3.1 Primary ObjectiveTo evaluate the safety and tolerability of a single IV dose of SPK-3006 administered at escalating dose levels to participants with clinically moderate LOPD.3.2 Secondary ObjectivesTo evaluate potential efficacy and bioactivity…
ID
Source
Brief title
Condition
- Metabolic and nutritional disorders congenital
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
3.4 Primary Endpoints
The primary endpoints of this study include the following:
• 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
• Immune responses against the AAV capsid (neutralizing antibody [NAb] assay)
and GAA transgene product (binding and NAb assays)
Secondary outcome
3.5 Secondary Endpoints
Secondary endpoints include the following:
• Changes from baseline in the Six-Minute Walk Test (6MWT)
• Changes from baseline in the Forced Vital Capacity (FVC)
• Peak and steady-state vector-derived GAA enzyme levels assessed by total GAA
protein and activity measured in circulation
• Biomarkers of muscle injury and glycogen accumulation (creatine kinase [CK],
urine glucose tetrasaccharide [Hex 4])
3.6 Exploratory Endpoints
Exploratory endpoints will assess changes from baseline in the following:
• Other muscle function tests including Gait, Stairs, Gower, Chair (GSGC) and
Rasch built Medical Research Council (MRC)
• Other respiratory function tests including sniff nasal inspiratory pressure
(SNIP), and maximum inspiratory and expiratory pressures (MIP and MEP)
• Muscle biopsy (optional and at selected study centers)
• qMRI of muscles (at selected study centers)
• Liver health biomarkers
• FluoroSpot assay (cellular immune response to AAV-Spark100 or GAA)
• Lysosomal health biomarker (βHexosaminidase [βHexo])
• Activities measured utilizing biosensors (wearable devices)
• Health outcome measures including the below patient reported outcomes:
o Short Form-36 Health Survey (SF-36)
o Rasch-built Pompe-specific Activity (R-PAct) scale
o Fatigue Severity Scale (FSS)
• Patient Reported Outcomes Measurement Information System (PROMIS) item banks
Background summary
Late onset Pompe disease (LOPD, glycogen storage disease type 2) patients
experience the consequences of intracellular glycogen accumulation resulting
from deficient activity of acid alpha glucosidase enzyme (GAA). While many
tissues may be affected, in LOPD the most frequent and debilitating clinical
consequences arise from the inability to normally clear tissue glycogen from
skeletal muscle including respiratory muscle, resulting in myocyte death, loss
of motor function and respiratory failure.
ERT with alglucosidase alfa, a recombinant human acid α-glucosidase, is
currently the only disease-specific therapy approved for the treatment of Pompe
disease in the United States (US) and European Union (EU). In contrast to the
substantial effects of ERT in IOPD, the clinical benefits of ERT in LOPD are
less conclusive.
Based on the unsatisfactory clinical outcomes in a large proportion of
patients, adverse drug reactions, the frequency and duration of treatment, and
substantial economic burden associated with ERT, a significant unmet medical
need exists for patients with Pompe disease.
Gene therapy with SPK-3006 could potentially overcome many of the clinical
limitations associated with ERT for the treatment of LOPD.
Study objective
3.1 Primary Objective
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.
3.2 Secondary Objectives
To evaluate potential efficacy and bioactivity of SPK-3006.
3.3 Exploratory Objectives
To evaluate additional muscle function and respiratory measures, muscle
biopsies (optional and at selected study centers), quantitative magnetic
resonance imaging (qMRI) of muscles (at selected study centers), biomarkers of
liver health and lysosomal health, immune responses against AAV-Spark100 and
GAA, as well as health outcome measures.
Study design
4.1 Overall Design
This is a Phase 1/2, prospective, multinational, multicenter, open-label,
non-randomized, first-in- human, dose-escalation study to evaluate the safety,
tolerability and exploratory efficacy of a single intravenous infusion of
SPK-3006 in adults with clinically moderate, LOPD (as defined in the inclusion
criteria).
After provision of written informed consent, screening assessments may begin.
The study design includes a screening period that may extend for a period of up
to 14 weeks to allow sufficient time for assessment of all screening criteria
and scheduling of SPK-3006 infusion. Sirolimus therapy will begin on Day -6
prior to dosing and continue through week 12. All participants will be
monitored for approximately 60 months (±4 weeks) (End-of-Study) after SPK-3006
infusion (see Schedule of Assessments).
Intervention
4.1.2 Study Intervention
Assessments and procedures to be performed on Dosing Day (Day 0) are shown in
the Schedule of Assessments. Participants will receive a single intravenous
infusion of SPK-3006 at an infusion center staffed with the necessary personnel
and equipment to address any urgent medical event (e.g., hypersensitivity
reactions, including anaphylaxis) that may occur. The infusion center will have
access to a local ICU. The complete dose of SPK-3006 will be infused via
infusion pump over approximately 60 minutes. Vital signs will be measured prior
to infusion of SPK-3006, at designated timepoints during infusion - infusion
start, 30 minutes after start and end of infusion (all approximately ±10
minutes), and at designated timepoints during the post-infusion observation
period on Day 0, [i.e., 2 hours, 3.5 hours, 5 hours (all approximately ±10
minutes), and 24 hours (±1) hour) after the start of SPK-3006 infusion]. Sites
may choose to have participants stay overnight to logistically accommodate Day
0 and Day 1 procedures and timepoints (see Schedule of Assessments). Such a
hospitalization will not be considered an SAE unless an untoward event meeting
the definition of an SAE occurs.
Study burden and risks
Exams that will be done and repeated at most of the visits:
- physical exam (these require a hospital visit, of PE is not applicable for a
visit, that visit can be completed at patient's home)
- ECG
- Liver ultrasound
- FibroScan
- 6MWT
- pulmonary function tests (FVC)
- drug dispense log (receive/complete/review)
- ECHO,
- blood and urine analysis (incl pregnancy test if applicable)
- SARS-CoV-2 test
- collection biosensors
- other muscle function tests ,
- review potential Adverse events
- Questionnaires,
- dispense Sirolimus (to lower the chance that an immune reaction cancels the
effect of the study drug)
- Infusion SPK-3006
- ERT infusion and log to complete
The side effects of PCV in humans are unknown as this is a first-in-men study.
Participants will be closely monitored during and up to 5 hours after the IV
administration of SPK-3006 and during the follow-up visits. Participants will
also be informed of early signs and symptoms of hypersensitivity reactions.
3737 Market Street Suite 1300
Philadelphia 19104
US
3737 Market Street Suite 1300
Philadelphia 19104
US
Listed location countries
Inclusion criteria
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 and no longer improving on ERT;
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 two timepoints prior to initiating
immunosuppression (Day -6) with <10% variance between the assessments. If the
variance is >=10%, a third timepoint will be collected;
b. Have a percentage of the 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 dose of sirolimus,
whichever occurs later. Female candidates of child-bearing potential must have
a negative pregnancy test prior to initiating immunosuppression (Day -6) and on
Day 0 prior to administration of SPK-3006. See Section 13 (Appendix 1) for
guidance on reliable contraception and the definition of women of child-bearing
potential (WOCBP);
6. Agree to refrain from blood, plasma, platelets, egg or sperm, and organ
donation after receiving SPK-3006.
Exclusion criteria
1. Have active hepatitis B and/or C;
All candidates must be screened for both active hepatitis B and C, regardless
of prior known history.
a. Screening for hepatitis B.
All 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 DNA (HBV-DNA viral
assay).A candidate is not eligible if either HbsAg is positive or HBV-DNA is
positive/detectable.
i. A candidate is not eligible if either HBsAg is positive or HBV-DNA is
positive/detectable.
ii. 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
trial in candidates with no prior history of hepatitis B.
iii. A candidate who is currently undergoing antiviral therapy for chronic
hepatitis B is not eligible.
b. Screening for hepatitis C:
iv. A candidate who is currently undergoing antiviral therapy for chronic
hepatitis C is not eligible.
v. 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 RNA (HCV-RNA single load assay) at Screening.
• A candidate is not eligible if the HCV-RNA load assay is positive/detectable.
• Candidates treated with anti-viral therapy for chronic hepatitis C, must have
completed anti-viral therapy at least 6 months prior to Screening and have a
negative HCV-RNA at Screening.
• Candidates with a documented or self-reported history of hepatitis C must
have a single negative HCV-RNA at Screening.
2. Have significant underlying liver disease. A candidate is not eligible if
any of the following pre-existing diagnoses, which are indicative of
significant underlying liver disease, are present in the medical record:
• Liver cirrhosis;
• Portal hypertension; or
• Hepatic encephalopathy
• Gamma-glutamyl transferase (GGT) >1.2X upper limit of normal (ULN) adjusted
for age and gender; or
• Bilirubin >1.2X ULN adjusted for age and gender. 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:
• Measurement of serum albumin. A candidate is not eligible if the serum
albumin level is below the testing laboratory*s lower limit of normal;
• Liver fibrosis >= stage 3. The following results are indicative of fibrosis >=
stage 3 and exclude the candidate from participation:
- FibroScan, with a score > 8.3 kPa units
- FibroTest/ FibroSURE with a result > 0.48
- AST-Platelet Ratio Index (APRI) >1;
Of note, if results from more than one modality for evaluation of liver
fibrosis are available (e.g., results from both FibroScan and FibroSURE are
available) the result from FibroScan should be consulted for determination of
liver fibrosis as it will take precedence over other modalities.Human
immunodeficiency virus infection;
3. Have human immunodeficiency virus (HIV) infection;
4. Have a prior hypersensitivity to recombinant human GAA (rhGAA);
5. Have pre-existing AAV-Spark100 Neutralizing Antibody titers >1:1;
6. Have high titer antibody responses to rhGAA (anti-GAA >1:30,000);
7. Had participated in a clinical study with an investigational drug in the
past 6 months (vaccination studies are accepted; observation studies are
accepted after discussion with the Medical Monitor);
8. Requires 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 a medication that is contraindicated with
sirolimus (see Section 19.6.4.1), such as, medication known to be a strong or
moderate inducer or inhibitor of CYP3A4 - excluded only during the sirolimus
immunosuppressive period;
12. Received live vaccines within 30 days prior to informed consent to at least
52 weeks after receiving SPK-3006 infusion
13. Used a systemic immunosuppressive agents (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 a pregnant or nursing female;
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, 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.
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2019-001283-30-NL |
| ClinicalTrials.gov | NCT04093349 |
| CCMO | NL72791.000.20 |