Autosomal dominant acute porphyrias are rare inherited disorders of haem biosynthesis characterised by accumulation of potentially neurotoxic porphyrin precursors and attacks of severe abdominal pain with autonomic and neuropsychiatric features. Disease severity ranges from asymptomatic individuals to those with recurrent, life-threatening attacks. The International Porphyria Network invited 34 acute porphyria specialists from 17 countries to form an expert panel. The invited group included clinicians from diverse specialities (ie, internal medicine, haematology, endocrinology, gastroenterology, hepatology, neurology, and biochemistry), together with laboratory scientists and patient representatives. The panel met online (in 2023-25) to develop 15 evidence-based recommendations with the use of the Grading of Recommendations, Assessment, Development, and Evaluations framework addressing attack prevention, management of sporadic and recurrent attacks, long-term follow-up, surveillance for primary liver cancer, and family screening. The guidelines support safe, consistent clinical care and improved outcomes, recognising global variation in resources and access to high-cost drugs, and highlighting priorities for future research.

BACKGROUND AND AIMS:Acute intermittent porphyria (AIP) is a rare disorder with diverse clinical presentations, ranging from latent at-risk individuals to recurrent acute attacks with severe complications. Differences between clinical states and risk factors for severe outcomes remain incompletely defined. APPROACH AND RESULTS:In this cross-sectional study, personal, biochemical and clinical data were recorded for non-givosiran treated AIP patients across all clinical states by European porphyria expert centres into the European Porphyria Registry during 2012-2018. Logistic regression models assessed associations between clinical factors and outcomes, with disease states defined according to clinical practice at study initiation. Urinary δ-aminolevulinic acid (u-ALA) and porphobilinogen (u-PBG) were normalized to each centre's upper reference limits. Data from 239 participants were included and patients were classified as sporadic attack(s) (n = 61), recurrent (n = 49), in-remission (n = 58), asymptomatic high excreters (n = 23) and latent at-risk (n = 48). Hospitalization for an acute attack was associated with ≥ 10-fold u-PBG increase (adjusted Odds Ratios [aOR] = 22.40, 95% CI = 5.34-94.03), 4-9-fold (6.35 [2.87-14.02]) and ≥ 10-fold (177.50 [8.03-3923]) u-ALA increase, BMI < 18.5 (12.68 [2.86-56.23]) and age 20-39 (4.35 [1.82-10.42]). A 10-fold u-PBG increase (8.22 [2.31-29.28]) and a positive family history at diagnosis (0.30 [0.14-0.64]) were associated with recurrent classification. Recurrent AIP (7.28 [2.77-19.14]) and sporadic heme-treated acute attacks (5.30 [1.89-14.91]) were associated with reduced work capacity and unemployment. Chronic hypertension, chronic kidney disease and primary liver cancer were observed across all clinical groups. CONCLUSIONS:In this multicentre European study, we describe disease burden across all clinical AIP states including non-givosiran treated recurrent patients and identify risk factors associated with hospitalization and recurrent disease.

Clinically manifest porphyria cutanea tarda (PCT) is a rare condition in childhood; however, several cases have been reported in the literature and at our centre. Porphyria Center Sweden is a national knowledge centre, and since 1987, we have diagnosed approximately 1400 new cases of manifest PCT, of which only five have been children. All children have been identified as heterozygous carriers of a pathogenic UROD gene variant and homozygous for hemochromatosis. In our experience, the diagnosis of children with PCT has been delayed, even in the presence of cutaneous symptoms, without known family history. In this case report, and in another child from our centre, the disease has been suspected due to reddish discolored urine in the absence of cutaneous symptoms. In these two cases, the mothers associated the beetroot red urine with known cases of PCT in the family history. The remaining three cases documented in this report were diagnosed based on cutaneous symptoms.

BACKGROUND:Dysfunction of δ-aminolevulinic acid dehydratase (ALAD), the second enzyme involved in heme biosynthesis, leads to two pathologies: genetic and acquired. The genetic form is an ultrarare, severe childhood-onset disease inherited in an autosomal recessive manner, whereas the acquired form usually affects adults due to enzyme inhibition by specific chemicals. AIMS AND PATIENT COHORT:This study reports the molecular characterization of three pediatric patients with genetic ALAD deficiency porphyria (ADP), including two siblings, and five adults who exhibited features suggestive of heavy metal poisoning. Furthermore, using an innovative mouse liver model, we performed in vivo functional analysis of the pathogenic variants and lead susceptibility alleles identified in the ALAD gene. RESULTS:Siblings (one female) were found to carry the c440_441delinsTT (p.Arg147Leu) variant in homozygosis. However, the vector expression system confirmed a pathogenic role only for the c.440C > T substitution. The third patient exhibited compound heterozygosity, with a c.839G > A (p.Gly280Glu) dominant variant and a hypomorphic c.724G > A (p.Val242Ile) allele. The rs1805313 and rs8177800 common intron variants were most prevalent in patients with acquired ADP. However, increased ALAD activity for the rs1139488 synonymous variant and a hexameric ALAD conformation for the rs1800435 missense variant have been established. CONCLUSION:These findings underscore the molecular heterogeneity of the ALAD gene and present the first reported case of ADP in a female patient.

We describe developments in understanding of the porphyrias associated with each step in the haem biosynthesis pathway and the role of individuals whose contributions led to major advances over the past 150 years. The first case of erythropoietic porphyria was reported in 1870, and the first with acute porphyria in 1889. Photosensitisation by porphyrin was confirmed by Meyer-Betz, who self-injected haematoporphyrin. Günther classified porphyrias into haematoporphyria acuta, acuta toxica, congenita and chronica. This was revised by Waldenström into porphyria congenita, acuta and cutanea tarda, with the latter describing those with late-onset skin lesions. Waldenström was the first to recognise porphobilinogen's association with acute porphyria, although its structure was not solved until 1953. Hans Fischer was awarded the Nobel prize in 1930 for solving the structure of porphyrins and the synthesis of haemin. After 1945, research by several groups elucidated the pathway of haem biosynthesis and its negative feedback regulation by haem. By 1961, following the work of Watson, Schmid, Rimington, Goldberg, Dean, Magnus and others, aided by the availability of modern techniques of porphyrin separation, six of the porphyrias were identified and classified as erythropoietic or hepatic. The seventh, 5-aminolaevulinate dehydratase deficiency porphyria, was described by Doss in 1979. The discovery of increased hepatic 5-aminolaevulinate synthase activity in acute porphyria led to development of haematin as a treatment for acute attacks. By 2000, all the haem biosynthesis genes were cloned, sequenced and assigned to chromosomes and disease-specific mutations identified in all inherited porphyrias. These advances have allowed definitive family studies and development of new treatments.

Acute intermittent porphyria (AIP) is a rare hereditary metabolic disease characterized by acute attacks and accumulation of the porphyrin precursors 5-aminolevulinic acid (ALA) and porphobilinogen (PBG). Patients with AIP have a high risk of primary liver cancer (PLC). We aimed to assess the association between porphyrin precursor excretion and the risk for PLC in patients with AIP. We studied 48 patients with AIP who developed PLC between 1987 and 2015 and 140 age and sex matched controls with AIP but no PLC. Data on all available urinary PBG and ALA samples collected from 1975 until 1 year before PLC diagnosis were analyzed and compared between cases and controls using logistic regression. Porphyrin precursor excretion was higher in patients with PLC (PBG median 7.9 [IQR 4.4-21.9] mmol/mol creatinine) than in controls (3.8 [1.2-9.8]) (adjusted odds ratio 1.07, 95% confidence interval: 1.02-1.12). None of the 28 patients with all registered samples below the upper limit of normal (ULN) developed PLC, and only one of the 45 patients with all samples <2× ULN developed PLC. Among non-PLC controls, ALA and PBG levels decreased after age 50-60 while an increasing trend was observed after age 65 among those who developed PLC. Increased urinary porphyrin precursors are associated with a high risk of developing PLC. Patients with normal levels appear to have a low risk while high or increasing ALA and PBG after age 65 indicates high risk, which should be considered in surveillance decisions.

The acute hepatic porphyrias (AHP) are associated with long-term complications such as primary liver cancer, hypertension, and chronic kidney disease. Data on other related comorbidities are scarce. In this register-based, matched cohort study, we assessed the risks of nonhepatic cancers, cardiovascular diseases, renal diseases, psychiatric disorders, and mortality in relation to porphyria type, sex, and biochemical disease activity. All patients in the Swedish porphyria register with a verified AHP diagnosis during 1987-2015 were included. The biochemical activity of acute intermittent porphyria was assessed using recorded maximal urinary porphobilinogen (U-PBG). Data on incident comorbidities and mortality were collected from national health registries. Cumulative incidences, rates, and hazards were compared to reference individuals from the general population, matched 1:10 by age, sex, and county. We identified 1244 patients with AHP with a median follow-up of 19 years. Health registries identified 149 AHP-subjects (12.0%) with nonhepatic cancer, similar to 1601 (13.0%) in the matched reference population (n = 12 362). Patients with AHP had a higher risk of kidney cancer (0.8% vs. 0.2%, p < 0.001), hypertension, and chronic kidney disease but no increase in risk for cardiovascular disease, except for cerebrovascular disease in patients with elevated U-PBG, (aHR = 1.40 [95% CI:1.06-1.85]). Mortality risk during follow-up was higher among patients with AHP (21% vs. 18%, p = 0.001), and associated with primary liver cancer, female sex, and biochemical activity. In conclusion, AHP is associated with an increased risk of kidney cancer, hypertension, chronic kidney disease, and mortality but not with cardiovascular disease or other nonhepatic cancers.

The acute hepatic porphyrias (AHP) are associated with a risk of primary liver cancer (PLC), but risk estimates are unclear, and what AHP characteristics that predict PLC risk are unknown. In this register-based, matched cohort study, we assessed the PLC risk in relation to biochemical and clinical porphyria severity, genotype, age, and sex. All patients in the Swedish porphyria register with acute intermittent porphyria (AIP), variegate porphyria (VP), or hereditary coproporphyria (HCP) during 1987‒2015 were included. This AHP cohort was compared with age-, sex-, and county-matched reference individuals from the general population. National register-based hospital admissions for AHP were used to indicate the clinical severity. For AIP, the most common AHP type, patients were stratified by genotype and urinary porphobilinogen (U-PBG). Incident PLC data were collected from national health registers. We identified 1244 individuals with AHP (1063 [85%] AIP). During a median follow-up of 19.5 years, we identified 108 incident PLC cases, including 83 AHP patients (6.7%) and 25 of 12,333 reference individuals (0.2%). The adjusted hazard ratio for AHP-PLC was 38.0 (95% confidence interval: 24.3‒59.3). Previously elevated U-PBG and hospitalizations for porphyria, but not AIP genotype or sex, were associated with increased PLC risk. Patients aged >50 years with previously elevated U-PBG ( n = 157) had an annual PLC incidence of 1.8%. This study confirmed a high PLC risk and identified a strong association with clinical and biochemical AIP activity. Regular PLC surveillance is motivated in patients older than 50 years with a history of active AIP.

Background The acute hepatic porphyrias (AHP) are associated with a risk of primary liver cancer (PLC), but risk estimates are unclear, and what AHP characteristics that predict PLC risk are unknown. In this register-based, matched cohort study, we assessed the PLC risk in relation to biochemical and clinical porphyria severity, genotype, age, and sex. Methods All patients in the Swedish porphyria register with acute intermittent porphyria (AIP), variegate porphyria (VP), or hereditary coproporphyria (HCP) during 1987-2015 were included. This AHP cohort was compared with age-, sex-, and county-matched reference individuals from the general population. National register-based hospital admissions for AHP were used to indicate the clinical severity. For AIP, the most common AHP type, patients were stratified by genotype and urinary porphobilinogen (U-PBG). Incident PLC data were collected from national health registers. Results We identified 1244 individuals with AHP (1063 [85%] AIP). During a median follow-up of 19.5 years, we identified 108 incident PLC cases, including 83 AHP patients (6.7%) and 25 of 12,333 reference individuals (0.2%). The adjusted hazard ratio for AHP-PLC was 38.0 (95% confidence interval: 24.3-59.3). Previously elevated U-PBG and hospitalizations for porphyria, but not AIP genotype or sex, were associated with increased PLC risk. Patients aged >50 years with previously elevated U-PBG (n = 157) had an annual PLC incidence of 1.8%. Conclusion This study confirmed a high PLC risk and identified a strong association with clinical and biochemical AIP activity. Regular PLC surveillance is motivated in patients older than 50 years with a history of active AIP.

Acute hepatic porphyria (AHP) is a group of inherited metabolic disorders that affect hepatic heme biosynthesis. They are associated with attacks of neurovisceral manifestations that can be life threatening and constitute what is considered an acute porphyria attack. Until recently, the sole specific treatment for acute porphyria attacks consisted of the intravenous administration of hemin. Although attacks are often sporadic, some patients develop recurrent acute attacks, with devastating effects on quality of life. Liver transplantation has historically been the sole curative treatment option. The clinical manifestations of AHP are attributed to the accumulation of the heme precursor 5-aminolevulinic acid (ALA) and porphobilinogen (PBG). Advances in molecular engineering have provided new therapeutic possibilities for modifying the heme synthetic pathway. We reviewed the background and current status of AHP treatment using liver-directed small interfering RNA targeting ALAS1 . The therapeutic aim was to normalize the levels of ALAS1, which is highly upregulated during acute porphyria attacks. Givosiran is now an approved drug for use in adults and adolescents aged 12 years and older. The results of clinical trials have shown that givosiran treatment leads to a rapid and sustained reduction of ALAS1 mRNA, decreased heme precursor levels, and a decreased rate of acute attacks compared with placebo. The clinical trials (phases I, II, and III) were all randomized and placebo controlled. Many patients enrolled in the initial clinical trials have continued treatment in open label extension and extended/compassionate-use programs in countries where givosiran is not yet commercially available.

Acute hepatic porphyria (AHP) is a group of inherited metabolic disorders that affect hepatic heme biosynthesis. They are associated with attacks of neurovisceral manifestations that can be life threatening and constitute what is considered an acute porphyria attack. Until recently, the sole specific treatment for acute porphyria attacks consisted of the intravenous administration of hemin. Although attacks are often sporadic, some patients develop recurrent acute attacks, with devastating effects on quality of life. Liver transplantation has historically been the sole curative treatment option. The clinical manifestations of AHP are attributed to the accumulation of the heme precursor 5-aminolevulinic acid (ALA) and porphobilinogen (PBG). Advances in molecular engineering have provided new therapeutic possibilities for modifying the heme synthetic pathway. We reviewed the background and current status of AHP treatment using liver-directed small interfering RNA targeting ALAS1. The therapeutic aim was to normalize the levels of ALAS1, which is highly upregulated during acute porphyria attacks. Givosiran is now an approved drug for use in adults and adolescents aged 12 years and older. The results of clinical trials have shown that givosiran treatment leads to a rapid and sustained reduction of ALAS1 mRNA, decreased heme precursor levels, and a decreased rate of acute attacks compared with placebo. The clinical trials (phases I, II, and III) were all randomized and placebo controlled. Many patients enrolled in the initial clinical trials have continued treatment in open label extension and extended/compassionate-use programs in countries where givosiran is not yet commercially available.

Givosiran (trade name GIVLAARI) is a small interfering ribonucleic acid that targets hepatic delta‐aminolevulinic acid synthase 1 (ALAS1) messenger RNA for degradation through RNA interference (RNAi) that has been approved for the treatment of acute hepatic porphyria (AHP). RNAi therapeutics, such as givosiran, have a low liability for drug‐drug interactions (DDIs) because they are not metabolized by cytochrome 450 (CYP) enzymes, and do not directly inhibit or induce CYP enzymes in the liver. The pharmacodynamic effect of givosiran (lowering of hepatic ALAS1, the first and rate limiting enzyme in the heme biosynthesis pathway) presents a unique scenario where givosiran could potentially impact heme‐dependent activities in the liver, such as CYP enzyme activity. This study assessed the impact of givosiran on the pharmacokinetics of substrates of 5 major CYP450 enzymes in subjects with acute intermittent porphyria (AIP), the most common type of AHP, by using the validated “Inje cocktail,” comprised of caffeine (CYP1A2), losartan (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), and midazolam (CYP3A4). We show that givosiran treatment had a differential inhibitory effect on CYP450 enzymes in the liver, resulting in a moderate reduction in activity of CYP1A2 and CYP2D6, a minor effect on CYP3A4 and CYP2C19, and a similar weak effect on CYP2C9. To date, this is the first study evaluating the DDI for an oligonucleotide therapeutic and highlights an atypical drug interaction due to the pharmacological effect of givosiran. The results of this study suggest that givosiran does not have a large effect on heme‐dependent CYP enzyme activity in the liver.

Objectives: Acute Hepatic Porphyria (AHP) is a family of rare genetic diseases leading to an enzyme deficiency in the heme biosynthesis pathway, causing accumulation of neurotoxic heme intermediates, resulting in neurovisceral attacks and chronic manifestations. Givosiran, an investigational RNAi therapeutic, is being evaluated for its ability to reduce the levels of neurotoxic intermediates thus decreasing attacks and disease manifestations.

Introduction: Acute hepatic porphyria (AHP) is a family of rare genetic diseases due to enzyme defects in hepatic heme biosynthesis. Induction of 5-aminolevulinic acid synthase 1 (ALAS1), the rate-limiting step in heme biosynthesis, leads to accumulation of heme intermediates, 5-aminolevulinic acid (ALA) and porphobilinogen (PBG) that may result in neurovisceral attacks. ENVISION (NCT03338816) is an ongoing study, evaluating efficacy and safety of givosiran in symptomatic AHP patients in a 6-month double blind (DB) period and a 30-month open label extension (OLE) period. While the efficacy and safety profile of givosiran has previously been reported in the DB period, here its effect through Month 18 of the OLE period is reported. Methods: ENVISION is an ongoing Phase 3 global, randomized, placebo-controlled study. Exploratory efficacy outcome measures in the OLE included composite porphyria attacks (i.e. those requiring hospitalization, urgent care, or IV-hemin at home), ALA/PBG levels and hemin use. In addition, quality of life assessments (Physical Component Summary Short Form-12 [PCS SF-12], EuroQoL Visual analog scale [EQ-VAS]), the Porphyria Patient Experience Questionnaire (PPEQ), and missed days of work were assessed. Analyses were descriptive and represent the timepoint after which all patients completed at least their Month 18 visit (01/10/2020). Results: As of January 10, 2020, 94 patients completed the DB period and 93 patients entered the OLE (placebo/givosiran=46; givosiran/givosiran=47). Mean exposure to givosiran at data cutoff was 12.97 [SD=3.6] months for placebo/givosiran and 18.86 [3.6] months for givosiran/givosiran, with maximum exposure of 25.1 months. Continued treatment in givosiran/givosiran patients led to a median annualized attack rate (AAR) of 0.58 (range: 0-16.2) through Month 18. Patients in the placebo/givosiran group had an AAR of 1.62 (range: 0-11.8) after receiving givosiran for ≥12 months during the OLE period, compared with 10.65 (range: 0-51.6) whilst receiving placebo during the 6-month DB period. The average number of attacks per patient over time following givosiran treatment continued to decline during the OLE period for both groups (Figure 1). Sustained ALA/PBG lowering during the OLE was accompanied by sustained reductions in hemin use, and more than half of the placebo/givosiran patients experienced 0 days of hemin use. Improvements in PCS SF-12 scores at Month 6 (mean change from baseline=+5.1 [SD=9.0]) were maintained at Month 18 (mean change from baseline=+7.0 [7.0]) for givosiran/givosiran patients, with similar improvements observed in placebo/givosiran patients at Month 18 (mean change from baseline=+9.9 [8.2]). Continued givosiran treatment in givosiran/givosiran patients led to further improvements in EQ VAS compared with DB period (mean change from baseline 5.2 at completion of the DB period [SD=22.2] and 13.7 [22.5] at Month 18 during the OLE period), with placebo/givosiran patients also showing improvements at Month 18 (mean change from baseline 8.3 [SD=18.5]). Placebo/givosiran patients reported improvements in PPEQ scores (traveling, social activities, planning future events, household chores, exercise, and treatment satisfaction) since initiating givosiran, comparable to the improvement observed in the givosiran group during the DB period. Additionally there was a decrease in the number of work days missed due to porphyria in the past 4 weeks at Month 6 (mean=6.7 days [SD=7.8], n=20/46) compared with Month 18 (2.5 [5.1], n=23/46), for patients in the placebo/givosiran group who were able to work. The most common related adverse events (AEs) occurring during givosiran treatment were injection site reactions, nausea and fatigue. Hepatic and renal events were both reported in 17% of patients each during givosiran treatment. No new safety concerns occurred in the OLE compared with DB period. Conclusion: In the ongoing OLE period of the ENVISION study, patients receiving long-term treatment with givosiran demonstrated a durable response in clinical efficacy, across a wide range of clinical parameters. Following the initial 6 months of givosiran treatment during the OLE, placebo/givosiran patients had a similar clinical response to that observed in givosiran/givosiran patients in the OLE period through Month 18. The safety profile of givosiran remained acceptable and consistent with that previously observed. Disclosures Kuter: Bristol-Myers Squibb: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Dova: Consultancy, Honoraria; Momenta: Consultancy, Honoraria; Argenx: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Agios: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Daiichi Sankyo: Consultancy, Honoraria; Actelion (Syntimmune): Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Protalex: Consultancy, Honoraria, Research Funding; Shionogi: Consultancy; UCB: Consultancy, Honoraria; Platelet Disorder Support Association: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Caremark: Consultancy, Honoraria; CRICO: Consultancy, Honoraria; Immunovant: Other: Travel Expenses, Research Funding; Kezar Life Sciences, Inc: Other, Research Funding; Principia Biopharma: Consultancy, Honoraria, Other, Research Funding; Protalex: Consultancy, Honoraria, Other, Research Funding; Sanofi (Genzyme): Consultancy, Honoraria; Genzyme: Consultancy, Honoraria; Immunovant: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Kyowa-Kirin: Consultancy, Honoraria; Merck Sharp Dohme: Consultancy, Honoraria; Protalix Biotherapeutics: Consultancy; Principia: Consultancy, Research Funding; Shire: Consultancy, Honoraria; Shionogi: Consultancy, Honoraria; Up-To-Date: Consultancy, Honoraria, Patents & Royalties; Zafgen: Consultancy, Honoraria; Takeda (Bioverativ): Consultancy, Honoraria, Other, Research Funding; Rigel: Consultancy, Honoraria, Other, Research Funding; Alnylam: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Amgen: Consultancy, Honoraria, Other: Travel Expenses, Research Funding. Rees:AstraZeneca: Other: Data monitoring committee membership; Novartis: Consultancy, Honoraria; TauRx: Other: Data And Safety Monitoring; Alnylam Pharmaceuticals: Consultancy, Honoraria; Emmanus Medical: Consultancy, Honoraria. Ventura:Alnylam Pharmaceuticals: Consultancy, Honoraria; Recordati Rare Diseases: Consultancy, Honoraria. Balwani:Recordati Rare Diseases: Consultancy, Honoraria, Other: Disease information video recording; Alnylam Pharmaceuticals: Consultancy, Honoraria, Research Funding. Gouya:Alnylam Pharmaceuticals: Consultancy, Honoraria, Other: Scientific meeting. Simon:Alnylam Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Liu:Alnylam Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Ko:Alnylam Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Rhyee:Alnylam Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Silver:Alnylam Pharmaceuticals: Other: Travel reimbursement, Research Funding; Blue Care Network: Consultancy; Oncology Business Review: Speakers Bureau.

Background Up-regulation of hepatic delta-aminolevulinic acid synthase 1 (ALAS1), with resultant accumulation of delta-aminolevulinic acid (ALA) and porphobilinogen, is central to the pathogenesis of acute attacks and chronic symptoms in acute hepatic porphyria. Givosiran, an RNA interference therapy, inhibits ALAS1 expression. Methods In this double-blind, placebo-controlled, phase 3 trial, we randomly assigned symptomatic patients with acute hepatic porphyria to receive either subcutaneous givosiran (2.5 mg per kilogram of body weight) or placebo monthly for 6 months. The primary end point was the annualized rate of composite porphyria attacks among patients with acute intermittent porphyria, the most common subtype of acute hepatic porphyria. (Composite porphyria attacks resulted in hospitalization, an urgent health care visit, or intravenous administration of hemin at home.) Key secondary end points were levels of ALA and porphobilinogen and the annualized attack rate among patients with acute hepatic porphyria, along with hemin use and daily worst pain scores in patients with acute intermittent porphyria. Results A total of 94 patients underwent randomization (48 in the givosiran group and 46 in the placebo group). Among the 89 patients with acute intermittent porphyria, the mean annualized attack rate was 3.2 in the givosiran group and 12.5 in the placebo group, representing a 74% lower rate in the givosiran group (P<0.001); the results were similar among the 94 patients with acute hepatic porphyria. Among the patients with acute intermittent porphyria, givosiran led to lower levels of urinary ALA and porphobilinogen, fewer days of hemin use, and better daily scores for pain than placebo. Key adverse events that were observed more frequently in the givosiran group were elevations in serum aminotransferase levels, changes in serum creatinine levels and the estimated glomerular filtration rate, and injection-site reactions. Conclusions Among patients with acute intermittent porphyria, those who received givosiran had a significantly lower rate of porphyria attacks and better results for multiple other disease manifestations than those who received placebo. The increased efficacy was accompanied by a higher frequency of hepatic and renal adverse events. (Funded by Alnylam Pharmaceuticals; ENVISION ClinicalTrials.gov number,.) In a randomized phase 3 trial involving patients with acute intermittent porphyria, the use of givosiran, an oligonucleotide drug designed to target messenger RNA encoding aminolevulinic acid synthase, led to a 74% lower annualized porphyria attack rate than the use of placebo at 6 months.

In cases of recurrent attacks of acute porphyria during pregnancy, prophylactic administration of heme arginate should be considered. Clinical and biochemical monitoring of the disease and a close collaboration with a porphyria center are crucial.

INTRODUCTION: Acute Hepatic Porphyria (AHP) is a family of rare genetic diseases due to enzyme defects in heme synthesis in the liver. Accumulation of toxic heme intermediates ALA and PBG may result in neurovisceral attacks and chronic manifestations. Intravenous (IV) hemin is approved to treat acute attacks and is sometimes used off-label prophylactically. In the ENVISION study in AHP patients, givosiran, an RNAi therapeutic, reduced the composite porphyria annualized porphyria attack rate (AAR) vs. placebo (pbo). A post-hoc analysis was conducted to evaluate outcomes in AHP patients with or without prior hemin prophylaxis prior to screening. METHODS: ENVISION (NCT03338816) is an ongoing Phase 3 global, randomized, pbo-controlled study, evaluating givosiran efficacy and safety in symptomatic AHP patients in a 6-month double blind (DB) period and an open label extension (OLE) period (30 months). Patients were required to discontinue prophylactic hemin treatment at study entry, but could receive hemin for acute attacks. Outcome measures included the composite porphyria AAR (defined as attacks requiring hospitalization, urgent care, or IV hemin at home). Analyses were descriptive. RESULTS: For AHP patients on prior hemin prophylaxis (median historical AAR: 9.0), a 77% reduction in mean AAR was observed with givosiran treatment vs. pbo in the DB period (Table 1). A similar reduction (63%) in mean AAR was observed in those without prior hemin prophylaxis (median historical AAR: 7.0). In both groups, further reduction in AAR was observed in patients who continued on givosiran in the OLE period (Table 1). A similar reduction in AAR was also observed in both groups of pbo patients who received givosiran in the OLE (Table 1). The percentage of patients with 0 composite attacks increased in each group following 6-months of givosiran treatment in the OLE with 55% and 67% in the patients who had continued givosiran treatment (Table 1). Additional analyses of outcome measures between the two groups will be presented. CONCLUSION: Clinically meaningful reduction in the AAR was observed in AHP patients treated with givosiran regardless of whether they received hemin prophylaxis prior to study entry, with further AAR reduction observed in those who continued to receive givosiran during the OLE. In addition, a similar benefit was observed in pbo patients who received givosiran for 6-months during the OLE period regardless of prior hemin prophylaxis use.Table 1