A Phase 1/2 Open-label Clinical Study of hLB-001 Gene Therapy in Pediatric Patients With Methylmalonic Acidemia Characterized by MMUT Mutations
Phase: PHASE1
Conditions: Methylmalonic Acidemia
Sponsor: LogicBio Therapeutics, Inc

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Confidential 
CONFIDENTIAL 
A Phase 1/2 Open-label Clinical Study of hLB-001 Gene Therapy 
in Pediatric Patients With Methylmalonic Acidemia Characterized 
by MMUT Mutations 
Protocol Number: 
LB001-001 
Investigational Product: 
hLB-001 (recombinant AAV vector encoding human 
MMUT gene) 
Sponsor Name and Address: 
LogicBio Therapeutics 
65 Hayden Ave, Floor 2 
Lexington, MA 02421 
Protocol Date: 
Version 8.1, May 4, 2022 
Protocol approved by
______________ Date: _______________ 
CONFIDENTIALITY STATEMENT 
The information in this document contains commercial information and trade secrets that are privileged or 
confidential and may not be disclosed unless such disclosure is required by applicable laws and 
regulations. In any event, persons to whom the information is disclosed must be informed that the 
information is privileged or confidential and may not be further disclosed by them. These restrictions on 
disclosure will apply equally to all future information supplied to you, which is indicated as privileged or 
confidential. 
5/4/2022
NCT04581785

LogicBio Therapeutics 
Investigational New Drug 
hLB-001 
IND 019463 
Clinical Protocol – LB001-001 
2022 
 
Version 8.1                                 Page 2 of 75 
Confidential 
INVESTIGATOR’S STATEMENT 
 
Protocol Number: 
LB001-001 
Protocol Version and Date: 
Version 8.1, May 4, 2022  
 
I have read and understood the protocol and its attachment, I agree to conduct the study as 
described in the protocol and in accordance with the relevant laws/regulations and standards 
outlined in the Clinical Trial Agreement.  
It is understood that all information pertaining to the study will be held strictly confidential and 
that this confidentiality requirement applies to all study staff at this site. 
Investigator’s Signature:  
 
 
Name (printed): 
 
 
Date 
 
 

LogicBio Therapeutics 
Investigational New Drug 
hLB-001 
IND 019463 
Clinical Protocol – LB001-001 
2022 
 
Version 8.1                                 Page 3 of 75 
Confidential 
SUMMARY OF PROTOCOL AMENDMENTS 
Version 1 
 NA; no patients treated under this version 
Version 2 
 Schedule of events: updated to include additional timepoints for 
antibody response and ammonia, nutritional laboratory 
parameters, dietary optimization, and anti-albumin antibody 
testing have been added, and the screening period has been 
reduced 
 Section 4: survival added as secondary endpoint; multiple 
endpoints moved from secondary to exploratory 
 Section 5.1: cohort design updated to include 2 doses of hLB-
001 and age de-scalation within each cohort; sentinel patient 
safety review increased to 6 weeks 
 Section 5.2: study suspension rules have been updated  
 Section 5.3.3. and 5.3.4: Retesting criteria for screening has been 
updated 
 Section 6.2: Inclusion criteria #5 has been updated  
 Section 6.3: Exclusion criteria #6 has been updated 
 Section 7.9: Details regarding dietary management have been 
added  
 Section 10.2: Additional information regarding the use and 
monitoring for adverse effects due to prophylactic steroids has 
been added  
 Throughout: Multiple clarifications and administrative 
corrections have been implemented
Version 3 
 Schedule of events: added urine ketones to Day -1 to Day 3 and 
week 6 
 Clarified 2-month corticosteroid administration (high-dose and 
taper) 
 Added a maximum daily dose of corticosteroids of 60 mg 
 Clarified DSMB review to focus on potential catabolic events 
 Section 10.2: updated monitoring language and added 
instructions for tapering, potential continuation of steroids, and 
cortisol testing 
 Updated DSMB reviews to reflect timing of safety review and 
steroid tapering 
 Updated study suspension rules
Version 3.1 
 Schedule of events: added albumin-2A at week 6; removed 
exploratory DNA sample 
 Endpoints and section 7.15: removed exploratory DNA sample
Version 3.2 
 Schedule of events and endpoints: methylcitrate added 
 Endpoints: Albumin 2A moved from exploratory to secondary  
 Schedule of events: removed neutralizing antibody titer at week 
52

LogicBio Therapeutics 
Investigational New Drug 
hLB-001 
IND 019463 
Clinical Protocol – LB001-001 
2022 
 
Version 8.1                                 Page 4 of 75 
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Version 4.0 
 Added Saudi Arabia 
 Schedule of events: added collection of height/weight to baseline 
visit  
 Included language regarding pregnancy testing, female patients 
of child-bearing age
Version 5.0 
 Schedule of events: removal of albumin locus DNA sample at 
screening 
 Schedule of events: changed timing of neutralizing antibody titer 
from 90 days to 30 days prior to dosing out of an abundance of 
caution in case of seroconversion  
 Removal of sick day diet measurement in inclusion criteria and 
in healthcare utilization, as this measure is not consistently 
defined across study sites 
 Clarified that methylmalonic acid testing is performed via serum 
 Added section 5.3.4 to allow for subject rescreening  
 
Updated exclusion criteria # 11: Incorporating liver function 
testing in the exclusion criteria of AAV-based gene therapy trials 
is a standard practice aimed at minimizing risk of hepatic 
damage and inflammation, but the levels of these measures at 
which the risk becomes excessive have not been established. In 
the absence of sufficient evidence supporting a specific 
approach, we performed a review of the literature and 
www.clinicaltrials.gov to determine common practice, which 
showed that studies using liver-targeted AAV vectors typically 
include measurements of alanine aminotransferase (ALT), 
aspartate aminotransferase (AST), and total bilirubin, with 
exclusion criteria cut-offs set at >2 or >3x the upper limit of 
normal (NCT 0248092, 02395342, 03306277, 02651675, 
04105166). AST is present in several tissues outside the liver, 
including muscle, brain, pancreas, lung, kidney, RBCs, and 
leukocytes, and therefore is a non-specific indicator of liver 
disease (Botros M 2013). On the other hand, ALT is specific to 
the liver, and the two tests are usually highly correlated (i.e. 
when ALT is high, AST is as well). Therefore, mild and isolated 
elevations in AST typically do not indicate liver disease but 
rather originate from non-hepatic sources, or are an artefact 
caused by hemolyzed RBCs (Xu Q 2015). No adverse events or 
altered liver function were reported in preclinical toxicology 
studies of cLB-001 in juvenile non-human primates. Isolated, 
spontaneous, reversible and low magnitude changes in ALT 
were described in some animals, which were mostly <2xULN, 
not dose dependent, and rarely accompanied by a mild AST 
elevation (<2xULN). Because of these factors, we have adjusted 
the cut-offs for ALT and bilirubin, and will require that an 
elevation in AST must be accompanied by an abnormality in 

LogicBio Therapeutics 
Investigational New Drug 
hLB-001 
IND 019463 
Clinical Protocol – LB001-001 
2022 
 
Version 8.1                                 Page 5 of 75 
Confidential 
another liver function test. Increased cut-off for amylase and 
lipase in order to detect acute pancreatitis but allow for the 
presence of mild chronic pancreatitis, which is often seen in 
methylmalonic acidemia (Hwang 2021). 
 
Added instructions to stop continuous feeding for 1 hour prior to 
study blood draws  
Version 6.0 
 Creation of a single global protocol version; harmonization of 
the Saudi Arabia specific version of the protocol to include all 
Version 5 changes above as well as to specify that 
neurocognitive testing will be performed only in the US due to 
lack of availability of translations 
 Updated inclusion criteria #4 to reflect country specific 
vaccinations schedules 
 Updated inclusion criteria #6 to allow screening hematology to 
be used to meet criteria  
 Updated corticosteroid administration to reflect necessity of 
administering via g-tube as this patient population may not be 
able to ingest oral steroids  
 Updated sections 5.3.4 and 5.3.5 to clarify which lab tests need 
to be repeated for rescreening or extended screening windows  
 Schedule of events: updated baseline visit labs 
hematology/chemistry/coagulation/cystatin/eGFR/ammonia to 
be drawn only if screening labs are drawn > 14 days prior in 
order to reduce unnecessary duplicate labs; added MMUT 
antibody testing at several timepoints to allow additional 
monitoring 
 Added clarification/corrections to endpoint measurements for 
Propionate Oxidation, Albumin 2A and oral feeding 
 Section 7.15: Clarified analytes to be collected for local 
laboratory analysis
Administrative letter 
for Protocol V6.0; sent 
to sites to incorporate 
prior to Version 7.0 of 
protocol 
Per the letter dated 03November2021 in regards to the SUSAR of 
29Oct2021, the following changes impact LB001-001 Protocol 
Version 6.0 : 
 
 Patients will not be dosed within 2 weeks of a viral illness.  
 Regular home monitoring with urine dipsticks to enable rapid 
detection of hematuria or proteinuria between days 7 and 14. 
[Please note that this was removed in Version 7.0 as patients will 
be hospitalized during this time]
Version 7.0 
 Please refer to the separate Summary of Changes document.  
Version 8.0 
 Please refer to the separate Summary of Changes document.  
Version 8.1 
 Please refer to the separate Summary of Changes document.  

LogicBio Therapeutics 
Investigational New Drug 
hLB-001 
IND 019463 
Clinical Protocol – LB001-001 
2022 
 
Version 8.1                                 Page 6 of 75 
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1 PROTOCOL SYNOPSIS 
Sponsor: LogicBio Therapeutics 
Study Treatment: hLB-001 is a liver-targeted, recombinant engineered adeno-associated viral (rAAV) 
vector utilizing the LK03 capsid (rAAV-LK03), designed to integrate the human methylmalonyl-CoA 
mutase gene (MMUT also referred to as MUT)  
Title: A Phase 1/2 Open-label Clinical Study of hLB-001 Gene Therapy in Pediatric Patients with 
Methylmalonic Acidemia Characterized by MMUT Mutations 
Protocol Number: LB001-001 
Number of Patients: Approximately 8, with the option to increase to 12  
Study Sites: Approximately 8 in the United States and Saudi Arabia 
Study Duration: 12- 13 months (screening run-in and 1-year follow-up postdosing)  
Note: At the end of the study, patients will be asked to rollover into a long-term follow up study  
Objectives and Endpoints: 
Primary Objective: 
To assess the safety and tolerability of hLB-001 in pediatric patients with methylmalonic acidemia 
(MMA) 
Endpoints 

Incidence of treatment-emergent adverse events (AEs) 

Incidence of infusional toxicities (hLB-001-related AEs that limit, delay, or require medical 
intervention during administration) 
Secondary Objectives: 
1. To assess change from baseline in pharmacodynamic biomarkers post hLB-001 dosing in pediatric 
patients with MMA 
Endpoints 

Serum methylmalonic acid and methylcitrate (week 52-end-of-study (EOS) visit absolute value 
and percent change from average predosing level) 

Serum fibroblast growth factor 21 (FGF21) level (week 52-EOS visit absolute value and percent 
change from predosing level) 

Propionate oxidation rate (week 52-EOS visit change from predosing level)  

Serum albumin-2A level (alternative albumin isoform synthesized from loci with hLB-001 
integration, change from predosing baseline to week 52-EOS visit) 
2. To assess clinical efficacy outcomes post hLB-001 dosing in pediatric patients with MMA 
Endpoints 

Survival at 1-year post hLB-001 dosing 
Exploratory Objectives  
1. To assess hLB-001 viral shedding 
Endpoints 

Viral shedding (presence and copy number of viral genomes determined by polymerase chain 
reaction [PCR] on urine, saliva, and stool samples) 
2. To assess clinical efficacy outcomes post hLB-001 dosing in pediatric patients with MMA 

LogicBio Therapeutics 
Investigational New Drug 
hLB-001 
IND 019463 
Clinical Protocol – LB001-001 
2022 
 
Version 8.1                                 Page 7 of 75 
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
Hospitalizations for MMA-related complications (number, reason for, and duration of MMA-
related hospitalizations from dosing through week 52-EOS visit with comparison to 1-year 
period predosing)  

Surgical liver and/or kidney transplant (number of patients with liver, kidney, or combined 
liver-kidney transplants) 

Growth parameters (change in age-specific z-scores for weight, height/length, and head 
circumference from predosing to week 52-EOS visit as determined from standard growth 
curves) 

Vineland Adaptation Behavior Score (change in patient score from predosing to week 52-EOS 
visit) 

Parenting Stress Index (change in parenting total stress score (PSI-IV, 36-item short form) from 
predosing to week 52-EOS visit) 

Healthcare utilization (number of Emergency Room (ER) visits and unscheduled physician 
visits from dosing through week 52-EOS visit with comparison to 1-year period predosing) 

Neurodevelopmental status (change in age-appropriate testing score from predosing to week 52-
EOS visit, eg, Bayley, Wechsler) [note that these will be collected in the US only] 
3. To assess change from predosing baseline in diet, oral intake, and medications 
Endpoints 

Protein intake (determined from 3-day nutrition diary at week 52-EOS visit) 

Oral feeding (determined from 3-day nutrition diary at week 52-EOS visit) 

MMA-related medication use (prescription medications started/discontinued or change in dose 
other than weight-related adjustments) 
4. To investigate exploratory pharmacodynamic (PD) biomarkers 
Endpoints 

Exploratory serum/plasma biomarkers associated with MMA   
5. To assess immunological changes  
Endpoints 

Incidence of immunological changes (defined as antibody or cellular immune response to 
hLB-001 itself or the proteins expressed following integration)  
Study Design 
Study LB001-001 is a first-in-human (FIH) phase 1/2 open-label interventional study to evaluate the 
safety, tolerability, biologic activity, and clinical efficacy of hLB-001 in pediatric patients with MMA. 
Patients to be enrolled will have a severe form of MMA associated with deficiency of methylmalonyl-
CoA mutase (commonly referred to as MMUT) with the following criteria: 
a. Isolated MMA with genetically confirmed, pathogenic mutations in the MMUT gene 
b. Screening serum methylmalonic acid level of >100 µmol/L 
c. One or more of the following considered by the PI to be MMA-related: 
i. 
An unscheduled ER visit or hospitalization in the year prior to screening visit 
ii. 
Developmental delay, movement disorder, optic neuropathy or feeding disorder with 
tube feeding requirement 
d. Medically stable for the 2 months prior to the start of screening, defined as following a dietary 
management plan meeting the standard practice guidelines for patients with MMA  
(7.9 
Dietary Management) in addition to having no changes in chronic treatment other than 
adjustments to medications and diet for weight gain and nutritional laboratory evaluations as 
required for optimal care 

LogicBio Therapeutics 
Investigational New Drug 
hLB-001 
IND 019463 
Clinical Protocol – LB001-001 
2022 
 
Version 8.1                                 Page 8 of 75 
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Patients will undergo an initial screening, which will include general health and disease complications, 
MMA diagnosis confirmation, dietary assessment, concomitant medications, AAV neutralizing 
antibody titers, and liver and renal function testing. The screening assessments may take place over 
multiple days. Patients who are receiving MMA-related medications should continue these medications 
as per the standard-of-care at the clinical site. 
Patients meeting all initial screening criteria will undergo a run-in period of at least 16 days from start 
of screening to hLB-001 dosing. During this period, patients will establish a baseline for methylmalonic 
acid levels and demonstrate ongoing clinical stability. During the week prior to dosing, it will be 
confirmed that the patient continues to meet all inclusion/exclusion criteria and the patient will be 
admitted to the study site for study drug administration.   
Once eligibility for the study has been assessed, a peripherally inserted central catheter (PICC line) will 
be placed for any patient who does not already have one, to allow for easier blood draws during the 
initial part of the study.  
AAV administration to pediatric patients has been associated with clinically significant liver enzyme 
elevations, resulting in a recommendation of prophylactic steroid administration for a minimum 
duration of 1 month (ZOLGENSMA prescribing information, 2019). A standardized regimen of 
prednisolone 1 mg/kg/day or its equivalent (not to exceed 60 mg per day) will be initiated 24 ± 4 hours 
prior to starting the hLB-001 infusion. Administration may be oral or via g-tube if oral administration is 
not possible. Daily corticosteroid dosing will continue for a planned 60-day course followed by a 26-
day taper  The taper will be delayed if the patient has alanine aminotransferase (ALT) values > 2 X 
Upper Limit Normal (ULN), or aspartate aminotransferase (AST) > 2.0 × ULN together with ALT, 
alkaline phosphatase or total bilirubin > ULN. If liver function abnormalities persist at 60 days, 
systemic corticosteroids (equivalent to prednisolone at 1 mg/kg/day) may be continued for up to 2 
weeks until findings return to baseline levels or in discussion with the medical monitor, and the 
corticosteroid dose will be tapered over the next 26 days. Two weeks after steroid discontinuation, 
normalized adrenal function will be confirmed by AM cortisol level, and stimulation testing will be 
performed if cortisol < 18 mcg/dL or within normal limits. 
The anticipated period of study patient hospitalization is 8 days, from day -1 to Day 7 postdose. For a 
period of 1 week following hospital discharge, patients will be asked to remain within a 1-hour access 
of the study site due to the possible risk for metabolic imbalance associated with corticosteroid 
administration and to allow for daily study visits until day 14/week 2. Patients will then return to the 
study site for weekly visits during month 1 (week 3 and 4), every other week until month 3 (week 6, 8 
and 10), and twice every quarter thereafter until the completion of the study (weeks 13, 19, 26, 32, 39, 
45 and 52). Home healthcare visits may be conducted at weeks 3, 6, 10, 19, 32 and 45; additional home 
visits may be discussed with the study physician and Sponsor for consideration. Dietary assessments 
including laboratory evaluations will take place at study entry and every three months throughout the 
study. Study participants will follow dietary recommendations on adequate energy and protein intake to 
support normal growth, development and physical activity level. Nutritional goals to be met by all study 
participants will be assessed at study entry and on a regular basis during study participation by a 
nutritional specialist familiar with dietary management in MMA. Following completion of their EOS 
visit, study patients will be asked to participate in a separate long-term follow-up study to continue 
monitoring the long-term safety and efficacy of hLB-001.  

LogicBio Therapeutics 
Investigational New Drug 
hLB-001 
IND 019463 
Clinical Protocol – LB001-001 
2022 
 
Version 8.1                                 Page 9 of 75 
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A schematic of the study design is as follows: 
 
Two dose levels of hLB-001 are planned to be administered in 8, up to 12, patients across one to two 
cohorts, cohort 1 (5 x 1013 vg/kg) and cohort 2 (1 x 1014 vg/kg). 
 
Cohort 1: Dose level 5 x 1013 vg/kg IV 
 
Part A: 2 patients, aged 3-12 years will be enrolled. A minimum of 6 weeks of postdosing 
safety-related data will be evaluated by the DSMB chair and the Sponsor Medical Monitor 
between the dosing of each patient. The first patient must be at least midway through the 
corticosteroid tapering period for the safety review to be completed. At a minimum of 6 weeks 
after the second patient is dosed, the independent DSMB will review all available safety data. 
The second patient must be at least midway through the corticosteroid tapering period for the 
safety review to be completed. 
 
If the safety review is sufficient and there is evidence of albumin-2A, enrollment into 
Cohort 1 Part B may begin.  
 
Part B: 2 patients, aged 6 months-2 years will be enrolled. A minimum of 6 weeks of postdosing 
safety-related data will be evaluated by the DSMB chair and the Sponsor Medical Monitor 
between the dosing of each patient. The first patient must be at least midway through the 
corticosteroid tapering period for the safety review to be completed. At a minimum of 6 weeks 
after the second patient is dosed, the independent DSMB will review all available safety data. 
The second patient must be at least midway through the corticosteroid tapering period for the 
safety review to be completed. 
 
Part C: Four additional patients, aged 6 months to 12 years of age, will be enrolled. A minimum 
of 4 weeks of postdosing safety-related data will be evaluated by the DSMB chair, the Sponsor 
Medical Monitor and TMA experts between the dosing of each patient. At a minimum of 4 
weeks after the fourth patient is dosed, the independent DSMB will review all available safety 
data. If the safety review is sufficient, enrollment into Cohort 2 Part A may begin, however the 
Sponsor will assess all safety and efficacy data before dosing of this cohort will take place. If 
the risk/benefit is deemed unacceptable, cohort 2 will not be enrolled. The risk/benefit analysis 
will be shared with the FDA prior to commencing enrollment in cohort 2. 
Cohort 2: Dose level 1 x 1014 vg/kg IV 
 
Part A: At least 2 patients, aged 3-12 years will be enrolled. A minimum of 4 weeks of 
postdosing safety-related data will be evaluated by the DSMB chair, the Sponsor Medical 
Monitor, and TMA experts between the dosing of each patient. At a minimum of 4 weeks after 
the second patient is dosed, the independent DSMB will review all available safety data.  
 
If the safety review from Cohort 2 Part A is sufficient and there is evidence of albumin-
2A in Cohort 2 Part A, enrollment into Cohort 2 Part B may begin. 
 
If the safety review is insufficient, or a patient needs to be replaced, an additional 
patient in Cohort 2 Part A may be enrolled.

LogicBio Therapeutics 
Investigational New Drug 
hLB-001 
IND 019463 
Clinical Protocol – LB001-001 
2022 
 
Version 8.1                                 Page 10 of 75 
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 
Part B: At least 2 patients, aged 6 months-2 years will be enrolled. A minimum of 4 weeks of 
postdosing safety-related data will be evaluated by the DSMB chair, the Sponsor Medical 
Monitor, and TMA experts between the dosing of each patient. At a minimum of 4 weeks after 
the second patient is dosed, the independent DSMB will review all available safety data.  
 
If the safety review is insufficient, or a patient needs to be replaced, an additional 
patient in Cohort 2 Part B may be enrolled. 
 
The cohort schematic is below: 
 
  
Long-term Follow-up: Long-term follow-up will be completed under a separate study protocol. In 
brief, through 5 years postdosing, study patients will be followed by their health care providers (HCPs) 
in addition to annual visits to the clinical study site for safety and efficacy evaluations. From 6 to 
15 years postdosing, they will be followed for potential delayed AEs to match the current regulatory 
recommendation of 15-year follow-up. 
hLB-001 Administration 
hLB-001 is prepared as a sterile, nonpyrogenic solution stored at -65°C or below until ready for use. It 
is thawed for administration as a one-time intravenous infusion over at least 30 minutes and at a flow 
rate of no more than 5 mL/kg per hour through a syringe pump. 

LogicBio Therapeutics 
Investigational New Drug 
hLB-001 
IND 019463 
Clinical Protocol – LB001-001 
2022 
 
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Dose Cohorts, Study Suspension, and Study Stopping Rules 
Dose Cohorts 
Age de-escalation in Cohort 1 Part B and dose escalation in Cohort 2 Part A will not be opened for 
enrollment if either of the following is noted following hLB-001 treatment in Cohort 1 Part A or Part C. 
If either of the following is noted following hLB-001 treatment in Cohort 2 Part A, Cohort 2 Part B will 
not be opened for enrollment: 

Any Common Terminology Criteria for Adverse Events (CTCAE) grade 4 organ toxicity that does 
not improve to grade 2 within 4 weeks 

Any grade 3 or greater autoimmune toxicity  
The Sponsor will assess all safety and efficacy data before dosing of cohort 2 will take place. The 
risk/benefit analysis will be shared with the FDA prior to commencing enrollment in cohort 2. If the 
risk/benefit is deemed unacceptable, cohort 2 will not be enrolled. 
Study Suspension Rules 
Study hLB-001 dosing will be suspended if any of the following occurs: 

Any event of TMA 

A patient experiences a Grade 4 or higher AE  

A patient develops a malignancy 

A patient dies 
 
Any grade 4 SAE that could be related to study procedures (e.g., complications from prophylactic 
steroids) 
 
Any grade 3 SAE of Special Interest (as defined in 11.2.1 
Adverse Events of Special Interest 
(AESI))  
 
The same or related grade 3 SAE in two subjects that is related to the study product or study 
procedures 
 
Despite corticosteroid use as described in 10.2 
Prophylactic Administration of Corticosteroids 
and Monitoring/Risk Mitigation, alanine aminotransferase (ALT) values remain above the threshold 
of 2 X Upper Limit Normal (ULN). 

The DSMB chair and/or sponsor determine that an event or current data warrant further evaluation 
by the full DSMB 
Upon study suspension, the DSMB will evaluate all clinical safety data and provide recommendation on 
whether dosing should continue, whether changes should be made in the study, or in consultation with 
the sponsor, whether the study should be stopped. 
During any period of study suspension, enrollment and treatment will be paused while the DSMB 
investigates whether a grade 3 or grade 4 SAE could be related to the study product or study procedures. 
Patients who have been dosed with hLB-001 will continue to be followed for safety and PD/clinical 
efficacy through their scheduled EOS visit. 
Study Stopping Rules 
Study enrollment and dosing will be discontinued permanently if any of the following occurs: 

Sponsor or a regulatory agency decides for any reason that an event or current data warrant study 
termination 

A patient develops a malignancy assessed as related to hLB-001 by the investigator and/or sponsor 

A patient death is assessed as related to hLB-001 by the investigator and/or sponsor 

Any medically unacceptable risk of hLB-001 is identified by the DSMB and/or sponsor 
If study dosing is stopped, patients who have already been dosed with hLB-001 will continue to be 
followed for safety and PD/clinical efficacy through their scheduled EOS visit. 

LogicBio Therapeutics 
Investigational New Drug 
hLB-001 
IND 019463 
Clinical Protocol – LB001-001 
2022 
 
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Inclusion/Exclusion Criteria 
Inclusion Criteria 
A patient must meet all the following inclusion criteria to be eligible for participation in this study: 
1. At the time of dosing, patient must be 6 months to 12 years of age  
2. Patient (and/or legally authorized representative) has voluntarily agreed to participate by giving 
written informed consent/assent in accordance with International Council for Harmonisation (ICH) 
Good Clinical Practice (GCP) guidelines and applicable local regulations  
3. Willingness and ability to comply with study procedures and scheduled visits 
4. Current with local recommended vaccination schedule based on age (no vaccinations within 
6 weeks pre- or post-hLB-001 dosing expectation of the need for live vaccinations while on 
corticosteroids and for 3 months following completion of corticosteroid dosing) 
5. Males and females with diagnosis of severe MMA meeting all the following; 
a. Isolated MMA with genetically confirmed, pathogenic mutations in the MMUT gene 
b. Screening serum methylmalonic acid level of >100 µmol/L 
c. One or more of the following considered by the PI to be MMA-related: 
i. 
An unscheduled ER visit or hospitalization in the year prior to screening visit 
ii. 
Developmental delay, movement disorder, optic neuropathy or feeding disorder with 
tube feeding requirement 
 d. Medically stable for the 2 months prior to the start of screening, defined as following a dietary 
management plan meeting the standard practice guidelines for patients with MMA (7.9
 
Dietary Management) in addition to having no changes in chronic treatment other than 
adjustments to medications and diet for weight gain and nutritional laboratory evaluations as 
required for optimal care 
6. Hematology laboratory results confirming: 
a. Hemoglobin  9 g/dL 
b. Absolute neutrophils count  1000/µL 
c. Platelet count  150,000/µL 
Exclusion Criteria 
A patient meeting any of the following exclusion criteria is not eligible for participation in the study: 
1. Patients with organic acidemias other than isolated MMA, or with any other causes of 
hyperammonemia 
2. Having received MMA-targeted gene therapy or nucleic acid therapy 
3. Having received an investigational drug within 28 days or 5 half-lives of the drug, whichever is 
shorter, prior to initiation of screening 
4. Patients on insulin or high dose hydroxocobalamin (> 1 mg/day OHB12 parenteral) 
5. Kidney or liver transplant, including hepatocyte cell therapy  
6. Estimated glomerular filtration rate (eGFR) of < 60 mL/min/1.73 m2 based on the creatinine-based 
“Bedside Schwartz” equations (2009), or ongoing dialysis for renal disease 
7. Patient tests positive for anti-rAAV-LK03-neutralizing antibodies with titers above protocol-
specified threshold of 1:10  
8. Patient has received immune-modulating agents within 3 months prior to initiation of screening (use 
of inhaled corticosteroids to manage chronic respiratory conditions permissible) 
9. Patient has a history of, or currently has, a clinically important condition not directly related to 
MMA, in the opinion of the investigator 

LogicBio Therapeutics 
Investigational New Drug 
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Clinical Protocol – LB001-001 
2022 
 
Version 8.1                                 Page 13 of 75 
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10. History or presence of arrhythmia or other clinically significant abnormality on electrocardiogram 
(ECG) 
11. Any of the following hepatic/gastrointestinal factors: 
a. Liver laboratory testing: 
o alanine aminotransferase (ALT) > 2.0 × upper limit of normal (ULN) 
o aspartate aminotransferase (AST) > 2.0 × ULN together with ALT, alkaline phosphatase or 
total bilirubin > ULN 
o total bilirubin > 2.0 × ULN 
o prothrombin time > 1.5 x ULN 
b. Pancreatic enzymes (amylase, lipase) > 3.0 × ULN 
c. Hyperammonemia characterized by ammonia  3 × ULN, or signs of active metabolic 
decompensation (eg, lethargy, irritability, and vomiting) 
12. Any of the following oncologic factors: 
a. Liver abnormalities suspicious for malignancy on screening ultrasound 
b. History of any malignancy, test-positive for a cancer-predisposition syndrome, or family history 
for a cancer-predisposition syndrome and patient has not been tested 
13. History of anaphylaxis or severe allergic reaction or allergy to antibiotics to be potentially 
administered 
14. Patient has experienced a viral or bacterial illness and is still symptomatic within 6 weeks of dosing  
15. Vaccinations administered within 6 weeks of dosing 
16. History of deep vein thrombosis (DVT) or coagulopathy  
Statistical Methods 
The study will consist of at least 1 cohort with the option to add a second cohort at a higher dose level 
for a total sample size of approximately 8 patients and potentially up to 12 patients. The sample size is 
based on practical consideration considering the ultra-orphan patient population. The primary focus will 
be on determining the safety, tolerability, and biomarker/clinical efficacy profile of hLB-001. No 
specific statistical hypotheses are being evaluated with respect to the primary, secondary, or exploratory 
objectives and endpoints. Each patient will serve as his or her own control. 
All analyses will be descriptive. Descriptive statistics on continuous data will include means, medians, 
standard deviations, and ranges. Categorical data will be summarized using frequency counts and 
percentages. 
Graphical summaries of the data may be presented. Assessments will be displayed by cohort and time, 
as well as across cohorts for specific parameters.  
 
 
 

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Table 1. 
Schedule of Events 
 
Throughout study 
Adverse events 
Adverse event and concomitant medication collection begins with ICF and continues until end of study. 
Concomitant 
medications 
 
Prior to Dosing 
Study Visit 
Screening/ 
Run-in 
Baseline 
Day -1 
Admission c 
Window 
Screening to start at least 16 days 
prior to Day 1 
Day -7 to -2 
 
Informed consent/assent 
X 
 
 
Demographics 
X 
 
 
Inclusion/ 
exclusion criteria 
X 
X 
X 
Medical history 
X 
 
 
Meningococcal vaccination 
X 
 
 
Administer at least 6 weeks prior to planned dosing day, if the subject has not 
already been vaccinated 
DNA for genetic analysis 
(MMUT) 
X 
 
 
Collect if no documentation from a CLIA certified lab of test result 
Neutralizing antibody titer 
(rAAV-LK03) b 
X 
X 
 
Exclusion criterion to be evaluated from screening sample; to be repeated if sample taken 
more than 30 days prior to dosing 
Antibody response (rAAV-
LK03, MMUT, ALB2A) b 
X 
LK03 only 
 
T cell response b 
X  
X  
 
rAAV-LK03, MMUT, ALB2A. Collect at either screening or baseline visit (do not collect at 
both) 
Hematology and blood smear 
b  
X 
Draw unless safety lab testing has 
occurred within the 2 weeks prior 
to consent/assent as part of 
routine care and dosing is within 
30 days 
X 
Draw only if screening 
sample taken >14 days prior 
X 
Chemistry b 
BMP 
Coagulation b 
 
TMA genetic panel 
X 
 
 
CRP, ESR 
X 
 
X 
Von Willebrand Disease 
profile 
X 
 
 
LDH 
X 
 
 
Haptoglobin 
 
 
X 
CH50 
X 
X 
X 

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Prior to Dosing 
Study Visit 
Screening/ 
Run-in 
Baseline 
Day -1 
Admission c 
Cb5-9, Bb  
 
X 
X 
C3, C4 
 
X 
X 
Ketones (urine dipstick) 
X 
 
 
Urinalysis 
 
X 
Approximately 12 hours 
post start of steroids 
Additional labs: eGFR 
calculation b 
X 
Draw only if screening 
sample taken >14 days prior 
 
Additional lab: Ammonia b 
X 
Draw only if screening 
sample taken >14 days prior 
 
Pancreatic enzymes (lipase, 
amylase) b 
X 
 
 
Plasma amino acids, 
albumin, prealbumin and 
carnitine 
X 
Draw only if screening 
sample taken >14 days prior 
 
Fasting for 3-4 hours (if possible); preferably morning draw 
Methylmalonic acid and 
methylcitrate b 
X 
At least 14 days prior to baseline 
sample 
X 
 
Albumin-2A level b 
 
X 
 
FGF21 b 
X 
X 
 
Serum and plasma for 
exploratory biomarkers b 
X 
 
 
Samples for viral shedding 
(saliva, stool, urine) 
 
 
X 
Physical examination 
X 
 
X 
Vital signs  
X 
 
X 
BP, respiration rate, temp, heart rate 
ECG (single, 12-lead) 
X 
X 
 
Liver ultrasound and alpha-
fetoprotein 
X  
 
 
If ultrasound was performed within 3 months prior to screening, it does not need to be 
repeated at screening. 
1-13C propionate oxidation 
X 
X 
 
Fasting for approximately 4 hours. Test will take approximately 2 hours to complete. 
Growth parameters  
X 
Include 1-year prior data 
collection 
Height/ length and weight 
X 
weight, height/length, up to age 3: head circumference 
Patient diet diary 
X  
Provide once informed consent 
signed 
Provide the Day -1 diary in 
advance of Day -3 to allow 
for Day -1 completion 
X 
Record for 3 days prior to each visit 
Diet optimization 
X 
X 
 

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Prior to Dosing 
Study Visit 
Screening/ 
Run-in 
Baseline 
Day -1 
Admission c 
See 7.9 Dietary Management 
Vineland Adaptive 
Behavioral Scale 
 
 
X 
Motor and cognitive function 
assessments  
 
 
X 
US only 
Parenting stress index short 
form  
 
 
X 
Pregnancy risk assessment 
and testing  
X 
 
 
Female patients of child-bearing age with pregnancy risk 
Hospitalizations and 
healthcare utilization 
X 
Include 1-year prior data 
collection 
Record hospitalizations, including duration and primary 
reason 
Healthcare utilization includes ER visits and unscheduled 
visits to physician/hospital 
PICC line placement 
At least 7 days prior to dosing date, for patients who do not 
already have a line 
 
Corticosteroid administration  
 
Initiate 24 hours (± 4 
hours) prior to hLB-001 
infusion 
 
 
 

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Dosing to Hospital Discharge 
Patients to be hospitalized for 8 days, from day -1 to Day 7 post-dose 
Study Visit 
Day 1 
Treatment 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 / 
Week 1 
Antibody 
response b 
 
 
 
 
 
 
LK03 only 
Hematology and 
blood smear b 
Pre-infusion 
X 
X 
X 
X 
X 
X 
Chemistry b 
BMP 
X 
BMP 
BMP 
BMP 
X 
Coagulation b 
 
X 
 
 
 
X 
LDH 
Pre-infusion 
 
X 
 
X 
 
X 
Haptoglobin 
 
X 
 
X 
 
X 
 
CH50 
 
 
X 
 
 
X  
 
 
Cb5-9, Bb 
 
 
X 
 
 
X  
 
 
C3, C4 
 
X 
X 
X 
X 
X 
X 
Ketones (urine 
dipstick) 
 
 
 
 
 
 
 
Urinalysis 
Pre-infusion 
X 
X 
X 
X 
X 
X 
Additional lab: 
Ammonia b 
 
 
 
 
 
 
X 
Serum and 
plasma for 
exploratory 
biomarkers b 
 
 
 
 
 
 
Serum only 
Samples for viral 
shedding (saliva, 
stool, urine) 
 
 
 
 
 
 
X 
Physical 
examination 
targeted, predosing 
 
 
 
 
 
targeted 
Vital signs (BP, 
respiration rate, 
temp, and heart 
rate) 
Take pre-dose (within 15 min of 
dosing); 30 min, 1, 2, 4, 6, and 8 hours 
(± 10 min) after start of infusion 
Pulse oximetry continuous monitoring 
starting prior to dosing then for 24 
hours postdosing 
X 
X 
X 
X 
X 
X 
ECG (single, 12-
lead) 
 
X 
 
 
 
 
 
hLB-001 
administration 
X 
 
 
 
 
 
 
Screening weight to be used for dose calculation unless taken more than 30 days prior to dosing 
Corticosteroid 
administration 
Daily dosing; potential corticosteroid steroid-associated adverse events will be monitored as described in 
10.2 
Prophylactic Administration of Corticosteroids and Monitoring/Risk Mitigation 

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Dosing to Hospital Discharge 
Patients to be hospitalized for 8 days, from day -1 to Day 7 post-dose 
Study Visit 
Day 1 
Treatment 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 / 
Week 1 
Hospital 
discharge 
 
 
 
 
 
 
X 
 
 
 

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Hospital Discharge to Week 6 
Study Visit 
Day 8 
Day 9 
Day 10 Day 11
Day 12 
Day 13 
Day 14 / 
Week 2 
Week 3
Week 4
Week 6
Window 
 
 
 
 
 
 
 
± 2 d 
± 2 d 
± 3 d 
Antibody 
response b 
 
 
 
 
 
 
rAAV-
LK03 
only 
rAAV-
LK03 
only 
rAAV-
LK03, 
ALB2A, 
MMUT  
 
Hematology 
and blood 
smear b 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chemistry b 
BMP 
BMP 
BMP 
BMP 
BMP 
BMP 
X 
X 
X 
X 
Coagulation b 
 
 
X 
 
 
 
X 
X 
X 
X 
LDH 
 
X 
 
X 
 
X 
 
 
 
 
Haptoglobin 
X 
 
X 
 
X 
 
X 
 
 
 
CH50 
 
X 
 
 
X 
 
X 
Complement testing weekly 
until CH50 normalizes, if not 
normalized by Day 14 
Cb5-9, Bb 
 
X 
 
 
X 
 
X 
C3, C4 
X 
X 
X 
X 
X 
X 
X 
Ketones (urine 
dipstick) 
 
 
 
 
 
 
 
X 
X 
X 
Ketostick or 
equivalent 
(home 
administration) 
As indicated – see 7.15 
Laboratory Tests for additional information 
Urinalysis 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Additional lab: 
Ammonia b 
 
 
 
 
 
 
 
 
X 
 
Methylmalonic 
acid and 
methylcitrate b 
 
 
 
 
 
 
 
 
X 
X 
Albumin-2A 
level b 
 
 
 
 
 
 
 
 
X 
X 
Serum and 
plasma for 
exploratory 
biomarkers b 
 
 
 
 
 
 
 
serum 
only 
serum 
only 
 
Samples for 
viral shedding 
(saliva, stool 
and urine) 
 
 
 
 
 
 
X 
X 
X 
X 
Physical 
examination 
 
 
 
 
 
 
targeted  
targeted 
targeted 
targeted 
Vital signs (BP, 
respiration rate, 
temp, and heart 
rate) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 

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Hospital Discharge to Week 6 
Study Visit 
Day 8 
Day 9 
Day 10 Day 11
Day 12 
Day 13 
Day 14 / 
Week 2 
Week 3
Week 4
Week 6
Window 
 
 
 
 
 
 
 
± 2 d 
± 2 d 
± 3 d 
Hospitalization
s and healthcare 
utilization 
Record hospitalizations, including duration and primary reason 
Healthcare utilization includes ER visits and unscheduled visits to physician/hospital 
Corticosteroid 
administration 
Daily dosing followed by weaning schedule as described in section 10.2 
Prophylactic Administration 
of Corticosteroids and Monitoring/Risk Mitigation 
 
 
 

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Week 8 to Week 52 
Study Visit 
Week 8
Week 10
Week 13
Week 19
Week 26
Week 32
 
Week 39
Week 45
Week 
52/EOS
Window 
± 3 d 
± 3 d 
± 7 d 
± 7 d 
± 7 d 
± 7 d 
± 7 d 
± 7 d 
± 7 d 
Antibody 
response b 
 
 
rAAV- 
LK03, 
ALB2A, 
MMUT 
 
rAAV- 
LK03 
only 
 
rAAV- 
LK03 
only 
 
rAAV-
LK03, 
ALB2A, 
MMUT 
See 7.15 Laboratory Tests for potential for additional testing, including testing for anti-albumin antibodies 
T cell response b  
 
X 
 
 
 
 
 
 
Hematology and 
blood smear b 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chemistry b 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation b 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CH50 
Complement testing weekly until CH50 normalizes, if not normalized by Day 14 
Cb5-9, Bb 
C3, C4 
Ketones (urine 
dipstick) 
X 
X 
X 
X 
X 
X 
X 
X 
 
Ketostick or 
equivalent 
(home 
administration) 
As indicated – see 7.15 
Laboratory Tests for additional information 
Urinalysis 
 
 
 
 
 
 
 
 
X 
Additional labs: 
eGFR 
calculation b 
 
 
X 
 
 
 
 
 
X 
Additional lab: 
Ammonia b 
X 
 
X 
 
X 
 
X 
 
X 
Plasma amino 
acids, albumin, 
prealbumin and 
carnitine 
 
 
X 
 
X 
 
X 
 
X 
Fasting for at 3-4 hours (if possible); preferably morning draw  
Methylmalonic 
acid and 
methylcitrate b 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Albumin-2A 
level b 
X 
X 
X 
X 
X 
X 
X 
X 
X 
FGF21 b 
 
 
X 
X 
X 
X 
X 
X 
X 
Serum and 
plasma for 
exploratory 
biomarkers b 
 
 
X 
 
serum 
only 
 
serum 
only 
 
X 
Samples for viral 
shedding 
X 
 
Stool, 
urine 
 
Stool, 
urine 
 
Stool, 
urine 
 
Stool, 
urine 

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Week 8 to Week 52 
Study Visit 
Week 8
Week 10
Week 13
Week 19
Week 26
Week 32
 
Week 39
Week 45
Week 
52/EOS
Physical 
examination 
targeted 
targeted 
X 
targeted 
targeted 
targeted 
targeted 
targeted 
X 
Vital signs  
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG  
 
 
X 
 
 
 
 
 
X 
Liver ultrasound 
and alpha-
fetoprotein 
 
 
 
 
 
 
 
 
X 
1-13C propionate 
oxidation 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
Fasting for approximately 4 hours. Test will take approximately 2 hours to 
complete. This test will not be performed if the visit is completed via home 
healthcare. 
Growth 
parameters 
 
 
X 
Height/ 
length and 
weight 
X 
Height/ 
length and 
weight 
X 
Height/ 
length and 
weight 
X 
Patient diet diary
 
 
X 
 
X 
 
X 
 
X 
Record for 3 days prior to each visit 
Diet 
optimization  
 
 
X 
 
X 
 
X 
 
X 
Vineland 
Adaptive 
Behavioral Scale
 
 
 
 
 
 
 
 
X 
Motor and 
cognitive 
function 
assessments  
 
 
 
 
 
 
 
 
X 
US only
Parenting stress 
index short form 
 
 
 
 
 
 
 
 
X 
Hospitalizations 
and healthcare 
utilization 
Record hospitalizations, including duration and primary reason 
Healthcare utilization includes ER visits and unscheduled visits to physician/hospital 
Corticosteroid 
administration 
Daily dosing followed by 
weaning schedule as described in 
section 10.2 
Prophylactic 
Administration of Corticosteroids 
and Monitoring/Risk Mitigation. 
Cortisol collection 2 weeks after 
discontinuation of steroids. 
 
 
 
 
 
 
 
ALB2A = albumin-2A; BP = blood pressure; CLIA = Clinical Laboratory Improvement Amendments; CRP = c-reactive protein; 
ECG = electrocardiogram; ESR – erythrocyte sedimentation rate; eGFR = estimated glomerular filtration rate; EOS = end-of-
study; FGF21 = fibroblast growth factor 21; ICF = informed consent form; MMUT = human methylmalonyl-CoA mutase gene 
a = Screening may occur over multiple days. Refer to sections 5.3.4 and 5.3.5 for rescreening and extended screening period 
requirements.  
b = Continuous feeds should be stopped 1 hour prior to collection 

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c = 
If dosing (Day 1) is delayed after completing Day -1, it will not be necessary to repeat the scheduled assessments if dosing 
is rescheduled within 2 weeks. The following tests will not need to be repeated if dosing is rescheduled within 2 months: 
Viral shedding, Vineland Adaptive Behavioral Scale, Motor and cognitive function assessments [US only] and Parenting 
stress index. 
 
 
 
 
 
 
 

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Table of Contents 
Description 
Page 
Investigator’s Statement ................................................................................................................2 
Summary of Protocol Amendments .............................................................................................3 
1 Protocol Synopsis .....................................................................................................................6 
2. List of Abbreviations and Definition of Terms ...................................................................28 
3 Introduction and Rationale for Dose Selection ...................................................................30 
3.1 
Background Information ...................................................................................................30 
3.2 
Rationale for Study ...........................................................................................................31 
4 Study Objectives and Endpoints...........................................................................................32 
4.1 
Primary Objective and Endpoints .....................................................................................32 
4.2 
Secondary Objectives and Endpoints ................................................................................32 
4.3 
Exploratory Objectives and Endpoints .............................................................................33 
5 Study Description ...................................................................................................................35 
5.1 
Study Design .....................................................................................................................35 
5.1.1 
Long-term Follow-up ................................................................................................39 
5.1.2 
Overall Safety Plan ...................................................................................................39 
5.2 
Dose Cohorts, Study Suspension, and Study Stopping Rules ..........................................40 
5.3 
Patient Staggering .............................................................................................................41 
5.4 
Study Schedule ..................................................................................................................41 
5.4.1 
Informed Consent/Assent .........................................................................................42 
5.4.2 
Screening ..................................................................................................................42 
5.4.3 
Retesting ...................................................................................................................42 
5.4.4 
Rescreening ...............................................................................................................42 
5.4.5 
Run-in Period to Dosing ...........................................................................................43 
5.4.6 
Baseline Assessment and Dosing .............................................................................43 
5.4.7 
Follow-up ..................................................................................................................43 
5.4.8 
End of Study .............................................................................................................43 
5.4.9 
Unscheduled Visits ...................................................................................................44 
6 Patient Eligibility and Withdrawal Criteria........................................................................45 
6.1 
Number of Patients ...........................................................................................................45 
6.2 
Inclusion Criteria ..............................................................................................................45 

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6.3 
Exclusion Criteria .............................................................................................................46 
6.4 
Patient Withdrawal ............................................................................................................47 
6.5 
Patient Replacement ..........................................................................................................48 
7 Study Procedures and Assessments ......................................................................................49 
7.1 
Demographics and Medical History .................................................................................49 
7.2 
Physical Examination ........................................................................................................49 
7.3 
Vital Signs .........................................................................................................................49 
7.4 
ECG ...................................................................................................................................49 
7.5 
Liver Ultrasound and Alpha-fetoprotein ...........................................................................49 
7.6 
1-13C-propionate Oxidation .............................................................................................50 
7.7 
Growth Parameters ............................................................................................................50 
7.8 
Protein and Nutritional Intake/Patient Diary ....................................................................50 
7.9 
Dietary Management .........................................................................................................50 
7.10 Cognitive and Motor Function Assessments ....................................................................50 
7.11 Quality-of-Life Assessments ............................................................................................51 
7.12 Hospitalizations and Healthcare Utilization .....................................................................51 
7.13 Change in Requirement for MMA-related Medications ...................................................51 
7.14 Adverse Events .................................................................................................................51 
7.15 Laboratory Tests ...............................................................................................................52 
7.16 Pregnancy Risk Assessment and Testing ..........................................................................55 
7.17 PICC line ...........................................................................................................................55 
8 Conduct of Study....................................................................................................................56 
8.1 
Data Safety Monitoring Board ..........................................................................................56 
9 Study Medication ...................................................................................................................57 
9.1 
Description of Study Medication ......................................................................................57 
9.2 
Packaging and Labeling ....................................................................................................57 
9.3 
Administration of Treatment .............................................................................................57 
9.4 
Dose Levels .......................................................................................................................58 
9.5 
Storage, Handling, and Drug Accountability ....................................................................58 
10 Concomitant Medications and Vaccinations .......................................................................59 
10.1 General Considerations .....................................................................................................59 
10.2 Prophylactic Administration of Corticosteroids and Monitoring/Risk 
Mitigation ..........................................................................................................................59 

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10.3 Routine Vaccinations ........................................................................................................60 
10.4 Administration of eculizumab and antibiotics ..................................................................61 
11 Adverse Events .......................................................................................................................63 
11.1 Pretreatment Adverse Event .............................................................................................63 
11.2 Adverse Event Definition .................................................................................................63 
11.2.1 Adverse Events of Special Interest (AESI)...............................................................63 
11.3 Serious Adverse Event Definition ....................................................................................64 
11.4 Reporting of Adverse Events and Serious Adverse Events ..............................................65 
11.5 Adverse Event Reporting Period ......................................................................................66 
12 Statistical Methods and Data Analysis .................................................................................67 
12.1 Sample Size Justification ..................................................................................................67 
12.2 Study Populations .............................................................................................................67 
12.3 Demographic/Baseline Information ..................................................................................67 
12.4 Analysis of Safety Data ....................................................................................................67 
12.5 Analysis of Efficacy Data .................................................................................................68 
12.6 Interim Analysis ................................................................................................................68 
13 Study Management and Data Collection .............................................................................69 
13.1 Ethical Conduct of the Study ............................................................................................69 
13.2 Institutional Review Board/Local Ethics Committee .......................................................69 
13.3 Patient Informed Consent/Assent .....................................................................................69 
13.4 Compliance with the Protocol ...........................................................................................69 
13.5 Study Monitoring ..............................................................................................................69 
13.6 Case Report Form .............................................................................................................70 
13.7 Audits ................................................................................................................................70 
13.8 Retention of Records .........................................................................................................70 
13.9 Insurance and Indemnity ...................................................................................................71 
13.10 Termination of the Study ..................................................................................................71 
14 Use of Information .................................................................................................................72 
14.1 General Aspects ................................................................................................................72 
14.2 Patient Confidentiality and Data Protection .....................................................................72 
14.3 Final Report and Publication Policy .................................................................................72 
15 Appendix 1: FAO/WHO/UNU 2007 Safe Levels of Protein and Energy Intake 
for Different Age Groups ......................................................................................................73 

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16. References ...............................................................................................................................74 
List of Tables 
Description 
Page 
Table 1. 
Schedule of Events ...............................................................................................14 
Table 2. 
Cognitive and Motor Function Scales by Age Group .......................................51 
Table 3. 
Laboratory Priority .............................................................................................54 
Table 4. 
Composition of hLB-001 Drug Product .............................................................57 
Table 5. 
 Eculizumab Dosing Schedule .............................................................................61 
 

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2. LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
AAV 
adeno-associated viral vector 
ADA 
Anti-drug antibodies 
AE 
adverse event 
AESI 
adverse events of special interest 
Albumin-2A 
alternative albumin isoform synthesized from loci with hLB-001 integration 
BMP 
basic metabolic panel 
BP 
blood pressure 
CDC 
Center for Disease Control 
CTCAE 
Common Terminology Criteria for Adverse Events 
DSMB 
Data Safety Monitoring Board 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
Electronic Data Capture 
eGFR 
estimated glomerular filtration rate 
ELISA 
enzyme-linked immunosorbent assay 
ELISPOT 
enzyme-linked immunospot 
EOS 
end-of-study 
ER 
emergency room 
ESR 
erythrocyte sedimentation rate 
FGF21 
fibroblast growth factor 21 
FIH 
first-in-human 
GCP 
Good Clinical Practice 
HCC 
hepatocellular carcinoma 
HCP 
health care provider 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
ID 
infectious disease 
IRB 
Institutional Review Board 
LEC 
Local Ethics Committee 
MMA 
methylmalonic acidemia 
MMUT or 
MUT 
the gene encoding methylmalonyl-CoA mutase; newer nomenclature may use MMUT 
MUT or mut 
methylmalonyl-CoA mutase enzyme; newer nomenclature may use mmut 
NF 
National Formulary 
PCR 
polymerase chain reaction 
PD 
pharmacodynamics 

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Ph Eur 
European Pharmacopoeia 
PICC 
peripherally inserted central catheter 
PK 
pharmacokinetics 
PSI-IV 
parenting total stress score 
rAAV 
recombinant adeno-associated virus 
SOP 
Standard Operating Procedure 
SRM 
Study Reference Manual 
TMA 
thrombotic microangiopathy 
ULN 
upper limit of normal  
vg/kg 
vector genomes/kilogram 
USP 
United States Pharmacopeia 
 

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3 INTRODUCTION AND RATIONALE FOR DOSE SELECTION 
3.1 
Background Information 
LogicBio is developing hLB-001 for the treatment of patients with isolated methylmalonic 
acidemia (MMA) associated with mutations in the gene encoding methylmalonyl-CoA mutase 
(MMUT) gene (SNOMED CT: 42393006|Methylmalonic acidemia [disorder]).  
MMA is a metabolic disorder in which the body is unable to process certain amino acids and fats 
properly. Infants considered to have severe MMA are diagnosed in the first days to weeks of life 
either based on newborn screening results or following presentation with clinical signs including 
vomiting, lethargy, respiratory distress, hypotonia, hypothermia, hepatomegaly, and progressive 
encephalopathy. Key laboratory findings to support diagnosis include hyperammonemia, 
elevated serum lactate, abnormally high methylmalonic acid in the blood and urine  
(Hörster et al, 2007), pancytopenia, and elevated urine ketone bodies (Baumgartner et al, 2014). 
Infants with the severe form of MMA are at risk for neurologic injury including basal ganglia 
stroke, failure to thrive, and poor feeding. Subsequently, they may progress to impaired 
cognition, severe infections, and renal failure with devastating impact on patient quality of life 
and survival (Manoli et al, 2016). 
MMA has an autosomal recessive pattern of inheritance with an incidence in the United States 
and European Union of approximately 1 in 50,000 to 100,000 live births (Therell et al, 2014) 
(Almási et al, 2019). It is caused most commonly (60%) by mutations in the gene encoding the 
mitochondrial enzyme methylmalonyl-CoA mutase (MMUT), resulting in a failure of conversion 
of methylmalonyl-CoA to succinyl-CoA and a subsequent accumulation of methylmalonic acid 
in tissues and blood. Patients with MMA caused by MMUT gene mutations are typically non-B12 
responsive, present at a younger age, and have a more severe phenotype (Manoli et al, 2016).  
Severity of symptoms within the MMUT mutation patient population is correlated with the 
mutation type and the level of residual enzyme activity. Based on in vitro fibroblast assessments 
and/or gene allele correlations, MMA patients may have a complete loss of enzyme activity, 
designated as mut0, or a partial reduction, designated as mut-. The mut0 subtype is more 
prevalent and associated with higher morbidity and mortality at an early age (Manoli et al, 2016). 
While rapid MMA diagnosis via universal newborn screening can lead to early institution of 
medical and dietary management, the natural history of MMA remains characterized by periods 
of relative health alternating with intermittent and potentially life-threatening metabolic 
decompensations. Thus MMA continues to be associated with substantial morbidity despite 
improved survival (de Baulny et al, 2005) (Dionisi-Vici et al, 2006) (Kölker et al, 2015).  
Currently, MMA has no curative therapies. Patients with mutase-deficient MMA are treated 
lifelong with a demanding dietary regimen of protein restriction in addition to ammonia 
scavenger therapy in an attempt to mitigate acute illnesses that contributes to metabolic brain 
injury and progression to renal failure. Liver transplantation is an emerging intervention in MMA 
patients, increasingly performed at an early age to suppress hyperammonemia episodes, stabilize 
neurocognitive function, and improve long-term survival (Niemi et al, 2015). However, donor 

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liver availability is limited; and transplantation has significant acute and long-term risks 
associated with the surgical procedure as well as prolonged immunosuppression. 
3.2 
Rationale for Study 
In the first-in-human (FIH) hLB-001 clinical trial, LogicBio proposes to enroll pediatric patients 
with severe MMA who have not had liver transplantation. As a form of “molecular” liver 
transplantation, the outcome goals following hLB-001 administration are to provide similar 
clinical and biochemical benefits of surgical transplantation without the morbidity and mortality 
associated with the procedure and its immunosuppressive therapies. Additionally, hLB-001 is 
designed to be administered to the youngest of MMA patients before surgical liver 
transplantation is a viable option. 
Patients who are likely to benefit from this intervention are primarily mutase-null (mut0) but may 
include those with partial mutase deficiency (mut-) if they present with a severe phenotype. As 
patients with severe MMA are more likely to suffer debilitating, life-threatening events, these 
patients would most benefit by early and efficacious treatment. 
hLB-001 is a novel gene therapy intended to provide durable hepatocyte expression of the 
MMUT gene without the use of exogenous promoters or nucleases. hLB-001 uses the natural 
cellular process of homologous recombination to integrate a copy of the human mutase gene into 
the albumin locus. The albumin target site was selected to permit high level expression of 
MMUT protein in transduced hepatocytes, which is anticipated to restore mitochondrial function, 
reduce serum MMA levels, and ameliorate the MMA disease state. 
Restoration of normal and sustained levels of hepatic MMUT enzymatic activity through 
hLB-001 gene therapy could be transformative for patients and their caregivers, providing 
substantial clinical benefit by converting the disease to a more manageable if not asymptomatic 
state. This is supported by the clinical course of the majority of mut- MMA patients who retain 
some residual MMUT activity and have relatively delayed onset of symptoms with lower 
frequency of morbidity, mortality, and neurological complications (Hörster et al, 2007). 
Importantly, enrollment of patients with MMA in an hLB-001 trial would not preclude future 
intervention with liver transplantation. 
In summary, mutase-deficient MMA patients with an early and severe clinical presentation have 
a well-documented unmet medical need. hLB-001, through its sustained restoration of hepatic 
mutase activity, offers an opportunity to intervene at an early age before patients succumb to the 
disease or suffer irreversible neurologic injury. 
Further summary information on hLB-001 is provided in the Investigator’s Brochure (IB). 
Dose selection rationale, based on nonclinical data, may be found in the IB. To summarize, in an 
early proof of concept study, treatment of a mouse model of MMA with 1 × 1014 vg/kg mLB-
001b, a mouse surrogate of hLB-001, demonstrated a significant improvement in animal survival 
whereas treatment with 2.5 × 1013 vg/kg mLB-001b did not.  Later studies with intravenous 
administration of mLB-001b at 5 × 1013 vg/kg and 1 × 1014 vg/kg demonstrated evidence of 
efficacy that allowed a therapeutically active dose range to be identified. Specifically, these 

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studies demonstrated comparable bioactivity/efficacy for the 2 above-mentioned dose levels, 
based on clear improvement in clinically meaningful endpoints (animal survival, protection from 
body weight loss) and relevant biomarkers (maintenance of lower circulating methylmalonic acid 
levels) in the treated animals compared to the vehicle-treated control animals in response to 
protein challenge that is designed to mimic metabolic stress. These studies identified 5 × 1013 
vg/kg as the minimum efficacious dose, and single IV administration of hLB-001 at this dose is 
expected to be biologically active and will be the first dose explored in this first clinical study.  
4 STUDY OBJECTIVES AND ENDPOINTS 
4.1 
Primary Objective and Endpoints 
To assess the safety and tolerability of hLB-001 in pediatric patients with MMA 
Endpoints 
 Incidence of treatment-emergent adverse events (AEs) 
 Incidence of infusional toxicities (hLB-001-related AEs that limit, delay, or require medical 
intervention during administration) 
4.2 
Secondary Objectives and Endpoints 
1. To assess change from baseline in pharmacodynamic biomarkers post hLB-001 dosing in 
pediatric patients with MMA 
Endpoints 
 Serum methylmalonic acid and methylcitrate (week 52-end-of-study (EOS) visit absolute 
value and percent change from average predosing level) 
 Serum fibroblast growth factor 21 (FGF21) level (week 52-EOS visit absolute value and 
percent change from predosing level) 
 Propionate oxidation rate (week 52-EOS visit change from predosing level)  
 Serum albumin-2A level (alternative albumin isoform synthesized from loci with hLB-001 
integration, change from predosing baseline to week 52-EOS visit) 
2. To assess clinical efficacy outcomes post hLB-001 dosing in pediatric patients with MMA 
Endpoints 
 Survival at 1-year post hLB-001 dosing

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4.3 
Exploratory Objectives and Endpoints 
1. To assess hLB-001 viral shedding 
Endpoints 
 Viral shedding (presence and copy number of viral genomes determined by polymerase chain 
reaction [PCR] on urine, saliva and stool samples) 
2. To assess clinical efficacy outcomes post hLB-001 dosing in pediatric patients with MMA 
 Hospitalizations for MMA-related complications (number, reason for, and duration of MMA 
related hospitalizations from dosing through week 52-EOS visit with comparison to 1year 
period predosing) 
 Surgical liver and/or kidney transplant (number of patients with liver, kidney, or combined 
liver-kidney transplants) 
 Growth parameters (change in age-specific z-scores for weight, height/length, and head 
circumference from predosing to week 52-EOS visit as determined from standard growth 
curves) 
 Vineland Adaptation Behavior Score (change in patient score from predosing to week 52-
EOS visit) 
 Parenting Stress Index (change in parenting total stress score (PSI-IV, 36-item short form) 
from predosing to week 52-EOS visit) 
 Healthcare utilization (number of Emergency Room (ER) visits and unscheduled physician 
visits from dosing through week 52-EOS visit with comparison to 1-year period predosing) 
 Neurodevelopmental status (change in age-appropriate testing score from predosing to week 
52-EOS visit, eg, Bayley, Wechsler) [note that these will be collected in the US only] 
3. To assess change from predosing baseline in diet, oral intake, and medications 
Endpoints 
 Protein intake (determined from 3-day nutrition diary at week 52-EOS visit) 
 Oral feeding (determined from 3-day nutrition diary at week 52-EOS visit) 
 MMA-related medication use (prescription medications started/discontinued or change in 
dose other than weight-related adjustments) 
4. To investigate exploratory pharmacodynamic (PD) biomarkers 
Endpoints 
 Exploratory serum/plasma biomarkers associated with MMA  

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5. To assess immunological changes  
Endpoints 
 Incidence of immunological changes (defined as antibody or cellular immune response to 
hLB-001 itself or the proteins expressed following integration) 

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5 STUDY DESCRIPTION 
5.1 
Study Design 
Study LB001-001 is a FIH phase 1/2 open-label interventional study to evaluate the safety, 
tolerability, biologic activity, and clinical efficacy of hLB-001 in pediatric patients with MMA. 
Patients to be enrolled will have a severe form of MMA associated with deficiency of 
methylmalonyl-CoA mutase (commonly referred to as MMUT) with the following criteria: 
a. Isolated MMA with genetically confirmed, pathogenic mutations in the MMUT gene 
b. Screening serum methylmalonic acid level of >100 µmol/L 
c. One or more of the following considered by the PI to be MMA-related: 
i. 
An unscheduled ER visit or hospitalization in the year prior to screening visit 
ii. 
Developmental delay, movement disorder, optic neuropathy or feeding disorder with 
tube feeding requirement 
d. Medically stable for the 2 months prior to the start of screening, defined as following a 
dietary management plan meeting the standard practice guidelines for patients with 
MMA (7.9 
Dietary Management) in addition to having no changes in chronic 
treatment other than adjustments to medications and diet for weight gain and nutritional 
laboratory evaluations as required for optimal care 
Approximately 8, with the option to increase to 12, patients will be enrolled at approximately 8 
centers in the United States and Saudi Arabia.  
Patients will undergo an initial screening, which will include general health and disease 
complications, MMA diagnosis confirmation, dietary assessment, concomitant medications, 
adeno-associated viral vector (AAV) neutralizing antibody titers, and liver and renal function 
testing. The screening assessments may take place over multiple days. Patients who are receiving 
MMA-related medications should continue these medications as per the standard of care at the 
clinical site. 
Patients meeting all initial screening criteria will undergo a run-in period of at least 16 days from 
start of screening to hLB-001 dosing. During this period, patients will establish a baseline for 
methylmalonic acid levels and other disease biomarkers and demonstrate ongoing clinical 
stability. During the week prior to dosing, it will be confirmed that the patient continues to meet 
all inclusion/exclusion criteria and the patient will be admitted to the study site for study drug 
administration. 
Once eligibility for the study has been assessed, a peripherally inserted central catheter (PICC 
line) will be placed for any patient who does not already have one, to allow for easier blood 
draws during the initial part of the study.  
Administration of several AAV-based genetic therapies, including hLB-001, has been reported to 
be associated with the development of thrombotic microangiopathy (TMA), resulting in the use 
of a variety of mitigation approaches. Subjects with certain known risk factors such as 

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concurrent infection, recent vaccinations, and history of DVT or coagulopathy will be excluded. 
Additionally, subjects will be intensely monitored during the high-risk TMA period (i.e. two 
weeks post-dosing) in order to detect signs of TMA as early as possible, should they develop. 
The monitoring regimen will include frequent testing for laboratory signs of hemolysis, 
thrombocytopenia, kidney dysfunction, and complement activation. Results of this testing will be 
reviewed as they are available by the investigator, the TMA experts on the DSMB, and the 
Sponsor Medical Monitor. 
 
AAV administration to pediatric patients has been associated with clinically significant liver 
enzyme elevations, resulting in a recommendation of prophylactic steroid administration for a 
minimum duration of 1 month, followed by a taper (ZOLGENSMA prescribing information, 
2019). In practice, the mean duration of steroids treatment is often longer, due to persistent 
elevations in transaminases, which has also been observed with hLB-001 (Chand 2021). A 
standardized regimen of prednisolone 1 mg/kg/day or its equivalent (not to exceed 60 mg per 
day) will be initiated 24 ± 4 hours prior to starting the hLB-001 infusion. Administration may be 
oral or via g-tube if oral administration is not possible. Daily corticosteroid dosing will continue 
for a planned 60-day course followed by a 26-day taper. The taper will be delayed if the patient 
has alanine aminotransferase (ALT) values > 2 X Upper Limit Normal (ULN), or aspartate 
aminotransferase (AST) > 2.0 × ULN together with ALT, alkaline phosphatase or total bilirubin 
> ULN. If liver function abnormalities persist at 60 days, systemic corticosteroids (equivalent to 
prednisolone at 1 mg/kg/day) may be continued for up to 2 weeks until findings return to 
baseline levels or in discussion with the medical monitor, and the corticosteroid dose will be 
tapered over the next 26 days. Two weeks after steroid discontinuation, normalized adrenal 
function will be confirmed by AM cortisol level. If the cortisol level is < 18 mcg/dL or within 
normal limits, patient will be referred to an endocrinologist for CRH or ACTH stimulation 
testing. 
The anticipated period of study patient hospitalization is 8 days, from day -1 to Day 7 postdose. 
For a period of 1 week following hospital discharge, patients will be asked to remain within a 1-
hour access of the study site due to the possible risk for metabolic imbalance associated with 
corticosteroid administration and to allow for daily study visits until day 14/week 2. Patients will 
return to the study site for weekly visits during month 1 (week 3 and 4), every other week until 
month 3 (weeks 6, 8 and 10), and twice every quarter thereafter until completion of the study 
(weeks 13, 19, 26, 32, 39, 45 and 52). Home healthcare visits may be conducted at weeks 3, 6, 
10, 19, 32 and 45; additional home visits may be discussed with the study physician and Sponsor 
for consideration. Dietary assessments including laboratory evaluations will take place at study 
entry and every three months throughout the study. Study participants will follow dietary 
recommendations on adequate energy and protein intake to support normal growth, development 
and physical activity level. Nutritional goals to be met by all study participants will be assessed 
at study entry and on a regular basis during study participation by a nutritional specialist familiar 
with dietary management in MMA.  Following completion of their EOS visit, study patients will 
be asked to participate in a separate long-term follow-up study to continue monitoring the long-
term safety and efficacy of hLB-001.  
 

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A schematic of the study design is as follows: 
 
 
Two dose levels of hLB-001 are planned to be administered in 8, up to 12, patients across one to 
two cohorts, cohort 1 (5 x 1013 vg/kg) and cohort 2 (1 x 1014 vg/kg). 
Cohort 1: Dose level 5 x 1013 vg/kg IV 
The DSMB will review safety data as described below. The safety review will include a focus on 
any potential signs of steroid-induced catabolic stress. The DSMB may recommend optimizing 
the steroid regimen, or delaying enrollment into the next group by two weeks in order to more 
fully assess the corticosteroid period. 
 Part A: 2 patients, aged 3-12 years will be enrolled. A minimum of 6 weeks of postdosing 
safety-related data will be evaluated by the DSMB chair and the Sponsor Medical Monitor 
between the dosing of each patient. The first patient must be at least midway through the 
corticosteroid tapering period for the safety review to be completed. At a minimum of 6 
weeks after the second patient is dosed, the independent DSMB will review all available 
safety data. The second patient must be at least midway through the corticosteroid tapering 
period for the safety review to be completed. 
 If the safety review is sufficient and there is evidence of albumin-2A, enrollment into 
Cohort 1 Part B may begin.  
 Part B: 2 patients, aged 6 months-2 years will be enrolled. A minimum of 6 weeks of 
postdosing safety-related data will be evaluated by the DSMB chair and the Sponsor Medical 
Monitor between the dosing of each patient. The first patient must be at least midway 
through the corticosteroid tapering period for the safety review to be completed. At a 
minimum of 6 weeks after the second patient is dosed, the independent DSMB will review all 
available safety data. The second patient must be at least midway through the corticosteroid 
tapering period for the safety review to be completed. 
 Part C: Four additional patients, aged 6 months to 12 years of age, will be enrolled. A 
minimum of 4 weeks of postdosing safety-related data will be evaluated by the DSMB chair, 

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the Sponsor Medical Monitor and TMA experts between the dosing of each patient. At a 
minimum of 4 weeks after the fourth patient is dosed, the independent DSMB will review all 
available safety data. If the safety review is sufficient, enrollment into Cohort 2 Part A may 
begin, however the Sponsor will assess all safety and efficacy data before dosing of this 
cohort will take place. The risk/benefit analysis will be shared with the FDA prior to 
commencing enrollment in cohort 2. If the risk/benefit is deemed unacceptable, cohort 2 will 
not be enrolled. 
Cohort 2: Dose level 1 x 1014 vg/kg IV 
 Part A: At least 2 patients, aged 3-12 years will be enrolled. A minimum of 4 weeks of 
postdosing safety-related data will be evaluated by the DSMB chair, the Sponsor Medical 
Monitor, and TMA experts between the dosing of each patient. At a minimum of 4 weeks 
after the second patient is dosed, the independent DSMB will review all available safety data.  
 If the safety review from Cohort 2 Part A is sufficient and there is evidence of albumin-
2A in Cohort 2 Part A, enrollment into Cohort 2 Part B may begin. 
 If the safety review is insufficient, or a patient needs to be replaced, an additional patient 
in Cohort 2 Part A may be enrolled. 
 Part B: At least 2 patients, aged 6 months-2 years will be enrolled. A minimum of 4 weeks of 
postdosing safety-related data will be evaluated by the DSMB chair, the Sponsor Medical 
Monitor, and TMA experts between the dosing of each patient. At a minimum of 4 weeks 
after the second patient is dosed, the independent DSMB will review all available safety data.  
 If the safety review is insufficient, or a patient needs to be replaced, an additional patient 
in Cohort 2 Part B may be enrolled. 

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The cohort schematic is below: 
 
 
5.1.1 
Long-term Follow-up 
Long-term follow-up will be completed under a separate study protocol. In brief, through 5 years 
postdosing, study patients will be followed by their health care providers (HCPs) in addition to 
annual visits to the clinical study site for safety and efficacy evaluations. From 6 to 15 years 
postdosing, they will be followed for potential delayed AEs to match the current regulatory 
recommendation of 15-year follow-up. 
5.1.2 
Overall Safety Plan 
Safety monitoring will begin once the informed consent form (ICF) has been signed.  
All new or worsening AEs regardless of causality, including laboratory abnormalities that meet 
the definition of an AE, will be monitored and recorded in the designated electronic case report 
form (eCRF) through the last study visit. Emergence of any new clinical conditions (eg, 
transplantation, major decompensation event that triggers a change in status, basal ganglia 
stroke, death) that are reported or observed, and the action taken in response, will be reported to 
the sponsor. All study patients will be asked to participate in a long-term follow-up protocol for 
continued monitoring of gene therapy-related AEs.  

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5.2 
Dose Cohorts, Study Suspension, and Study Stopping Rules 
Dose Cohorts 
Age de-escalation in Cohort 1 Part B and dose escalation in Cohort 2 Part A will not be opened 
for enrollment if either of the following is noted following hLB-001 treatment in Cohort 1 Part A 
or Part C. Also, if either of the following is noted following hLB-001 treatment in Cohort 2 Part 
A, Cohort 2 Part B will not be opened for enrollment.  
 Any Common Terminology Criteria for Adverse Events (CTCAE) grade 4 organ toxicity that 
does not improve to grade  2 within 4 weeks 
 Any grade 3 or greater autoimmune toxicity  
The Sponsor will assess all safety and efficacy data before dosing of cohort 2 will take place. 
The risk/benefit analysis will be shared with the FDA prior to commencing enrollment in cohort 
2. If the risk/benefit is deemed unacceptable, cohort 2 will not be enrolled. 
Study Suspension Rules 
Study hLB-001 dosing will be suspended if any of the following occurs: 
 Any event of TMA 
 A patient experiences a Grade 4 or higher AE  
 A patient develops a malignancy  
 A patient dies 
 Any grade 4 SAE that could be related to study procedures (e.g., complications from 
prophylactic steroids) 
 Any grade 3 SAE of Special Interest (as defined in 11.2.1 
Adverse Events of Special 
Interest (AESI)) 
 The same or related grade 3 SAE in two subjects that is related to the study product or study 
procedures 
 Despite corticosteroid use as described in 10.2 Prophylactic Administration of 
Corticosteroids and Monitoring/Risk Mitigation, alanine aminotransferase (ALT) values 
remain above the threshold of 2 X Upper Limit Normal (ULN). 
 The DSMB chair and/or sponsor determine that an event or current data warrant further 
evaluation by the full DSMB 
Upon study suspension, the DSMB will evaluate all clinical safety data and provide 
recommendation on whether dosing should continue, whether changes should be made in the 
study, or in consultation with the sponsor whether the study should be stopped. 

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During any period of study suspension, enrollment and treatment will be paused while the 
DSMB investigates whether a grade 3 or grade 4 SAE could be related to the study product or 
study procedures. Patients who have been dosed with hLB-001 will continue to be followed for 
safety and PD/clinical efficacy through their scheduled EOS visit. 
Study Stopping Rules 
Study enrollment and dosing will be discontinued permanently if any of the following occurs: 
 Sponsor or a regulatory agency decides for any reason that an event or current data warrant 
study termination 
 A patient develops a malignancy assessed as related to hLB-001 by the investigator and/or 
sponsor 
 A patient death is assessed as related to hLB-001 by the investigator and/or sponsor 
 Any medically unacceptable risk of hLB-001 is identified by the DSMB and/or sponsor 
If study dosing is stopped, patients who have already been dosed with hLB-001 will continue to 
be followed for safety and PD/clinical efficacy through their scheduled EOS visit. 
5.3 
Patient Staggering 
The interval between doses for each subject is defined as follows: 
 Cohort 1 Part A and B: A minimum of 6 weeks of postdosing safety-related data will be 
evaluated by the DSMB chair and the Sponsor Medical Monitor between the dosing of each 
patient. Each patient must be at least midway through the corticosteroid tapering period for 
the safety review to be completed. 
 Cohort 1 Part C: A minimum of 4 weeks of postdosing safety-related data for the prior 
subject will be evaluated by the DSMB chair, the Sponsor Medical Monitor and TMA 
experts before dosing the next patient. 
 Cohort 2 Part A and B: A minimum of 4 weeks of postdosing safety-related data for the prior 
subject will be evaluated by the DSMB chair, the Sponsor Medical Monitor and TMA 
experts before dosing the next patient. 
Safety-related data is defined in the DSMB charter and will contain at a minimum: medical 
history, adverse events, chemistry, hematology and other local laboratory values, concomitant 
medications, and prednisolone administration. The DSMB will be presented with a listing that 
indicates if any study stopping or suspension criteria are met.  
5.4 
Study Schedule 
The time and events schedule for this study can be found in Table 1. 
Schedule of Events. 

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5.4.1 
Informed Consent/Assent 
After the study has been fully explained, written informed consent and assent, as applicable, will 
be obtained from the patient and his/her guardian or legal representative before study 
participation. The method of obtaining and documenting the informed consent/assent and the 
contents of the consent/assent must comply with the ICH-GCP and all applicable regulatory 
requirements as well as site standard operating procedures (SOPs). 
5.4.2 
Screening 
After obtaining informed consent/assent, subjects will be evaluated for initial eligibility through 
the inclusion/exclusion criteria. The duration of screening is likely to be variable dependent upon 
testing turnaround times and is anticipated to be 16-30 days. Required screening procedures may 
take place over multiple days. If safety lab testing (hematology, chemistry, coagulation, renal 
markers, urinalysis) has occurred within the 2 weeks prior to consent/assent as part of routine 
care, and results are available, then those tests do not need to be repeated. Subjects will receive 
the meningococcal vaccine, if they have not already received it, at least 6-weeks prior to the 
planned dosing date.  
5.4.3 
Retesting 
Subjects may have the following tests repeated once as part of inclusion/exclusion assessments: 
Inclusion criterion #5- Screening serum methylmalonic acid level. Methylmalonic acid levels 
fluctuate and repeat testing once is allowed.  
Inclusion criterion #6- Hematology. Transient decreases may occur in some patients and repeat 
testing once is allowed.   
Exclusion criterion #7- Screening anti-recombinant adeno-associated virus (AAV) LK03-
neutralizing antibodies. The screening assay for neutralizing antibody level may reflect waning 
maternal antibodies in young patients (Perocheau et al, 2019). Thus, it may be repeated once to 
assess whether the titer has now dropped to the 1:10 level or below. 
Exclusion criterion #11- Laboratory testing results for hepatic/gastrointestinal function and 
pancreatic enzymes. Transient elevations may occur in some patients and repeat testing once is 
allowed.  
5.4.4 
Rescreening 
Subjects not meeting one or more of the inclusion or the exclusion criteria will be considered 
screen failures. Subjects may rescreen once for the study. Screening assessments that were 
previously performed and are still within the specified window do not need to be repeated. See 
the following section if screening labs were taken more than 30 days prior to the expected dosing 
date.     

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5.4.5 
Run-in Period to Dosing 
The run-in period is defined as the time from initiation of screening to hLB-001 dosing and will 
be a minimum of 16 days to allow for at least 2 serum methylmalonic acid levels before dosing 
(at least 14 days apart) and confirmation of patient stability.  
If this run-in period exceeds 3 months, repeat testing of the following will be required to assess 
eligibility for hLB-001 dosing: pancreatic enzymes (exclusion criterion 11). 
The following should be repeated if screening labs were taken more than 30 days prior to the 
expected dosing date to assess eligibility: hematology/chemistry/coagulation, urine ketones, 
ammonia, methylmalonic acid, methylcitrate and neutralizing antibodies. Patient weight needs to 
be measured within 30 days of the dosing date.  
A PICC line will be placed at least 7 days prior to dosing for any patient who does not already 
have one. 
5.4.6 
Baseline Assessment and Dosing 
Study patients who have completed the run-in period will be eligible for hLB-001 dosing after 
the following have been confirmed in order to reduce procedure risk: 
1. Continues to meet all screening inclusion/exclusion criteria (see Table 1 for baseline visit 
procedures, conducted at day -7 to day -2) 
2. In the judgement of the site investigator the patient is medically stable 
For dosing, the patient will be admitted to the hospital on day -1 and started on prophylactic 
steroids 24 hours (± 4 hours) prior to hLB-001 infusion. Treatment via a single administration of 
hLB-001 will occur on day 1. The patient will remain in the hospital for approximately 7 days 
after hLB-001 administration in order to evaluate safety. The patient will be required to remain 
within close proximity of the study site (within 1-hour access) for the first week of corticosteroid 
administration due to the risk of metabolic imbalance associated with corticosteroid 
administration.  
5.4.7 
Follow-up 
Patients will return to the investigative site for regularly scheduled visits through 1-year 
postdosing as detailed in Table 1. 
Schedule of Events to evaluate the safety and efficacy of 
hLB-001. Home healthcare visits may be conducted at weeks 3, 6, 10, 19, 32 and 45; additional 
home visits may be discussed with the study physician and Sponsor for consideration. 
5.4.8 
End of Study 
Patients who complete the week 52 visit will have completed the study. If a patient withdraws 
early, an early EOS visit should be conducted at the time of study withdrawal. At study 
completion or early discontinuation, patients will be asked to participate in a long-term follow-up 
study to continue monitoring the long-term safety and efficacy of hLB-001. 

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5.4.9 
Unscheduled Visits 
Should there be need for an unscheduled visit, eg, to manage or follow-up on unresolved AEs, 
the investigator should use his/her judgment and perform adequate evaluation of the patient. All 
examination and testing results should be recorded in the unscheduled visit section of the eCRF. 
Healthcare utilization and hospitalization events will be collected as efficacy measures. 

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6 PATIENT ELIGIBILITY AND WITHDRAWAL CRITERIA 
6.1 
Number of Patients 
The study is anticipated to enroll approximately 8, with the option to increase to 12, patients with 
severe MMA at approximately 8 sites in the United States and Saudi Arabia. 
6.2 
Inclusion Criteria 
A patient must meet all the following inclusion criteria to be eligible for participation in this 
study: 
1. At the time of dosing, patient must be 6 months to 12 years of age  
2. Patient (and/or legally authorized representative) has voluntarily agreed to participate by 
giving written informed consent/assent in accordance with ICH GCP guidelines and 
applicable local regulations 
3. Willingness and ability to comply with study procedures and scheduled visits 
4. Current with the local recommended vaccination schedule based on age (no vaccinations 
within 6 weeks pre- or post-hLB-001 dosing; no expectation of the need for live vaccinations 
while on corticosteroids and for 3 months following completion of corticosteroid dosing) 
5. Males and females with diagnosis of severe MMA meeting all the following; 
a. Isolated MMA with genetically confirmed, pathogenic mutations in the MMUT gene 
b. Screening serum methylmalonic acid level of >100 µmol/L 
c. One or more of the following considered by the PI to be MMA-related: 
i. 
An unscheduled ER visit or hospitalization in the year prior to screening visit 
ii. 
Developmental delay, movement disorder, optic neuropathy or feeding disorder 
with tube feeding requirement 
d. Medically stable for the 2 months prior to the start of screening, defined as following a 
dietary management plan meeting the standard practice guidelines for patients with 
MMA (7.9 
Dietary Management) in addition to having no changes in chronic 
treatment other than adjustments to medications and diet for weight gain and nutritional 
laboratory evaluations as required for optimal care 
6. Hematology laboratory results confirming: 
a. Hemoglobin  9 g/dL 
b. Absolute neutrophils count  1000/µL 
c. Platelet count  150,000/µL 

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6.3 
Exclusion Criteria 
A patient meeting any of the following exclusion criteria is not eligible for participation in the 
study: 
1. Patients with organic acidemias other than isolated MMA, or with any other causes of 
hyperammonemia 
2. Having received MMA-targeted gene therapy or nucleic acid therapy 
3. Having received an investigational drug within 28 days or 5 half-lives of the drug, whichever 
is shorter, prior to initiation of screening 
4. Patients on insulin or high-dose hydroxocobalamin (> 1 mg/day OHB12 parenteral) 
5. Kidney or liver transplant, including hepatocyte cell therapy  
6. Estimated glomerular filtration rate (eGFR) of < 60 mL/min/1.73 m2 based on the creatinine-
based “Bedside Schwartz” equation (2009), or ongoing dialysis for renal disease 
7. Patient tests positive for anti-rAAV LK03-neutralizing antibodies with titers above protocol-
specified threshold of 1:10  
8. Patient has received immune-modulating agents within 3 months prior to initiation of 
screening (use of inhaled corticosteroids to manage chronic respiratory conditions 
permissible) 
9. Patient has a history of, or currently has, a clinically important condition not directly related 
to MMA, in the opinion of the investigator 
10. History or presence of arrhythmia or other clinically significant abnormality on 
electrocardiogram (ECG) 
11. Any of the following hepatic/gastrointestinal factors: 
a. Liver laboratory testing values  
o alanine aminotransferase (ALT) > 2.0 × upper limit of normal (ULN) 
o aspartate aminotransferase (AST) > 2.0 × ULN together with ALT, alkaline 
phosphatase or total bilirubin > ULN 
o total bilirubin > 2.0 × ULN 
o prothrombin time > 1.5 x ULN 
b. Pancreatic enzymes (amylase, lipase) > 3.0 × ULN 
c. Hyperammonemia characterized by ammonia  3 × ULN, or signs of active metabolic 
decompensation (eg, lethargy, irritability, and vomiting) 
12. Any of the following oncologic factors: 
a. Liver abnormalities suspicious for malignancy on screening ultrasound 
b. History of any malignancy, test-positive for a cancer-predisposition syndrome, or family 
history for a cancer-predisposition syndrome and patient has not been tested 

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13. History of anaphylaxis or severe allergic reaction or allergy to antibiotics to be potentially 
administered 
14. Patient has experienced a viral or bacterial illness and is still symptomatic within 6 weeks of 
dosing 
15. Vaccinations administered within 6 weeks of dosing 
16. History of deep vein thrombosis (DVT) or coagulopathy 
6.4 
Patient Withdrawal 
The patient has the right to withdraw from the study at any time. As hLB-001 is a one-time 
administration and safety follow-up is of high priority, every reasonable attempt should be made 
to have patients continue to be assessed at all scheduled visits.   
The patient will be withdrawn from the study if: 
1. Withdrawal of consent 
2. Administrative decision by the sponsor or the investigator 
3. Violation of the protocol inclusion and/or exclusion criteria prior to study drug 
administration, as deemed relevant by the investigator and discussed with the sponsor 
medical monitor 
4. Patient noncompliance prior to dosing 
5. In the investigator’s judgment, it is in the best interest of the patient 
6. Any transplant procedure 
7. Lost to follow-up 
Patients who withdraw from the study should be encouraged to enter the long-term follow-up 
study.  
In cases where the patient is deemed ‘lost to follow-up,’ the investigator or designee must make 
every effort to regain contact with the patient; eg, 3 documented attempts, 1 of which must be a 
certified letter to the patient’s last known mailing address or local equivalent methods. These 
contact attempts should be documented in the patient’s medical records. Should the patient 
continue to be unreachable, only then will he/she be considered to have withdrawn from the 
study with the primary reason as ‘lost to follow-up.’ 
If hLB-001 infusion is stopped due to an AE, the patient will be considered discontinued from 
study treatment due to an AE, but the patient should be followed in the study as outlined in the 
schedule of events and all AEs followed until resolution or stabilization. 
Withdrawal of full consent for the study means that the patient does not wish to undergo 
procedures and the patient does not wish to continue further study follow‐up. Patient data 
collected up to withdrawal of consent will be retained and included in the analysis of the study; 

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and where permitted, publicly available data (death records) can be included after withdrawal of 
consent (FDA Guidance for Industry: Guidance for Sponsors, Clinical Investigators, and IRBs 
Data Retention When Subjects Withdraw from FDA–Regulated Clinical Trials [October 2008]).  
An early EOS visit should be conducted at the time of study withdrawal.  
6.5 
Patient Replacement 
Withdrawn patients who have received hLB-001 will be replaced if there is insufficient safety 
data for DSMB evaluation. Patients who have signed the ICF but have not received hLB-001 will 
be replaced. 

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7 STUDY PROCEDURES AND ASSESSMENTS 
Study procedures are indicated in the Table 1. 
Schedule of Events. Additional details of 
procedures may be found in the Study Reference Manual (SRM). 
7.1 
Demographics and Medical History 
Demographics and medical history, including disease history, will be collected. 
7.2 
Physical Examination 
Complete and targeted physical examinations will be performed per Table 1. 
Schedule of 
Events. Please refer to the SRM for body systems to be covered in these examinations. Skin will 
be examined for rash or peeling as a possible indicator of protein over-restriction or nutrient 
deficiency.  
Significant changes in the physical examination from screening will be recorded as AEs.  
7.3 
Vital Signs 
Vital signs will include heart rate (HR), respiratory rate (RR), blood pressure systolic and 
diastolic (BP), and temperature. Age-specific techniques and devices should be used. Whenever 
possible, the measurements should be made by the same personnel using the same device at each 
evaluation. Pulse oximetry will be monitored starting prior to dosing then for 24 hours post 
dosing. 
Note: vital signs the day of hLB-001 dosing should be taken: 
1. Within 15 min of start of infusion 
2. After start of infusion: at 30 minutes, 1 hour, 2, 3, 4, 6 and 8 hours (± 10 minutes) 
Example for 10:00 morning infusion: 
9:45-10:00, 10:30, 11:00, 12:00, 13:00, 14:00 16:00, 18:00 
Additional vital signs may be taken as deemed necessary. 
7.4 
ECG 
A 12-lead ECG will be obtained at the visits indicated.  
7.5 
Liver Ultrasound and Alpha-fetoprotein 
Liver ultrasound and alpha-fetoprotein level will be followed as part of the recommended 
assessments for evaluation of patients at theoretical risk of hepatic malignancy. If a liver 
ultrasound was performed within 3 months prior to screening, it does not need to be repeated at 
screening.  

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7.6 
1-13C-propionate Oxidation 
Total body propionate oxidation can be quantified through breath collection of labelled 13CO2 
after oral dosing with 13C-propionate (Gagné et al, 2016). When the oxidation assay is performed 
pre- and post-hLB-001 dosing, the difference represents a systemic, quantitative biomarker for 
mutase activity. These samples will be analyzed at a central laboratory. 
7.7 
Growth Parameters 
Weight, height/length, and head circumference (up to age 3) will be assessed according to 
standard procedures.  
7.8 
Protein and Nutritional Intake/Patient Diary 
Protein (intact and medical food), nutritional intake, and tube feeding details/days with oral feeds 
will be determined from the 3-day nutritional diary completed prior to specified visits.  
7.9 
Dietary Management 
Dietary management in patients with MMA is critical to their health and safety. In addition, 
potential variability in dietary management may be a confounding factor in clinical trials for 
inborn errors of metabolism where diet is a mainstay of treatment, and the effect of diet can 
make interpretation of results difficult. To those ends, the following general guidelines will need 
to be met by all patients entering into and participating in the trial (Baumgartner et al, 2014)  
(Manoli et al, 2016) to ensure patients have optimized and stable diets prior to and throughout 
the study: 
1. Study participants will follow dietary recommendations on adequate energy and protein 
intake to support normal growth, development and physical activity level (15 Appendix 1: 
FAO/WHO/UNU 2007 Safe Levels of Protein and Energy Intake for Different Age Groups) 
2. Medical foods with free amino acid supplements are likely to be a part of the nutritional 
program.  Their use and percent of total intake should be based on tolerance of protein load 
as assessed by plasma amino acid levels, MMA and ammonia levels 
3. Nutritional goals to be met by all study participants will be assessed at study entry and on a 
regular basis during study participation by a nutritional specialist familiar with dietary 
management in MMA 
Breastfeeding is allowed provided the intake is measured for diet diaries as required in Table 1.
 
Schedule of Events 
7.10 Cognitive and Motor Function Assessments 
Cognitive and motor function assessments will be completed and scored based on patient age per 
Table 2. Due to the lack of available validated translations, these tests will be performed only in 
the US. Neurodevelopment will be assessed using age-appropriate testing as summarized below. 
The same test used at screening should be used again at week 52-EOS, for a given patient (Note: 

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if a child will have exceeded the upper age limit for a test’s norms at the 52-EOS, then the test 
appropriate for the older age should be given on both occasions). Personal ability will be 
assessed using the Vineland Adaptive Behavior Scales, Third Edition (Vineland-3) tool, which 
includes a motor subscale for patients up to 9 years of age. Details on the assessments used in the 
study will be provided in the SRM.  
These assessments must be completed prior to any other study assessments being performed.  
Table 2. 
Cognitive and Motor Function Scales by Age Group 
Age Group 
Scalea 
6 months to 36 months 
Bayley Scales of Infant and Toddler Development, 4th Edition 
(includes norms for 1-42 months) 
37 months to 6 years 
Wechsler Preschool and Primary Scale of Intelligence, 4th 
Edition 
(includes norms for 2 years 6 months to 7 years 7 months) 
6 years 1 month to 12 years 
Wechsler Intelligence Scale for Children, 5th Edition 
(includes norms for 6 years 0 months to 16 years 11 months) 
a
= 
As noted above, if a child will have exceeded the upper age limit for a test’s norms at the 52-EOS, 
then the test appropriate for the older age should be given on both occasions.
7.11 Quality-of-Life Assessments 
The endpoint for this assessment is the well-validated Parenting Stress Index, PSI-IV. The 
36-question short form is recommended. Details on this assessment will be provided in the SRM. 
7.12 Hospitalizations and Healthcare Utilization 
The investigator will record the number, duration, and primary diagnosis for any hospitalizations 
or healthcare utilization. 
Healthcare utilization includes ER visits and unscheduled visits to physician/hospital.  
7.13 Change in Requirement for MMA-related Medications 
All prescription and over-the-counter medications taken from initiation of screening through 
the EOS visit will be recorded in the eCRF, including any changes in dose or frequency per 
Section 10. Changes in medications related to MMA will be analyzed.  
7.14 Adverse Events  
The investigator (or designee) will determine during the course of all study periods whether any 
AEs have occurred. Patients will be questioned in a general way and no specific symptoms will 
be suggested. Section 11 contains additional information with regard to the definitions and 
reporting period for AEs. 

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7.15 Laboratory Tests 
Clinical laboratory tests will be performed by a qualified laboratory, analyzed either at the 
investigative site or a central laboratory. Please refer to the SRM/Laboratory Manual for 
preparation and collection instructions of each sample. If a patient is on a continuous feed, the 
feed should be stopped for 1 hour prior to collecting blood samples.  
Neutralizing antibody titer to rAAV-LK03: Samples for neutralizing antibodies to rAAV-LK03 
will be collected to monitor for a humoral immune response to rAAV-LK03. The assay will be 
performed via a cell-based functional assay.  
Albumin-2A: hLB-001 integration at the albumin locus in hepatocytes results in synthesis of 
both human MMUT enzyme and the modified protein albumin-2A (ALB2A). ALB2A is secreted 
into the bloodstream and thus represents a surrogate biomarker detectable in patient serum by an 
enzyme-linked immunosorbent assay (ELISA). 
Antibody response: Samples for antibodies to rAAV-LK03, MMUT, and ALB2A will be 
collected and analyzed using an ELISA assay.  
Anti-albumin antibodies: 
Patients will be tested for the presence and titer of anti-ALB-2A antibodies as described 
in Table 1. 
Schedule of Events.  The presence of sustained anti-ALB-2A antibodies 
(2 consecutive positive results above baseline) or an unexplained drop in serum albumin 
concentration will trigger investigations utilizing a specific assay that identifies the 
presence and titers of antibodies to native albumin. If the 3-month titer is above baseline, 
additional monitoring will occur every 6 weeks until titers return to baseline on 2 
consecutive samples. 
If anti-albumin antibodies are present in the setting of clinically-significant 
hypoalbuminemia or a worsening in clinical status, the option for immunosuppression 
should be discussed with an expert in autoimmune disorders. 
T-cell response: The presence of T-cells specific for rAAV-LK03, MMUT, and ALB2A will be 
determined by an enzyme-linked immunospot (ELISPOT) assay. 
Viral shedding: Saliva, urine, and stool will be collected to monitor for the presence of shed 
virus. Quantitative polymerase chain reaction will be used for analysis.  
FGF21: Samples will be collected to assess systemic metabolism and analyzed using a multi-
analyte, microsphere-based profiling system. 
TMA genetic panel: Subjects will be tested for variants in genes associated with TMA to help 
determine a potential relationship between these genetic changes and the risk for TMA 
development. 
 

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Samples to be analyzed at local laboratory: 
 Hematology and blood smear (hematocrit, hemoglobin, red blood count (RBC), white blood 
count (WBC), differentials (neutrophils, eosinophils, basophils, lymphocytes and 
monocytes), platelets and blood smear  
 Chemistry (albumin, alkaline phosphatase, ALT, AST, blood urea nitrogen, calcium, 
chloride, CO2, creatinine, glucose, phosphorus, potassium, sodium and total bilirubin) 
Note: eGFR to be calculated using the Serum creatinine (scr)-based “Bedside Schwartz” 
equation (2009):  
 𝑒GFR (mL/min/1.73 𝑚ଶ) = 0.413 × ℎ𝑒𝑖𝑔ℎ𝑡(𝑐𝑚) ÷ 𝑐𝑟𝑒𝑎𝑡𝑖𝑛𝑖𝑛𝑒(𝑚𝑔/𝑑𝐿) 
 BMP: blood urea nitrogen, calcium, chloride, CO2, creatinine, glucose, potassium, sodium 
 Coagulation (prothrombin time, aPTT or PTT) 
 Alpha-fetoprotein 
 Pancreatic enzymes (lipase, amylase) 
 Ammonia 
 Renal markers (eGFR calculation) 
 Urinalysis and urine ketones (dipstick) 
 Plasma amino acids, prealbumin, carnitine 
 LDH/haptoglobin 
 C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) 
 von Willebrand profile 
Samples to be sent to central laboratories: 
 Serum methylmalonic acid and methylcitrate 
 Serum albumin-2A 
 Serum FGF21 
 Immunogenicity and immune response parameters: Neutralizing antibody titer 
(rAAV-LK03), antibody response (rAAV-LK03, MMUT, ALB2A, albumin), T-cell response 
(rAAV-LK03, MMUT, ALB2A) 
 Serum and plasma for exploratory biomarkers  
 Viral shedding: saliva, stool, and urine 
 TMA genetic panel 
 Complement testing: CH50, Cb5-9, Bb 
 

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Samples to be sent to local or central laboratories: 
 Complement testing: C3, C4 
Home samples:  
 Ketostix (or equivalent): sample to be collected and analyzed at patient’s home, as instructed 
by the physician to detect the presence of ketone bodies in a home setting between site visits.  
Sample testing may need to be prioritized based on blood volume required and age/weight of the 
patient. Institutional guidelines for allowable blood volumes will not be exceeded. Lab 
assessments may be collected over several days within the visit window. 
As this is a pediatric trial, there will be cases where sufficient blood volume will not be 
available. Please see below for the priority order of blood draws in these cases. 
For visits between screening and Day 14, please see below for priority order for blood draws, 
from top to bottom:  
 
Table 3.
Laboratory Priority 
Screening 
Baseline 
Day -1 
Day 3 
Day 6 
Day 7 
Day 9 
Day 12 
Day 14 
Methylmalo
nic acid / 
methylcitric 
acid
Methylmalo
nic acid / 
methylcitric 
acid
Hematolo
gy
Hematolo
gy
Hematolo
gy
Hematolo
gy
Hematolo
gy
Hematolo
gy
Hematolo
gy
Neutralizing 
antibodies
Hematology
BMP
Chemistry
BMP
Chemistry
BMP
BMP
Chemistry
Hematology
Chemistry
CH50
CH50
CH50
Coagulati
on
CH50
CH50
CH50
Chemistry
Coagulation
CRP
LDH
Haptoglob
in
LDH
LDH
Haptoglob
in
Coagulati
on
Coagulation
ALB2A
C5b-9
C5b-9
C5b-9
LK03 
ADA
C5b-9
C5b-9
Haptoglob
in
FGF21
C3
C3
C3
C3
C3
C3
LK03 
ADA
eGFR
LK03 ADA
C4
C4
C4
C4
C4
C4
C5b-9
ADAs
C5b-9
Haptoglob
in
Coagulati
on
Bb
ammonia
Bb
Bb
C3
T-cell
Bb
ESR
Bb
biomarker
s
C4
TMA 
genetic panel
C3
Bb
Bb
von 
Willebrand 
disease panel 
C4
Alpha-
fetoprotein
Neutralizing 
antibodies
CH50
T-cell
Pancreatic 
enzymes
CRP
Ammonia
ESR
Amino acids

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LDH
FGF21
Ammonia
Amino acids
Biomarkers
 
Days 2, 4, 5, 8, 10, 11, 13 (in order of priority): Hematology, BMP, C3, C4, LDH or haptoglobin 
After Day 14 (in order of priority): Safety (hematology, chemistry, coagulation, renal markers), 
methylmalonic acid, albumin-2A, complement testing, antibody response (ADAs), FGF21, 
plasma amino acids, ammonia, T-cell response, serum and plasma for biomarkers 
Local laboratory reports should be reviewed, signed, and dated by the investigator or delegated 
physician. Each abnormal result will be assessed as clinically or not clinically significant and a 
comment will be provided for all out-of-range analytes deemed clinically significant 
(ie, document probable cause for abnormal results). Laboratory data will be collected and entered 
into the eCRF, if collected at the site or by home health care, or transferred electronically if from 
a central laboratory.  
7.16 Pregnancy Risk Assessment and Testing 
At screening, female patients of child-bearing age will be questioned regarding potential 
pregnancy risk. If a risk is identified, a urine pregnancy test will be administered at screening. 
7.17 PICC line 
Once eligibility for the study has been assessed, a peripherally inserted central catheter (PICC 
line) will be placed for any patient who does not already have one, to allow for easier blood 
draws during the initial part of the study. The PICC line will be placed at least one week prior to 
the expected dosing date to allow for adequate healing. The PICC line will stay in place until at 
least week 3. 

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8 CONDUCT OF STUDY 
8.1 
Data Safety Monitoring Board  
This study will utilize an independent DSMB, which will monitor patient safety and provide 
recommendations regarding dosing in each cohort. The composition of the DSMB and details of 
its function are described in the DSMB Charter. Section 5.1 provides an overview of DSMB 
activities. The DSMB may meet at additional timepoints as required for safety review. Following 
Cohort 1 Part B, TMA experts will be added to the DSMB. These experts will be convened to 
monitor safety and provide recommendations on prevention and management of TMA. In 
addition to the Principal Investigator and the Sponsor Medical Monitor, these experts will review 
the TMA-related laboratory results as they are available for each patient in Cohort 1 Part C, 
Cohort 2 Part A and Cohort 2 Part B during the high-risk period (first two weeks post-dosing). 
Additionally, these experts will meet in the event a patient receiving hLB-001 experiences signs 
of TMA to review the laboratory values and provide recommendations. 

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9 STUDY MEDICATION 
9.1 
Description of Study Medication 
hLB-001 is a genetically engineered, liver-targeted, rAAV chimera (rAAV-LK03) containing 5’ 
and 3’ DNA homology arms corresponding to the human albumin locus, and a codon-optimized 
form of the human MMUT sequence preceded by a 2A-peptide encoding sequence. Details of 
this gene therapy product may be found in the IB. 
The composition of the hLB-001 drug product is summarized in Table 4. 
Table 4. 
Composition of hLB-001 Drug Product 
Component 
Reference to Quality Standards 
Function 
hLB-001 drug substance 
In-house 
Active 
Sodium phosphate monobasic, 
monohydrate 
USP 
Buffering agent 
Sodium phosphate dibasic, 
anhydrous 
USP 
Buffering agent 
Sodium chloride 
USP 
Tonicity agent 
Poloxamer 188 
USP-NF, Ph Eur 
Surfactant 
NF = National Formulary; Ph Eur = European Pharmacopoeia; USP = United States Pharmacopeia.
9.2 
Packaging and Labeling 
hLB-001 is filled into a West 5-mL cyclic olefin polymer vial, sealed using a West chromobutyl, 
FluroTec B2 coated stopper, and a West overseal for single-use administration. It will be stored 
at -65°C or below and shipped to sites by LogicBio or designee.  
The study drug labels will fulfill all requirements required by governing regulations.  
9.3 
Administration of Treatment 
Study patients may be dosed with hLB-001 no earlier than 16 days following screening 
initiation. Prior to hLB-001 administration, study patients will have baseline hematology and 
chemistry laboratory studies as prescribed in Section 5.3.5. In addition, if the interval from 
screening laboratory studies to dosing exceeds 30 days, study patients should have repeat 
assessments as described in Section 5.3.5.  
hLB-001 is thawed for administration as a one-time intravenous infusion on day 1 over at least 
30 minutes and at a flow rate of no more than 5 mL/kg/hour through a syringe pump. Additional 
instructions may be found in the Pharmacy Manual. To alleviate potential immune response, a 
standard regimen of corticosteroids will be administered prophylactically starting approximately 
24 ± 4 hours prior to hLB-001 (Day -1) per Section 10.2. 

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9.4 
Dose Levels 
Dose level 5 × 1013 vg/kg will be explored, with an option to increase explore a second dose 
level of 1 × 1014 vg/kg. Total dose will be calculated using the weight measured at screening/run-
in; if the weight was measured more than 30 days prior to dosing, weight will be re-measured for 
the dosing calculation within the 30 days prior to dosing to allow shipping of study drug.  
9.5 
Storage, Handling, and Drug Accountability 
On receipt at the investigative site, the study drug should remain in the box provided until use. 
The container should be stored frozen at -65°C or lower. All excursions should be reported to the 
sponsor or its designee for assessment and quarantined until authorized for use. The site will 
ensure that the drug is used before the expiry date provided by LogicBio.  
Only trained staff should handle hLB-001. Please refer to the Pharmacy Manual for complete 
handling instructions.  
A drug accountability record should be maintained by the person responsible for dispensing the 
study drug to the patient. This should record which supplies are issued to which patients. 
LogicBio or its designee should be notified immediately of details of any supplies which are 
inadvertently damaged. Details of any supplies which are inadvertently damaged or unusable for 
any reason should be noted on this drug accountability record, which will be collected by 
LogicBio or its designee at the end of the study.  
All drugs will be inventoried by LogicBio or its designee during and at the conclusion of the 
study. Secure disposal at the site or return of unused supplies to the sponsor at the end of the 
study will be arranged. 

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10 CONCOMITANT MEDICATIONS AND VACCINATIONS 
10.1 General Considerations 
The investigator is to record the use of all concomitant medications, both prescribed and 
over-the-counter, in the eCRF, starting at informed consent until the end of study visit.  
Concomitant medications for standard of care for patients with MMA will be permitted. Patients 
who are already receiving medications to treat hyperammonemia may continue. Additional 
medications should be discussed with the investigator and administered based on medical need. 
10.2 Prophylactic Administration of Corticosteroids and Monitoring/Risk 
Mitigation 
In patients with MMA, systemic corticosteroids should be used judiciously and with careful 
consideration of the associated benefit/risk to the patient. In the context of pediatric gene therapy 
trials, intravenous AAV administration of a different drug product at doses similar to those 
proposed in the LB001-001 study has been associated with acute serious liver injury and 
substantial elevations in aminotransferases (ZOLGENSMA prescribing information, 2019). 
More commonly, across studies of different AAV products at lower doses and a range of patients 
ages, systemic administration was associated with subacute, asymptomatic aminotransferase 
elevations and a significant loss of transgene expression (Scallan CD 2006) (Nathwani A 2014). 
While not expected for hLB-001 based on preclinical data, the risk of significant liver reaction to 
hLB-001 cannot be ruled out and hence the inclusion of corticosteroid administration in the 
LB001-001 study design. 
Dosing Regimen 
A standardized regimen of prednisolone 1 mg/kg/day or its equivalent will be initiated 24 ± 4 
hours prior to beginning hLB-001 infusion and continuing for a total of 60 days. Administration 
may be oral or via g-tube if oral administration is not possible. The maximum dose to be 
administered is 60 mg per day. After 60 days of treatment, the dose of prednisolone can be 
tapered for patients in accordance with the following treatment guideline: 1 mg/kg/day until at 
least 60 days post-infusion, followed by a tapering protocol as follows: 0.5 mg/kg/day for 5 days, 
then 0.25 mg/kg/day for 5 days, then 0.25 mg/kg every other day for 16 days to complete a 26 
day taper. Specific instructions on corticosteroid administration will be provided to patient 
caregivers by the treating physician. The taper will be delayed if the patient has alanine 
aminotransferase (ALT) values > 2 X Upper Limit Normal (ULN), or aspartate aminotransferase 
(AST) > 2.0 × ULN together with ALT, alkaline phosphatase or total bilirubin > ULN. If liver 
function abnormalities persist at 60 days, systemic corticosteroids (equivalent to prednisolone at 
1 mg/kg/day) may be continued for up to 2 weeks until findings return to baseline levels or in 
discussion with the medical monitor, and the corticosteroid dose will be tapered over the next 26 
days. Consult immunology expert(s) if patients do not respond adequately to the equivalent of 1 
mg/kg/day prednisolone.   
To date, four subjects have received corticosteroid prophylaxis in LB001-001. The first three 
subjects have completed their course, for a total of 55, 101, and 55 days. The fourth patient 

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treatment with steroids has received corticosteroids for 72 days and treatment is ongoing. One 
grade 1 AE of hyperglycemia was reported in one subject as related to steroid use on day 15 of 
the steroid course; the glucose value was found to be normal with the next test 6 hours later. No 
other steroid-related AEs or SAEs were reported, and no evidence for metabolic decompensation 
during full-dose steroids or the steroid taper was observed. 
Monitoring and risk mitigation for corticosteroid-associated adverse effects including metabolic 
dysregulation: 
 In addition to the regularly scheduled physical examinations, vital signs and behavioral 
assessments, key metabolic parameters will be monitored at the clinical site frequently in the 
first two months of the study and include acidosis, lactate, ammonia, serum methylmalonic 
acid and urinary ketones per Table 1. 
Schedule of Events.  
 Because the time course in which steroid-related metabolic decompensation might occur is 
unknown, families will be provided with and instructed on the use of Ketostix Reagent 
Strips, in order to detect the presence of ketone bodies in a home setting between site visits. 
If urine ketones are present, the family will be instructed to contact their physician 
immediately for appropriate interventions. 
 If metabolic decompensation occurs despite standard-of-care outpatient management, the 
recommendation will be for hospitalization with appropriate treatment measures to stabilize 
critically ill individuals under the care of a biochemical genetics expert  
(Manoli et al, 2016). 
 Two weeks after discontinuing the glucocorticoid taper, adrenal suppression will be assessed 
based on the first morning cortisol (Ahmet et al, 2017).  If the morning cortisol is 18 mcg/dL 
or higher or within normal limits, no further testing is needed. If the morning cortisol is less 
than 18 mcg/dL or not within normal limits, the patient should be referred to a pediatric 
endocrinologist for a CRH or ACTH stimulation test to further evaluate the HPA axis. If the 
HPA axis is determined to be recovered by stimulation testing, no further testing or stress 
doses of steroids is indicated. If not, patients should be referred to a pediatric endocrinologist 
for further management and should have access to stress doses of steroids in the event of an 
acute illness or metabolic stress, which will be discontinued after the acute illness has 
resolved. 
10.3 Routine Vaccinations 
Childhood vaccinations may be associated with AEs that could complicate assessment of 
potential hLB-001-associated safety signals. No vaccinations should be administered within a 6-
week window either prior to or following hLB-001 administration. 
In the special case of live vaccines, due to the potential for immunosuppression associated with 
corticosteroid administration, the CDC recommends that no live vaccines be administered during 
corticosteroid administration and for at least 3 months after stopping high-dose corticosteroids.  

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As mentioned in the next section, the meningococcal vaccine will be administered at least 6-
weeks prior to the planned dosing date for any subjects who have not been previously 
vaccinated.  
10.4 Administration of eculizumab and antibiotics 
 Eculizumab is a complement inhibitor indicated for the treatment of patient with atypical 
hemolytic uremic syndrome (aHUS) to inhibit complement-mediated thrombotic 
microangiopathy (TMA). In the event that a subject develops signs or symptoms suggestive 
of TMA or imminent TMA, eculizumab should be administered to block the complement 
pathway. TMA-related laboratory results will be reviewed as they are available by the 
investigator, the TMA experts on the DSMB and the Sponsor Medical Monitor, and advice 
on intervention will be provided based on these laboratory results. In general, treatment with 
eculizumab should be initiated for any of the following findings accompanied by evidence of 
activated complement: hemolysis (LDH above normal, presence of schistocytes on blood 
smear, and/or  hemoglobin below normal), thrombocytopenia (platelets < 100K/µL), or 
proteinuria ≥30mg/dL.   
 All subjects will receive the meningococcal vaccine at least 6-weeks prior to dosing in the 
event that eculizumab is administered. Subjects who receive eculizumab should be provided 
with antibacterial prophylaxis  per the eculizumab label.   
Table 5. 
 Eculizumab Dosing Schedule 
Body Weight 
 
Eculizumab dosing 
>40 kg 
900 mg every 3 days until C5b-9 normalizes x 2, then weekly 
10 – <40 kg 
600 mg every 3 days until C5b-9 normalizes x 2, then weekly  
5 – <10 kg 
300 mg every 3 days until C5b-9 normalizes x 2, then weekly  
In the case of incomplete complement inhibition (CH50 >10 U/mL), the subsequent 
eculizumab dose may be increased by 300 mg or an additional dose administered, after 
discussion with the Sponsor.  
 
 Caregivers will be informed about the signs and symptoms of meningococcal infection and 
strongly advised to seek immediate medical attention if these signs or symptoms occur. 
Caregivers will be given a Patient Safety Information Card that they should carry with them 
at all times. This card describes symptoms which, if experienced, should prompt the patient 
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 Beginning with the first dose of eculizumab, all subjects will be started on antimicrobial 
prophylaxis using an agent with activity against Neisseria meningitides. 
o Option 1: Age/weight based therapeutic dosing of oral amoxicillin. 45 mg/kg in 
divided doses every 12 hours. 
o Option 2: Age/weight based therapeutic dosing of ciprofloxacin. 15 mg/kg per dose 
every 12 hours. 
o If local strains of N. meningitis bacteria are resistant to either of these antibiotics or 
the patient is allergic or cannot otherwise tolerate the standard prophylactic treatment, 
the choice of antibiotic will be made upon local guidelines or the recommendation of 
the local Infectious Disease (ID) consultant. 
 Antibiotic prophylaxis will be continued until CH50 recovery to normal or above normal 
levels is documented. 
 

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11 ADVERSE EVENTS 
11.1 Pretreatment Adverse Event 
A pretreatment event is any untoward medical occurrence in a patient who has signed informed 
consent/assent but prior to administration of hLB-001.  
11.2 Adverse Event Definition 
An AE is any untoward medical occurrence in a patient administered a pharmaceutical product, 
which does not necessarily have to have a causal relationship with the pharmaceutical product 
treatment. An AE can, therefore, be any unfavorable and unintended sign, symptom, or disease 
temporally associated with the use of a medicinal (investigative) product, whether or not related 
to the medicinal product. This includes any newly occurring event, or a previous condition that 
has increased in severity or frequency since the administration of the study drug.  
An abnormal laboratory value will not be assessed as an AE unless that value leads to 
discontinuation or delay in treatment, therapeutic intervention, or is considered by the 
investigator to be a clinically significant change from baseline. Any abnormal test result that is 
determined to be an error does not require reporting as an AE. 
If known, the diagnosis should be recorded, rather than listing individual signs and symptoms. 
11.2.1 Adverse Events of Special Interest (AESI) 
To date no experience exists regarding the administration of hLB-001 to humans, and therefore, 
no safety profile is available. However, it has been recognized in studies involving human AAV 
administration that asymptomatic transaminase elevation, even at levels between 1× and 
2× ULN, may be a biologically significant finding consistent with patient immune response to 
and loss of transfected hepatocytes. The transaminitis is seen most commonly between 6 to 
10 weeks post AAV infusion but may be detected earlier or later. This laboratory finding may be 
a harbinger of loss of AAV transgene expression and hence efficacy, and in some cases may rise 
to the level of a serious AE.  
AESI #1 elevated transaminase: The LB001-001 study involves prophylactic corticosteroid 
dosing that may continue for as short a period as approximately 3 months following hLB-001 
infusion (2-month full dose and 26 day taper). The presence of continuously rising transaminases 
while on corticosteroids, or transaminase elevation above the ULN when patient is no longer 
receiving corticosteroid, should be reported immediately to the sponsor for discussion of 
appropriate therapeutic response. 
AESI #2 hepatocellular carcinoma/adenoma: While preclinical studies using murine and 
cynomolgus monkey surrogates of hLB-001 have not demonstrated an increased occurrence of 
hepatocellular carcinoma (HCC), the timing and occurrence risk to human subjects is unknown. 
Long-term monitoring during the 15-year follow-up (which will be conducted under a separate 
protocol) will include a-fetoprotein levels and liver imaging following guidance of the FDA, 
European Medicines Agency, and American Association for the Study of Liver Disease for 

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monitoring individuals at risk for HCC (Marrero et al, 2018). Any suspicion of hepatic adenoma 
or malignancy should be reported immediately to the sponsor. 
AESI #3 Thrombotic microangiopathy (TMA) and TMA-like events: Two patients in Cohort 1 
Part B experienced TMA with an onset within 2 weeks of LB-001 infusion. Both subjects were 
hospitalized, but each event has resolved. Features of TMA including microangiopathic 
hemolytic anemia, thrombocytopenia and/or acute kidney injury have been previously described 
in pediatric patients receiving AAV gene therapy at doses ≥ 5x1013 vg/kg (e.g., in SMA and 
DMD, using AAV9 vectors); in those reported cases, events have manifested within the first 2 
weeks after dosing (typically day 6-10) and, although some cases have required hospitalization 
and interventional treatment, reported patients have recovered well within days or a few weeks. 
TMA or Atypical Hemolytic Uremic Syndrome (aHUS) after AAV administration have been 
linked to endothelial injury due to excessive activation of the classical or alternative complement 
pathways.  
As a preventive measure and for early detection of any TMA-like signs, patients will be 
hospitalized for 7 days post dosing. Patients will be monitored daily until day 14. Additionally, 
in order to mitigate a known risk factor for TMA, patients will be excluded if a viral or bacterial 
infection has occurred within 6 weeks prior to dosing.  
 In addition to the Principal Investigator and the Sponsor Medical Monitor, ongoing 
laboratory results collected during the high-risk period will be reviewed as they are available 
by TMA experts serving on the DSMB, who will provide recommendations on management 
and monitoring of each subject. 
 Should signs of TMA develop (see section 10.4), consultation with hematology and 
nephrology will be obtained immediately, and eculizumab should be instituted, and 
additional treatment should be initiated as per local guidelines, which may include red blood 
cell and/or platelet transfusions, dialysis, intravenous hydration, nutrition support, and other 
supportive management. Signs of TMA may include a decrease in platelets or hemoglobin, 
presence of schistocytes on blood smear, an increase in creatinine, an increase in LDH or 
haptoglobin, an increase in C5b-9, decreased C3 and/or C4, elevated blood pressure, or 
presence of blood or protein in urine.  
 Eculizumab may be administered per Section 10.4 
Administration of eculizumab and 
antibiotics 
 Hematology and nephrology consultants should be made aware of the potential need for their 
involvement prior to dosing of LB-001.  
11.3 Serious Adverse Event Definition  
An SAE is any untoward medical occurrence that, at any dose: 
Results in death 
Is life-threatening (refers to an AE in which the patient was at risk of death at the time of the 
event; it does not refer to an event which hypothetically might have caused death if it were 
more severe) 

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Requires inpatient hospitalization or prolongation of existing hospitalization (This is defined 
as the patient being hospitalized overnight, or the patient’s hospital stay being prolonged for 
at least an additional overnight stay. Preplanned hospital stays or hospital stays for 
nonmedical social reasons will not be considered as hospitalization. “Twenty-three hour 
hospitalizations” for observation should be discussed with the medical monitor to determine 
whether they are appropriate for SAE reporting.) 
Results in persistent or significant disability/incapacity (disability is defined as a substantial 
disruption of a person’s ability to conduct normal life functions) 
Is a congenital anomaly/birth defect 
Medical and scientific judgment should be exercised in deciding whether reporting is appropriate 
in other situations, such as important medical events that may not be immediately life-
threatening or result in death or hospitalization, but may jeopardize the patient or may require 
intervention to prevent one of the other outcomes listed in the definition above. These should 
also be considered to be SAEs. 
11.4 Reporting of Adverse Events and Serious Adverse Events 
All AEs spontaneously reported and/or in response to an open question from study personnel or 
revealed by observation, physical examination, or other diagnostic procedures will be recorded 
on the appropriate page of the eCRF.  
The severity of the AE will be graded using CTCAE Version 5.0 
(https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_
Reference_8.5x11.pdf). 
The investigator will make a judgment regarding whether or not the AE was related to study 
drug, as outlined below.  
None: 
The AE is caused by the patient’s clinical state, or the study 
procedure/conditions (ie, it has no association with the study drug). 
Unlikely: 
The temporal association between the AE and the study drug is such that the 
study drug is not likely to have any reasonable association with the AE. 
Possible: 
The AE follows a reasonable temporal sequence from the time of drug 
administration but could have been produced by the patient’s clinical state or 
the study procedures/conditions. 
Definite: 
The AE follows a reasonable temporal sequence from the time of study drug 
administration, abates upon discontinuation of the study drug, and reappears 
when the study drug infusion is continued, or the study drug is the most likely 
cause of the AE. 
The investigator will record the action taken and outcome for each AE. 

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LogicBio or its designee has procedures that will be followed for the recording and expedited 
reporting of SAEs that are consistent with global regulations and the associated detailed 
guidances. 
11.5 Adverse Event Reporting Period 
Adverse events, whether serious or nonserious, will be monitored from the date of ICF/assent 
until the EOS visit.  
Any SAE, whether or not related to the study treatment, must be reported within 24 hours to the 
sponsor’s medical monitor or designee as instructed in the SRM. 
LogicBio or its designee will provide details to the investigator of all serious, unexpected, and 
related AEs (or other events depending on the specific requirements) from any other ongoing 
clinical trials that should be reported to the IRB/LEC, as appropriate. Confirmation that these 
serious, unexpected, and related AEs have been submitted to the IRB/LEC per local site 
regulations must be kept in the investigator files. 
If any AEs are present when a patient completes the study or is withdrawn from the study, the 
patient should be re-evaluated within 2 weeks. At the investigator’s discretion, minor AEs can be 
re-evaluated via telephone and documented. If the AE has still not resolved, additional follow-up 
should be performed as appropriate. Every effort is to be made by the investigator or delegate to 
contact the patient until the AE has resolved or stabilized or the medical monitor and investigator 
agree that further follow-up is not necessary. This should be documented in the patient’s medical 
records. 

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12 STATISTICAL METHODS AND DATA ANALYSIS 
12.1 Sample Size Justification 
No formal power calculations were performed to estimate appropriate group sizes since this is 
the first clinical evaluation of hLB-001. Cohort size was selected to achieve an appropriate 
balance between unnecessarily exposing a large number of patients to a novel therapeutic 
regimen, and having sufficient patients administered study drug to make a reasonable assessment 
of the dose-related safety of hLB-001. Each patient will serve as his or her own control. 
12.2 Study Populations 
Given that the study evaluates a single-dose of hLB-001, the safety population will consist of all 
patients receiving study drug and will be used for all safety analyses. For efficacy, each patient 
will serve as his or her own control. Therefore, the intent-to-treat population will include patients 
receiving study drug who have baseline data and at least 1 postdose measurement. Further 
analyses will be specified in the statistical analysis plan. 
12.3 Demographic/Baseline Information 
Given the small sample size and open-label nature of the study, demographic/baseline 
information will not be compared between dose groups but will be summarized by treatment 
group using descriptive statistics. For continuous variables, mean, standard deviation, median, 
minimum, and maximum will be presented. For categorical variables, frequency count and 
percentage will be presented. 
12.4 Analysis of Safety Data 
The safety endpoint data will be summarized for the safety population. 
The AEs will be coded using the latest version of Medical Dictionary for Regulatory Activities. 
The incidence of treatment-emergent AEs (TEAEs) will be summarized by body system and 
preferred term. A general summary of TEAEs and SAEs will be prepared, with overall numbers 
of AEs, and their intensity and relationship to study drug, per treatment group. All AEs will be 
presented in a listing. The numbers of AEs leading to withdrawal or SAEs leading to death will 
also be summarized. The World Health Organization Drug Dictionary Enhanced will be used to 
classify concomitant medications by therapeutic class and drug name. 
The safety laboratory data and vital signs will be summarized by visit and treatment group, along 
with the change from baseline.  
The ECG data will be summarized by standard parameter by time point/visit and treatment 
group, along with the change from baseline. 

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12.5 Analysis of Efficacy Data 
This FIH dose-finding study is not powered for statistical analysis of efficacy or biomarker 
endpoints.  
Results of secondary and exploratory results will be descriptive with presentation of the 
following endpoints: 
 Number of days of hospitalizations due to MMA in the year following hLB-001 
administration compared to the year prior to administration 
 Change in weight, length/height or head circumference z-scores at 1 year following hLB-001 
administration  
 Changes in the Adaptive Behavioral Score at 1 year following hLB-001 administration  
 Changes in standard scores on the cognitive and motor function scales at 1-year following 
hLB-001 administration 
 Changes in the Parenting Stress Index at 1 year following hLB-001 administration 
 Changes in serum methylmalonic acid level from pre-dosing (average of all pre-dose levels) 
at 1 year following hLB-001 administration  
 FGF21 levels  1500 pg/mL at 1 year following hLB-001 administration  
(Molema et al, 2018) 
 Change in 13C-propionate oxidation at 1 year following hLB-001 administration 
 Number of patients requiring a liver and/or kidney transplant 
12.6 Interim Analysis 
No formal interim analysis is planned for this study. Given the open-label nature of the study 
design and the first administration of hLB-001, the data will be reviewed in an ongoing manner.  

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13 STUDY MANAGEMENT AND DATA COLLECTION 
13.1 Ethical Conduct of the Study 
The study will be conducted in accordance with the ICH-GCP and the appropriate regulatory 
requirement(s).  
13.2 Institutional Review Board/Local Ethics Committee 
The study will be conducted in accordance with applicable regulatory requirement(s) and will 
adhere to GCP standards. The IRB/LEC will review all appropriate study documentation to 
safeguard the rights, safety, and well-being of the patients. Other regulatory or institutional 
specific committee reviews may also need to be conducted per site guidelines.  
The study will be conducted only at sites where IRB/LEC and other required approval has been 
obtained. The protocol, ICF, advertisements (if applicable), written information given to the 
patients, and any revisions to these documents will be provided to the IRB/LEC by the 
investigator or the sponsor, as allowed by local regulations. 
13.3 Patient Informed Consent/Assent 
After the study has been explained, written informed consent and assent, as applicable, will be 
obtained from either the patient or his/her guardian or legal representative before study 
participation. The method of obtaining and documenting the informed consent/assent and the 
contents of the consent/assent must comply with the ICH-GCP and all applicable regulatory 
requirements as well as site SOPs.  
13.4 Compliance with the Protocol 
The investigator will conduct the study in compliance with the protocol provided by LogicBio 
and given approval by the IRB/LEC and the appropriate regulatory authority(ies). Modifications 
to the protocol are not to be made without agreement of both the investigator and LogicBio. 
Changes to the protocol will require written IRB/LEC approval before implementation. 
LogicBio, or its designee, will submit all protocol modifications to the appropriate regulatory 
authority(ies) in accordance with the governing regulations. 
Any failure to follow the protocol for any reason must be documented by the investigator or 
designee and provided to LogicBio. 
13.5 Study Monitoring 
Monitoring procedures developed or approved by LogicBio or its designee will be followed to 
comply with GCP guidelines. 
All information recorded on the eCRFs for this study must be consistent with the patient’s source 
documentation. During the course of the study, the study monitor will make study site visits to 
review protocol compliance, verify eCRFs against source documentation, review pharmacy 

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records and study drug accountability, and ensure that the study is being conducted according to 
pertinent regulatory requirements. The review of medical records will be performed in a manner 
that ensures that patient confidentiality is maintained.   
13.6 Case Report Form 
LogicBio or its designee will provide the study sites with secure access to and training on the 
Electronic Data Capture (EDC) application, sufficient to permit site personnel to enter or correct 
information in the eCRFs for the patients for whom they are responsible. 
An eCRF will be completed for each study patient. It is the investigator’s responsibility to ensure 
the accuracy, completeness, clarity, and timeliness of the data reported in the patient’s eCRF. 
The investigator, or designated representative, should complete the eCRF as soon as possible. 
The investigator must provide through the EDC application formal approval of all the 
information in the eCRFs and changes to the eCRFs to endorse the final submitted data for the 
patients for whom he or she is responsible. The audit trail entry will show the user’s 
identification information and the date and time of the correction. 
LogicBio, or its designee, will retain the eCRF data and corresponding audit trails. A copy of the 
final archival eCRF in the form of a compact disk or other electronic media will be placed in the 
investigator’s study file. 
13.7 Audits 
Regulatory authorities, the IRB/LEC, and/or LogicBio or its designee may request access to all 
source documents, eCRFs, and other study documentation for on-site audit or inspection. Direct 
access to these documents must be guaranteed by the investigator, who must provide support at 
all times for these activities. 
13.8 Retention of Records 
The investigator will maintain all study records according to the ICH-GCP and applicable 
regulatory requirement(s). Records will be retained for at least 2 years after the last marketing 
application approval or 2 years after formal discontinuation of the clinical development of 
hLB-001 or according to applicable regulatory requirement(s). If the investigator withdraws from 
the responsibility of keeping the study records, custody must be transferred to a person willing to 
accept the responsibility and LogicBio must be notified.   
The investigator agrees to keep records and those documents that include (but are not limited to) 
the identification of all participating patients, medical records, study-specific source documents, 
source worksheets, all original signed and dated ICF, copies of all CRF, query responses, and 
detailed records of drug disposition, to enable evaluations or audits from regulatory authorities 
and LogicBio or its designees. 

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13.9 Insurance and Indemnity 
In the event that a patient suffers injury or death as a direct result of participation in this study, 
LogicBio will reimburse the reasonable cost of appropriate treatment and/or reasonable 
compensation will be paid to the patient by LogicBio in accordance with applicable federal and 
international laws and/or guidelines. Payments will not be offered for other expenses (such as 
time off work, lost wages, childcare, etc.). 
13.10 Termination of the Study 
The sponsor may terminate the study at any time. Furthermore, if it becomes apparent that 
patient recruitment into the study is unsatisfactory with respect to quality or quantity, or that data 
recording is inaccurate or incomplete on a chronic basis, the sponsor has the right to terminate 
the study and remove all study materials from the investigational site. A written statement will be 
provided to the investigator, the IRB/LEC, and regulatory authorities, if required. 

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14 USE OF INFORMATION 
14.1 General Aspects 
All information concerning LogicBio that may be provided, such as patent applications, formula, 
manufacturing processes, basic scientific data, or formulation information supplied by LogicBio 
and not previously published, are considered LogicBio’s confidential information and shall 
remain the sole property of LogicBio and shall be treated in accordance with the Clinical Trial 
Agreement between the contract research organization or sponsor and investigator’s site or 
institution. The investigator agrees to use this information only in accomplishing this study and 
will not use it for other purposes without the written consent of LogicBio, except for official 
representatives, such as regulatory authorities. 
It is understood by the investigator that the information derived from this study, in or related to 
connection with this study or the development of hLB-001, will be used by LogicBio and, 
therefore, may be disclosed by LogicBio as required to other clinical investigators, other 
pharmaceutical companies, and to other government agencies. In order to allow for the use of the 
information derived from clinical studies, it is understood that there is an obligation to provide to 
LogicBio complete test results and all data compiled in this study. 
14.2 Patient Confidentiality and Data Protection 
LogicBio and its designees affirm and uphold the principle of the patient’s right to protection 
against invasion of privacy. Throughout this study, all data will be linked to the CRF via a 
unique identification number and the patient’s initials, as allowed. The data will be blinded 
correspondingly in all data analyses. 
However, in compliance with the guidelines of the US FDA concerning the acceptance of 
clinical studies in support of an NDA and the ICH Guidelines (whether performed in the United 
States or elsewhere), and in fulfillment of its obligations to LogicBio to verify compliance with 
this protocol, the LogicBio designee requires that the investigator permit its study monitor, 
representatives from the FDA, LogicBio-designated auditors, IRB/LEC, and other governmental 
regulatory authorities to review the patient’s primary medical records (source data or 
documents), including but not limited to, laboratory test result reports, ECG reports, admission 
and discharge summaries for hospital admissions occurring during a patient’s study participation, 
and autopsy reports of deaths occurring during the study. 
Should access to such medical records require a waiver or authorization separate from the 
statement of informed consent, the investigator will obtain such permission in writing from the 
patient before the patient is entered into the study. 
14.3 Final Report and Publication Policy 
Upon completion of the clinical study and evaluation of results by LogicBio, the hospital or 
institution and/or investigator may publish or disclose the clinical trial results pursuant to the 
terms contained in the applicable Clinical Trial Agreement. At the conclusion of the study, after 
the data are analyzed, LogicBio or its designee will prepare a final clinical study report. 

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15 APPENDIX 1: FAO/WHO/UNU 2007 SAFE LEVELS OF PROTEIN AND 
ENERGY INTAKE FOR DIFFERENT AGE GROUPS 
 
Baumgartner MR, Hörster F, Dionisi-Vici C, et al. Proposed guidelines for the diagnosis and 
management of methylmalonic and propionic acidemia. Orphanet J Rare Dis. 2014;9:130. 

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