Orfadin (nitisinone) / Astellas, SOBI - LARVOL DELTA

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

Killing of Anopheles stephensi mosquitoes by selective triketone 4-hydroxyphenylpyruvate dioxygenase inhibitors depends on a high protein meal. (PubMed, Insect Biochem Mol Biol) - "Membrane feeding assays showed that nitisinone's insecticidal activity relies on ingestion of a high-protein meal, with haemoglobin identified as the potent dietary factor driving toxicity. These results highlight HPPD inhibition as a promising blood-meal-dependent vector control strategy specifically targeting haematophagous mosquitoes."

Journal • Infectious Disease • Malaria

Nitisinone desensitization protocol, case report of hereditary Tyrosinemia type 1 with successful treatment and outcomes. (PubMed, Orphanet J Rare Dis) - "Hence, the importance of acknowledging the management of these adverse events is crucial. The aim of this article is to present a rare clinical case and propose a desensitization protocol for Nitisinone for those cases that present adverse reactions to the medication."

Journal • Hepatology • Oncology • Rare Diseases

Musculoskeletal ultrasound features in alkaptonuria with ochronotic arthropathy (EULAR 2025) - "Given the rarity of this condition, diagnostic delay reaches up to decades and most patients miss the therapeutic window offered by the timely administration of Nitisinone... Our MSUS study has been conducted in one of the world’s largest cohort of patients affected by this condition. MSUS seems able to describe the deposition of hyperechoic deposits in tendon, cartilage and fibro-cartilages, and the consequent damages of involved soft tissues (with both reactive inflammatory and degenerative abnormalities). The echoic deposits (probably HGA associated with calcium salts) have an US appearance substantially undistinguishable from those described in CPP deposition disease (CPPD) (i.e."

Ankylosing Spondylitis • Cardiovascular • Heart Failure • Metabolic Disorders • Musculoskeletal Diseases • Nephrology • Osteoarthritis • Pain • Renal Calculi • Renal Disease • Rheumatology • Seronegative Spondyloarthropathies

Validation of Clinical-Grade Electroporation Systems for CRISPR-Cas9-Mediated Gene Therapy in Primary Hepatocytes for the Correction of Inherited Metabolic Liver Disease. (PubMed, Cells) - "Here, we explore the use of the clinical-grade electroporator, the MaxCyte ExPERT GTx, utilized in the first FDA-approved CRISPR therapy, Casgevy, and evaluate its potential in primary hepatocytes in terms of delivery efficiency and cell viability...After surgery, Fah-/- graft recipients were cycled off and on nitisinone to achieve independence from drug-induced Hpd inhibition, an indicator of HT1 disease correction...Mean donor cell engraftment was significantly higher in GTx-recipient mice compared to untransfected control recipients (97.9% and 81.6%, respectively). Our results indicate that the GTx system does not negatively impact hepatocyte functionality and engraftment potential, thereby demonstrating the promise of GTx electroporation in hepatocytes as a viable cell therapy for treating genetic diseases that affect the liver."

Journal • Gene Therapies • Genetic Disorders • Hepatology • Transplantation

Genome Wide rAAV Integration Analysis in a Tyrosinemia Mouse Model Revealed Preference for R-loops in Actively Transcribed Genes and in the Absence of Homology Arms . (ASGCT 2025) - "Standard of care consists on a diet restrictive in tyrosine and phenylalanine and nitisinone (or NTBC) treatment, which results in the cease of toxic metabolite accumulation...It is important to note that the observed levels of rAAV integration are favoured by the disease model, in which FAH expressing hepatocytes are selected for liver repopulation and in which considerable levels of DNA damage are observed. Disease Focus of Abstract:Inborn Errors in Metabolism"

Preclinical • Gene Therapies • Hepatocellular Cancer • Oncology • Solid Tumor • ALB • FANCA

Deep Learning Study of Alkaptonuria Spinal Disease Assesses Global and Regional Severity and Detects Occult Treatment Status. (PubMed, J Inherit Metab Dis) - "Intriguingly, DL models predicted nitisinone treatment status with 68%-77% accuracy, while expert clinicians appeared unable to discern nitisinone status (51% accuracy) (p = 2.0 × 10-9). This highlights the potential for DL to augment certain types of clinical assessments in rare disease, as well as identifying occult features like treatment status."

Journal • CNS Disorders • Metabolic Disorders • Rare Diseases

Specific drugs for rare diseases in a province of eastern China under catalog management: from 2021 to 2023. (PubMed, Front Pharmacol) - "Spesolimab, Sodium Phenylbutyrate, Nitisinone and Emapalumab are currently in short supply, and the delivery rate of 16 drugs such as Selumetinib, Sirolimus (tablet), Octreotide, Dimethyl Fumarate and Lanreotide is below 80%...This indicates a generally high level of accessibility to drugs for rare diseases in China. However, attention should be given to improving the supply capacity for drugs that are in short supply and have a low delivery rate."

Journal • Rare Diseases

A Comprehensive In Vitro and In Silico Approach for Targeting 4-Hydroxyphenyl Pyruvate Dioxygenase: Towards New Therapeutics for Alkaptonuria. (PubMed, Int J Mol Sci) - "Current treatment options are limited, with Nitisinone (Orfadin or NTBC) being the only approved drug...In particular, we evaluated several features of a set of triketone compounds including their inhibitory efficacy, residence time, and ochronotic pigment accumulation. By means of our integrated approach, we investigated the pharmacokinetic and pharmacodynamics properties of novel 4-HPPD inhibitors and provided a promising foundation for the development of safer and more effective treatments for AKU."

Journal • Preclinical • Genetic Disorders • Metabolic Disorders • Pain

CRISPR/Cas9 gene therapy increases the risk of tumorigenesis in the mouse model of hereditary tyrosinemia type I. (PubMed, JHEP Rep) - "We compared the standard of care-nitisinone, a small molecule inhibitor of hydroxyphenylpyruvate dioxygenase (HPD)-with the deletion of the Hpd gene by CRISPR gene therapy...Although the CRISPR-based therapy effectively treated the metabolic condition, it was associated with a higher incidence of liver cancer than the current standard of care. These findings highlight the potential risks of using CRISPR gene therapy in conditions predisposed to cancer development."

Journal • Preclinical • Gene Therapies • Hepatocellular Cancer • Hepatology • Liver Cancer • Oncology • Solid Tumor