| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Hunter Syndrome (Mucopolysaccharidosis Type II [MPS II]) |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10056917 |
| E.1.2 | Term | Hunter's syndrome |
| E.1.2 | System Organ Class | 100000004850 |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To investigate the safety and tolerability of DNL310 in paediatric subjects with MPS II |
|
| E.2.2 | Secondary objectives of the trial |
To characterize the effects of DNL310 on Hunter Syndrome (HS) concentrations in CSF
• To characterize the PK of once-weekly IV infusions of DNL310 in serum
• To characterize immunogenicity of DNL310 in serum
• To characterize the effects of DNL310 on HS concentrations in urine |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1) Informed consent signed by the subject, if able to legally provide consent, or signed by the parent(s) or LAR and subject assent if required based on local regulations, Ethics Committee (EC), and subject age
2) Body weight at screening as follows:
• Cohort A: ≥ 19 kg
• Cohort B: ≥ 10 kg
3) Age at study entry as follows:
• Cohort A (first 4 subjects): nMPS II subjects aged 5 to 10 years, inclusive, at screening
• Cohort B: subjects aged 2 to 18 years, inclusive, at screening, after DMC recommendation to expand both the age range and include all phenotypes of MPSII (e.g., nMPS II, non-neuronopathic, or unknown).
Cohort B will have 3 subcohorts (B1, B2, B3) based on starting dose. Subjects will be assigned sequentially to subcohort B1, B2, and B3, but stratified by age, with the first 2 subjects aged 2 to < 5 years enrolled to B1 and a minimum of one subject aged 10 to 18 years in each group.
4) Subject and parent(s) or LAR are willing and have the ability to comply with protocol requirements, according to the investigator’s judgment
5) Male subjects with a confirmed diagnosis of MPS II based on the following:
• Reduced IDS activity in plasma, white blood cells, and/or skin fibroblasts consistent with MPS II (≤ 10% of the lower limit of the normal range, based on the testing laboratory’s range), and
• A documented mutation in the IDS gene
6) Subjects enrolled prior to DMC’s approval of enrolling non-neuronopathic subjects must have nMPS II based on at least one of the following:
• Cognitive ability standard score ≤ 85 at the screening assessment and/or a documented decline of at least 7.5 points in the standard score in the previous 6 to 18 months based on any one of the following tests, all performed without clinically significant hearing loss or with hearing aids present:
o BSID (BSID-III preferred; BSID-II is acceptable if BSID-III unavailable)
o NVI of the KABC-II
o DAS-II
o Mullen Scales of Early Learning
o Wechsler Preschool and Primary Scale of Intelligence IV
• The subject has the same genetic mutation as a blood relative with confirmed nMPS II. Confirmed nMPS II requires a genetic diagnosis of MPS II and clinically established cognitive delay or regression based on a standard score of cognitive ability ≤ 85, and/or a documented decline of at least 7.5 points in the standard score in the previous 6 to 18 months based on any one of the following tests, all performed without clinically significant hearing loss or with hearing aids present:
o BSID (BSID-III preferred; BSID-II is acceptable if BSID-III unavailable)
o NVI of the KABC-II
o DAS-II
o Mullen Scales of Early Learning
o Wechsler Preschool and Primary Scale of Intelligence IV
• The subject has a large deletion(s) or rearrangement(s) in the IDS gene or other definitive mutation indicative of nMPS II as determined by an independent external review panel
7) For subjects receiving IV IDS ERT (e.g., Elaprase): tolerated a minimum of 4 months of therapy during the period immediately prior to screening
8) For subjects with hearing impairment requiring hearing aids, every effort has been made to encourage compliance with the use of functioning hearing aid(s) before baseline neurocognitive assessments, and parent/LAR or subject agrees to encourage wearing them during the study and on neurocognitive testing days.
9) When engaging in sex with a woman of childbearing potential, both the male subject and his female partner must use highly effective contraception consisting of two forms of birth control, one of which must be a male barrier method such as a latex or polyurethane condom) from start of dosing throughout the clinical study period, and for 90 days after the final study drug administration. |
|
| E.4 | Principal exclusion criteria |
1) Unstable or poorly controlled medical condition(s) or significant medical or psychological comorbidity or comorbidities) based on medical history, screening laboratory values, ECGs, or other screening procedures that, in the opinion of the investigator, would interfere with safe participation in the trial or interpretation of study assessments
2) Use of any CNS-targeted MPS II ERT (e.g., IT IDS, transferrin- or insulin receptor–mediated IDS delivery to CNS) within 3 months before Study Day 1 for subjects aged ≥ 5 years, and within 6 months before Study Day 1 for subjects aged < 5 years. Subjects may be rescreened for this study after the appropriate washout has been completed.
3) Use of an IDS gene therapy or stem cell therapy, including hematopoietic stem cell transplantation, at any time
4) Use of genistein within 30 days of screening, or intended use of genistein during the study. Subjects who discontinue genistein may be rescreened after a 30-day washout has been completed.
5) Participation in any other investigational drug trial or use of an investigational drug within 60 days prior to screening and thereafter. Subjects may rescreen for this study after the 60-day washout has been completed.
6) Documented mutation of other genes, including loci adjacent to the IDS gene (e.g., fragile X mental retardation 1 [FMR1] or AF4/FMR2 family member 2 [i.e., AFF2 or FMR2]), that are known to be associated with developmental delay, seizures, or other significant CNS disorders
7) Documented loss of activity of sulfatases other than IDS, indicating multiple sulfatase deficiency
8) Clinically significant thrombocytopenia (< 100 GI/L [100,000/mm3]), other clinically significant coagulation abnormality, or significant active bleeding, or require treatment with an anticoagulant or more than two antiplatelet agents. Subjects excluded for this reason may be rescreened for this study at least 30 days after the coagulopathy, anticoagulant, or antiplatelet treatments have stopped.
9) Contraindication for LPs, for any reason
10) Have a clinically significant history of stroke, status epilepticus, head trauma with loss of consciousness, or any CNS disease that is not Hunter syndrome–related within 1 year of screening
11) Have had a ventriculoperitoneal (VP) shunt placed or any other brain surgery, or have a clinically significant VP shunt malfunction within 30 days of screening. Subjects may be rescreened after the 30-day waiting period has elapsed.
Note: subjects who have newly diagnosed intracranial hypertension (e.g., CSF opening pressure > 30 cm H2O) requiring placement of a VP shunt may rescreen 30 days after shunt placement.
12) Have any clinically significant CNS trauma or disorder, including severe untreated intracranial hypertension, that, in the opinion of the investigator, may interfere with assessment of study endpoints or make participation in the study unsafe
13) History of serious adverse reaction to IDS enzyme or any component of the IMP, e.g., hypersensitivity or anaphylaxis requiring hospitalization, that cannot be managed with SOC treatment for infusion reactions
14) Have had a donation or loss of more than 10% total blood volume over 8 weeks preceding entry into the treatment period. Subjects excluded for this reason may be rescreened after the 8 weeks have elapsed. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Safety endpoints:
• Frequency and severity of AEs, including IRRs (which include allergic reactions and anaphylaxis)
• Vital sign measurements
• 12-lead ECGs
• Physical examinations, including neurological examinations
• Safety laboratory assessments (including hematology, serum clinical chemistry, urinalysis, and coagulation)
• Urine total GAG concentrations (normalized to creatinine)
• Characterization of immunogenicity of DNL310 in serum, as measured by the incidence of ADAs during the study relative to baseline
• Use of concomitant medications
• Liver and spleen volumes as assessed by ultrasound
• Change from baseline in CGI-S
• CGI-I
• Change from baseline in PGI-S
• PGI-I
• Change from baseline in the total score on the ADL-HS scale
• Change from baseline in stool consistency, per the Bristol Stool Scale
• Change from baseline in 6MWT for subjects ≥ 6 years old who are able to follow instructions at baseline |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| A DMC will be established to provide an ongoing review and assessment of the safety data, and to safeguard the interests and safety of the participating subjects in the study. An interim analysis for futility will be conducted to determine whether the dose should be increased or the trial should be terminated early based on lack of potential for benefit or unacceptable benefit-to-risk ratio. The analysis is planned for when at least 10 subjects have completed the study (i.e., 6 months of treatment with DNL310 or premature discontinuation from the trial). |
|
| E.5.2 | Secondary end point(s) |
Pharmacodynamics and Exploratory Measures:
• Change from baseline in CSF concentration of HS and DS
• Change from baseline in urine concentration (normalized to creatinine) of HS and DS
• Change from baseline in serum concentration of HS and DS
• Change from baseline in levels of CSF biomarkers of lysosomal function (including sphingolipids, gangliosides and/or bis(monoacylglycerol)phosphate [BMP]), inflammation (including soluble triggering receptor expressed on myeloid cells 2 [sTREM2] and cytokines), and neuronal injury (including neurofilament light chain [Nf-L])
• Change from baseline in levels of serum biomarkers of neuronal injury (including Nf-L)
• Change from baseline in the toileting abilities percentage (TAP), defined as a percentage of the maximum score that could be achieved on the TAS
• Change from baseline in the cognitive-domain and the language- and motor-domain age-equivalent score (AES) and standard scores on either the BSID-III or the nonverbal index (NVI) of the KABC-II
• Change from baseline in the composite AES and standard scores on the VABS-II
• Change from baseline in ABR parameters
• Change from baseline in ITQOL for subjects < 5 years of age
• Change from baseline in CHQ-PF28 for subjects ≥ 5 years of age
• Change from baseline in PedsQL-FIM
Pharmacokinetics endpoints may include but will not be limited to the following parameters:
• Cmax
• Trough concentration (Cmin)
• Tmax
• Area under the concentration-time curve from time zero to the time of last quantifiable concentration (AUC0–last)
• Area under the concentration-time curve from time zero extrapolated to infinity (AUC0–∞)
• Area under the concentration-time curve over a dosing interval (AUC0–τ)
• Apparent terminal elimination rate constant (λz)
• Apparent terminal elimination t1/2
• Accumulation ratio |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| PD and exploratory endpoints will be evaluated at the end of study (6-months of treatment) as the analysis is described as change from baseline. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | Yes |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 5 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Germany |
| Italy |
| Netherlands |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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