Phase 1/2 dose-escalation study to evaluate the safety, tolerability, and efficacy of a single intravenous infusion of SPK-3006 in adults with late-onset Pompe disease

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Genentech Inc.

Participant type

Patients

Age range

18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16], Diseases [C] - Nutritional and Metabolic Diseases [C18]

Trial duration

19 Oct 2021 → ongoing

Decision date (initial)

2024-09-20

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

Funding sources

Genentech Inc.

External identifiers

EU CT number

2023-509303-32-00

EudraCT number

2019-001283-30

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety, Dose response

To evaluate the safety and tolerability of a single IV dose of SPK-3006 administered at escalating dose levels to participants with clinically moderate LOPD.

Secondary objectives 1

1. To evaluate potential efficacy and bioactivity of SPK-3006

Conditions and MedDRA coding

Pompe Disease (also known as glycogen storage disease type II)

Regulatory references

Scientific advice from competent authorities

National Agency For The Safety Of Medicine And Health Products, Italian Medicines Agency

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 6

1. 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.
2. 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.
3. 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.
4. 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.
5. 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.
6. Agree to refrain from blood, plasma, platelets, egg or sperm, and organ donation after receiving SPK-3006.

Exclusion criteria 20

1. 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.
2. 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).
3. Have human immunodeficiency virus (HIV) infection.
4. Have a prior hypersensitivity to recombinant human GAA (rhGAA).
5. 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).
6. 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).
7. 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.
8. Require any invasive ventilation or requires noninvasive ventilation while awake and upright.
9. 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.
10. Received any prior vector or gene transfer agent.
11. 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).
12. 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.
13. Used a systemic immunosuppressive agent (e.g., corticosteroids) within 30 days prior to informed consent and to Day 0 prior to SPK-3006 administration.
14. Have an active malignancy (except non-melanoma skin cancer).
15. Have a history of liver cancer.
16. Are pregnant or nursing women.
17. Have any evidence of an active infection at the time of SPK-3006 infusion.
18. Have a known allergy or hypersensitivity to SPK-3006 investigational product, sirolimus, or corticosteroids.
19. 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.
20. Are unable or unwilling to comply with the visit schedule and study assessments described in the clinical protocol.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Incidence of adverse and serious adverse events (AEs/SAEs), clinically significant abnormal laboratory values, change in vital signs, change in physical examination (PE), vector shedding in bodily fluids, and liver function tests
2. Immune responses against the AAV-Spark100 capsid (neutralizing antibody [NAb] assay) and GAA transgene product (binding and NAb assays)

Secondary endpoints 4

1. Changes from baseline in Six-Minute Walk Test (6MWT)
2. Changes from baseline in % predicted forced vital capacity (FVC)
3. Peak and steady-state vector-derived GAA enzyme levels assessed by total GAA protein and activity measured in circulation
4. Biomarkers of skeletal muscle injury, glycogen accumulation (creatine kinase [CK], urine glucose tetrasaccharide [Hex4])

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Genentech Inc.

Sponsor organisation

Genentech Inc.

Address

1 Dna Way

City

South San Francisco

Postcode

94080-4918

Country

United States

Scientific contact point

Organisation

Genentech Inc.

Contact name

US Program Manager Product Development Regulatory

Public contact point

Organisation

Genentech Inc.

Contact name

US Program Manager Product Development Regulatory

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 8 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

6 submissions — initial application plus substantial / non-substantial modifications