A Study to Evaluate the Efficacy and Safety of Orally Administered VX-01

This is a Phase 2, multi-center, double-masked, randomized, placebo-controlled, parallel group study to evaluate the efficacy of oral doses of VX-01 in subjects with moderate to severe NPDR, without CI-DME.

Approximately 100 male and female subjects aged ≥ 18 years with a documented diagnosis of Type 1 Diabetic Mellitus or Type 2 Diabetic Mellitus with moderate to severe NPDR (without CI-DME) will be enrolled, if they meet all the eligibility criteria for the study.

Subjects will be randomized 1:1 to 1 of 2 study cohorts:

• Cohort 1 (n = 50): VX-01 (film-coated tablets, 150 mg administered BID)
• Cohort 2 (n = 50): Placebo (film-coated tablets, administered BID)

Subjects will be stratified by the presence or absence of proliferative diabetic retinopathy (PDR) and by glycated hemoglobin (HbA1c) of ≥ 8.5% or < 8.5% at Screening. All subjects will take 1 tablet of VX-01 or placebo BID for 52 consecutive weeks. All subjects will be followed for 12 weeks after completion of treatment at Week 52.

The Sponsor, study site staff, monitors, personnel, and subjects will be masked to treatment assignment during the entirety of the study.

Inclusion criteria

• Written informed consent must be obtained from the subject prior to any study-related procedures.
• Subject must be aged > 18 years at the time of Screening.
• Subject must have a body mass index (BMI) of between 18 and 40 kg/m2, inclusive.
• Subject has a documented diagnosis of T1DM or T2DM.
• Subject has moderate to severe NPDR, as determined by a Central Reading Centre (CRC) using DRSS in at least one eye
• Subject must have clear ocular media and be able to undergo adequate pupil dilation to allow adequate fundus imaging of both eyes.
• Female subject must be either:

• Of non-childbearing potential: post-menopausal or documented surgically sterile post hysterectomy (at least 1 month prior to Screening)
• Or, if of childbearing potential, must have a negative serum pregnancy test at Screening and must use 2 acceptable forms of contraception, starting at Screening and throughout the study period and for 28 days after the final IP administration.
• Female subject must not be breastfeeding at Screening or during the study period, and for 28 days after the final IP administration.
• Male subject must be surgically sterile (> 30 days since vasectomy with no viable sperm), or if engaged in sexual relations with a female of childbearing potential, the couple should agree to use 2 acceptable contraceptive methods from Screening, during the study, and for 28 days after last IP administration.

Female subject must not donate ova or male subject must not donate sperm starting at Screening and throughout the study period, and for 28 days after the final IP administration.

• Subject must have Best Corrected Visual Acuity (BCVA) assessed by Early Treatment Diabetic Retinopathy Study (ETDRS) protocol letters score of ≥ 70 letters in study eye, and ≥ 20 letters in the non-qualified fellow eye.
• Subject must have the ability, in the opinion of the Investigator, and willingness to return for all scheduled visits and perform all assessments.
• Subject agrees not to participate in another interventional study after signing the informed consent and until the End of Study (EOS) visit has been completed.

Exclusion criteria

Ophthalmic:

• Presence of CI-DME (with central subfield thickness [CST] measured greater than 325 μm on spectral domain optical coherence tomography [SD-OCT]) threatening the center of the macula (within 1,000 μm of the foveal center) in either eye, or presence of DME requiring treatment.
• Presence of moderate to high-risk PDR (DRSS level 65 or higher).
• Any prior treatment (in either eye) with:

• Focal or grid laser photocoagulation within the past 6 months prior to Screening or pan-retinal photocoagulation (PRP) at any time.
• Systemic or intravitreal anti-vascular endothelial growth factor (VEGF) agents within the last 12 months prior to Screening.
• Intraocular, sub-tenon or periocular steroids, including triamcinolone and dexamethasone implant within the last 6 months, or suprachoroidal triamcinolone within the last 3 months prior to Screening.
• Fluocinolone implant within the last 3 years prior to Screening.
• Prior treatment for NPDR with any other treatment which is not labelled for NPDR within 1 year prior to Screening (e.g., calcium dobesilate, fibrate medication).
• Vitrectomy at any timepoint prior to Screening.
• Yttrium-Aluminium-Granate (YAG) capsulotomy within 3 months prior to Screening.
• Active uveitis, vitritis, or infection in either eye including infectious conjunctivitis, keratitis, scleritis, or endophthalmitis.
• History of corneal transplant and/or vitrectomy or any other ocular incisional surgery in either eye (e.g., shunt surgery). Note: Subjects who have had cataract or refractive surgery in either that was more than 3 months prior to Screening may be permitted at the discretion of the Investigator.
• Uncontrolled glaucoma, as evidenced by intraocular pressure (IOP) > 25 mmHg despite up to 4 glaucoma medications, or evidence of glaucomatous visual field loss or has advanced glaucoma (e.g., prior shunt surgery) in either eye.
• Clinically significant ocular disease in either eye that in the opinion of the Investigator would preclude participation in the study.
• Presence of macular or retinal vascular disease including DME and/or retinopathy from causes other than diabetes, age-related macular degeneration, pattern dystrophy, choroidal neovascularisation of any cause, retinal vein occlusion, retinal artery occlusion in either eye.
• History of retinal detachment or full-thickness macular hole post intraocular surgery in either eye, or idiopathic or autoimmune uveitis in either eye.
• Any other ocular disease that may cause substantial reduction in BCVA.

Systemic:

• Known, suspected hypersensitivity or contraindication to IP.
• Uncontrolled diabetes mellitus with HbA1c of ≥ 12%.
• Initiation of treatment with glucagon-like peptide-1 (GLP-1) modulators for glycaemic control and other indications within the last 3 months prior to Screening.
• Initiation of intensive insulin treatment (a pump or multiple daily injections) within 3 months prior to Screening or plans to do so in the next 3 months.
• Current use of coumarin anticoagulants (Coumadin/Warfarin).
• On dialysis or an estimated glomerular filtration rate (eGFR) of < 30 mL/min/1.73m2 as per CKD-EPI evaluation at Screening. (Active Diabetic Ketoacidosis or Hyperglycemic Hyperosmolar Nonketotic State).
• Hypertension with resting diastolic blood pressure (BP) > 100 mmHg or systolic BP > 180 mmHg on 2 consecutive measurements at least 5 minutes apart. Note: If the result is out of range, the assessment may be repeated once prior to randomisation for confirmation.
• Resting heart rate outside the specified range (50 to 110 beats per minute). Note: If the result is out of range, the assessment may be repeated once prior to randomisation for confirmation.
• History of chronic liver disease or presence of elevated (defined as > 3 × upper limit of normal) alanine aminotransferase (ALT) and aspartate aminotransferase (AST) consistent with such diagnosis.
• Known to be immunocompromised or receiving immunosuppressive therapy. Note: Subjects receiving low dose corticosteroids may be eligible, at the discretion of the Investigator.
• Currently receiving treatment with a strong inhibitor of the P-glycoprotein transporter (see Section 6.4.2), which may interfere with the IP.
• History of allergy to fluorescein.
• Any disease or medical condition that in the opinion of the Investigator would interfere with the study, prevent the subject from successfully participating in the study, or which might confound the study results.
• Participation in any investigational study within 30 days prior to Screening or planning to participate in any other investigational drug or device clinical trials within 30 days of study completion.
• History of blood transfusion or severe blood loss within 3 months prior to Screening, known hemoglobinopathy, and severe anaemia.