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

GRWD0715 is an orally administered, selective inhibitor of the Endoplasmic Reticulum Aminopeptidase 1 [ERAP1] enzyme being explored as a potential new treatment for axial spondyloarthritis (axSpA), a long term condition caused by inflammation predominantly affecting the sacroiliac joints (SIJs) and spine.

ERAP1 is involved in trimming antigens from foreign bodies (e.g. bacteria, viruses) which are presented on the surface of a cell to trigger an immune response. In axSpA, it is thought an antigen from the person's own body, called a 'self-peptide' is presented by the ERAP1 processing pathway and incorrectly recognised by the immune system. The hypothesis is that stimulation of the immune system by the presentation of this self-peptide causes the inflammatory symptoms experienced by people living with axSpA.

As an inhibitor of ERAP1, GRWD0715 aims to prevent the generation of the antigenic self-peptide, and thus remove the stimulus of the immune system. If the immune system is not activated, the immune attack on the sacroiliac joint (SIJ) and spine would stop, halting the axSpA disease progress.

The study will consist of 4 parts: Part A conducted in healthy human volunteers, and Part B, Part C and/or D in participants with axSpA. The primary goal of Parts A, B and C is to assess whether GRWD0715 is safe and well tolerated in healthy human volunteers and participants with axSpA. The primary goal of Part D is to review whether GRWD0715 is efficacious when compared to placebo.

Key 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 willing to adhere to contraception requirements as detailed in the protocol
• Non-smokers or ex-smokers who have not smoked within the previous 6 months, as determined 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 ASAS classification criteria including:
• HLA-B27 +ve (local testing)
• Objective evidence of inflammation at screening, defined as active sacroiliac joint inflammation on MRI fulfilling the ASAS MRI criteria (MRI+), assessed by the Principal Investigator or appropriately trained delegate, and/or elevated C-reactive protein (CRP+) ≥5.0mg/L.

o Objective evidence of inflammation may not be required for Part B. Participants who do not require objective evidence of inflammation require Sponsor approval prior to screening for and/or enrolling to the study.

• A score of:
• ≥ 2.1 (High Disease Activity) on the Ankylosing Spondylitis Disease Activity Score (ASDAS) on current treatment* OR
• In Part B only, A: a score of >1.3 (Low to Moderate Disease Activity) on the ASDAS on current treatment. Participants with a score of ≥1.3 and < 2.1 require Sponsor approval prior to screening for the study.
• At least one of the following:
• Current treatment with a NSAID, at a n adequate dose and duration per local clinical guidelines, with inadequate clinical response OR
• Intolerance to ≥1 NSAID or contraindication(s) to NSAIDs

Participants may have received 1 or 2 (Australia only) prior b/tsDMARD and discontinued due to intolerance or inadequate efficacy provided that:

Part B: Participants who have received two prior b/ts DMARDs require Sponsor approval prior to screening.

Part D: Participants with prior b/tsDMARD treatment may be capped.

• Participants who have received 1/(Australia only) 2 prior treatments are required to undergo a washout at minimum: Biologic DMARDs 4 weeks or 5 half-lives prior to Day 1, whichever is longer. Any JAK inhibitor DMARDs 2 weeks prior to Day 1

Part C only: Participants enrolling into Part C must:

• Have completed Part B or Part D treatment per protocol.
• Have not permanently discontinued GRWD0715 due to safety concerns.
• Have no ongoing safety issues that, in the opinion of the Investigator, would preclude further treatment.
• Provide written informed consent to participate in Part C.

Part D only: Participants must be GRWD0715 naïve.

Contacts/Locations Central Contact Person: Grey Wolf Therapeutics Patient enquiries Telephone: +44 1235644970

Key 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 of the Investigator, would preclude inclusion in the study
• Participation in a New Chemical Entity clinical study within the previous 124 days or 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
• Parts B and D only: Participants previously treated with three or more b/tsDMARDs
• Participants not meeting inclusion criteria for prior b/tsDMARD exposure or required washout period for their respective study part.
• Participants currently receiving prohibited conventional DMARDS cDMARDS), thalidomide (including previous use) or other prohibited concomitant medications.
• Inadequate Haematologic function, defined as:

• Haemoglobin <10 g/dL.
• Absolute white blood cell count <3.0 x 10^9 /L (<3000 mm^3)
• Absolute neutrophil count <1.2 x 10^9 /L (<1200 mm^3)
• Absolute lymphocyte count <1.0 x 10^9 /L (<1000 mm^3)
• Platelet count <100 x 10^9 /L (<100.000 mm^3)
• Inadequate liver function, defined as; total bilirubin, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) more than 1.5 times the upper limit of normal at screening visit. For subjects with Gilberts syndrome, upper limit of normal 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 history of IBD are allowed to participate
• Presence of active anterior uveitis