Study of a Gene Therapy Treatment for Hemophilia A (KEYSTONE 1)

A Phase 3, Single-arm, Open-label, Multicenter Study of the Safety and Efficacy of Dirloctocogene Samoparvovec (SPK 8011, Adeno-associated Viral Vector With B-domain Deleted Human Factor VIII Gene) in Adults With Severe or Moderately Severe Hemophilia A

The purpose of this study is to evaluate the efficacy of SPK-8011 in preventing bleed episodes compared with FVIII prophylaxis in participants with hemophilia A without FVIII inhibitors on routine FVIII prophylaxis.

Study Overview

• Status: Withdrawn
• Conditions: Hemophilia A
• Intervention / Treatment: Genetic: SPK-8011

• Study Type: Interventional
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Phoenix, Arizona, United States, 85016
      • Phoenix Children's Hospital
  • California
    • Loma Linda, California, United States, 92354
      • Loma Linda University Health
    • Los Angeles, California, United States, 90007
      • Orthopaedic Institute for Children/Orthopaedic Hemophilia Treatment Center
    • Oakland, California, United States, 94611
      • Kaiser Permanente-Oakland Medical Center
    • Roseville, California, United States, 95661
      • Kaiser Permanente-Roseville Medical Center
    • Sacramento, California, United States, 95814
      • Kaiser Permanente -Sacramento Medical Center
    • San Francisco, California, United States, 94143
      • University of California - San Francisco
    • San Francisco, California, United States, 94115
      • Kaiser Permanente -San Francisco Medical Center
    • Santa Clara, California, United States, 94115
      • Kaiser Permanente- Santa Clara Medical Center
    • Vallejo, California, United States, 94589
      • Kaiser Permanente-Vallejo Medical Center
    • Walnut Creek, California, United States, 94596
      • Kaiser Permanente -Walnut Creek Medical Center
  • Florida
    • Gainesville, Florida, United States, 32610
      • University of Florida
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Boston Children's Hospital
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota
  • New Jersey
    • Newark, New Jersey, United States, 07112
      • Newark Beth Israel
  • New York
    • New York, New York, United States, 10065
      • Weill Cornell Medical Hospital
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27514
      • University of North Carolina - Chapel Hill
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital
    • Cleveland, Ohio, United States, 44106
      • University Hospitals Cleveland
    • Columbus, Ohio, United States, 43205
      • Nationwide Children's Hospital
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health & Sciences University
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • Penn State Hershey Medical Center
    • Philadelphia, Pennsylvania, United States, 19103
      • University of Pennsylvania
  • Texas
    • Fort Worth, Texas, United States, 76104
      • Cook Children's Hospital
    • Houston, Texas, United States, 77030
      • The University of Texas Health Science Center at Houston-Gulf States Hemophilia & Thrombosis Center
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • University of Utah
  • Washington
    • Seattle, Washington, United States, 98101
      • Bloodworks NW

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Have a negative anti-AAV-Spark200 neutralizing antibody (NAb) test result.
• Are adult males with severe or moderately severe hemophilia A, defined as endogenous FVIII activity ≤3%, as documented by a certified laboratory (historically or during the Screening Period) and where the FVIII:C level is measured more than 96 hours after the prior dose of an extended-half-life FVIII
• Have ≥150 documented exposure days to an FVIII protein product such as recombinant, plasma-derived, or extended half-life FVIII product
• Have no prior history of hypersensitivity or anaphylaxis associated with the administration of any FVIII product.
• Have screening hepatic ultrasound without evidence of cirrhosis and no laboratory or clinical evidence per the Investigator's judgment of advanced liver disease or cirrhosis.
• Have a negative test for inhibitor against FVIII (ie, <0.6 Bethesda units [BU]) during screening.
• Have no documented FVIII inhibitor (ie, <0.6 BU), FVIII half-life <6 hours, or FVIII recovery <66% in the 5 years prior to screening.
• Candidates who completed successful immune tolerance induction (ITI) at least 5 years before screening are eligible, provided they have had no evidence of inhibitor recurrence (permanent or temporary) within 5 years prior to screening as may be indicated by detection of an inhibitor, FVIII half-life <6 hours, or FVIII recovery <66% since completing ITI.
• If human immunodeficiency virus (HIV)-positive at screening, have an adequate cluster of differentiation 4 (CD4) count (>200/mm3) and undetectable viral load (<50 genome copies [gc]/mL), are on an antiretroviral drug regimen, and have completed at least 12 weeks of this treatment regimen prior to screening.

• Meet the following inclusion criteria by cohort:

  • Cohort A: have documented history of prior treatment with FVIII prophylaxis (defined as receiving a prescribed dose and frequency of FVIII infusions with the intent to treat continuously for 52 weeks per year) for a minimum of 6 months prior to screening; and are willing to continue their FVIII prophylaxis during the Lead-In Period of this study (minimum of 24 weeks).
  • Cohort B: have documented history of prior treatment with FVIII on demand for a minimum of 6 months that shows ≥5 treated bleeds in the last 6 months prior to screening.
  • Cohort C: have documented history of prior treatment with emicizumab prophylaxis for a minimum of 6 months prior to screening.

Exclusion Criteria:

• Have an inherited or acquired bleeding disorder other than hemophilia A
• Have inherited or acquired thrombophilia, have signs of thromboembolic disease in the Investigator's judgment, or are on current treatment for thromboembolic disease. A history of previous catheter-associated thrombosis for which anti-thrombotic treatment is not currently ongoing is not considered an exclusion criterion.
• Have concurrent disease, treatment, or abnormality in clinical laboratory tests that could interfere with the conduct of the study or that would, in the opinion of the Investigator or Sponsor, preclude the candidate's safe participation in and completion of the study, or the interpretation of the study results.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort A (Primary Cohort); Participants with severe or moderately severe hemophilia A without FVIII inhibitors using routine FVIII prophylaxis	Genetic: SPK-8011; Participants will receive a single dose of SPK-8011, administered by intravenous (IV) infusion, on Day 1.; Other Names: AAV-Spark200-BDD-hFVIII; Dirloctocogene samoparvovec
Experimental: Cohort B; Participants with severe or moderately severe hemophilia A without FVIII inhibitors using on-demand FVIII replacement therapy	Genetic: SPK-8011; Participants will receive a single dose of SPK-8011, administered by intravenous (IV) infusion, on Day 1.; Other Names: AAV-Spark200-BDD-hFVIII; Dirloctocogene samoparvovec
Experimental: Cohort C; Participants with severe or moderately severe hemophilia A without FVIII inhibitors using emicizumab prophylaxis	Genetic: SPK-8011; Participants will receive a single dose of SPK-8011, administered by intravenous (IV) infusion, on Day 1.; Other Names: AAV-Spark200-BDD-hFVIII; Dirloctocogene samoparvovec

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Annualized Bleed Rate (ABR) for All Bleeds [Cohort A]	Up to 66 weeks post-SPK-8011 infusion

Secondary Outcome Measures

Outcome Measure	Time Frame
Proportion of Resolved Target Joints [Cohort A]	Up to approximately 10 years
Proportion of Participants Who Receive IV Methylprednisolone (IVMP) Prior to Week 8 (Early IVMP) [Cohorts A, B, C]	Up to approximately 10 years
Proportion of Participants Who Receive Secondary Oral Immunomodulation [Cohorts A, B, C]	Up to approximately 10 years
Median Time to First Immunomodulation-related Corticosteroid Dose [Cohorts A, B, C]	Up to approximately 10 years
Median Duration of Secondary Oral Immunomodulation [Cohorts A, B, C]	Up to approximately 10 years
Proportion of Participants with FVIII Inhibitor Development [Cohorts A, B, C]	Up to approximately 10 years
Median FVIII: C levels [Cohort A]	Up to approximately 10 years
ABR for treated bleeds [Cohort A]	Up to approximately 10 years
Percentage of Participants with ABR=0 for all bleeds; treated bleeds; treated spontaneous bleeds; and treated joint and target joint bleeds [Cohort A]	Up to approximately 10 years
ABR for treated spontaneous, joint, and target joint bleeds [Cohort A]	Up to approximately 10 years
Annualized FVIII dosage [Cohort A]	Up to approximately 10 years
Mean Change of Total Hemophilia Joint Health Score [Cohort A]	Baseline, up to 66 weeks post-SPK-8011 infusion
FVIII:C levels over time [Cohort A]	Up to approximately 10 years
Mean ABR for all bleeds and treated bleeds [Cohort C]	Up to approximately 10 years
FVIII: C levels over time from Week 26 [Cohort C]	Up to approximately 10 years
Proportion of participants with Treatment-related AEs of ALT Elevation [Cohorts A, B, C]	Up to approximately 10 years
Proportion of participants with treatment-related AEs of Infusion Reaction [Cohorts A, B, C]	Up to approximately 10 years
Number of participants with abnormal physical exam findings, abnormal vital signs, and abnormal selected clinical laboratory test results [Cohorts A, B, C]	Up to approximately 10 years
Proportion of participants with AEs and SAEs [Cohorts A, B, C]	Up to approximately 10 years
Proportion of participants with AESIs [Cohorts A, B, C]	Up to approximately 10 years

Collaborators and Investigators

• Sponsor: Spark Therapeutics, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): March 13, 2024
• Primary Completion (Estimated): May 1, 2027
• Study Completion (Estimated): September 4, 2035

Study Registration Dates

• First Submitted: February 29, 2024
• First Submitted That Met QC Criteria: March 6, 2024
• First Posted (Actual): March 7, 2024

Study Record Updates

• Last Update Posted (Estimated): December 13, 2024
• Last Update Submitted That Met QC Criteria: December 9, 2024
• Last Verified: December 1, 2024

More Information

Terms related to this study

• Keywords: Gene Therapy; FVIII; Dirloctocogene samoparvovec; SPK 8011; Blood coagulation factor VIII; AAV-Spark200-BDD-hFVIII
• Additional Relevant MeSH Terms: Genetic Diseases, Inborn; Hematologic Diseases; Blood Coagulation Disorders; Hemorrhagic Disorders; Blood Coagulation Disorders, Inherited; Coagulation Protein Disorders; Hemophilia A
• Other Study ID Numbers: SPK-8011-302; 2023-504537-46 (EudraCT Number)

Drug and device information, study documents

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