EAST-1 (ERAP-inhibition in Axial Spondyloarthritis Trial - 1)

Inclusion Criteria:

Healthy Volunteers

• Healthy male and female subjects aged 18-55 years inclusive, at the Screening visit

• Participant must provide written informed consent to participate in the study

• Participant must be able and willing to comply with the requirements of the protocol (including dietary restrictions and exclusion of grapefruit juice)

• Male participants (and their female partners) / female participants must be willingto adhere to contraception requirements as detailed in the protocol

• Non-smokers or ex-smokers who have not smoked within the previous 6 months, asdetermined at the Screening visit

• Participant with a Body Mass Index (BMI) of 19-30. Body Mass Index = Body weight (kg) / [Height (m)]2

AxSpA Participants

• Male or female, 18-65 years of age

• Participants diagnosed with Axial Spondyloarthritis, also fulfilling ASASclassification criteria including:

1. HLA-B27 +ve (local testing)

2. Objective evidence of inflammation at screening, specifically active sacroiliacjoint inflammation on MRI fulfilling the ASAS MRI criteria (MRI+), assessed bythe Principal Investigator or appropriately trained delegate, and/or elevatedC-reactive protein (CRP+) ≥5.0mg/L.

• Symptom duration of ≥3 months

• Age at onset of active disease of <40 years

• A score of ≥ 2.1 on the Ankylosing Spondylitis Disease Activity Score (ASDAS) oncurrent treatment.

• At least one of the following:

1. Current treatment with a NSAID, at a sufficient dose and following anappropriate dosing duration per local clinical guidelines, with inadequateclinical response OR

2. Intolerance to ≥1 NSAID or contraindication(s) to NSAIDs

• Participants may have received 1 prior/(Australia only) 2 prior b/ts DMARD anddiscontinued due to intolerance or inadequate efficacy.

• Participants who have received 1/(Australia only) 2 prior treatments are required toundergo a washout at minimum:

1. Biologic DMARDs 4 weeks or 5 half-lives prior to Day 1, whichever is longer.

2. JAK inhibitor DMARDs 2 weeks prior to Day 1

Exclusion Criteria:

Healthy Volunteers

• History or presence of any clinically significant findings in medical history,physical examination, vital signs and/or laboratory tests that, in the opinion ofthe Investigator, would preclude inclusion in the study

• Participation in a New Chemical Entity clinical study within the previous 124 daysor a marketed drug clinical study within the previous 93 days

• Known infection or lifestyle risk factors for human immunodeficiency virus (HIV)and/or hepatitis B or C infection, as determined at the Screening visit

AxSpA Participants

• Participants who have received >1/(Australia only) >2 biologic or JAK inhibitorDMARD or are receiving any other disease-modifying antirheumatic drugs (other thanthose allowed), thalidomide (including previous use) and other prohibitedconcomitant medications.

• Inadequate Haematologic function, defined as:

1. Haemoglobin <10 g/dL.

2. Absolute white blood cell count <3.0 x 109 /L (<3000 mm3)

3. Absolute neutrophil count <1.2 x 109 /L (<1200 mm3)

4. Absolute lymphocyte count <1.0 x 109 /L (<1000 mm3)

5. Platelet count <100 x 109 /L (<100.000 mm3)

• Inadequate liver function, defined as; total bilirubin, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) more than 1.5 times the upper limit ofnormal at screening visit. For subjects with Gilberts syndrome, upper limit ofnormal for total bilirubin will be 2.9mg/dl

• History of any other autoimmune rheumatic disease (e.g., psoriatic arthropathy,systemic lupus erythematosus, mixed connective tissue disease, scleroderma,polymositis) or known diagnosis of fibromyalgia

• Participants with a previous history of or currently stable psoriasis are eligible

• Active or symptomatic inflammatory bowel disease (IBD). Participants with a historyof IBD are allowed to participate

• Presence of active anterior uveitis

Please note the following Country-Specific Inclusion Criteria, for study participants in Australia:

• Participants with a score of ≥ 2.1 (High Disease Activity) on the Ankylosing Spondylitis Disease Activity Score (ASDAS) on current treatment.

For study participants in Part B only:

• Objective evidence of inflammation may not be required for some participants withlow to moderate disease activity.

• Participants with an ASDAS score between ≥1.3 and < 2.1 (Low to Moderate DiseaseActivity) will require Sponsor approval prior to screening for the study, as theymay not require an MRI to provide objective evidence of inflammation if on currenttreatment. For participants with low to moderate disease activity, MRI should onlybe performed if required to confirm ASAS classification.

For axSpA participants in Part B, MRI assessment of the SI joints is only required for participant eligibility criteria evaluation to assess objective inflammation in case CRP measurement at baseline is negative and the objective evidence of inflammation is required.