This study has been transitioned to CTIS with ID 2022-502492-32-00 check the CTIS register for the current data. PrimaryPart I: Evaluate the safety and tolerability of mRNA-3705 administered via IV infusion to participants with isolated MMA due to…
ID
Source
Brief title
Condition
- Metabolism disorders NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Part I: Incidence and severity of TEAEs, including study drug-related and not
related TEAEs, SAEs, and TEAEs leading to treatment discontinuation
Part II: Annualized frequency of MDEs after 12 months of treatment
Secondary outcome
Part I:
• Change in plasma methylmalonic acid levels from baseline (predose levels) to
postdose levels measured after single and repeated administrations of mRNA 3705
• Estimation of PD parameters after single and repeated administrations of mRNA
3705, including maximum observed effect (Emax), area under the effect curve
(AUEC), and duration of response
• Change in plasma 2-methylcitric acid (2-MC) levels from baseline (predose
levels) to levels measured after single and repeated administrations of mRNA
3705
• Estimation of hMUT mRNA PK parameters including, but not limited to, maximum
observed concentration (Cmax), time of Cmax (Tmax), area under the
concentration time curve (AUC), terminal elimination half-life (t*), total body
clearance (CL), and volume of distribution (Vz)
• Presence and titers of anti PEG antibodies
Part II:
Efficacy
- Change in blood methylmalonic acid levels
- Annualized frequency of MMA-related hospitalizations after 12 months of
treatment
- Change from Baseline in prescribed protein intake (g/kg/day and %RDA)
- Change from Baseline in:
• PedsQL* and PedsQL* Family Impact Module
• MMAPAQ-PSS
• IGA-I and IGA-S
Safety
- Incidence and severity of TEAEs
- Incidence and severity of SAEs
- Incidence and severity of AESIs (eg, IRR and hypersensitivity)
- Incidence and severity of TEAEs leading to treatment discontinuation
- Presence and titers of ADAs against PEG (anti-PEG) and hMUT (anti-hMUT)
- Estimation of PK parameters of hMUT (anti hMUT) mRNAs including Cmax, tmax,
AUC, t*, CL, Vz, and Vss
- Measurement of SM-86 after single and repeated dosing
Background summary
Isolated MMA is caused by a change to one of genes, called the
Methylmalonyl-CoA Mutase (MUT) gene. The MUT gene provides instructions for
making an enzyme that is responsible for the proper breakdown of certain
proteins and fats. When this enzyme is missing or does not work properly, this
makes it harder for the cells to turn food into energy and leads to a build-up
of some substances that can hurt the cells, which is the case in MMA.
The study will test a new drug, mRNA-3705. It is designed to enter the cells
and allow them to make an enzyme that works.
The mRNA-3705 has not yet been approved by any health authority. It can only be
used in a clinical study. Other mRNA drugs have been tested in people. This
study is the first time that mRNA-3705 has been tested in people.
Study objective
This study has been transitioned to CTIS with ID 2022-502492-32-00 check the CTIS register for the current data.
Primary
Part I: Evaluate the safety and tolerability of mRNA-3705 administered via IV
infusion to participants with isolated MMA due to MUT deficiency.
Part II: Evaluate the efficacy of mRNA-3705 as determined by the frequency of
MDEs as compared with standard of care
Secondary
Part I:
• Characterize the pharmacodynamic (PD) response to mRNA 3705 as determined by
changes from baseline in plasma methylmalonic acid measurement after single and
repeated administrations of mRNA 3705
• Characterize the changes from baseline in plasma 2 methylcitric acid (2 MC)
levels after single and repeated administrations of mRNA 3705
• Characterize the pharmacokinetics (PK) of human MUT (hMUT) messenger
ribonucleic acid (mRNA) after single and repeated administrations of mRNA-3705
• Assess the presence and formation of anti polyethylene glycol (PEG)
antibodies (antidrug antibodies [ADAs])
Part II:
• Characterize the PD response to mRNA-3705 as determined by blood
methylmalonic acid measurement
• Evaluate efficacy of mRNA-3705 as assessed by MMA-related hospitalizations
• Evaluate prescribed protein intake
• Evaluate patient-centered outcome assessments on signs, symptoms, quality of
life, and overall assessment
• Evaluate the safety and tolerability of mRNA-3705
• To evaluate for the presence of anti-polyethylene glycol antibodies and
anti-hMUT antibodies
• Characterize the repeated-dose PK of mRNA-3705
• Assessment of SM-86 exposure after single and repeated dose
Exploratory
Part I:
• Evaluate changes in clinically significant events (CSEs)
• Evaluate changes in MDEs occurring prior to study enrollment, during
treatment, and during the Follow up Period
• Assess health related quality of life (HRQoL) measures
• Evaluate changes in healthcare resource utilization (HCRU)
• Characterize changes in disease impact on missed school/workdays
• Characterize the PK of SM-86 after single and repeated administrations of
mRNA-3705
• Assess the relationship between PK and PD with safety and disease related
parameters
• Characterize the PD response to mRNA 3705 as determined by other biomarkers
after single and repeated administrations
• Assess the presence of antibodies to hMUT protein
• Longitudinally assess changes in cardiac and renal function over the course
of the study
• Evaluate changes in novel observer-reported outcomes before and after
treatment with mRNA-3705
• Evaluate changes in neurocognitive function
• Effect of diet on PD biomarkers
Part II:
• Evaluate the efficacy of mRNA-3705 as determined by the duration of MDEs as
compared with standard of care
• Evaluate efficacy of mRNA-3705 as assessed by MMA-related urgent healthcare
visits
• Evaluate changes in HCRU
• Evaluate changes in cardiac function
• Evaluate changes in neurocognitive function, adaptive behavior, and motor
function
• Evaluate growth in pediatric participants
• Evaluate changes in vision and hearing
• Evaluate the effect of mRNA-3705 on MMA-related complications
• Evaluate changes in hematologic parameters
• Evaluate changes in renal function
• Evaluate the efficacy of mRNA-3705 as determined by mortality
• Evaluate progression to liver and/or kidney transplantation
• Evaluate changes in liver function
• Evaluate changes in exploratory patient-centered outcome assessments
• Characterize the PD response to mRNA-3705 as determined by blood biomarkers
• Change in selected biomarkers
• Characterize SM-86, OL-56, and their metabolites
Study design
This is a 2-part, Phase 1/2, global, open-label, multicenter study in
participants >=1 year of age with isolated MMA due to MUT deficiency to assess
the safety, PK/PD response, and efficacy of mRNA-3705.
This study comprises 2 parts: a Dose Optimization part (Part 1) followed by a
Dose Expansion part (Part 2). Part 1 is designed to evaluate multiple doses and
dosing intervals of mRNA-3705, optimized based on the safety and PD of the
preceding cohort, and to characterize the safety,
tolerability, and pharmacological activity (as assessed by biomarker
measurements) of mRNA-3705 in participants with MMA. Part 2 is designed to
evaluate the efficacy of the optimal dose of mRNA-3705 identified in Part 1 and
to further characterize the safety, tolerability, and pharmacological activity
in participants with MMA.
In both parts, after confirmation of eligibility within the Screening Period
(up to 42 days), participants will enter the Observation Period (48 to 72 hours
in Part 1 and 24 hours before dose 1 in Part 2), followed by the Treatment
Period. In the Treatment Period, participants in Part 1 will receive up to 10
doses of study drug, unless exceptional circumstances specified in Section
8.1.5 occur. Participants in Part 2 will receive study drug for up to 12
months. Participants who complete the Treatment Period, including the EOT
Visit, are offered participation in the mRNA-3705 extension study. If the
participant chooses to participate and meets eligibility criteria, they will be
enrolled in the extension study; otherwise, they will transition to the
follow-up part of the study (approximately 2-year follow-up in Part 1 and
6-months follow-up in Part 2). Participants who choose to enroll in the
extension study will continue to receive mRNA-3705 at the same dose regimen
last received during this study, unless the Sponsor recommends modification.
The overall maximum duration will be up to approximately 154 weeks for each
participant who enters the 2-year Follow-up Period in Part 1 and up to
approximately 82 weeks for each participant who enters the 6-month Follow-up
Period in Part 2.
During the study, participants will attend inpatient and outpatient visits and
may have the option for home healthcare services for some visits (see Section
8), per the SoAs. The overall study design and study schema for participants
are illustrated in Figure 1 and Figure 2, respectively.
Participants may experience AEs that necessitate an unscheduled visit (Section
8.1.5). There may also be situations in which the Investigator asks a
participant to report for an unscheduled visit following the report of an AE.
Additional examinations may be conducted at these visits as
necessary to ensure the safety and wellbeing of participants during the study.
Electronic case report forms (eCRFs) should be completed for each unscheduled
visit.
Part 1 (Dose Optimization)
The Dose Optimization part will follow a *3 + 3* method; each dose cohort will
consist of 3 participants, unless 1 of the 3 participants meets the
dose-limiting toxicity (DLT) criteria (see Section 4.1.1), in which case, an
additional 3 participants will be enrolled to further characterize the safety
and tolerability at that dose.Up to 48 participants will be enrolled into this
part, as follows:
• Enrollment of the first 3 participants within each dose cohort will be
staggered using
a sentinel dosing strategy approach, unless the dose has been reduced for
nonsafety
reasons or unless the dosing interval is increased without an increase in dose.
* Each of the 3 participants will be dosed and then observed for safety
for 14 days after their first dose (the DLT observation window) in succession.
* If after the 14-day DLT observation window, no DLT event has occurred,
the next participant in the cohort can be dosed.
* If a single DLT AE occurs in 1 of the first 3 participants enrolled
into the dose cohort, 3 more participants may be enrolled into the affected
dose cohort after the SMC*s review (Section 4.1.1).
• The starting dose and interval for the study is 0.1 mg/kg Q3W.
• After each dose cohort is fully enrolled (3 participants, or a maximum of 6
participants if a DLT has occurred in 1 of the first 3 participants), the study
enrollment will enter a planned pause. After the DLT window has been completed
(14 days after the final participant in the cohort receives their first dose of
study drug), the totality of available safety and PK/PD data will be reviewed
by the Sponsor and the SMC. Based on this review, the Sponsor will recommend a
revised dose and/or dosing interval. The Sponsor will abide by predefined
constraints as to the maximum percentage change in dose and dose interval
(Section 4.1.2). The independent SMC will determine if it is acceptable to
proceed with the proposed dose or change in dosing interval after the review of
safety and available PK/PD data of the preceding cohort.
• A maximum of 9 cohorts will be enrolled into Part 1.
An independent SMC will be used throughout the conduct of this study. The role
of the SMC will be to ensure that there are no safety concerns before moving
between dose cohorts or at any point in the study (Section 10.1.11.1). Once
participants complete the Dose Optimization Period (10 doses), they will be
offered enrollment in the Extension (mRNA-3705-EXT) study to continue receiving
mRNA-3705 to evaluate long-term safety and efficacy. Participants who are not
eligible or do not wish to enroll on the mRNA-3705-EXT will enter a 2-year
safety follow-up period.
This dose optimization review process will continue until the optimized dose is
reached, at which time, the Dose Expansion may be initiated.
Part 2 (Dose Expansion)
During the Dose Expansion, participants (approximately 15) will receive
mRNA-3705 at the selected dose level and frequency for approximately 12 months.
Dose Confirmation Group(s) of approximately 5 participants will be enrolled to
confirm the selected dose(s) and dose interval(s).
These participants will be evaluated for safety and PK/PD parameters through
Dose 3 Day 8. Following this, the SMC will meet to review safety and PK/PD
data. If the dose is confirmed, a Dose Expansion Group of approximately 10
additional participants will be enrolled.
Once participants complete the 12-month Dose Expansion Treatment Period, they
will be offered enrollment in the Extension (mRNA-3705-EXT) study to continue
receiving mRNA-3705 to evaluate long-term safety and efficacy. Participants who
are not eligible or do not wish to enroll
in the mRNA-3705-EXT will enter a 6-month safety follow-up period. Data from
the Treatment Period of Part 2 (Dose Expansion) will be compared with standard
of care from external control and pretreatment in participants in Part 2.
Intervention
The study drug being evaluated is mRNA-3705. In the Treatment Period,
participants will be3treated with study drug once every 2 to 3 weeks (every
2 weeks to every 4 weeks) by IV infusion over 1 to 4 hours. Participants
will receive up to 10 doses of mRNA-3705, unless exceptional
circumstances specified in Section 8.1.5 occur.
Participants will receive premedication with acetaminophen/paracetamol or
ibuprofen and H1- and H2-receptor blockers 60 ±10 minutes before the
infusion of study drug.
The starting dose and interval for the study is 0.1 mg/kg every 3 weeks.
For participants in the Dose Expansion Stage, the study drug assigned will
be mRNA-3705 at a dose and interval selected by data review in the Dose
Optimization Stage.
Study burden and risks
The study drug may or may not help treat MMA. But the participation will help
the investigators to learn more about the study drug and the disease and this
may help future patients. It is possible that the symptoms of the condition
will not improve during the study or may even worsen. Treatment with this study
drug may also involve risks to the future health of the study participant that
we currently do not know about.
Taking part in the study can have these cons:
- Side effects or adverse effects of study drug infusion.
- There may be some discomfort from the measurements during the study. For
example: pain or bruise of taking a blood sample, or an infection (very
rarely).
- The physical exams may cause temporary discomfort.
- There may be mild discomfort from the sticky pads used for your ECG.
- Taking part in the study will cost extra time (traveling and attending study
visits).
- Hospitalisation.
It is possible that an accidental discovery is made during the study that is
not directly related to the research but does concern participant*s health or
that of his/her family members.
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Age
Inclusion criteria
Participants are eligible to be included in the study only if all the following
criteria apply:
1. Participant is >= 1 year of age at the time of informed consent/assent.
2. Participant has a body weight of >= 11.0 kg at the Screening Visit.
3. Participant has a diagnosis of isolated MMA due to MUT deficiency confirmed
by molecular genetic testing (see guidance in Section 8.1.1 for participants <
23.3 kg).
4. Participant has a blood vitamin B12 level equal to or above the lower limit
of normal (based on laboratory reference range) confirmed in the Screening
Period. For those participants found to have an elevated blood vitamin B12
level, the participant may enter if, in the opinion of the Investigator, the
cause of the elevation is secondary to B12 supplementation.
5. Participant or their legally authorized representative is willing and able
to provide informed consent and/or assent as mandated by local regulations and
willing and able to comply with study-related assessments.
6. Sexually active females of childbearing potential and sexually active males
of reproductive potential agree to use a highly effective method of
contraception during the study and for 3 months after the last administration
of study drug (Section 11.5).
7. Participants with parameters that indicate MMA clinical severity as
described in Section 11.2.3.
8. (Part 2 only) At least 1 documented MDE in the 12-month period before
consent.
Exclusion criteria
1. Participant has a diagnosis of isolated MMA cb1A, cb1B, or cb1D enzymatic
subtypes or methylmalonyl CoA epimerase deficiency or combined MMA with
homocystinuria.
2. Participant has any individual laboratory abnormalities achieving
exclusionary thresholds defined in Table 20.
3. Participant has previously received gene therapy for the treatment of MMA.
4. Participant has an eGFR < 30 mL/min/1.73 m2, as estimated by the Schwartz
formula for participants < 18 years of age (Schwartz et al 2009), or by the
Chronic Kidney Disease Epidemiology Collaboration creatinine-based formula for
participants >= 18 years of age (Inker et al 2021), or receives long-term
dialysis.
5. Participant has a corrected QT interval > 480 ms using Bazett*s correction.
6. For female participants of reproductive potential, the participant has a
positive pregnancy test at the Screening Visit.
7. Participant is pregnant or breastfeeding.
8. Participant has a history of organ transplantation or planned organ
transplantation during the period of study participation.
9. Participant has a history of hypersensitivity to any components of the study
drug.
10. Participant has a history of hypersensitivity or contraindication to
acetaminophen/paracetamol and/or ibuprofen or H1/H2receptor blockers.
11. Participation in another clinical study of another investigational agent
within 30 days before study entry or within 5 elimination half-lives of the
investigational agent, whichever is longer.
12. Participant has undergone a major surgical procedure within 30 days before
the Screening Visit (excludes central line, port, or feeding tube placement).
13. Participant has new uses or adjustments in dose within 2 weeks before first
dose of study drug to antibiotic therapy used to reduce propionate production.
Any participant whose new or adjusted dose in antibiotics conflicts with the
rules described above may enter the Treatment Period after stabilization of the
antibiotic regimen and reconfirmation of study eligibility.
14. Participant has an active, unstable, or clinically significant medical
condition not related to MMA or history of noncompliance that, in the
Investigator*s opinion, could potentiate the risk while participating in this
study, interfere with the interpretation of study results, or limit the
participant*s participation in the study. This may include, but is not limited
to, history of relevant food or drug allergies; history of cardiovascular,
central nervous, gastrointestinal, or infectious disease; history of clinically
significant pathology; and/or history of cancer.
15. Participant has received coronavirus disease 2019 vaccination (generally 2
doses or a booster) within 6 weeks between their last COVID 19 vaccination dose
and first study drug administration.
16. Participant has any individual vital sign abnormalities achieving
exclusionary thresholds as defined in Table 21.
17. Participant has a history of anaphylaxis/anaphylactoid reaction or severe
hypersensitivity with infusions.
18. (Part 2 only) History of hepatitis B (known positive hepatitis B surface
antigen [HbsAg]), hepatitis C virus (HCV), or HIV (positive HIV1/HIV-2
antibodies). Participants with a past or resolved hepatitis virus B (HBV)
infection (defined as the presence of hepatitis B core antibody and absence of
HbsAg) are eligible. Participants with history of positive results for HCV
antibody are eligible only if polymerase chain reaction is negative for HCV
RNA.
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 |
|---|---|
| EU-CTR | CTIS2022-502492-32-00 |
| EudraCT | EUCTR2020-004980-24-NL |
| ClinicalTrials.gov | NCT04899310 |
| CCMO | NL81760.000.22 |