Evaluation of Safety, Tolerability, and Efficacy of Intravenous Vanglusagene Ensiparvovec in Adults with Late-Onset Pompe Disease

Trial ID: 2023-509303-32-00
Protocol: XE45632
Sponsor: Genentech Inc.

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Diseases & Conditions

Glycogen storage disease type II

Objectives

The primary objective of this Phase 1/2 dose-escalation study is to evaluate the **safety** and **tolerability** of a single intravenous (IV) dose of SPK-3006, administered at escalating dose levels, in participants with clinically moderate late-onset **Pompe Disease**. This objective is clinically relevant as it aims to determine the appropriate dosage and potential adverse effects of SPK-3006, which is crucial for ensuring patient safety and optimizing therapeutic outcomes in this patient population.

Secondary objectives include:

Evaluating the potential **efficacy** and **bioactivity** of SPK-3006. This involves assessing the therapeutic impact and biological response to the treatment, which is essential for understanding the potential benefits of SPK-3006 in managing late-onset Pompe Disease.

Participants

The clinical trial involves a total of **two participants** diagnosed with **Pompe Disease**, specifically the late-onset form (LOPD). The study population includes both male and female subjects aged 18 years and older. Participants were selected based on their ability to understand the study's purpose and risks, and they provided informed consent. They have a confirmed diagnosis of LOPD through genetic testing or documented enzyme deficiency and have been on a stable enzyme replacement therapy (ERT) regimen for at least 24 months. The participants exhibit clinically moderate LOPD characteristics, such as the ability to walk between 75 and 500 meters on the 6-minute walk test (6MWT) and have a forced vital capacity (FVC) between 30% and 80% in the upright position. The trial does not include a vulnerable population, and lifestyle considerations such as the use of reliable contraception and restrictions on donations post-treatment are noted. The sponsor has not provided additional information regarding the general health status or specific lifestyle habits of the participants.

Plans and Procedures

The clinical trial is a **Phase 1/2** dose-escalation study designed to evaluate the safety, tolerability, and efficacy of a single intravenous infusion of **SPK-3006** in adults with late-onset **Pompe Disease**. The trial employs a **randomized, double-blind, controlled** design to ensure unbiased results. The estimated duration of the trial extends from the recruitment start date on October 31, 2024, to the anticipated end date on December 17, 2032. Participants will be involved in the study for a period that includes initial screening, treatment, and follow-up visits.

The sequence of study visits begins with an inclusion (screening) visit, where participants are assessed for eligibility based on criteria such as age, confirmed diagnosis of late-onset Pompe Disease, and previous treatment history. Following successful screening, participants will receive a single dose of SPK-3006 via intravenous administration. Subsequent follow-up visits will be scheduled to monitor safety and efficacy outcomes, including the incidence of adverse events, changes in laboratory values, and immune responses. The end-of-study visit will conclude the participant's involvement, with comprehensive assessments to evaluate the primary and secondary endpoints.

Participants are expected to remain in the study for the entire duration unless specific conditions necessitate early termination. Such conditions include the occurrence of serious adverse events, non-compliance with study protocols, or withdrawal of consent. The primary endpoints focus on the incidence of adverse events and immune responses, while secondary endpoints include changes in the Six-Minute Walk Test, forced vital capacity, and biomarkers of muscle injury. The trial aims to provide valuable insights into the therapeutic potential of SPK-3006 for individuals with late-onset Pompe Disease.

Treatment

The clinical trial involves the administration of **SPK-3006**, an experimental medication designed to evaluate its safety, tolerability, and efficacy in adults with Late-Onset Pompe Disease (LOPD). **SPK-3006** is a **solution for infusion** containing the active substance **vanglusagene ensiparvovec**. This substance is a recombinant adeno-associated viral vector, which includes a bioengineered capsid derived from AAV-RH74 and a codon-optimized expression cassette to drive the expression of a secretable form of human acid alpha-glucosidase. The pharmaceutical form of **SPK-3006** is a solution intended for **intravenous administration**. The trial protocol specifies a single intravenous infusion of **SPK-3006** at escalating dose levels to assess its impact on participants with clinically moderate LOPD.

In this study, **SPK-3006** is classified as an orphan drug, indicating its designation for a rare condition. The trial does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatment. The administration of **SPK-3006** is monitored to ensure participant compliance, with a focus on the safety and tolerability of the single-dose regimen. The trial is structured as a Phase 1/2 dose-escalation study, aiming to gather comprehensive data on the effects of the treatment in the specified patient population.

Efficacy

Efficacy in the clinical trial will be assessed using several secondary endpoints. These include changes from baseline in the Six-Minute Walk Test (6MWT) and changes from baseline in the percentage of predicted forced vital capacity (FVC). Additionally, the trial will evaluate peak and steady-state vector-derived **GAA enzyme** levels, which will be assessed by measuring total GAA protein and activity in circulation. Biomarkers of skeletal muscle injury and glycogen accumulation, such as creatine kinase (CK) and urine glucose tetrasaccharide (Hex4), will also be monitored. These parameters will provide a comprehensive evaluation of the therapeutic impact of SPK-3006 in participants with late-onset Pompe disease. The collection and analysis of these efficacy parameters will be conducted at specified timepoints throughout the trial to ensure accurate and reliable data. The use of validated scales and laboratory tests will facilitate the objective measurement of these endpoints.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Be able to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information (PHI) in accordance with national and local privacy regulations.
Are male or female ≥18 years of age with a confirmed diagnosis (e.g., GAA genetic testing) of LOPD, or based on a documented deficiency of GAA enzyme activity.
Have received a marketed ERT for at least the previous 24 months and maintained a stable dose, frequency, and compliance for the past 6 months with no dose variation.
Have clinically moderate LOPD characteristics: a. Be able to walk ≥75 meters on the 6MWT (assistive devices permitted) but less than 500 meters assessed at 2 timepoints prior to initiating immunosuppression (Day ˗6 visit) with <10% variance between the assessments. If the variance is ≥10%, a third timepoint will be collected. b. Have a % predicted FVC ≥30% and ≤80% in the upright position.
Agree to use reliable contraception for a minimum of 6 months after administration of SPK-3006 or 12 weeks after the final immunomodulatory agent dose, whichever occurs later, and until after vector shedding is confirmed to be cleared from the semen. Female candidates of childbearing potential must have a negative pregnancy test prior to initiating immunosuppression (Day -6 visit) and on Day 0 prior to administration of SPK-3006.
Agree to refrain from blood, plasma, platelets, egg or sperm, and organ donation after receiving SPK-3006.

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Exclusion Criteria

Have active hepatitis B and/or C; all candidates must be screened for active hepatitis B and C, regardless of prior known history. a. Screening for hepatitis B: i. A candidate who is currently undergoing antiviral therapy for chronic hepatitis B is not eligible. ii. All other candidates must have a single sample at Screening for each of the following tests: hepatitis B surface antigen (HBsAg), total hepatitis B core antibody (anti-HBc), and a nucleic acid test for hepatitis B virus (HBV) DNA (HBV-DNA viral assay). • A candidate is not eligible if either HBsAg is positive or HBV-DNA is positive/detectable. • A candidate is eligible if the anti-HBc is positive and both HBsAg and HBV-DNA are negative, as this would be consistent with a prior infection of hepatitis B. Anti-HBc must be obtained in all candidates to discriminate between acute infection and possible reactivation of hepatitis B during the study in candidates with no prior history of hepatitis B. b. Screening for hepatitis C: i. A candidate who is currently undergoing antiviral therapy for chronic hepatitis C is not eligible. ii. All other candidates, including those who have never been treated or who have completed antiviral therapy for chronic hepatitis C, must have a nucleic acid test for hepatitis C viral (HCV) RNA (HCVRNA single load assay) at screening. A candidate is not eligible if the HCV-RNA load assay is positive/detectable. • A candidate treated with anti-viral therapy for chronic hepatitis C who has completed anti-viral therapy at least 6 months prior to screening and has a negative HCV-RNA at screening is eligible. • A candidate with a documented or self-reported history of hepatitis C who has a single negative HCV-RNA at screening is eligible.
Have significant underlying liver disease. A candidate is not eligible if any of the following pre-existing diagnoses are present in the medical record: a. Liver cirrhosis b. Portal hypertension c. Hepatic encephalopathy d. Gamma-glutamyl transferase (GGT) >1.2x upper limit of normal (ULN) e. Bilirubin >1.2x ULN. Candidates with asymptomatic elevated bilirubin (e.g., Gilbert syndrome) can be considered after discussion with the Sponsor Medical Monitor. All candidates who do not have the pre-existing diagnoses listed above must have the following assessments performed at screening. They are not eligible for enrollment if they have either of the following: a. Serum albumin below the testing laboratory’s lower limit of normal (LLN). b. Liver fibrosis ≥stage 3. The following results are indicative of fibrosis ≥stage 3 and exclude the candidate from participation: i. FibroScan with a score >8.3 kPa units if the candidate has mild steatosis (Grade S1 - see Steatosis Grade table below) ii. FibroScan with a score >9.5 kPa units if the candidate has moderate steatosis. iii. FibroScan with a score >11 kPa units if the candidate has severe steatosis (Grade S3 - see Steatosis Grade table below) iv. FibroTest/ FibroSURE with a result >0.48 v. Aspartate aminotransferase (AST)-Platelet Ratio Index (APRI) >1; this is calculated using the following industry standard formulation: ([AST in IU/L/AST ULN in IU/L] x 100) / (platelet count in 109/L) (Wai, 2003).
Have human immunodeficiency virus (HIV) infection.
Have a prior hypersensitivity to recombinant human GAA (rhGAA).
Have pre-existing anti-AAV-Spark100 NAb titer >1:1 at either the Prescreening Visit or at Screening Visit 1 (SV1), if the Prescreening Visit is not conducted (e.g., for candidates with prior results from another Spark-sponsored study).
Have high titer antibody responses to rhGAA (anti-GAA ≥1:31,250) at either the Prescreening Visit or at SV1, if the Prescreening Visit is not conducted (e.g., for candidates with prior results from another Spark-sponsored study).
Had participated in a clinical study with an investigational drug in the past 6 months (with the exception of prior participation in vaccination or next-generation ERT studies); observational studies are acceptable after discussion with the Medical Monitor.
Require any invasive ventilation or requires noninvasive ventilation while awake and upright.
Had any change to respiratory muscle strength training within 90 days prior to informed consent (for participants receiving respiratory muscle strength training) or initiation of respiratory muscle strength training prior to Day 0.
Received any prior vector or gene transfer agent.
Require concomitant use of medication during the sirolimus immunosuppression period that is contraindicated with sirolimus, such as a medication known to be a strong or moderate inducer or inhibitor of cytochrome P450 3A4 (CYP3A4).
Received live vaccines within 30 days prior to informed consent or plan to receive live vaccines within at least 52 weeks after receiving SPK-3006 infusion.
Used a systemic immunosuppressive agent (e.g., corticosteroids) within 30 days prior to informed consent and to Day 0 prior to SPK-3006 administration.
Have an active malignancy (except non-melanoma skin cancer).
Have a history of liver cancer.
Are pregnant or nursing women.
Have any evidence of an active infection at the time of SPK-3006 infusion.
Have a known allergy or hypersensitivity to SPK-3006 investigational product, sirolimus, or corticosteroids.
Have any concurrent clinically significant condition that would not allow the potential participant to complete the follow-up examinations during the course of the study, or other condition that, in the opinion of the Investigator and/or Medical Monitor and/or Sponsor, makes the candidate unsuitable for participation in the study.
Are unable or unwilling to comply with the visit schedule and study assessments described in the clinical protocol.