Ravicti (glycerol phenylbutyrate) / Immedica, Amgen - LARVOL DELTA

LC-MS/MS and LC-PDA Methods for Robust Determination of Glycerol Phenylbutyrate in Biological Fluids and High-Resolution Mass Spectrometric Identification of Forced Degradation Product and Its Whiteness. (PubMed, ACS Omega) - "Moreover, in forced degradation experiments, the active substance was unstable in acid, alkali, and oxide conditions, and an elimination reaction forms the novel degradation product. Lastly, the method was evaluated to have excellent whiteness, efficiency, and practicality, making it suitable for application in all analytical method development laboratories."

Journal • Metabolic Disorders

Cerebral Edema Due to Hyperammonemia: A Case of Suspected Urea Cycle Disorder in Adult Patient (ATS 2025) - "The patient was dialyzed for hyperammonemia, treated with hypertonic saline for cerebral edema, and managed for seizures with levetiracetam, lacosamide, and topiramate...This can then be followed by outpatient amino acid supplementation, dietary protein restriction, in some cases, nitrogen scavenger therapy (such as sodium phenylbutyrate or glycerol phenylbutyrate) and avoidance of medications that raise ammonia levels, such as valproic acid in our patient. Mild cases of UCDs can present in adults during physiologic distress, requiring high suspicion as delays may lead to irreversible cerebral injury or death. In patients with unclear neurologic symptoms, particularly new-onset seizures or cerebral edema checking ammonia levels is crucial for prompt identification and treatment."

Clinical • CNS Disorders • Epilepsy • Metabolic Disorders • Pediatrics • Psychiatry • Schizophrenia

Glutamine and Hypoxic Brain Injury: A Mechanistic Insight. (PAS 2025) - "Hypoxia resulted in significant metabolic acidosis, cerebral lactic acidosis, and cerebral edema (Table 1). Hypoxic piglets reoxygenated for 4 hours with or without HT had increased GLN, but decreased GLU in their CC compared to controls (Figure 1). Astrocytes incubated in GLN had an increased number of cellular processes indicative of activated astrocyte morphology."

Anesthesia • CNS Disorders • Metabolic Disorders • Vascular Neurology

Clinical Study on the Treatment of STXBP1 Gene-related Encephalopathy with Glycerol Phenylbutyrate (ChiCTR) - P=N/A | N=13 | Not yet recruiting | Sponsor: Hunan Children‘’s Hosptial; Hunan Children‘’s Hosptial

New trial • CNS Disorders • Developmental Disorders • Psychiatry • XBP1

A Clinical Study of Glycerol Phenylbutyrate in Chinese Patients With Urea Cycle Disorders (clinicaltrials.gov) - P=N/A | N=40 | Not yet recruiting | Sponsor: Tongji Hospital

New trial • Metabolic Disorders

PDH-RAVICTI: A Phase II, Multicentric, Prospective, Non-comparative Clinical Trial to Assess the Efficacy and Safety of the Treatment of Pyruvate Dehydrogenase Deficiency (PDH) Patients with Glycerol Phenybutyrate (RAVICTI®) (clinicaltrials.gov) - P2 | N=15 | Not yet recruiting | Sponsor: Assistance Publique - Hôpitaux de Paris

New P2 trial • Metabolic Disorders

Perspectives on long-term medical management of urea cycle disorders: insights from a survey of UK healthcare professionals. (PubMed, Orphanet J Rare Dis) - "To standardise the treatment of UCDs within and between metabolic centres in the UK, there is merit in developing a UK-specific treatment guideline."

Journal • Metabolic Disorders

4-Phenylbutyrate restored GABA uptake, mitigated seizures in SLC6A1 and SLC6A11 microdeletions/3p- syndrome: From cellular models to human patients. (PubMed, Epilepsy Res) - P1 | "Haploinsufficiency of SLC6A1 and SLC6A11 contributes to the epileptic phenotypes observed in 3p- syndrome, marking this as the first study to biochemically characterize the functional impact of these deletions. Treatment with PBA may provide therapeutic benefits, particularly for addressing seizures and motor deficits, though further exploration of PBA's long-term effects in patients with 3p- syndrome is warranted."

Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Epilepsy • Pediatrics

Single centre retrospective review of plasma branched-chain amino acid levels in children with urea cycle disorders: Impact of treatment modalities and disease severity. (PubMed, Mol Genet Metab Rep) - "Scavenger treatment groups comprised sodium benzoate (NaBz, n = 20), sodium phenylbutyrate (NaPBA, n = 5), NaBz+NaPBA (n = 14), and a control group receiving neither NaBz nor NaPBA (n = 14)...We speculate that individuals with greater disease severity may be prone to BCAA deficiency, caused by BCAA consumption when alternative urea disposal pathways are used. Practical reflections on our audit were that to increase the proportion of plasma BCAA levels in the normal range, we needed to alter the biological value of protein intake, prescribe higher doses of scavenger to facilitate safe levels of protein intake, and give EAA supplements if indicated."

Journal • Retrospective data • Metabolic Disorders

STXBP1-E: Phenylbutyrate for Monogenetic Developmental and Epileptic Encephalopathy (clinicaltrials.gov) - P1 | N=50 | Enrolling by invitation | Sponsor: Weill Medical College of Cornell University | Trial primary completion date: Jan 2025 ➔ Dec 2025

Trial primary completion date • CNS Disorders • Developmental Disorders • Epilepsy • Psychiatry • XBP1

PBA Use for Treatment of ATF6-/- Patients (clinicaltrials.gov) - P1 | N=2 | Not yet recruiting | Sponsor: Columbia University | Trial completion date: May 2025 ➔ May 2027 | Trial primary completion date: May 2025 ➔ May 2027

Trial completion date • Trial primary completion date • Achromatopsia • Ophthalmology • ATF6

Mechanistic Insights into Pharmacological Interventions for SLC6A1 Variant-related Disorders (AES 2024) - "The reduction in GABA reuptake likely contributes to the observed phenotypes in patients with SLC6A1 variant-related disorders, including epilepsy, neurodevelopmental delay, and autism spectrum disorder. These findings suggest that the pharmacological agents tested may offer viable therapeutic options. Ravicti (glycerol-phenylbutyrate) is currently in clinical trials for SLC6A1-related disorders, but this study aims to tease out mechanisms to identify alternative therapeutic treatments."

Autism Spectrum Disorder • CNS Disorders • Developmental Disorders • Epilepsy • Gene Therapies • Genetic Disorders • Mood Disorders • Psychiatry

Phenylbutyrate for syngap1-related Developmental and Epileptic Encephalopathy (AES 2024) - "Glycerol phenylbutyrate is a promising novel therapy for children with SYNGAP1. In ongoing work, we are (1) reviewing developmental assessment data and (2) enrolling additional children with SYNGAP1 and other monogenetic developmental and epileptic encephalopathies."

CNS Disorders • Epilepsy • Hematological Disorders • Metabolic Disorders • XBP1

Characteristics, Treatments, and Clinical Outcomes of Patients With Ornithine Transcarbamylase Deficiency in the United States (ISPOR-EU 2024) - "Real-world evidence demonstrates a high symptomatic burden and HAE/crisis event rates, indicating a significant clinical burden in OTCD patients."

Clinical • Clinical data • Cognitive Disorders • Genetic Disorders • Metabolic Disorders • Pain

Think Outside the Box! Not All Hyperammonemia is Due to Liver Disease (ACG 2024) - "These patients will not respond to oral lactulose or rifaximin unlike in cases of hepatic encephalopathy. Detailed history, genetic testing, and a markedly abnormal increase of orotic acid excretion after an allopurinol challenge test will clinch the diagnosis of OTC. Urea cycle disorders should be considered in patients who present with neuropsychiatric symptoms in the emergency room with hyperammonemia. A prompt recognition of symptoms will prevent permanent neurological damage or even death."

Ataxia • Cardiovascular • CNS Disorders • Epilepsy • Genetic Disorders • Hepatic Encephalopathy • Hepatology • Metabolic Disorders • Movement Disorders • Pain • Psychiatry

Perinatal management and follow-up in a child with a prenatal diagnosis of OTC deficiency: a case report. (PubMed, Front Nutr) - "To date, after 3.5 years of follow up, growth and neurological development have been adequate, biochemical control has been appropriate except for a simple and mild decompensation during the course of a gastroenteritis. This case emphasises the importance of early diagnosis and treatment to avoid potential complications."

Journal • Gastroenterology • Gastrointestinal Disorder • Genetic Disorders • Metabolic Disorders

ARGINASE-1 DEFICIENCY: ΑN INBORN ERROR OF METABOLISM AS A RARE CAUSE OF DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY (SSIEM 2024) - "At 22 y/o, seizures reappeared with generalized tonic-clonic spasms with initiation of combination of levetiracetam, clobazam and phenytoin, with poor seizure control...The enzyme replacement therapy, pegzilarginase, is the first possible disease-modifying therapy of the disease. Early diagnosis is of importance as it is a treatable cause of DEE. Palavras-chave : Arginase-1 deficiency, Urea cycle disorders, Developmental and epileptic encephalopathy, Metabolic epilepsy, Inborn errors of metabolism"

CNS Disorders • Cognitive Disorders • Developmental Disorders • Epilepsy • Genetic Disorders • Metabolic Disorders • Movement Disorders

MODELING THE PHARMACOKINETICS OF PHENYLBUTYRATE IN FED AND FASTED STATES (SSIEM 2024) - "Fasting administration of NaPBA in the applied model showed greater absorption and bioavailability with increased drug exposure. NaPBA administration in the fasted state is predicted to increase efficacy proportionally to increased drug exposure. This theoretically allows for a 30% dose decrease while maintaining comparable efficacy outcomes as NaPBA or GPB administered in the fed state."

PK/PD data • Metabolic Disorders • Rare Diseases

AMMONIA SCAVENGER IN UREA CYCLE DISORDERS: EFFICACY OF GLYCEROL PHENYLBUTYRATE (SSIEM 2024) - "Our aim was to compare GPB with sodium phenylbutyrate (NaPB) and sodium benzoate (NaBZ)...We excluded patients treated by liver transplant or pegzilarginase... We provide evidence for a decrease of ammonia levels under GPB and observe a borderline association with reduced frequency of acute decompensations. This is consistent with previously reported data. Further studies are warranted in larger patients cohorts with isoequivalent GPB switching."

Clinical • Gastrointestinal Disorder • Hepatology • Metabolic Disorders

Investigating the Effect of Glycerol Phenylbutyrate on Neurofilament Light Chain Levels in Patients with Corticobasal Syndrome: The PROFIL Study (CTAD 2024) - No abstract available

Clinical • NEFL

PBA Use for Treatment of ATF6-/- Patients (clinicaltrials.gov) - P1 | N=2 | Not yet recruiting | Sponsor: Columbia University | Trial completion date: Mar 2024 ➔ May 2025 | Trial primary completion date: Mar 2024 ➔ May 2025

Trial completion date • Trial primary completion date • Achromatopsia • Ophthalmology • ATF6

Glycerol Phenylbutyrate Treatment of Two Patients with Monocarboxylate Transporter 8 Deficiency (ENDO 2024) - "Recent studies have shown that the chemical chaperone sodium phenylbutyrate (NaPB) restored mutant MCT8 function and increased TH content in patient-derived induced pluripotent stem cells, making it a potential treatment for MCT8 deficiency... In the first report of GPB treatment in MCT8 deficiency patients we found an improvement in TH profile and body-mass index (BMI). The reduction in T3 levels could contribute to the remarkable increase in BMI-SDS, since various aspects of peripheral hyperthyroidism in MCT8 deficiency, including poor weight gain, were attributed to elevated T3. The limited effects of GPB treatment on cognitive and motor functions can derive from the advanced age of the patients at the time of the intervention.Unless otherwise noted, all abstracts presented at ENDO must not be released to the press or the public until the date and time of presentation."

Clinical • Developmental Disorders • Endocrine Disorders • Genetic Disorders

Quantifying preferences for urea cycle disorder treatments using a discrete choice experiment. (PubMed, J Med Econ) - "Survey respondent selection, the use of hypothetical product profiles, and exclusion of non-pharmacologic treatment options could have contributed to potential biases. Among attributes tested, taste/odor was the most important attribute influencing overall preference for both prescribing and patient adherence, with taste/odor masking preferred. Optimizing nitrogen-binding medications through masking taste/odor may support improved patient adherence and outcomes in UCDs."

Journal • Metabolic Disorders

Glycerol Phenylbutyrate treatment of two patients with Monocarboxylate Transporter 8 deficiency. (PubMed, J Clin Endocrinol Metab) - "In the first report of GPB treatment in MCT8 deficiency we found an improvement in TH profile and body-mass index, with minor neuro-developmental changes."

Journal • Developmental Disorders • Endocrine Disorders • Genetic Disorders

PROFIL Study to Investigate the Effect of GPB on NfL Levels in Patients With Corticobasal Syndrome (CBS) (clinicaltrials.gov) - P2 | N=32 | Recruiting | Sponsor: Technical University of Munich | Not yet recruiting ➔ Recruiting

Enrollment open • NEFL