Oral ERAP1 blocker GRWD0715 for axial spondyloarthritis (EAST-1)

A Multi-part, Phase I/II Study to Evaluate the Safety and Tolerability of GRWD0715 in Healthy Human Volunteers and Participants With Axial Spondyloarthritis

This will test an oral drug called GRWD0715 that blocks the ERAP1 enzyme to see if it is safe and helps people with axial spondyloarthritis, with an early part in healthy adults.

Quick facts

• Phase: Phase1; Phase2
• Study type: Interventional
• Enrollment: 141 (estimated)
• Ages: 18 Years to 65 Years
• Sex: All
• Sponsor: Grey Wolf Therapeutics (Academic / other)
• Locations: 14 sites (Birtinya and 13 other locations)
• Trial ID: NCT07047703 on ClinicalTrials.gov

What this trial studies

GRWD0715 is an oral, selective inhibitor of ERAP1 intended to prevent generation of a self-peptide thought to trigger immune-driven inflammation in axial spondyloarthritis. The study has four parts: Part A is a single-ascending-dose safety study in healthy volunteers; Parts B and C are multiple-ascending-dose and safety-expansion cohorts in people with axSpA; and Part D is a randomized, placebo-controlled expansion to look for clinical effect. Early phases focus on safety, tolerability, pharmacokinetics and dosing, while the final expansion will compare active drug to placebo for efficacy signals. Participants will attend scheduled clinic visits at Australian sites for dosing, monitoring, labs, and imaging as required.

Who should consider this trial

Good fit: Ideal participants are adults with axial spondyloarthritis (typically 18–65 years) who meet ASAS classification with objective evidence of inflammation (and HLA-B27 status as required), while healthy adults 18–55 may join the single-dose part.

Not a fit: People with non-inflammatory back pain, those without objective signs of inflammation, individuals outside the study age/BMI or health criteria, or those with significant comorbidities are unlikely to receive benefit from this study.

Why it matters

Potential benefit: If successful, GRWD0715 could reduce immune-driven inflammation in the sacroiliac joints and spine and offer an effective oral treatment option for people with axSpA.

How similar studies have performed: Targeting ERAP1 is a novel and largely untested approach in humans, though other immune-targeting therapies such as TNF and IL-17 inhibitors have shown benefit in axSpA.

Eligibility criteria

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:

  1. HLA-B27 +ve (local testing)
  2. Objective evidence of inflammation at screening, specifically 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.
* 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) on current treatment.
* At least one of the following:

  1. Current treatment with a NSAID, at a sufficient dose and following an appropriate dosing duration per local clinical guidelines, with inadequate clinical 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 and discontinued due to intolerance or inadequate efficacy.
* Participants who have received 1/(Australia only) 2 prior treatments are required to undergo 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 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

* Participants who have received \>1/(Australia only) \>2 biologic or JAK inhibitor DMARD or are receiving any other disease-modifying antirheumatic drugs (other than those allowed), thalidomide (including previous use) and other prohibited concomitant 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 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

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 with low to moderate disease activity.
* Participants with an ASDAS score between ≥1.3 and \< 2.1 (Low to Moderate Disease Activity) will require Sponsor approval prior to screening for the study, as they may not require an MRI to provide objective evidence of inflammation if on current treatment. For participants with low to moderate disease activity, MRI should only be 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.

Where this trial is running

Birtinya and 13 other locations

• University of the Sunshine Coast (UniSC) — Birtinya, Australia (Recruiting)
• University of the Sunshine Coast (UniSC) — Morayfield, Australia (Completed)
• Pioneer Clinical Research — Sydney, Australia (Recruiting)
• University Ghent — Ghent, Belgium (Recruiting)
• UZ Leuven — Leuven, Belgium (Recruiting)
• Rheumazentrum Ruhrgebiet, Ruhr-University Bochum — Bochum, Germany (Recruiting)
• Universitätsklinikum Erlangen - Medizinische Klinik 3 — Erlangen, Germany (Not_yet_recruiting)
• Amsterdam University Medical Center — Amsterdam, Netherlands (Recruiting)
• Leids Universitair Medisch Centrum (LUMC) (Leiden University Medical Center) — Leiden, Netherlands (Not_yet_recruiting)
• ETG Lublin — Lublin, Poland (Not_yet_recruiting)
• Reumedika — Poznan, Poland (Not_yet_recruiting)
• La Paz University Hospital — Madrid, Fuencarral-El Pardo, Spain (Not_yet_recruiting)
• Reina Sofia University Hospital — Córdoba, Poniente Sur, Spain (Not_yet_recruiting)
• University hospital Parc Tauli de Sabadell — Sabadell, Spain (Not_yet_recruiting)

Study contacts

• Study coordinator: Grey Wolf Therapeutics Patient enquiries

Conditions Axial Spondyloarthritis; AxSpA