A Study of SEL-212 in Patients With Gout Refractory to Conventional Therapy II

Study Overview
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Brief Summary
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This is one of two replicate randomized, double-blind, placebo-controlled, parallel arm trials to determine the safety and efficacy of two different dose levels of SEL-212 compared to placebo. 112 and 153 patients, stratified as to the presence or absence of tophi, were randomized in a 1:1:1 allocation ratio prior to Baseline to receive treatment with one of two dose levels of SEL-212 or placebo every 28 days for approximately 6 months in each trial respectively (SEL-212/301 and SEL-212/302). Analysis of primary and key efficacy were performed at Day 28 of Treatment Period 6. Safety was monitored throughout the study.

Detailed Description
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This is one of two replicate randomized, double-blind, placebo-controlled, parallel arm trials to determine the safety and efficacy of two different dose levels of SEL-212 compared to placebo. 112 and 153 patients, stratified as to the presence or absence of tophi, were randomized in a 1:1:1 allocation ratio prior to Baseline to receive treatment with one of two dose levels of SEL-212 or placebo every 28 days for approximately 6 months in each trial respectively (SEL-212/301 and SEL-212/302). The SEL-212 doses differed as to the SEL-110.36 component. Participants received SEL-037 administered at a dose of 0.2 mg/kg via intravenous (IV) infusion immediately after receiving SEL-110.36 at a dose of either 0.1 mg/kg (SEL-212 low-dose) or 0.15 mg/kg (SEL-212 high-dose) via IV infusion. The placebo consisted of normal saline. Placebo subjects who completed the study will be offered enrollment in an open-label extension study for treatment with SEL-212 (SEL-212/303). Efficacy assessments were conducted at intervals that are appropriate to determine treatment effect with samples for the primary endpoint drawn during Treatment Period 6. Safety was monitored throughout the study with an independent data safety monitoring board (DSMB).

Official Title
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A Randomized Double-Blind, Placebo-Controlled Study of SEL-212 in Patients With Gout Refractory to Conventional Therapy

Conditions
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Chronic Gout

Intervention / Treatment
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* Drug: SEL-212 low-dose
* Drug: SEL-212 high-dose
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Has negative results of an FDA Emergency Use Authorized COVID-19 molecular assay for detection of SARS-CoV-2 RNA from a nasal or oropharyngeal specimen; History of symptomatic gout defined as: ≥ 3 gout flares within 18 months of Screening or Presence of ≥ 1 gout tophus or Current diagnosis of gouty arthritis At the Screening Visit: male age 21 - 80 years, inclusive, or female of non-childbearing potential age 21-80 years, inclusive, where nonchildbearing potential is defined as: > 6 weeks after hysterectomy with or without surgical bilateral salpingo-oophorectomy or Post-menopausal (> 24 months of natural amenorrhea or in the absence of >24 months of amenorrhea, one documented confirmatory FSH measurement) Has chronic refractory gout defined as having failed to normalize sUA and whose signs and symptoms are inadequately controlled with any of the xanthine oxidase inhibitors, or for whom these drugs are contraindicated for the patient; Has at the Screening Visit SUA ≥ 7 mg/dL Negative serology for HIV-1/-2 and negative antigen to hepatitis B and negative antibodies to hepatitis C; Exclusion Criteria: Has a history of anaphylaxis, severe allergic reactions, or severe atopy; Has a history of any allergy to pegylated products, including, but not limited to pegloticase (Krystexxa®), peginterferon alfa-2a (Pegasys®), peginterferon alfa-2b (PegIntron®), pegfilgrastim (Neulasta®), pegaptanib (Macugen®), pegaspargase (Oncaspar®), pegademase (Adagen®), peg-epoetin beta (Mircera®), pegvisomant (Somavert®) certolizumab pegol (Cimzia®), naloxegol (Movantik®), peginesatide (Omontys®), and doxorubicin liposome (Doxil®); Is taking and cannot discontinue known major CYP3A4/P-gp inhibitors or major CYP3A4/P-gp inducers at least 14 days before dosing. Patients must remain off these medications for the duration of the study, including natural products such as St. John's Wort or grapefruit juice. Is taking drugs known to interact with rapamycin (sirolimus - Rapamune®) such as cyclosporine, diltiazem, erythromycin, ketoconazole, posaconazole, voriconazole, itraconazole, rifampin, verapamil unless they are stopped 14 days prior to dosing and will not be used/prescribed during the trial. Had major surgery within 3 months of initial screening. Had a gout flare during Screening that was resolved for less than 1 week prior to first treatment with study drug (exclusive of chronic synovitis/arthritis) unless the patient has a history of inter-flare intervals of < 1 week. Has uncontrolled diabetes at Screening with HbA1c ≥ 8.5%; Has fasting Screening glucose > 240 mg/dL; Has fasting Screening triglyceride > 500 mg/dL; Has fasting Screening low-density lipoprotein (LDL) > 200 mg/dL; Has glucose-6-phosphate dehydrogenase (G6PD) deficiency; Has uncontrolled hypertension defined as blood pressure > 170/100 mmHg at Screening and 1 week prior to dosing Individual laboratory values which are exclusionary White blood cell count (WBC) < 3.0 x109/L Serum aspartate aminotransferase (AST) or alanine amino transferase (ALT) > 3x upper limit of normal (ULN) in the absence of known active liver disease Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2 Urine albumin creatinine ratio (UACR) > 30 mg/g Hemoglobin (Hgb) < 9 g/dL Serum phosphate < 2.0 mg/dL Is receiving ongoing treatment for arrhythmia, including placement of an implantable defibrillator, unless considered stable and on active treatment; Has evidence of unstable cardiovascular disease or unstable cerebrovascular vascular disease. This includes patients who have had a cardiac/vascular event(s) in the last 3 months including heart attack, stroke or vascular bypass surgery or patients who are deemed, by their physician or PI, to have active cardiovascular, cerebrovascular or peripheral vascular symptoms/disease inadequately controlled by medication; Has congestive heart failure, New York Heart Association Class III or IV; Unless clinically stable and/or appropriately treated, electrocardiogram (ECG) with evidence of clinically significant arrhythmia or other abnormalities that, in the opinion of the investigator, are consistent with significant underlying cardiac disease; History of significant hematological disorders within 5 years or autoimmune disorders, and/or patient is currently immunosuppressed or immunocompromised; Prior exposure to any experimental or marketed uricase (e.g., rasburicase (Elitek, Fasturtec), pegloticase (Krystexxa®®), pegadricase (SEL 037)) Patient has received a live vaccine in the previous 6 months. Patient is planning to receive any live vaccine during the study. History of malignancy within the last 5 years other than basal skin cancer; Patients with a documented history of moderate or severe alcohol or substance use disorder within the 12 months prior to randomization. History of or evidence of clinically severe interstitial lung disease Immunocompromised state, regardless of etiology

Ages Eligible for Study
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Minimum Age: 19 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SEL-212 low-dose<br>IV infusion of SEL-212 low-dose every 28 days for a total of up to 6 infusions | Drug: SEL-212 low-dose<br>* SEL-212 low-dose Drug: SEL-037 (0.2 mg/kg) SEL-037, PEGylated uric acid specific enzyme (uricase) Other Names: Pegadricase, pegsiticase Drug: SEL-110.36 (0.1 mg/kg) Other Names: SEL-110, ImmTOR<br>|
| Experimental: SEL-212 high-dose<br>IV infusion of SEL-212 high-dose every 28 days for a total of up to 6 infusions | Drug: SEL-212 high-dose<br>* SEL-212 high-dose Drug: SEL-037 (0.2 mg/kg) SEL-037, PEGylated uric acid specific enzyme (uricase) Other Names: Pegadricase, pegsiticase Drug: SEL-110.36 (0.15 mg/kg) Other Names: SEL-110, ImmTOR<br>|
| Placebo Comparator: Placebo<br>IV infusion of Normal Saline every 28 days for a total of up to 6 infusions | Other: Placebo<br>* Normal saline<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serum uric acid control during Month 6 | The percentage of patients who achieve and maintain reduction in serum uric acid (sUA) < 6mg/dL for at least 80% of the time during month 6 in patients with gout refractory to conventional treatment treated with two different dose levels of SEL-212 compared to placebo | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Reduction of mean serum acid | To assess changes in mean serum uric acid in patients with gout refractory to conventional treatment treated with two different dose levels of SEL-212 compared to placebo | 6 months | 
| Percent reduction of mean serum acid | To assess percent changes in mean serum uric acid in patients with gout refractory to conventional treatment treated with two different dose levels of SEL-212 compared to placebo | 6 months | 
| SF-36 | To assess change in Patient Reported Outcomes (PROs) including assessments of patients' quality of life (QoL) (SF-36) in patients with gout refractory to conventional treatment treated with two different dose levels of SEL-212 compared to placebo | 6 months | 
| Tophus burden | To assess change in tophus burden by photographic area assessments in patients with gout refractory to conventional treatment treated with two different dose levels of SEL-212 compared to placebo | 6 months | 
| Serum uric acid control in patients with tophi | To assess change in the percentage of patients with tophi at baseline who achieve and maintain reduction in serum uric acid (sUA) < 6mg/dL for at least 80% of the time during month 6 in patients with gout refractory to conventional treatment treated with two different dose levels of SEL-212 compared to placebo | 6 months | 
| Tender and Swollen Joint Counts | To assess changes in number of tender and swollen joints in patients with gout refractory to conventional treatment treated with two different dose levels of SEL-212 compared to placebo | 6 months | 
| HAQ-DI | To assess change in Patient Reported Outcomes (PROs) including assessments of activity limitation (HAQ-DI) in patients with gout refractory to conventional treatment treated with two different dose levels of SEL-212 compared to placebo | 6 months | 
| Gout flare Incidence | To assess changes in gout flare incidence in patients with gout refractory to conventional treatment treated with two different dose levels of SEL-212 compared to placebo | 6 months |