EXPLORE B : A prospective, long-term natural history study of patients with acute hepatic porphyria with chronic symptoms

One-year data from EXPLORE Part A showed high disease burden and impaired quality of life (QOL) in patients with acute hepatic porphyria (AHP) with recurrent attacks. We report baseline data of patients who enrolled in EXPLORE Part B for up to an additional 3 years of follow-up. EXPLORE B is a long-term, prospective study evaluating disease activity, pain intensity, and QOL in patients with AHP with >= 1 attack in the 12 months before enrollment or receiving hemin or gonadotropin-releasing hormone prophylaxis. Data were evaluated in patients with more (>= 3 attacks or on prophylaxis treatment) or fewer (= 80% of patients; most received hemin during attacks. Almost three-quarters of patients reported chronic symptoms between attacks, including 85% of patients with fewer attacks. Pain intensity was comparable among both attack subgroups; most patients required pain medication. All groups had diminished QOL on the EuroQol visual analog scale and the European Organisation for Research and Treatment of Cancer Quality-of-life Questionnaire Core 30 versus population norms. Patients with AHP with recurrent attacks, even those having fewer attacks, experience a high disease burden, as evidenced by chronic symptoms between attacks and impaired QOL.Peer reviewe

Disease Burden in Patients with Acute Hepatic Porphyria: Experience from the Phase 3 ENVISION Study

BACKGROUND: Acute hepatic porphyria (AHP) is a family of four rare genetic diseases, each involving deficiency in a hepatic heme biosynthetic enzyme. Resultant overproduction of the neurotoxic intermediates δ-aminolevulinic acid (ALA) and porphobilinogen (PBG) leads to disabling acute neurovisceral attacks and progressive neuropathy. We evaluated the AHP disease burden in patients aged ≥ 12 years in a post hoc analysis of the Phase 3, randomized, double-blind, placebo-controlled ENVISION trial of givosiran (NCT03338816), an RNA interference (RNAi) therapeutic that targets the enzyme ALAS1 to decrease ALA and PBG production. We analyzed baseline AHP severity via chronic symptoms between attacks, comorbidities, concomitant medications, hemin-associated complications, and quality of life (QOL) and evaluated givosiran (2.5 mg/kg monthly) in patients with and without prior hemin prophylaxis on number and severity of attacks and pain scores during and between attacks. RESULTS: Participants (placebo, n = 46; givosiran, n = 48) included patients with low and high annualized attack rates (AARs; range 0-46). At baseline, patients reported chronic symptoms (52%), including nausea, fatigue, and pain; comorbidities, including neuropathy (38%) and psychiatric disorders (47%); concomitant medications, including chronic opioids (29%); hemin-associated complications (eg, iron overload); and poor QOL (low SF-12 and EuroQol visual analog scale scores). A linear relationship between time since diagnosis and AAR with placebo suggested worsening of disease over time without effective treatment. Givosiran reduced the number and severity of attacks, days with worst pain scores above baseline, and opioid use versus placebo. CONCLUSIONS: Patients with AHP, regardless of annualized attack rates, have considerable disease burden that may partly be alleviated with givosiran

Acute Hepatic Porphyrias: Recommendations for Diagnosis and Management with Real-World Examples

Acute hepatic porphyria (AHP) is a group of four rare inherited diseases, each resulting from a deficiency in a distinct enzyme in the heme biosynthetic pathway. Characterized by acute neurovisceral symptoms that may mimic other medical and psychiatric conditions, lack of recognition of the disease often leads to a delay in diagnosis and initiation of effective treatment. Biochemical testing for pathway intermediates that accumulate when the disease is active forms the basis for screening and establishing a diagnosis. Subsequent genetic analysis identifies the pathogenic variant, supporting screening of family members and genetic counseling. Management of AHP involves avoidance of known exogenous and hormonal triggers, symptomatic treatment, and prevention of recurrent attacks. Here we describe six case studies from our own real-world experience to highlight current recommendations and challenges associated with the diagnosis and long-term management of the disease

DNA methylation patterns in alcoholics and family controls

AIM: To assess whether DNA methylation patterns in chronic alcoholics are different from non-alcoholic sibling controls

Disease Burden in Patients With Acute Hepatic Porphyria: Experience From the Phase 3 ENVISION Study

Introduction: Acute hepatic porphyria (AHP) is a family of rare genetic diseases caused by defects in hepatic heme biosynthesis. Intravenous (IV) hemin is the standard of care for acute attacks and is at times used off label prophylactically, but can have acute (e.g. phlebitis) and chronic (e.g. iron overload) complications. The phase 3 ENVISION study (NCT03338816) showed givosiran reduced annualized attack rate (AAR) by 73% versus placebo in the double-blind (DB) period. Open-label extension data showed 85% of patients continuing givosiran were attack free at >15–18 months. Here we summarize data from ENVISION to assess the spectrum of disease burden associated with AHP. Methods: Patients (N=94) enrolled in ENVISION had experienced ≥2 attacks requiring hospitalization, urgent care, or IV hemin at home in the 6 months before the study. This analysis assessed AAR, daily worst pain (eDiary), comorbidity, concomitant medication, and quality of life (12-Item Short Form Health Survey [SF-12]). Results: Patients had severe disease burden at study entry, consistent with AHP burden shown in natural history studies. Patients reported a median of 4 (range, 0–46) attacks during the previous 6 months, despite 40% being on prophylactic hemin. Of all patients, 34% did not have attacks requiring hospitalization. Chronic symptoms, including pain, were experienced by 52% of patients daily or on most days between attacks. Baseline median SF-12 bodily pain score was 40 (scale 0–100), suggesting interference with normal functioning. Overall, 29% of patients used opioids daily or on most days between attacks. Most patients had comorbidities at baseline (47% had psychiatric disorders) (Table 1) and were taking concomitant medications. The median (Q1–Q3) ferritin level was 209 (48–719) µg/L (normal: female, 13–150 µg/L; male, 30–400 µg/L). A moderate linear correlation between longer time since AHP diagnosis and higher AAR with placebo during the 6-month DB period (r=0.403) suggests patients may experience worsening disease and complications over time. Givosiran provided clinical benefit, including reduction of daily worst pain and analgesics use. Conclusion: AHP disease burden, including the number of attacks, comorbidities, and concomitant medication use, has negative impacts on daily functioning. Earlier initiation of treatments, such as givosiran, that prevent attacks and reduce chronic manifestations of AHP may lead to improved prognosis for patients

Evidence-based consensus guidelines for the diagnosis and management of erythropoietic protoporphyria and X-linked protoporphyria.

Erythropoietic protoporphyria and X-linked protoporphyria are rare genetic photodermatoses. Limited expertise with these disorders among physicians leads to diagnostic delays. Here, we present evidence-based consensus guidelines for the diagnosis, monitoring, and management of erythropoietic protoporphyria and X-linked protoporphyria. A systematic literature review was conducted, and reviewed among subcommittees of experts, divided by topic. Consensus on guidelines was reached within each subcommittee and then among all members of the committee. The appropriate biochemical and genetic testing to establish the diagnosis is reviewed in addition to the interpretation of results. Prevention of symptoms, management of acute phototoxicity, and pharmacologic and nonpharmacologic treatment options are discussed. The importance of ongoing monitoring for liver disease, iron deficiency, and vitamin D deficiency is discussed with management guidance. Finally, management of pregnancy and surgery and the safety of other therapies are summarized. We emphasize that these are multisystemic disorders that require longitudinal monitoring. These guidelines provide a structure for evidence-based diagnosis and management for practicing physicians. Early diagnosis and management of these disorders are essential, particularly given the availability of new and emerging therapies

Evidence-based consensus guidelines for the diagnosis and management of erythropoietic protoporphyria and X-linked protoporphyria

Erythropoietic protoporphyria and X-linked protoporphyria are rare genetic photodermatoses. Limited expertise with these disorders among physicians leads to diagnostic delays. Here, we present evidence-based consensus guidelines for the diagnosis, monitoring, and management of erythropoietic protoporphyria and X-linked protoporphyria. A systematic literature review was conducted, and reviewed among subcommittees of experts, divided by topic. Consensus on guidelines was reached within each subcommittee and then among all members of the committee. The appropriate biochemical and genetic testing to establish the diagnosis is reviewed in addition to the interpretation of results. Prevention of symptoms, management of acute phototoxicity, and pharmacologic and nonpharmacologic treatment options are discussed. The importance of ongoing monitoring for liver disease, iron deficiency, and vitamin D deficiency is discussed with management guidance. Finally, management of pregnancy and surgery and the safety of other therapies are summarized. We emphasize that these are multisystemic disorders that require longitudinal monitoring. These guidelines provide a structure for evidence-based diagnosis and management for practicing physicians. Early diagnosis and management of these disorders are essential, particularly given the availability of new and emerging therapies