LogicBio Therapeutics : 2021 ACMG Annual Meeting - Methylmalonic Acidemia

eP034

Retrospective Study of the Disease Course in Pediatric Patients With Severe MMA Caused by MMUT Mutations

Gregory M. Enns, MD1; Peter Baker, MD2; Hong Li, MD, PhD3; Tom Morgan, MD4; Jerry Vockley, MD, PhD, FACMG5

1Stanford University, Stanford, CA; 2University of Colorado, Aurora, CO; 3Emory University School of Medicine, Atlanta, GA;

4Vanderbilt University Medical Center, Nashville, TN; 5University of Pittsburgh School of Medicine, Pittsburgh, PA

LogicBio Therapeutics, Lexington, MA

Conclusions

• This retrospective study characterizes disease progression in pediatric patients with severe MMA associated with MMUT deficiency who were medically managed or were the recipients of a liver transplant
• All enrolled patients underwent newborn screening for MMA, and the majority received their initial diagnosis through this testing, reflecting the current treatment setting of widespread newborn screening
• Patients receiving liver transplants were 6 years or younger at the time of transplant; thus, the management they received reflects the evolving treatment paradigms for MMA, which emphasize liver transplant at increasingly younger ages

• Across all patients, length/height tended to be lower than normal throughout the study period while weight was mostly higher than normal, resulting in an elevated BMI
• • In patients who received a liver transplant, length/height stayed low, but weight and BMI increased significantly after liver transplant and then returned close to baseline levels
• Despite using MMA-related prescription medications, patients may continue to require emergency medical attention and may continue to exhibit elevated methylmalonic acid levels
• • In patients who received a liver transplant, there was a rapid and sustained decrease in methylmalonic acid levels and, while levels did not approach normalization, there was an apparent reduction in variability

Background

• Isolated methylmalonic acidemia (MMA) is an

inherited metabolic disorder most commonly

caused by a deficiency of the mitochondrial enzyme

methylmalonyl-CoA mutase (MMUT), which blocks

metabolism of methylmalonyl-CoA to succinyl-CoA1,2

• Patients who are asymptomatic at birth may be

diagnosed through expanded newborn screening

programs; patients with severe MMA may present in

the neonatal period with a metabolic crisis, displaying

signs including poor feeding, vomiting, hypotonia,

hypothermia, respiratory distress, and progressive

• Medical records available to cover the following

time periods:

- Cohort 1: period from birth to the patient's

third birthday (or earlier if deceased)

- Cohort 2 (patients who have received a liver

transplant, regardless of age at transplant):

» Diagnosis confirmation

» 1-year period before liver transplant

(or less if transplant prior to first birthday)

» 1- to 3-year period after liver transplant

(or earlier if deceased)

Results

Study Population

• A total of 18 patients were enrolled in the study
• • One patient from cohort 2 died due to cardiac arrest during liver transplant
• Demographics, disease characteristics, and medical management during the defined study periods for cohorts 1 and 2 are summarized in Table 1

Table 1. Demographics, Disease Characteristics, and Medical Management During the Study Period

Laboratory Parameters

• Mean alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, ammonia, prothrombin time, total bilirubin, estimated glomerular filtration rate, and methylmalonic acid are reported as multiples
  of the normal range to account for methodological variation in Figure 1

Figure 1. Laboratory Parameters During Study Period

A

Cohort 1 - ALP/ALT/AST/PT/Total Bilirubin

B

Cohort 2 - ALP/ALT/AST/PT/Total Bilirubin

Figure 2. Patient Methylmalonic Acid Levels

A	1800	B	1800	Pretransplant
		Posttransplant
(µmol/L)		(µmol/L)
1600	1600
1400	1400
1200	1200
Acid	Acid
1000	1000
Methylmalonic	Methylmalonic
800	800
600	600
	400

Dietary Management

• At baseline, the absolute value for protein intake was 1.8 g/kg for both cohort 1 and cohort 2
• • For cohort 1, the average daily protein intake consistently fluctuated above and below the baseline level over time (data not shown)
  • For cohort 2, the data on posttransplant protein intake were available for only 1 or 2 patients most months or not available at all, limiting the interpretation of the analysis

MMA- and Transplant-Related Healthcare Utilization

ALP

ALT

AST

PT

Total Bilirubin

ALP

ALT

AST

PT

Total Bilirubin

encephalopathy1,3,4

• In addition to intermittent, often life-threatening

metabolic crises, patients with MMA are at risk of

neurologic symptoms, failure to thrive, intellectual

disability, severe infections, and progressive renal

insufficiency1,2

• Currently, there are no curative therapies for MMA,

although liver transplants are increasingly performed

in patients with severe, early-onset disease to

partially correct the enzymatic defect3,5,6

• Natural history studies that provide longitudinal data

are needed to increase the understanding of disease

progression and support interventional studies of

genetically targeted therapies

Objective

• To characterize the disease course in the era of newborn screening for patients with severe MMA associated with MMUT deficiency among 2 cohorts: pediatric patients managed medically from birth to age 3 years (cohort 1) and pediatric-age recipients of liver transplant (cohort 2)

Methods

Study Design

• This was a retrospective natural history study that enrolled pediatric patients diagnosed with severe
  MMA by newborn screening, who were identified by participating investigators and/or appropriately delegated study staff
• Patients were assigned to cohort 1 and/or cohort 2 based on eligibility criteria

Study Population

Key inclusion criteria

• Diagnosis of severe, mutase-deficient MMA by

newborn screening based on the following criteria:

• Voluntary agreement from the patient (and/or

parent[s] or legally authorized representative) to

participate by giving written informed consent/

assent in accordance with the good clinical

practice guidelines of the International Council

for Harmonisation of Technical Requirements

for Pharmaceuticals for Human Use and with

applicable local regulations, unless the associated

institutional review board or ethics committee

provides an appropriate consent waiver

Key exclusion criteria

• History of a clinically significant medical condition unrelated to MMA, in the opinion of the investigator
• Expectation that relevant medical records will not be available, in the opinion of the investigator
• Diagnosis of organic acidemias other than isolated MMA, or with any other causes of hyperammonemia
• Prior treatment with an MMA-targeted gene therapy or nucleic acid therapy
• Prior kidney transplant

Data Collection

• Upon signing of the consent/assent and confirmation of subject eligibility via evaluation of the inclusion/exclusion criteria, deidentified patient data were entered into a confidential patient information (electronic) database
• A set of core elements related to the patient's diagnosis, growth and developmental parameters, dietary management, medications, healthcare utilization, and key laboratory parameters were collected from medical record review

Statistical Methods

• Statistical analyses were primarily descriptive

in nature, except for comparison of pre- and

posttransplant data for cohort 2, when a Wilcoxon

matched-pair signed rank test was used

Age at diagnosis, days

• Mean (SD)
• Range

Sex, n (%)

• Male
• Female

Initial method of diagnosis, n (%)

• Newborn screening
• Crisisa

Premature birth, n (%)

Subtype of MMUT mutation, n (%)

• mut -
• mut0

Feeding tube present, n (%)

• Nasogastric tube
• Gastrostomy tube

Age at insertion of gastrostomy tube, months

• Mean (SD)
• Range

Disease phenotype, n (%)

• Abnormal motor functionb
• Basal ganglia stroke
• Coma
• Failure to thrive
• Fatigue
• Language delay
• Lethargy
• Pancreatitis
• Seizures

Age at transplant, years

• Mean (SD)
• Range

Prescription medications, n (%)

• Antianemic preparationsc
• Antiprotozoalsd
• Blood substitutes and perfusion solutionse
• Corticosteroids for systemic usef
• Drugs for acid-related disordersg
• General nutrientsh
• Other alimentary tract and metabolism productsi
• Vitaminsj
• All other therapeutic productsk

Cohort 1	Cohort 2
(n=10)	(n=10)
7.5 (6.5)	5.7 (2.6)
1-23		2-10
5 (50.0)	4	(40.0)
5 (50.0)	6	(60.0)
8 (80.0)	7	(70.0)
2 (20.0)	3	(30.0)
1 (10.0)		0
3 (30.0)	1	(10.0)
7 (70.0)	9	(90.0)
9 (90.0)	10	(100.0)
5 (50.0)	4	(40.0)
5 (50.0)	6	(60.0)
4.7 (4.1)	3.9 (4.2)
1-11		0-11
7 (70.0)	8	(80.0)
1 (10.0)	2	(20.0)
1 (10.0)		0
4 (40.0)	5	(50.0)
1 (10.0)	5	(50.0)
7 (70.0)	8	(80.0)
7 (70.0)	8	(80.0)
1 (10.0)	4	(40.0)
3 (30.0)	2	(20.0)

• 2.0 (1.6)
• 0.6-6.2

9	(90.0)	8	(80.0)
1	(10.0)		0
1	(10.0)	1	(10.0)
	0	1	(10.0)
1	(10.0)	1	(10.0)
1	(10.0)	1	(10.0)
10	(100.0)	10	(100.0)
2	(20.0)	2	(20.0)
1	(10.0)		0

Range	14	Range	25	Transplant
12
Normal	10	Normal	10
8	8
6	6
of	of
Multiple	4	Multiple	4
2	2
0	0

	0	3	6	9	12	15	18	21	24	27	30	33	36		-12	-9	-6	-3	0	3	6	9	12	15	18	21	24	27	30	33	36
					Months from Baseline										Months from Baseline
ALP	n= 10	2	3	3	3	2	0	3	3	2	2	2	4	ALP	n= 1	4	2	2	10	8	1	4	5	2	0	0	4	0	2	3	2
ALT	n= 9	2	3	3	3	2	0	3	3	2	2	2	4	ALT	n= 1	3	2	2	10	8	2	4	5	3	1	1	4	1	2	3	2
AST	n= 10	2	3	3	3	2	0	3	3	2	2	2	4	AST	n= 1	4	2	2	10	8	2	4	5	3	1	1	4	1	2	3	2
PT	n= 7	0	1	0	1	2	0	1	1	1	0	0	1	PT n= 1 2 1 0 7 6 2 3 3 0 0 2 1 0 0 1	2
Total Bilirubin	n= 10	2	3	3	3	2	0	3	3	2	1	2	4	Total Bilirubin	n= 1	3	1	2	10	6	1	4	5	3	1	1	4	1	2	3	2

C

Cohort 1 - eGFR

D

Cohort 2 - eGFR

Range	6													Range	6			Transplant
NormalofMultiple	5													NormalofMultiple	5
4													4
	3														3
	2														2
	1														1
	0														0
	0	3	6	9	12	15	18	21	24	27	30	33	36		-12	-9	-6	-3	0	3	6	9	12	15	18	21	24	27	30	33	36

				Months from Baseline					Months from Baseline
n= 10 3	3	3	3	1	0	3	3	3	2	2	3	n= 1 4 3 2 10 7 2 4 5 2 1 1 3 1 1 1 2

E					Cohort 1 - Ammonia			F					Cohort 2 - Ammonia
Range	12							Range	12
	14								14			Transplant
Normal								Normal
8							8
	10								10
of	6							of	6
Multiple							Multiple
2							2
	4								4
	0								0
	0	3	6	9	12 15 18 21 24 27	30	33	36	-12	-9	-6	-3 0	3	6	9 12 15 18 21 24	27	30	33	36

Months from Baseline

Months from Baseline

	n= 10	6	3	6	5	5	3	1	5	2	5	4	3	n= 2 6 4 3 10 7 3 1 2 1 2 2 1 1 0 1 0
G			Cohort 1 - Methylmalonic Acid	H				Cohort 2 - Methylmalonic Acid
Range	4000												Range	4000			Transplant
3500												3500
Normal	3000												Normal	3000
2500												2500
of	2000												of	2000
1500												1500
Multiple												Multiple
500												500
	1000													1000
	0													0
	0	3	6	9	12	15	18	21	24	27	30	33	36	-12	-9	-6	-3 0	3	6	9 12 15 18 21 24 27 30	33	36

			Months from Baseline				Months from Baseline
n= 10 10 8	9	7	9	5	7	5	5	5	4	5	n= 7 7 8 8 10 9 5 7 6 3 5 5 4 4 3 3 3

Mean values for laboratory parameters (multiples of normal range) in cohorts 1 and 2, respectively: A and B, alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), prothrombin time, and total bilirubin; C and D, estimated glomerular filtration rate (eGFR); E and F, ammonia; G and H, methylmalonic acid. Error bars represent standard deviations; for values without error bars, standard deviation was not calculable. For any time point where the n value is less than 3, the n value is highlighted as red text.

- Any patient with confirmed mut0 genotype

(null mutation)

- Any patient with confirmed mut- genotype

• Baseline is the first nonmissing result prior to

1 month post birth for cohort 1 and the last

nonmissing result prior to the liver transplant

Note: If a patient is eligible for both cohorts, the patient is counted in both cohorts separately.

aPatients had positive newborn screening results for severe MMA. bIncludes gross or fine motor function. cHydroxocobalamin, ferrous sulfate, cyanocobalamin, folic acid, or iron. dMetronidazole. eArginine hydrochloride, sodium acetate, or sodium bicarbonate.

• Large variability in methylmalonic acid levels exists

across patients and within individual patients over

time (Figure 2, A and B)

- In cohort 2, compared with pretransplant

400
200	200

0							0
102-101	104-101	106-101	106-103	101-202	102-201	102-202	102-203102-204	102-205	104-201	104-202	102-301	103-301
101-101	102-102	104-102	106-102

Range of methylmalonic acid results in cohort 1 (A) and cohort 2 (B). Only 1 pretransplant methylmalonic acid result was available for patient 102-203, and no posttransplant methylmalonic acid results were available for patient 102-205. The minimum methylmalonic acid value for each patient is the lowest point in the graph; the maximum value is represented as the highest point in the graph and may be represented as an outlier. The ends of the boxes are the upper and lower quartiles, and the median is marked by a horizontal line within each box.

Growth Parameters

• For cohort 1, length/height remained below the median from baseline through
  36 months; weight and body mass index (BMI) remained at or above the median starting at months 12 and 6, respectively; and head circumference measurements were variable throughout the 36 months (Figure 3A)
• For cohort 2, length/height and head circumference remained below the median from baseline through 36 months; weight and BMI increased at months 3 and 6 posttransplant but then declined to near median levels and remained there through month 36 (Figure 3B)
• • There was a significant increase in weight and BMI (P=0.0391) at 3 months posttransplant and a significant increase in BMI (P=0.0391) at 6 months posttransplant compared with baseline

Figure 3. Summary of Growth Parameters Over Time

A

4

Length/Height

Weight

Head Circumference

BMI

score-	1
	3
z	2
Mean	0
-2
	-1

-3-4-5

		0	3	6	9	12	15	18	21	24	27	30	33	36
							Months from Baseline
Length/Height	n=	10	9	10	9	8	7	5	8	6	6	4	7	4
Weight	n=	10	9	10	9	8	9	5	8	6	7	4	8	4
Head Circumference	n=	10	8	9	7	6	5	3	8	4	4	3	6	3
BMI	n=	10	9	10	9	8	7	5	8	6	6	4	7	4

B

7

Length/Height

Weight

Head Circumference

BMI

score-	3	*
		Transplant
	5
z		*
Mean	1	*
	-1
	-3
	-5

		-12	-9	-6	-3	0	3	6	9	12	15	18	21	24	27	30	33	36
									Months from Baseline
Length/Height	n=	6	8	9	8	10	9	8	8	8	7	5	6	4	5	3	3	4
Weight	n=	6	8	9	9	10	9	8	8	8	7	5	6	5	5	3	5	4
Head Circumference	n=	5	6	8	5	8	6	4	3	3	3	1	3	1	2	1	0	1
BMI	n=	6	8	9	8	10	9	8	8	8	7	5	6	4	5	3	3	4

• Numbers of MMA- and transplant-related emergency department (ED) visits and hospitalizations are shown in Figure 4
• • Mean numbers of days in the ED were 2.5 (year 1) and 1.3 (year 3) for cohort 1 and 4.8 (pretransplant), 2.0 (year 1 posttransplant), 1.0 (year 2 posttransplant), and 2.0 (year 3 posttransplant) for cohort 2
  • No ED days were reported for cohort 1 in year 2
• In cohort 2, among patients whose healthcare utilization data were reported, there were no significant differences in MMA- or transplant-related ED visits, days in the ED, or number of hospitalizations between the pretransplant period and up to 3 years posttransplant
• • Data on healthcare utilization for years 2 and 3 posttransplant were available for only 1 or 2 patients, limiting the interpretation of the analyses past year 1

Figure 4. Summary of MMA- and Transplant-Related Healthcare Utilization

A

5

	4.5																																Cohort 1
Visits	4																																Cohort 2
3.5
ED	3
of	2.5
Number	2
1.5
	1
	0.5
	0		Year 1	Year 2	Year 3	Pre-LT	Post-LT	Post-LT			Post-LT
	n=	4	0	3	4	Year 1	Year 2			Year 3
	4	1	1
B
Hospitalizations	16																																Cohort 1
8																																Cohort 2
	14
	12
of	10
6
Number
4
	2
	0
		Year 1	Year 2	Year 3	Pre-LT	Post-LT	Post-LT	Post-LT
																			Year 1	Year 2		Year 3
	n=	9		7		4		8		8	2	1

(partial deficiency) with a documented peak

serum or plasma methylmalonic acid level

of ≥100 µmol/L

for cohort 2

fPrednisone. gCitric acid or sodium citrate acid. hCarbohydrates not otherwise specified (NOS), fats NOS, iron, linoleic acid, minerals NOS, potassium, protein, sodium, vitamins NOS, maltodextrin, or nutrients NOS. iLevocarnitine, valine, sodium benzoate, carglumic acid, isoleucine, levocarnitine hydrochloride, levoglutamine, or sodium phenylbutyrate. jThiamine, biotin, colecalciferol, pyridoxine, or riboflavin. kSodium benzoate or sodium phenylacetate.

methylmalonic acid levels, the overall

posttransplant methylmalonic acid levels were

lower and had a narrower range (Figure 2B)

Presented at	Acknowledgments
The 2021 Annual Clinical Genetics Meeting	This study was funded by LogicBio Therapeutics. We thank the patients and
April 13-16, 2021	site personnel involved with this study, and Sarah Qamar, PhD (Chameleon
Communications International, with funding from LogicBio Therapeutics) for
	editorial assistance in the preparation of this report.

Disclosures

Gregory M. Enns has served as a consultant for LogicBio Therapeutics, Inc, and has received personal fees outside the submitted work. Peter Baker has no disclosures to report.

Hong Li has received grants during the conduct of the study from LogicBio Therapeutics, Inc. Tom Morgan has received grants during the conduct of the study from LogicBio Therapeutics, Inc.

Jerry Vockley has served as a consultant and has received grants outside the submitted work from LogicBio Therapeutics, Inc.

Growth parameters are represented as z-scores based on the World Health Organization growth standards. *P=0.0391 vs baseline.	Mean number of emergency department (ED) visits (A) and mean number of hospitalizations (B) are shown for cohorts 1 and 2.
LT, liver transplant. Error bars represent standard deviations; for columns without error bars, standard deviation was not calculable.
Baseline (month 0) is the first nonmissing result post birth for cohort 1 (A) and the last nonmissing result prior to the liver transplant
For any time point where the n value is less than 3, the n value is highlighted as red text.
for cohort 2 (B). Error bars represent standard deviations; for data points without error bars, standard deviation was not calculable.
For any time point where the n value is less than 3, the n value is highlighted as red text.

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