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

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

皮質てんかんラットモデルでの視床背内側核刺激の効果

Objective: The mediodorsal thalamic nucleus (MD) has strong connectivity to the limbic systems and frontal lobe. The aim of this study was to determine whether the mediodorsal thalamic nucleus influences seizure induction by electrical stimulation in the rat frontal cortex. Materials and Methods: Juvenile male rats (n = 7) were used in the experiment. At postnatal day 28 (P28), stainless steel skull screws were inserted for stimulating cortices. Depth-stimulating electrodes were stereotaxically inserted into the MD of the bilateral thalamus. Electrical stimulation, which produces afterdischarges, was applied to the frontal cortices once/day for four consecutive days from postnatal day 38. Additional conditioning electrical stimulation to the bilateral MD was fixed at 0.1 mA, and the stimulus frequency was increased from 0 Hz, 1 Hz, and 5 Hz to 10 Hz. All seven rats were stimulated with those frequencies by rotation every other day. The data of animals with 0Hz MD stimulation were defined as controls. Afterdischarge thresholds and durations were measured at each frequency. Results: Seizures were accompanied by bilateral tonic-clonic convulsions and cortical spikes. Seizure behaviors were not different among the groups and there were no statistically significant differences in the cortical afterdischarge (AD) thresholds between animals with MD stimulations and controls in all frequencies. In the cortical AD durations, there were also no statistically significant differences between animals with MD stimulation and controls although the mean duration at 10-Hz stimulation was less than the control animals. Conclusion: These results indicated that thalamic MD stimulation might not suppress epileptic seizure induction. Further studies are needed to analyze other stimulus parameters, altered stimulus locations, and different test paradigms.背景：視床背内側核は前頭葉と辺縁系とに強く結合している．この研究では，前頭葉への電気刺激で励起されるてんかん発作に対し，視床背内側核電気刺激が影響を与えるか否かを検討した．対象と方法：生後28日目の成熟雄ラット（n=7）の脳表（両側前頭葉）にネジ電極を，両側視床背内側核に深部電極を埋め込み，10日間休ませた後38日目から1日1回前頭葉の電極に電気刺激を行い，全身けいれん発作を出現させた．刺激は明らかな後放電（前頭葉の脳表からのてんかん性放電）が出現するまで，徐々に上昇させ，後放電が出現した時点で刺激を終了した．また，一定の刺激電圧（0.1mA）で視床背内側核電気刺激を0Hz，1Hz，5Hz，10Hzの周波数で各ラットに前頭葉刺激と同時に１日おきに行った．それぞれの群で後放電の閾値と持続時間を計測し比較した．結果：けいれん発作は両側前頭葉の棘波とそれに伴う全身強直間代性けいれんであった．後放電の閾値には4群間で有意な差を認めなかった．持続時間に関しては10Hz刺激でコントロール群より軽度短かったものの，全体として有意差を認めなかった．結論：視床背内側核の電気刺激は，今回のような低頻度刺激ではてんかん発作を抑制することは難しいと思われる．今後視床刺激の部位や頻度を変更する必要がある