Givlaari (givosiran) / Ironwood Pharma, Alnylam - LARVOL DELTA

Enrollment Characteristics and Real-World Insights Into Disease Burden and Givosiran Treatment in Patients With Acute Hepatic Porphyria in the ELEVATE Registry (THSNA 2026) - P | "Enrollment results from patients in the ongoing ELEVATE registry provide insights into patient characteristics and treatment patterns. These results and continued data collection will inform subsequent analyses of the long-term safety and effectiveness of givosiran. These data also underscore the heterogeneous nature of AHP and the substantial burden of comorbidities among affected patients."

Clinical • Real-world • Real-world evidence • Cardiovascular • Chronic Kidney Disease • CNS Disorders • Depression • Genetic Disorders • Hematological Disorders • Hepatology • Hypertension • Metabolic Disorders • Mood Disorders • Nephrology • Renal Disease

Advances in siRNA-Loaded Nanocarriers: Harnessing Cutting-Edge Technologies for Precision Cancer Treatment. (PubMed, Curr Pharm Des) - "siRNA-based therapeutics represent a promising strategy for targeted cancer therapy due to their high specificity and ability to reduce off-target toxicity. Nanocarrier systems have greatly enhanced their clinical viability. However, continued efforts are required to overcome biological barriers and facilitate clinical translation. This review also summarizes FDA-approved siRNA-based drugs such as Onpattro®, Leqvio®, Givlaari®, Oxlumo®, Tavnelis®, and Amvuttra®, underscoring the clinical potential of RNAi-based therapies."

Journal • Oncology

Biallelic pathogenic hydroxymethylbilane synthase gene variants of a neurodegenerative disorder with progressive cystic leukoencephalopathy: a case report. (PubMed, J Med Case Rep) - "For differential diagnosis of cystic leukoencephalopathy, biallelic pathogenic hydroxymethylbilane synthase gene variants should be considered. Its pathogenesis probably differentiates from acute intermittent porphyria. To date, there is no promising therapeutic approach."

Journal • CNS Disorders • Genetic Disorders • Hematological Disorders • Metabolic Disorders • Pain • Psychiatry • Transplantation

Small RNA or oligonucleotide drugs and challenges in evaluating drug-drug interactions. (PubMed, Front Pharmacol) - "Widespread adoption of these strategies has further enabled the application of oligonucleotides as viable drugs and expanded the class of RNA therapeutics, with thirteen antisense oligonucleotides (ASOs) (fomiversen, mipomersen, nusinersen, inotersen, eteplirsen, golodirsen, casimersen, viltolarsen, tofersen, eplontersen, olezarsen, and donidalorsen), seven small interfering RNAs (siRNAs) (patisiran, givosiran, lumasiran, inclisiran, vutrisiran, nedosiran, and fitusiran), and two aptamers (pegaptanib and avacincaptad pegol) that have been approved by the United States Food and Drug Administration (FDA). This article provides an overview of FDA-approved oligonucleotide therapies, emphasizing chemical modifications, molecular targets for mechanistic actions, and available ADME and PK/PD properties, followed by the discussion of critical needs for risk assessment strategies suited for this unique modality that focuses on possible DDIs with concomitant drugs. The latter may..."

Journal • Review

Reproductive health across the lifespan in acute hepatic porphyria (ASH 2025) - "During the 5 years prior to survey completion, 51 patients received heminand 44 received givosiran (an RNAi that suppresses hepatic ALAS-1)... In this US nationwide study of 100 female patients with AHP, we characterized therelationships between reproductive health factors and disease burden. Use of cOCPs, POPs, and depotmedroxyprogesterone was associated with worsening of AHP symptoms, while LNG and copper IUDsappeared to be better tolerated. Pregnancy and lactation generally did not exacerbate symptoms of AHP,whereas perimenopause was associated with symptom worsening."

Cardiovascular • Genetic Disorders • Gynecology • Hematological Disorders • Hepatology • Hypertension • Long-acting Reversible Contraceptives • Metabolic Disorders

Class-Specific Adverse Events of Patients Treated with Small Interfering RNA Therapeutics: A Disproportionality Analysis of the United States Food and Drug Administration Adverse Event Reporting System Database Based on the MY FAERS Platform. (PubMed, Nucleic Acid Ther) - "This study aimed to identify and quantify CAE-siRNA associated with U.S. Food and Drug Administration (FDA)-approved siRNA drugs (patisiran, givosiran, vutrisiran, inclisiran, and lumasiran) using real-world pharmacovigilance data, focusing on potential class-wide effects. This study identified clinically relevant CAE-siRNA, particularly hepatic toxicity for inclisiran, supporting enhanced monitoring. While disproportionality analyses are hypothesis generating, these findings underscore the need for targeted pharmacovigilance to optimize the safety of this promising drug class."

Adverse events • Journal • Back Pain • Fatigue • Gastroenterology • Gastrointestinal Disorder • Musculoskeletal Pain • Pain

Acute hepatic porphyrias. (PubMed, Porto Biomed J) - "Treatment involves high-glucose diets, intravenous hemin for acute attacks, and givosiran for the prophylaxis of frequent attacks...AHP continues to be an underrecognized condition, warranting consideration in individuals experiencing unexplained abdominal pain, neuropathy, psychiatric symptoms, or skin lesions. There is a need for improved diagnostic techniques and treatment options."

Journal • Review • Cardiovascular • Diabetes • Genetic Disorders • Hematological Disorders • Hepatocellular Cancer • Hypertension • Metabolic Disorders • Nephrology • Neuralgia • Oncology • Pain • Psychiatry • Pulmonary Arterial Hypertension • Renal Disease • Solid Tumor • Transplantation

Rare Report of Simultaneous Liver and Kidney Transplant for Acute Intermittent Porphyria (KIDNEY WEEK 2025) - "At the time of transplant, she received simulect induction and was discharged on tacrolimus, cellcept, and prednisone...She has been able to stop givosiran and has had no porphyric attacks since SLKT. Discussion This case details a rare, successful SLKT for AIP, leading to complete remission of porphyric symptoms and full recovery of kidney function. AIP is among a group of select disorders where combined transplant should be considered for optimal outcomes."

Chronic Kidney Disease • Genetic Disorders • Hematological Disorders • Hepatology • Metabolic Disorders • Nephrology • Transplantation • HMBS

Integrating New Therapies into the Management of Classical Heme Disorders (ASH 2024) - "His presentation will overview the current evidence base for luspatercept as a novel disease-modifying agent targeting ineffective erythropoiesis in β-thalassemia. For Dr. Dickey's presentation, she will review the givosiran clinical trial data and the available clinical literature on givosiran, as well as highlight important unanswered questions."

Anemia • Beta-Thalassemia • Cardiovascular • Chronic Kidney Disease • Genetic Disorders • Hematological Disorders • Metabolic Disorders • Nephrology • Renal Disease

Givosiran: A Targeted Treatment for Acute Intermittent Porphyria (ASH 2024) - No abstract available

Genetic Disorders • Hematological Disorders • Metabolic Disorders

Neurovisceral Syndrome in a Patient with Monoclonal Gammopathy of Undetermined Significance: A Confirmed Case of Variegate Porphyria. (PubMed, Cureus) - "He was transitioned to Givosiran, resulting in symptom control and no further flares. This case reinforces the need to consider rare metabolic disorders in unexplained multisystem presentations and highlights the role of enzyme-targeting therapy when conventional treatment is not tolerated."

Journal • Alzheimer's Disease • Cognitive Disorders • Contact Dermatitis • Depression • Dermatitis • Dermatology • Genetic Disorders • Hematological Disorders • Hematological Malignancies • Immunology • Metabolic Disorders • Monoclonal Gammopathy • Pain • Psychiatry • Rare Diseases

A RARE CASE OF VARIEGATE PORPHYRIA IN A PEDIATRIC PATIENT WITH END-STAGE RENAL DISEASE AND SEVERE PSORIASIS (ESPN 2025) - "This case illustrates the diagnostic complexity of porphyria in pediatric patients with ESRD, particularly in the presence of overlapping symptoms. The confirmed PPOX mutation established the diagnosis, enabling targeted therapy with givosiranum and preventing further crises. The coexistence of psoriasis, CKD, and VP poses significant therapeutic challenges, especially regarding medication safety and dialysis management."

Clinical • Anemia • Chronic Kidney Disease • Dermatology • Genetic Disorders • Glomerulonephritis • Hematological Disorders • Immunology • Lupus Nephritis • Metabolic Disorders • Nephrology • Pediatrics • Psoriasis • Renal Disease • PPOX

PREVALENCE, GENETIC CHARACTERIZATION, AND LABORATORY PROFILING OF ACUTE INTERMITTENT PORPHYRIA IN SOUTHWESTERN SERBIA: A CROSS-SECTIONAL STUDY (UEGW 2025) - "Demographic data, family history of porphyria, the annual frequency of attacks, and givosiran therapy use were documented... This study provides the first epidemiological and genetic data on AIP in southwestern Serbia, revealing a notable prevalence in the local population. Despite clinical remission, subclinical laboratory abnormalities, including elevated urea, cholesterol, AST, and ALT, as well as reduced hemoglobin levels, were detectable in a subset of patients. A significant proportion of patients presented without a positive family history, emphasizing the importance of systematic screening."

Observational data • Genetic Disorders • Hematological Disorders • Hepatocellular Cancer • Metabolic Disorders • Solid Tumor

LONGITUDINAL STUDY OF ACUTE HEPATIC PORPHYRIAS IN THE US: BASELINE FEATURES OF 400 SUBJECTS FROM THE PORPHYRIAS CONSORTIUM (AASLD 2025) - "Data including demographic characteristics (gender, race, ethnicity, family history), signs and symptoms, genetic testing, biochemical parameters (ALA, PBG, urine/serum creatinine, AST, ALT), as well as treatment history involving Hematin and Givosiran was entered into a centralized database... AHP remain undiagnosed for many years following the onset of symptoms. This delayed diagnosis can impact the quality of life and lead to the development of chronic medical conditions over time. A comprehensive understanding of the porphyria population in the United States can assist healthcare providers in achieving earlier diagnoses and implementing appropriate management strategies."

Clinical • Longitudinal study • Observational data • Cardiovascular • Chronic Kidney Disease • Gastroenterology • Genetic Disorders • Hematological Disorders • Hepatology • Hypertension • Metabolic Disorders • Nephrology • Renal Disease

DIMENSION ANALYSIS OF ENVISION STUDY EQ-5D DATA TO ASSESS RELATIONSHIP BETWEEN ANNUALIZED ATTACK RATE AND CHRONIC SYMPTOMS IN PATIENTS WITH ACUTE HEPATIC PORPHYRIA (AASLD 2025) - "While attack frequency is often used to categorize AHP, data from the phase 3 ENVISION study of givosiran suggest patients may have chronic symptoms that are not necessarily related to acute attacks... Patients with AHP may experience chronic symptoms not necessarily predicted by historical AAR, including pain/discomfort and anxiety/depression. Broadening the AAR criteria did not meaningfully affect the results. The chronic burden of AHP on health-related quality of life should be assessed regularly to help guide disease management."

Clinical • CNS Disorders • Depression • Genetic Disorders • Hematological Disorders • Hepatology • Metabolic Disorders • Mood Disorders • Psychiatry • Rare Diseases

CLINICAL OUTCOMES AND HEMIN USE OF PATIENTS WITH ACUTE HEPATIC PORPHYRIA IN THE PHASE 3 ENVISION STUDY WHO WERE NOT ATTACK-FREE AFTER 6 MONTHS OF GIVOSIRAN TREATMENT (AASLD 2025) - "Both groups had fewer attacks and other treatment-related improvements with the first 6M of givosiran treatment regardless of the 6M attack status. Those who were not attack-free after the first 6M had further attack reductions and HRQoL improvements with prolonged treatment. The results suggest that the response to givosiran treatment helps with chronic symptoms as well as AHP attacks and further clinical improvement is expected over time."

Clinical • Clinical data • P3 data • Genetic Disorders • Hematological Disorders • Hepatology • Metabolic Disorders • Rare Diseases

Identification of oligonucleotide drug impurities using heart-cutting two-dimensional liquid chromatography-tandem mass spectrometry (2D-LC-MS/MS). (PubMed, Anal Chim Acta) - "This novel heart-cutting 2D-LC-MS/MS method offers a significant advancement in the analysis of impurities in oligonucleotide-based therapeutics. It provides high sensitivity, enabling the identification of subtle impurities that are often challenging to detect. By applying this technique to RNAi drugs, we demonstrate its potential to enhance the safety, efficacy, and stability of oligonucleotide-based therapies, making it a valuable tool for the pharmaceutical industry."

Journal

Successful Pregnancy After Combined Liver and Renal Transplantation in a Patient With Acute Intermittent Porphyria. (PubMed, Case Rep Transplant) - "Our case represents the third case in the literature with a successful combined liver/renal transplantation of a patient with acute porphyria. Thus, transplantation seems to be a viable backup option, should novel therapies such as siRNA treatment with givosiran fail."

Journal • Chronic Kidney Disease • Genetic Disorders • Hematological Disorders • Hepatology • Metabolic Disorders • Nephrology • Pain • Renal Disease • Transplantation

Long-term Outcomes of Acute Hepatic Porphyria Patients Not Attack-Free After 6 Months of Givosiran (ISTH 2025) - P3 | "Mean quality-of-life (QoL) scores improved from baseline in both groups after 6M/36M of treatment: SF-12 Physical Component Summary increased 7.3/8.3 (attack-free) and 4.1/9.1 (not attack-free); EQ-VAS increased 6.9/19.9 (attack-free) and 2.2/17.5 (not attack-free). After 6M/36M of treatment, median reductions from baseline were 88%/93% (attack-free) and 85%/92% (not attack-free) for aminolevulinic acid and 88%/97% (attack-free) and 86%/93% (not attack-free) for porphobilinogen."

Clinical • Genetic Disorders • Hematological Disorders • Hepatology • Metabolic Disorders

EQ-5D Dimensions vs Symptoms Between Attacks in Acute Hepatic Porphyria by Annualized Attack Rate (ISTH 2025) - P3 | "Pooled givosiran and placebo patients were categorized into quartiles by historical AAR...Odds of reporting a problem in any EQ-5D dimension were similar among all AAR quartiles. Table or Figure Upload"

CNS Disorders • Depression • Genetic Disorders • Hematological Disorders • Hepatology • Metabolic Disorders • Mood Disorders • Pain • Psychiatry

Differential Protein Precipitation-Based GalNAc-siRNA Sample Preparation with LC/MS Method Development Workflow in Plasma. (PubMed, Anal Chem) - "This approach achieved a lower limit of quantification in the single-digit ng/mL range for four FDA-approved GalNAc-siRNAs (Givosiran, Lumasiran, Inclisiran, and Vutrisiran) and a major Givosiran metabolite, AS(N-1)3'. The applicability of this approach was successfully demonstrated by analyzing plasma samples from an in vivo rat study involving three molecules (Givosiran, Givosiran AS(N-1)3', and Inclisiran). This method is straightforward, robust, highly sensitive, and cost-effective and should be readily adaptable for the bioanalysis of diverse GalNAc-siRNAs and, potentially, for late-stage sample analyses."

Journal

Efficacy and safety of givosiran in Japanese patients with acute hepatic porphyria: clinical findings from an expanded access study. (PubMed, Sci Rep) - "All adverse events were nonserious, and no deaths occurred. The study indicates that monthly givosiran administration is safe and clinically useful in Japanese patients with AHP."

Journal • Genetic Disorders • Hematological Disorders • Hepatology • Metabolic Disorders • Pain

First Quarter 2025 and Recent Significant Business Highlights (Businesswire) - "Achieved global net product revenues for AMVUTTRA and ONPATTRO for the first quarter of $310 million and $49 million, respectively, representing 36% growth compared to Q1 2024...Achieved global net product revenues for GIVLAARI and OXLUMO for the first quarter of $67 million and $42 million, respectively, representing 8% growth compared to Q1 2024."

Sales • Amyloidosis • Cardiomyopathy • Genetic Disorders • Renal Disease

The Fomivirsen, Patisiran, and Givosiran Odyssey: How the Success Stories May Pave the Way for Future Clinical Translation of Nucleic Acid Drugs. (PubMed, BioDrugs) - "Givosiran (Givlaari; Alnylam) further revolutionized the field with a carrier-free, targeted platform, utilizing N-Acetylgalactosamine (GalNAc)-siRNA conjugates to enable efficient delivery, expanding therapeutic applications beyond rare genetic disorders to more common conditions such as hyperlipidemia and hypertension. In this review paper, we highlight the evolution of nucleic acid-based drug development, focusing on the pioneering agents fomivirsen, patisiran, and givosiran, and discuss the ongoing challenges in advancing these therapeutics and vaccines."

Journal • Cardiovascular • Dyslipidemia • Genetic Disorders • Hypertension

Alnylam Pharmaceuticals Reports Fourth Quarter and Full Year 2024 Financial Results and Highlights Recent Period Progress (Businesswire) - "Achieved global net product revenues for ONPATTRO and AMVUTTRA for the fourth quarter of $56 million and $287 million, respectively, and $343 million combined, representing 35% total TTR growth compared to Q4 2023, and full year 2024 revenues of $253 million and $970 million, respectively, and $1,223 million combined, representing 34% total TTR growth compared to full year 2023...Achieved global net product revenues for GIVLAARI and OXLUMO for the fourth quarter of $65 million and $44 million, respectively, and $108 million combined, representing 18% total Rare growth compared to Q4 2023, and full year 2024 revenues of $256 million and $167 million, respectively, and $423 million combined, representing 29% total Rare growth compared to full year 2023."

Commercial • Amyloidosis • Genetic Disorders • Rare Diseases • Renal Calculi • Renal Disease