Efficacy and Safety of 5-Aminolevulinic Acid Hydrochloride Combined with Sodium Ferrous Citrate in Pediatric Patients with Leigh Syndrome and Central Nervous System Disorders: An Initial Exploratory Trial with a Double-Blind Placebo-Controlled Period, Followed by an Open-Label Period and a Subsequent Long-Term Administration Study
Abstract
1. Introduction
2. Materials and Methods
2.1. Study Drug and Placebo
2.2. Patients
2.3. LS Causative Gene Analysis
2.4. Study Design
2.5. Drug Administration Protocol
2.6. Dose Setting
2.7. Pharmacokinetic Analysis of the Significance of the Simultaneous Administration of 5-ALA and SFC
2.8. Pharmacokinetic Analysis
2.9. Efficacy and Safety
2.10. Statistical Analysis
2.11. Clinical Trial Institution
3. Results
3.1. Patient Enrolment and Pharmacokinetics of 5-ALA
3.2. Safety Results
3.3. Efficacy Results
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
ADR | Adverse drug reaction |
AE | Adverse event |
5-ALA | 5-Aminolevulinic acid |
ALT | Alanine aminotransferase |
AST | Aspartate aminotransferase |
ATR-X | Alpha thalassemia/mental retardation syndrome X-linked |
FAS | Full analysis set |
FGF21 | Fibroblast growth factor 21 |
FXTAS | Fragile X-associated tremor/ataxia syndrome |
GGT | Gamma-glutamyl transferase |
LS | Leigh syndrome |
MD | Mitochondrial disease |
MELAS | Mitochondrial myopathy encephalopathy, lactic acidosis, and stroke-like episodes |
MRC | Mitochondrial respiratory chain |
MTD | Maximally tolerated dose |
Non-Mito LS | Leigh syndrome due to a non-mitochondrial gene variant |
NPMDS | Newcastle Pediatric Mitochondrial Disease Scale |
SAE | Serious adverse event |
SD | Standard deviation |
SFC | Sodium ferrous citrate |
SOC | System organ class |
PPIX | Protoporphyrin IX |
PPS | Per protocol set |
PT | Preferred term |
Appendix A
Appendix A.1
Caucasian | Japanese | |||||||
---|---|---|---|---|---|---|---|---|
Dose of 5-ALA/SFC | AEs | SAEs | AEs | SAEs | ||||
Cases | % (Cases) | Events | Cases | % (Cases) | Events | |||
Placebo | (n = 6) | 50.0% (3/6) | 5 | 0 | (n = 4) | 50.0% (2/4) | 2 | 0 |
150 mg/235 mg | (n = 6) | 50.0% (3/6) | 4 | 0 | (n = 6) | 50.0% (3/6) | 3 | 0 |
300 mg/470 mg | (n = 6) | 66.7% (4/6) | 11 | 0 | (n = 6) | 0.0% (0/6) | 0 | 0 |
600 mg/940 mg | (n = 6) | 83.3% (5/6) | 19 | 0 |
Appendix A.2
Caucasian | Japanese | ||||||
---|---|---|---|---|---|---|---|
Placebo | 150 mg/235 mg | 300 mg /470 mg | 600 mg /940 mg | Placebo | 150 mg /235 mg | 300 mg /470 mg | |
(n = 6) | (n = 6) | (n = 6) | (n = 6) | (n = 6) | (n = 6) | (n = 6) | |
Abdominal distension | 2 | 2 | |||||
Nausea | 1 | 2 | 1 | ||||
Feces discolored | 2 | 1 | |||||
Headache | 1 | 1 | 2 | ||||
Dizziness | 1 | 1 | |||||
Chest discomfort | 2 | ||||||
Myalgia | 1 | 1 |
Appendix A.3
Body Weight | Daily Dose (5-ALA/SFC) | Number of Doses and Number of Capsules Taken for 5-ALA and SFC |
---|---|---|
>20 kg | 50 mg/78.44 mg | Twice a day, 1 capsule in the morning and 1 capsule in the evening |
≥20 kg and <30 kg | 75 mg/117.66 mg | Twice a day, 2 capsules in the morning and 1 capsule in the evening |
≥30 kg and <40 kg | 100 mg/156.88 mg | Twice a day, 2 capsules in the morning and 2 capsules in the evening |
≥40 kg and <50 kg | 125 mg/196.1 mg | Twice a day, 3 capsules in the morning and 2 capsules in the evening |
≥50 kg | 150 mg/235.32 mg | Twice a day, 3 capsules in the morning and 3 capsules in the evening |
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SPP-004 (n = 5) | Placebo (n = 5) | |
---|---|---|
Sex—n (%) | ||
Male | 3 (60.0) | 1 (20.0) |
Female | 2 (40.0) | 4 (80.0) |
Age at informed consent—months | ||
n | 5 | 4 |
Mean ± SD | 19.4 ± 2.88 | 19.5 ± 3.11 |
Median [Min, Max] | 20.0 [15, 23] | 19.5 [16, 23] |
Presence of preterm birth—n (%) | ||
None | 5 (100.0) | 4 (80.0) |
Yes | 0 (0.0) | 1 (20.0) |
Adjusted age—months | ||
n | 0 | 1 |
Mean | - | 16 |
Median [Min, Max] | - | 16.0 [16, 16] |
Primary disease—n (%) | ||
Chronic progressive external ophthalmoplegia | 0 (0.0) | 0 (0.0) |
Myoclonus epilepsy syndrome | 0 (0.0) | 0 (0.0) |
Leigh syndrome | 5 (100.0) | 5 (100.0) |
Leber hereditary optic neuropathy | 0 (0.0) | 0 (0.0) |
Pearson syndrome | 0 (0.0) | 0 (0.0) |
Presence of consanguineous marriage—n (%) | ||
None | 5 (100.0) | 5 (100.0) |
Yes | 0 (0.0) | 0 (0.0) |
Family history—n (%) | ||
None | 2 (40.0) | 3 (60.0) |
Yes | 3 (60.0) | 2 (40.0) |
Medical history—n (%) | ||
None | 5 (100.0) | 3 (60.0) |
Yes | 0 (0.0) | 2 (40.0) |
Presence of complications—n (%) | ||
None | 0 (0.0) | 2 (40.0) |
Yes | 5 (100.0) | 3 (60.0) |
SPP-004 | Placebo | |||||||||
---|---|---|---|---|---|---|---|---|---|---|
Pt No. | ALA-02-01 | ALA-02-02 * | ALA-07-01 | ALA-09-01 | ALA-10-01 | PLA-04-01 | PLA-04-02 | PLA-05-01 | PLA-06-01 | PLA-08-01 |
Sex | M | F | F | M | M | F | M | F | F | F |
Primary disease | LS | LS | LS | Non-Mito LS | LS | LS | LS | LS | Non-Mito LS | LS |
Onset age | 0Y 2M | 0Y 1M | 0Y 11M | 0Y 2M | 1Y 1M | 0Y10M | 0Y 5M | 0Y 10M | 0Y 10M | 0Y 1M |
Age at start of trial | 1Y 7M | 1Y 3M | 1Y 11M | 1Y 9M | 1Y 9M | 1Y 10M | 1Y 10M | 2Y 2M | 1Y 8M | 2Y 0M |
MRC activity | n.d. | |||||||||
Sample tissue | Fb | Fb | Fb | Mb | Mb | Fb | Mb | Mb | Fb | |
Abnormality | - | I | I | IV | I | I | II | IV | IV | |
Gene | MT-ND6 (T14487C) | MT-ND3 (T10158C) | ECHS1 | SCN8A | MT-ND5 (T13094C) | NDUFV2 | TRMT5 | SURF1 | n.d. | MT-ATP6 (T8993C) |
MRI abnormality | Basal ganglia lesion MRS lactate peak | Basal ganglia lesion | Basal ganglia lesion | Basal ganglia lesion | Basal ganglia lesion | Basal ganglia lesion | Basal ganglia lesion | Basal ganglia lesion | Basal ganglia lesion | Basal ganglia lesion |
NPMDS I+III3-8 | 19 | 25 | 6 | 23 | 7 | 10 | 15 | 16 | 3 | 11 |
Lactate (mmol/L) | 2.1 + | 3.0 + | 2.1 + | 1.9 | 3.2 + | 4.1 + | 1.5 | 1.8 | 1.8 | 3.0 + |
Pyruvate (mmol/L) | 0.02 | 0.09 | 0.13 | 0.07 | 0.15 | 0.21 | 0.06 | 0.09 | 0.08 | 0.13 |
L/P ratio | 97.0 + | 35.5 + | 16.2 | 27.9 + | 21.0 + | 19.8 | 27.8 + | 20.3 + | 23.3 + | 22.7 + |
FGF21 (pg/mL) | 891.640 | 10262.091 | ≤60 | 96.747 | ≤60 | 312.731 | 569.603 | 833.855 | ≤60 | ≤60 |
n | Mean ± SD | Median [Min, Max] | |
---|---|---|---|
5-ALA | |||
Cmax (μmol/L) | 8 | 7.00 ± 3.42 | 6.92 [2.48, 12.3] |
tmax (h) | 8 | 0.9 ± 0.2 | 1.0 [0.5, 1.0] |
t1/2 (h) | - | n.c. | n.c. |
AUC0-8 (h·μmol/L) | 8 | 12.8 ± 4.14 | 11.7 [8.13, 18.6] |
AUC0-t (h·μmol/L) | 8 | 10.4 ± 3.58 | 10.3 [6.63, 15.7] |
AUC0-∞ (h·μmol/L) | - | n.c. | n.c. |
PPIX | |||
Cmax (nmol/L) | 8 | 22.8 ± 16.3 | 17.0 [6.58, 49.2] |
tmax (h) | 8 | 3.0 ± 1.1 | 3.0 [2.0, 4.0] |
t1/2 (h) | 4 | 1.8 ± 0.3 | 1.9 [1.4, 2.2] |
AUC0-8 (h·nmol/L) | 8 | 94.3 ± 64.5 | 68.3 [31.2, 197] |
AUC0-t (h·nmol/L) | 8 | 94.3 ± 64.5 | 68.3 [31.2, 197] |
AUC0-∞ (h·nmol/L) | 4 | 76.3 ± 35.7 | 68.1 [43.5, 125] |
Initial study (SPED-ALA-001) | ||||||||||||
SPP-004 | Placebo | |||||||||||
Double-blind period (n= 5) | Open-label period (n = 4) | Total (n = 5) | Double-blind period (n = 5) | Open-label period (n = 5) | Total (n = 5) | |||||||
Cases n (%) | Events n | Cases n (%) | Events n | Cases n (%) | Events n | Cases n (%) | Events n | Cases n (%) | Events n | Cases n (%) | Events n | |
All AEs | 5 (100.0) | 17 | 4 (100.0) | 12 | 5 (100.0) | 29 | 5 (100.0) | 21 | 5 (100.0) | 24 | 5 (100.0) | 45 |
Severity | ||||||||||||
Mild | 2 (40.0) | 7 | 3 (75.0) | 9 | 2 (40.0) | 16 | 2 (40.0) | 18 | 2 (40.0) | 17 | 1 (20.0) | 35 |
Moderate | 2 (40.0) | 6 | 1 (25.0) | 3 | 2 (40.0) | 9 | 3 (60.0) | 3 | 3 (60.0) | 7 | 4 (80.0) | 10 |
Severe | 1 (20.0) | 4 | 0 (0.0) | 0 | 1 (20.0) | 4 | 0 (0.0) | 0 | 0 (0.0) | 0 | 0 (0.0) | 0 |
Relationship with investigational drug | ||||||||||||
Related | 2 (40.0) | 4 | 2 (50.0) | 2 | 4 (80.0) | 6 | 1 (20.0) | 1 | 3 (60.0) | 3 | 3 (60.0) | 4 |
Unrelated | 3 (60.0) | 13 | 2 (50.0) | 10 | 1 (20.0) | 23 | 4 (80.0) | 20 | 2 (40.0) | 21 | 2 (40.0) | 41 |
Death | 1 (20.0) | - | 0 (0.0) | - | 1 (20.0) | - | 0 (0.0) | - | 0 (0.0) | - | 0 (0.0) | - |
Serious AEs | 2 (40.0) | 7 | 2 (50.0) | 5 | 3 (60.0) | 12 | 3 (60.0) | 3 | 1 (20.0) | 5 | 3 (60.0) | 8 |
AEs leading to discontinuation | 0 (0.0) | 0 | 0 (0.0) | 0 | 0 (0.0) | 0 | 0 (0.0) | 0 | 0 (0.0) | 0 | 0 (0.0) | 0 |
Long-term administration study (SPED-ALA-002) | ||||||||||||
All (n = 9) | ||||||||||||
Cases—n (%) | Events—n | |||||||||||
All AEs | 9 (100.0) | 255 | ||||||||||
Severity | ||||||||||||
Mild | 1 (11.1) | 168 | ||||||||||
Moderate | 3 (33.3) | 79 | ||||||||||
Severe | 5 (55.6) | 8 | ||||||||||
Relationship with investigational drugs | ||||||||||||
Unelated | 7 (77.8) | 251 | ||||||||||
Related | 2 (22.2) | 4 | ||||||||||
Death | 1 (11.1) | - | ||||||||||
Serious AEs | 7 (77.8) | 61 | ||||||||||
AEs leading to discontinuation | 2 (22.2) | 2 |
Initial Study (SPED-ALA-001) | ||||||||||||||
SPP-004 | Placebo | |||||||||||||
Double-blind period | Open-label period | Total | Double-blind period | Open-label period | Total | |||||||||
n = 5 | n = 4 | n = 5 | n = 5 | n = 5 | n = 5 | |||||||||
SOC | Cases | Events | Cases | events | Cases | events | Cases | events | Cases | events | Cases | events | ||
PT (Med DRA/J Ver 19.0) | Severity | n (%) | n | n (%) | n | n (%) | n | n (%) | n | n (%) | n | n (%) | n | |
All | 2 (40.0) | 4 | 2 (50.0) | 2 | 4 (80.0) | 6 | 1 (20.0) | 1 | 3 (60.0) | 3 | 3 (60.0) | 4 | ||
Cardiac disorders | 1 (20.0) | 1 | 0 (0.0) | 0 | 1 (20.0) | 1 | 0 (0.0) | 0 | 0 (0.0) | 0 | 0 (0.0) | 0 | ||
Left ventricular failure | Severe | 1 (20.0) | 1 | 0 (0.0) | 0 | 1 (20.0) | 1 | 0 (0.0) | 0 | 0 (0.0) | 0 | 0 (0.0) | 0 | |
Gastrointestinal disorder | 1 (20.0) | 1 | 1 (25.0) | 1 | 2 (40.0) | 2 | 1 (20.0) | 1 | 1 (20.0) | 1 | 2 (40.0) | 2 | ||
Diarrhea | Mild | 1 (20.0) | 1 | 0 (0.0) | 0 | 1 (20.0) | 1 | 1 (20.0) | 1 | 0 (0.0) | 0 | 1 (20.0) | 1 | |
Hematochezia | Mild | 0 (0.0) | 0 | 1 (25.0) | 1 | 1 (20.0) | 1 | 0 (0.0) | 0 | 0 (0.0) | 0 | 0 (0.0) | 0 | |
Tooth discoloration | Mild | 0 (0.0) | 0 | 0 (0.0) | 0 | 0 (0.0) | 0 | 0 (0.0) | 0 | 1 (20.0) | 1 | 1 (20.0) | 1 | |
Investigations | 0 (0.0) | 0 | 1 (25.0) | 1 | 1 (20.0) | 1 | 0 (0.0) | 0 | 0 (0.0) | 0 | 0 (0.0) | 0 | ||
Electroencephalogram abnormal | Mild | 0 (0.0) | 0 | 1 (25.0) | 1 | 1 (20.0) | 1 | 0 (0.0) | 0 | 0 (0.0) | 0 | 0 (0.0) | 0 | |
Respiratory, thoracic, and mediastinal disorders | 1 (20.0) | 2 | 0 (0.0) | 0 | 1 (20.0) | 2 | 0 (0.0) | 0 | 0 (0.0) | 0 | 0 (0.0) | 0 | ||
Pulmonary alveolar hemorrhage | Severe | 1 (20.0) | 1 | 0 (0.0) | 0 | 1 (20.0) | 1 | 0 (0.0) | 0 | 0 (0.0) | 0 | 0 (0.0) | 0 | |
Respiratory failure | Severe | 1 (20.0) | 1 | 0 (0.0) | 0 | 1 (20.0) | 1 | 0 (0.0) | 0 | 0 (0.0) | 0 | 0 (0.0) | 0 | |
Skin and subcutaneous tissue disorders | 0 (0.0) | 0 | 0 (0.0) | 0 | 0 (0.0) | 0 | 0 (0.0) | 0 | 2 (40.0) | 2 | 2 (40.0) | 2 | ||
Urticarias | Moderate | 0 (0.0) | 0 | 0 (0.0) | 0 | 0 (0.0) | 0 | 0 (0.0) | 0 | 2 (40.0) | 2 | 2 (40.0) | 2 | |
Long-term administration study (SPED-ALA-002) | ||||||||||||||
SOC | Cases | Events | ||||||||||||
PT (MedDRA/J Ver. 22.1) | Severity | n (%) | n | |||||||||||
All | 2 (22.2) | 4 | ||||||||||||
Skin and subcutaneous tissue disorders | ||||||||||||||
Urticaria | Moderate | 2 (22.2) | 2 | |||||||||||
Mild | 2 (22.2) | 2 |
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Abe, Y.; Hamasaki, T.; Natsume, J.; Mogami, Y.; Murayama, K.; Shiraishi, H.; Abe, Y.; Kumada, S.; Tanaka, R.; Ihara, K.; et al. Efficacy and Safety of 5-Aminolevulinic Acid Hydrochloride Combined with Sodium Ferrous Citrate in Pediatric Patients with Leigh Syndrome and Central Nervous System Disorders: An Initial Exploratory Trial with a Double-Blind Placebo-Controlled Period, Followed by an Open-Label Period and a Subsequent Long-Term Administration Study. Life 2025, 15, 1168. https://doi.org/10.3390/life15081168
Abe Y, Hamasaki T, Natsume J, Mogami Y, Murayama K, Shiraishi H, Abe Y, Kumada S, Tanaka R, Ihara K, et al. Efficacy and Safety of 5-Aminolevulinic Acid Hydrochloride Combined with Sodium Ferrous Citrate in Pediatric Patients with Leigh Syndrome and Central Nervous System Disorders: An Initial Exploratory Trial with a Double-Blind Placebo-Controlled Period, Followed by an Open-Label Period and a Subsequent Long-Term Administration Study. Life. 2025; 15(8):1168. https://doi.org/10.3390/life15081168
Chicago/Turabian StyleAbe, Yuichi, Toshimitsu Hamasaki, Jun Natsume, Yukiko Mogami, Kei Murayama, Hideaki Shiraishi, Yuki Abe, Satoko Kumada, Ryuta Tanaka, Kenji Ihara, and et al. 2025. "Efficacy and Safety of 5-Aminolevulinic Acid Hydrochloride Combined with Sodium Ferrous Citrate in Pediatric Patients with Leigh Syndrome and Central Nervous System Disorders: An Initial Exploratory Trial with a Double-Blind Placebo-Controlled Period, Followed by an Open-Label Period and a Subsequent Long-Term Administration Study" Life 15, no. 8: 1168. https://doi.org/10.3390/life15081168
APA StyleAbe, Y., Hamasaki, T., Natsume, J., Mogami, Y., Murayama, K., Shiraishi, H., Abe, Y., Kumada, S., Tanaka, R., Ihara, K., Sakakibara, T., Okazaki, Y., Nakagawa, H., Takahashi, K., Yamauchi, M., Nakajima, M., & Ohtake, A. (2025). Efficacy and Safety of 5-Aminolevulinic Acid Hydrochloride Combined with Sodium Ferrous Citrate in Pediatric Patients with Leigh Syndrome and Central Nervous System Disorders: An Initial Exploratory Trial with a Double-Blind Placebo-Controlled Period, Followed by an Open-Label Period and a Subsequent Long-Term Administration Study. Life, 15(8), 1168. https://doi.org/10.3390/life15081168