Study of ATI-450 in Patients With Cryopyrin-Associated Periodic Syndrome (CAPS)

A Phase 2a, Open-Label, Single-Arm Study to Investigate the Safety and Efficacy of ATI-450 for the Maintenance of Remission in Patients With Cryopyrin-Associated Periodic Syndrome (CAPS) Previously Managed With Anti-IL-1 Therapy

This is a Phase 2 study to investigate the safety and efficacy of ATI-450 for the Maintenance of Remission in Patients with Cryopyrin-Associated Periodic Syndrome (CAPS) Previously Managed with Anti-IL-1 Therapy.

Study Overview

• Status: Terminated
• Conditions: Cryopyrin-Associated Periodic Syndrome
• Intervention / Treatment: Drug: ATI-450

Detailed Description

This is a Phase 2a, Open-Label, Single-Arm Study to Investigate the Safety and Efficacy of ATI-450 for the Maintenance of Remission in Patients with Cryopyrin-Associated Periodic Syndrome (CAPS) Previously Managed with Anti-IL-1 Therapy. The study will consist of up to an 8-week screening period, a 12-week treatment period, and a 4-week safety follow-up period. The total duration of the study for patients remaining until their final follow-up assessment will be up to 24 weeks.

• Study Type: Interventional
• Enrollment (Actual): 1
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • San Diego, California, United States, 92123
      • Aclaris Investigational Site
    • San Francisco, California, United States, 94116
      • Aclaris Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Diagnosis of Familial Cold Autoinflammatory Syndrome, Muckle-Wells Syndrome, or Neonatal Onset Multisystem Inflammatory Disease. Prior agreement between the Investigator and Aclaris for study eligibility is required for patients who do not have a molecular diagnosis of NALP3 mutations available (either testing not performed, or testing performed, but negative) upon study entry. For those patients who have not been molecularly tested for NALP3 mutations, molecular testing should be performed during the study.
• Patients with a PGA score of "minimal" or less and hsCRP and SAA values within the normal range (≤10mg/L), and who are considered to have achieved that response as a result of successful anti-IL-1 therapy.
• Continuous Treatment with anti-IL1 therapy for at least 6 months.
• Able to understand and comply with study procedures and able to provide informed consent.

• Male or non-pregnant, non-nursing female patients at least 18 years of age, inclusive.

  • Female patients who are of childbearing potential must use 2 methods of highly effective contraception* - one of which must be a physical barrier- for the duration of the study and for 30 days after the last dose.
  • Male patients of childbearing potential with a female partner of childbearing potential must agree to use a condom plus another highly effective form of birth control for the duration of the study and for 90 days after the last dose.
• Female patients must have a negative serum pregnancy test at screening and a negative urine pregnancy test prior to dosing on Day 1.
• Willing and capable of taking appropriate Covid-19 risk mitigation precautions (e.g. wearing a mask in public, adhering to social distancing, etc.) as required by local, state, or federal guidelines during participation in the study.

Exclusion Criteria:

• Participation in any clinical study with an investigative agent within 12 weeks prior to entry or within 5 half-lives of the investigational agent.
• Being treated with another immuno-suppressive agent (i.e., in addition to an anti-IL-1 product) for CAPS syndrome (anti- IL-1 therapy will have been used for at least 6 months and will be stopped at study entry).

• Use of any of the following treatments within the indicated washout period prior to the baseline visit:

  • Systemic immunosuppressant or immunomodulatory therapy (e.g., etanercept, alefacept, infliximab, methotrexate) within 16 weeks prior to Visit 2 (excluding anti- IL-1 therapy for CAPS).
  • Janus Kinase (JAK) inhibitors (systemic or topical) within 4 weeks prior to Visit 2.
  • Systemic corticosteroids within 4 weeks prior to Visit 2 (Intranasal, inhaled, and topical ocular corticosteroids are allowed).
• History of being immunocompromised, including a positive HIV at screening (ELISA and Western blot) test result. [Previous treatment with anti-IL1 therapy is not an exclusion]
• A positive Hepatitis B surface antigen (HBsAg) or Hepatitis C antibody test result.
• Live vaccinations within 3 months prior to the start of the trial, or during the trial.
• History of recurrent and/or evidence of active bacterial, fungal, or viral infections.
• History or evidence of active or latent tuberculosis (TB).

• Tests performed at a central laboratory at screening that meet any of the criteria below (out of range labs may be rechecked one time, after consultation with sponsor or designee, before patient is considered a screen failure):

  • White blood cell (WBC) count <3.0×103 cells/mm3
  • Absolute neutrophil count (ANC) <1.5×103 cells/mm3
  • Lymphocyte count <0.5×103 cells/mm3
  • Platelet count <100×103 cells/mm3
  • Hemoglobin <10 g/dL
  • Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥ 2×upper limit of normal (ULN)
  • Total bilirubin level >2×ULN, unless patient has been diagnosed with Gilberts' disease and this is clearly documented
  • Estimated glomerular filtration rate Estimated glomerular filtration rate (eGFR), <40 mL/min/1.73m2 based on Modification of Diet and Renal Disease formula
• Any clinically significant laboratory abnormality that would affect interpretation of study data or safety of the patient's participation in the study, per the judgment of the investigator.
• Patient has clinically significant abnormal findings other than CAPS from physical examination that may affect the interpretation of study data or the safety of the patient's participation in the study, per the judgment of the investigator.
• Patient has a clinically important history of a medical disorder that would compromise patient safety or data quality, per the judgement of the investigator.
• Blood pressure (BP) levels (in supine position after at least 5 minutes rest): <90 mmHg or >140 mmHg for systolic BP or <40 mmHg or >90 mmHg for diastolic blood pressure.
• Patients with history of stroke.
• Significant cardiac disease that would affect interpretation of study data or the safety of the patient's participation in the study, per the judgment of the investigator, including recent myocardial infarction or unstable angina, or heart failure with New York Heart Association Class III or IV symptoms.

• Patients with the following screening or pre-dose ECG findings, specifically:

  • Evidence of atrial fibrillation, atrial flutter, complete right or left bundle branch block, Wolff-Parkinson-White Syndrome, or other significant rhythm disturbance
  • Evidence of acute ischemia
  • Screening or pre-dose baseline mean QTcF >450 msec for males or >470 msec for females (use of the ECG algorithm is acceptable for this purpose)
  • Personal or family history of congenital long QT syndrome or sudden death
  • Any other finding that is considered clinically significant
• A confirmed diagnosis of Covid-19 at baseline or at any time during the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: ATI-450; Oral, small molecule MK2 inhibitor will be administered twice daily (BID) at a dose of 50 mg	Drug: ATI-450; Oral, small molecule MK2 inhibitor

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Number of Participants With Treatment-emergent Adverse Events (TEAEs)	Baseline up to week 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Total Number of participants who maintain disease remission (hsCRP)	Remission is defined as a high sensitivity C-reactive protein (hsCRP) within normal range (≤10 mg/L).	Baseline to week 12
Total Number of participants who maintain disease remission (SAA)	Remission is defined as a serum amyloid A (SAA) value within the normal range (≤10 mg/L).	Baseline to week 12
Total number of participants who maintain disease remission (PGA)	Remission is defined as a Physician Global Assessment (PGA) score of absent or minimal. The Physician's Global Assessment of Autoinflammatory Disease Activity (PGA) is a measure to be completed by the investigator or designee. The PGA uses a 5-point rating scale: absent, minimal, mild, moderate, and severe. The investigator will select a rating based on the patient's current disease activity at the time of the visit. Lower PGA scores represent better outcomes.	Baseline to week 12
Time to relapse	Relapse is defined as a two-point worsening on the PGA scale. The Physician's Global Assessment of Autoinflammatory Disease Activity (PGA) is a measure to be completed by the investigator or designee. The PGA uses a 5-point rating scale: absent, minimal, mild, moderate, and severe. The investigator will select a rating based on the patient's current disease activity at the time of the visit. Lower PGA scores represent better outcomes.	Baseline to week 12
Total number of participants who experience re-emergence of disease symptoms after discontinuation of ATI-450	Re-emergence is defined as a daily Key Symptom Score (KSS) ≥ 3 points higher than baseline for at least 2 consecutive days. The KSS is derived from the patient-administered DHAF, and is the average on a 0 to 10 scale (0 = None, 10 = Very Severe) of 5 separate scales - rash, feeling of fever and chills, joint pain, eye redness and pain, and fatigue. Lower KSS scores represent better outcomes.	Follow-up day 1 to follow-up day 7
Total number of participants with a mean KSS no more than 2 points higher than baseline for at least 6 out of 8 weeks during the treatment period	Key Symptom Score (KSS). The KSS is derived from the patient-administered DHAF, and is the average on a 0 to 10 scale (0 = None, 10 = Very Severe) of 5 separate scales - rash, feeling of fever and chills, joint pain, eye redness and pain, and fatigue. Lower KSS scores represent better outcomes.	Baseline to week 12
Change from baseline in PGA	Physician Global Assessment (PGA). The Physician's Global Assessment of Autoinflammatory Disease Activity (PGA) is a measure to be completed by the investigator or designee. The PGA uses a 5-point rating scale: absent, minimal, mild, moderate, and severe. The investigator will select a rating based on the patient's current disease activity at the time of the visit. Lower PGA scores represent better outcomes.	Baseline to week 12
Change from baseline in KSS	Key Symptom Score (KSS). The KSS is derived from the patient-administered DHAF, and is the average on a 0 to 10 scale (0 = None, 10 = Very Severe) of 5 separate scales - rash, feeling of fever and chills, joint pain, eye redness and pain, and fatigue. Lower KSS scores represent better outcomes.	Baseline to week 12
Change from baseline in CRP	C-reactive protein (CRP). CRP values ≤10 mg/L are considered normal range.	Baseline to week 12
Change from baseline in SAA	serum amyloid A (SAA). SAA values ≤10 mg/L are considered normal range.	Baseline to week 12

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from baseline in serum cytokines IL-1β	Exploratory endpoint to assess the change from baseline in serum cytokines IL-1β ATI-450 in patients with CAPS.	Baseline to week 12
Change from baseline in serum cytokines IL-1α	Exploratory endpoint to assess the change from baseline in serum cytokines IL-1α of ATI-450 in patients with CAPS.	Baseline to week 12
Change from baseline in serum cytokines IL-6	Exploratory endpoint to assess the change from baseline in serum cytokines IL-6 of ATI-450 in patients with CAPS.	Baseline to week 12
Change from baseline in serum cytokines IL-18	Exploratory endpoint to assess the change from baseline in serum cytokines IL-18 of ATI-450 in patients with CAPS.	Baseline to week 12
Change from baseline in serum cytokines TNF-α	Exploratory endpoint to assess the change from baseline in serum cytokines TNF-α of ATI-450 in patients with CAPS.	Baseline to week 12

Collaborators and Investigators

• Sponsor: Aclaris Therapeutics, Inc.
• Investigators: Study Director: David Gordon, Aclaris Therapeutics

Study record dates

Study Major Dates

• Study Start (Actual): October 23, 2020
• Primary Completion (Actual): February 25, 2021
• Study Completion (Actual): February 25, 2021

Study Registration Dates

• First Submitted: August 19, 2020
• First Submitted That Met QC Criteria: August 21, 2020
• First Posted (Actual): August 24, 2020

Study Record Updates

• Last Update Posted (Actual): September 21, 2023
• Last Update Submitted That Met QC Criteria: August 25, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Keywords: CAPS; Cryopyrin-Associated Periodic Syndrome
• Additional Relevant MeSH Terms: Pathologic Processes; Skin Diseases; Immune System Diseases; Hypersensitivity, Immediate; Disease Attributes; Disease; Genetic Diseases, Inborn; Hereditary Autoinflammatory Diseases; Skin Diseases, Genetic; Skin Diseases, Vascular; Hypersensitivity; Urticaria; Chronic Disease; Chronic Inducible Urticaria; Chronic Urticaria; Syndrome; Cryopyrin-Associated Periodic Syndromes
• Other Study ID Numbers: ATI-450-CAPS-201

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No