity analysis may be undertaken; details will 
be provided in the SAP. 


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Analysis of Pharmacokinetic Endpoints 
MBS2320 and MBS2473 plasma concentrations will be determined in pre-dose samples at 
Weeks 4 and 12, postdose samples collected 3 (±1) hours following last dose at Week 12, and 
at EOS.  
Plasma concentration of MBS2320 and MBS2473 (where applicable) will be determined for 
each sample, excluding placebo controls.  
All MBS2320 and MBS2473 plasma concentration data will be listed by participant and 
visit/sampling time point and summarised by administered treatment.  
SAS® software Version 9.4 or higher (SAS Institute, Inc, Cary, North Carolina) will be 
utilised for the generation of any tables, listings, and figures. 
Analyses of Safety  
The incidence of treatment-emergent AEs for the safety population will be summarised by 
treatment group. Adverse events will be coded using the Medical Dictionary for Regulatory 
Activities to classify events under primary system organ class and preferred term. Adverse 
event data will be presented in incidence tables. Adverse events will also be summarised by 
severity, seriousness, and relationship to IP for each treatment group. Data will also be listed 
in data listings. 
The incidence of laboratory abnormalities by type, frequency, and severity will be 
summarised by treatment groups. Change from baseline in continuous laboratory variables 
will be summarised by visit and treatment groups. 
All other safety variables (including vital signs and ECGs) will be summarised by treatment 
group and visit. 
Other Analyses 
Summary statistical analyses will be provided for demographics, medical history, and 
physical examination, and ophthalmological assessments at baseline. 


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Version and Date of Protocol: Version 2.0, 12 January 2023