Orfadin (nitisinone) / Astellas, SOBI - LARVOL DELTA

Drug-induced cataract: a real-world study based on the food and drug administration adverse event reporting system database. (PubMed, Front Med (Lausanne)) - "The highest-risk drugs identified were omidenepag isopropyl, clobazam, and nitisinone, with BCPNN scores of 7.69, 7.36, and 6.02, respectively. The majority of affected individuals were female (67.59%) and elderly (mean age 63.85 ± 14.54 years). This study provides real-world evidence regarding the risk of drug-induced cataract, offering empirical support for preventive strategies and informed clinical decision-making."

Adverse events • Journal • Real-world evidence • Cataract • Ophthalmology

SIADH as an Underrecognized Manifestation of Porphyria-like Crises in Hereditary Tyrosinemia Type 1: Clinical and Pathophysiological Insights. (PubMed, Int J Mol Sci) - "We report an 11-year-old boy with poorly controlled HT1 who presented with a severe neurovisceral crisis after suboptimal adherence to nitisinone (NTBC) therapy, characterized by abdominal pain, hypertension, paralytic ileus, seizures, and profound hyponatremia...In HT1, this susceptibility may be further amplified by FAA- and SA-mediated oxidative stress, mitochondrial dysfunction, and heme depletion, with an additional contribution from SA-associated renal tubular impairment. Overall, our findings underscore SIADH as a potentially underrecognized cause of acute hyponatremia in HT1 and highlight the importance of strict NTBC adherence and early monitoring of urinary ALA during metabolic decompensation."

Journal • Cardiovascular • CNS Disorders • Epilepsy • Genetic Disorders • Heart Failure • Hematological Disorders • Hypertension • Metabolic Disorders • Pain

Untargeted Metabolomics Reveals Metabolic Reprogramming Linked to HCC Risk in Late Diagnosed Tyrosinemia Type 1. (PubMed, Metabolites) - " High-resolution untargeted metabolomics coupled with liquid chromatography was applied for serum analysis of 16 late-diagnosed Chilean HT-1 patients on nitisinone (NTBC) therapy and 16 age- and sex-matched controls...Increased acylcarnitines, taurine-conjugated bile acids, modified nucleobases, and reduced lysophosphatidylcholines overlap with the metabolomic pattern previously reported in Wnt/β-catenin-associated HCC. Although direct mechanistic link cannot be established in this study, these alterations may reflect persistent disease-related metabolic adaptations and warrant further investigation to clarify their potential relevance with long-term complications."

Journal • Genetic Disorders • Hepatocellular Cancer • Oncology • Solid Tumor • CTNNB1

Effect of Nitisinone on Aortic Stenosis Disease Progression in Patients With Alkaptonuria: An Analysis of the Suitability of Nitisinone in Alkaptonuria (SONIA) 2 Study. (PubMed, Cureus) - "Given the small absolute effect size and post-hoc nature of the analysis, these findings should be interpreted as exploratory and hypothesis-generating rather than clinically definitive. Additional research is needed to determine whether nitisinone produces clinically meaningful outcomes for aortic stenosis in this population."

Journal • Cardiovascular • Metabolic Disorders

Morphological characterization of a novel model of steatohepatitis in the FAH-/- pig. (PubMed, Vet Pathol) - "In summary, we successfully developed and characterized a novel model of steatohepatitis in the FAH-/- pig within 3 months. Further studies with prolonged observation time and/or cycling of nitisinone administration are needed to evaluate whether progressive fibrosis and cirrhosis could be achieved with this model."

Journal • Fibrosis • Hepatology • Immunology • Inflammation • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • PTPRC

Expanding the HGD Variant Spectrum and Addressing Missing Heritability in a 96-Patient Cohort (ACMG 2026) - "This comprehensive analysis of 96 individuals with AKU expands the HGD variant spectrum by identifying 14 novel variants, two of which meet criteria for P, 10 for LP, and two Variants of Unknown Significance, thereby improving molecular diagnostic yield and refining HGD variant databases used in clinical testing. The recurrent intronic variant in five individuals with unresolved biallelic genotypes highlights the potential contribution of deep intronic alleles to missing heritability and underscores the value of RNA-based studies in variant reclassification. These findings are directly relevant to the design and interpretation of molecular testing for AKU, including future newborn screening strategies in the nitisinone era."

Clinical • Ankylosing Spondylitis • Cardiovascular • Immunology • Inflammatory Arthritis • Metabolic Disorders • Rheumatology • Seronegative Spondyloarthropathies • Spondylarthritis

Evaluating the impact of nitisinone at mosquito-lethal doses on Lutzomyia longipalpis. (PubMed, PLoS Negl Trop Dis) - "longipalpis exhibits tolerance to nitisinone, likely due to species-specific metabolic differences. Although nitisinone remains a promising tool for systemic vector control, its effectiveness against sand flies may require higher doses or alternative compounds."

Journal • Infectious Disease

Therapeutic Monitoring of Patients With Hereditary Tyrosinemia Type 1-A Belgian Monocentric Experience. (PubMed, JIMD Rep) - "Plasma remains the preferred matrix for amino acids monitoring. Larger multi-centre studies are needed to confirm these findings."

Journal • Hepatocellular Cancer • Metabolic Disorders • Oncology • Solid Tumor • AFP

Sobi.NTBC-008: A Non-interventional, Post-Marketing Study to Describe Outcome of Nitisinone Treatment in HT-1 Patients (clinicaltrials.gov) - P=N/A | N=0 | Withdrawn | Sponsor: Swedish Orphan Biovitrum | N=15 ➔ 0 | Recruiting ➔ Withdrawn

Enrollment change • Trial withdrawal

Harliku (nitisinone): first FDA-approved disease-modifying therapy for alkaptonuria. (PubMed, Ann Med Surg (Lond)) - "As the first single agent to be taken orally once daily, Harliku changes the paradigm of management for the rare metabolic disorder AKU from symptomatic treatment to disease-modifying therapy. It is a huge leap for other disorders of metabolism and paves the way for future innovations in therapy."

FDA event • Journal • Metabolic Disorders • Orthopedics

Alkaptonuria and Cervical Disc Herniation: Case Report. (PubMed, Int J Spine Surg) - "This study aims to enhance understanding of the pathophysiology of the spinal column in alkaptonuria and to explore the best surgical therapy strategies for this disease."

Journal • Metabolic Disorders • Musculoskeletal Pain • Pain • Rheumatology

An AAV-mediated liver-directed gene therapy metabolically corrects alkaptonuria in an Hgd deficient mouse model (SSIEM 2023) - "Nitisinone (NTBC) is currently used as the only effective treatment option for AKU patients in combination with a low protein diet but leads to severe and debilitating side effects... This study demonstrated that liver-directed AAV-HGD therapy in Hgd tm1a-/- mice sufficiently lowered HGA levels in serum, comparable to C57BL/6 wild-type mice (1.7 ± 0.6 μmol/L). Urine HGA levels of AAV-HGD treated mice were still elevated compared to C57BL/6 wild-type mice (0.8 ± 0.2 μmol/L) and only partially corrected."

Gene therapy • Preclinical • Gene Therapies • Metabolic Disorders

Development of a robust high-throughput screenings assay for the evaluation of bacterial tyrosine ammonia lyases in the context of tyrosine-inherited metabolic disorders. (SSIEM 2023) - "TIMD are currently treated with dietary restrictions and/or nitisinone (NTBC)... A robust, simple and cost-effective HTS assay was developed to evaluate the activity of bacterial TAL enzymes."

Metabolic Disorders

Cervicosacral stabilisation in alkaptonuria: seven-year surgical management of multisystem ochronosis including joint arthroplasties. (PubMed, BMJ Case Rep) - "Cardiovascular evaluation revealed aortic valve stenosis and mitral insufficiency, reflecting systemic disease burden.The patient's spinal interventions preceded regulatory approval of nitisinone for AKU in the European Union, a disease-modifying therapy with potential to modify disease progression. This case underscores the importance of distinguishing AKU from inflammatory spondyloarthropathy and highlights the need for early diagnosis and interdisciplinary care."

Journal • Ankylosing Spondylitis • Cardiovascular • Immunology • Inflammatory Arthritis • Metabolic Disorders • Orthopedics • Rheumatology • Seronegative Spondyloarthropathies • Spondylarthritis

Neurological crisis in tyrosinemia type 1: Essential roles of replacement therapy and nutrition in multidisciplinary management. (PubMed, Endocrinol Diabetes Nutr (Engl Ed)) - "Following the omission of his usual treatment with nitisinone and the withdrawal of dietary recommendations, the patient developed a severe neurological crisis requiring admission to the intensive care unit (ICU) due to profound diaphragmatic weakness. Despite the initial severity, appropriate management led to a favorable outcome and, eventually, weaning from mechanical ventilation. This case underscores the critical importance of a multidisciplinary approach in the management of inborn errors of metabolism, where nutritional therapy remains the cornerstone of treatment to prevent life-threatening complications."

Journal • Review • Critical care • Metabolic Disorders • Pain • Respiratory Diseases

Targeting the RH5-CyRPA-Ripr Complex: Discovery and Validation of Novel Inhibitors of Plasmodium falciparum Invasion. (ASTMH 2025) - "Nitisinone showed moderate activity, with IC₅₀ values of 82.57 µg/ml (W2mef) and 114.8-407.5 µg/ml across clinical isolates...This study has provided experimental evidence supporting the antiplasmodial potential of the computationally predicted inhibitors. The findings have identified promising lead compounds and demonstrate the value of combining computational screening with experimental validation in the search for new antimalarial drugs."

Late-breaking abstract • Infectious Disease • Malaria

Clinical Role of Tc-99m-MDP Bone Scintigraphy in Patients with Alkaptonuria. A Pilot Study in Ukraine (EANM 2025) - "At the same time, progress was observed in large joints that were not yet affected or slightly affected in 51% (23 of 45 patients) Conclusion Tc-99m bone imaging is likely to be an important tool for monitoring ochronotic or degenerative changes in the course of alkaptonuria. Accordingly, Tc-99m bone scanning may play a key role in the dynamic monitoring of Orfadin therapy"

Clinical • Metabolic Disorders

Variants in GSTZ1 Gene Underlying Maleylacetoacetate Isomerase Deficiency: Characterization of Two New Individuals and Literature Review. (PubMed, Genes (Basel)) - "MAAID should be considered in newborns showing elevated SA and no variants in the FAH gene. Our study reports for the first time the course of SA in a patient affected by MAAID. Furthermore, it expands the molecular epidemiology of this rare disease, also investigating the pathogenicity of a novel splicing mutation. Although our data argue against medical treatment in MAAID, longer follow-up data are warranted."

Journal • Review • Rare Diseases • FANCA

Nitisinone treatment protect hereditary tyrosinemia type I patients against inflammation, DNA and protein oxidative damage by decreasing succinylacetone levels. (PubMed, Metab Brain Dis) - "When evaluating lipoperoxidation (TBARS) we found a significant increase for untreated patients in relation to the control group. Our study was the first to evaluate these parameters in HT1 patients treated with NTBC, and our results allow to suggest that the treatment appears to protect against inflammation, DNA and protein oxidative damage by decreasing SA levels."

Journal • Inflammation • IL2 • IL4

Hereditary Tyrosinemia Type 1: Success and Challenges in Indian Subcontinent. (PubMed, Indian Pediatr) - "Native liver outcomes for HT-1 in the Indian subcontinent remain dismal with a high proportion developing HCC and requiring LT for optimum outcomes."

Journal • Fibrosis • Hepatocellular Cancer • Hepatology • Immunology • Metabolic Disorders • Oncology • Pediatrics • Solid Tumor • Transplantation

Overview of European Practices for Management of Tyrosinemia Type 1: Towards European Guidelines. (PubMed, J Inherit Metab Dis) - "The introduction of nitisinone (NTBC) and newborn screening for Tyrosinemia type 1 (TT1) enabled preemptive treatment of patients, thereby significantly improving outcomes by preventing liver, kidney, and neurological issues...These results align with trends seen in TT1 recommendations over the years. In addition to numerous consistencies, many aspects in TT1 management still differ widely across Europe, suggesting the need for uniform guidance in clinical management beyond existing recommendations."

Journal • Review

Combined alkaptonuria and osteoporosis contributing to chronic back pain. (PubMed, Endocrinol Diabetes Metab Case Rep) - "Diagnosis is established through biochemical testing and molecular genetic analysis of the HGD gene. Therapeutic options now include nitisinone as a causal treatment (available since 2020); however, due to often delayed diagnosis, symptomatic management and treatment of sequelae (pain control, joint care, and osteoporosis therapy) continue to play a major role."

Journal • Ankylosing Spondylitis • Back Pain • Gene Therapies • Immunology • Inflammatory Arthritis • Metabolic Disorders • Musculoskeletal Diseases • Musculoskeletal Pain • Osteoporosis • Pain • Rare Diseases • Rheumatology • Seronegative Spondyloarthropathies • Spondylarthritis

A robust bacterial high-throughput screening assay to identify pharmacological chaperones targeting human homogentisate 1,2-dioxygenase missense variants in alkaptonuria. (PubMed, Eur J Pharmacol) - "Current treatment with nitisinone (NTBC) in combination with a low-protein diet, is associated with severe side effects, underscoring the unmet need for alternative therapies...Our newly developed HTS assay provides a powerful tool for ranking HGD missense variants based on their residual activity, offering insights into genotype-phenotype correlations and enabling compound screening for their stabilization. These findings support the development of targeted therapies and a promising personalized alternative to NTBC for AKU patients."

Journal • Genetic Disorders • Metabolic Disorders

The β-triketone, nitisinone, kills insecticide-resistant mosquitoes through cuticular uptake. (PubMed, Parasit Vectors) - "This study demonstrates that nitisinone exhibits a novel mode of action distinct from current Insecticide Resistance Action Committee (IRAC) classifications by specifically targeting blood digestion processes. Its efficacy against resistant strains and potential for integration into existing vector control interventions, such as treated bednets and indoor residual spraying, highlight nitisinone as a promising candidate for expanding strategies against malaria, dengue, Zika, and other emerging viral diseases."

Journal • Dengue Fever • Infectious Disease • Malaria

Pharmacovigilance of drug-induced cataract using the FDA Adverse Event Reporting System. (PubMed, Sci Rep) - "Disproportionality analysis identified 24 drugs significantly associated with cataract risk, with the highest risks linked to glucocorticoids (e.g., fluticasone furoate, triamcinolone), insulin analogs (e.g., insulin glargine, insulin human), and other agents like nitisinone and ranibizumab. Difluprednate showed the strongest association (Bayesian Confidence Propagation Neural Network [BCPNN] = 7.83), followed by prednisolone (BCPNN = 6.84) and erdafitinib (BCPNN = 5.44)...The majority of cases were reported in females (57.9%), with a noticeable annual increase in cases. This study provides a comprehensive pharmacovigilance evaluation, offering insights into high-risk medications, their onset patterns, and demographic trends, contributing to improved clinical decision-making and cataract prevention strategies."

Adverse events • Journal • Cataract • Oncology • Ophthalmology