Fatigue Item Response among Hemoglobin-Normalized Patients with Paroxysmal Nocturnal Hemoglobinuria: PEGASUS Trial Results at 16 and 48 Weeks.

Background. A common symptom of paroxysmal nocturnal hemoglobinuria (PNH) is fatigue, which in some patients can be severe. Eculizumab (Ecu) has proven efficacy in controlling intravascular hemolysis, but commonly results in persistent anemia and fatigue. Pegcetacoplan's (Peg) efficacy was documented in the PEGASUS phase III clinical trial, showing improved hemoglobin (Hb) and patient-reported fatigue. This post-hoc analysis sought to describe this fatigue improvement related to Hb normalization using the Functional Assessment of Chronic Illness Therapy-Fatigue subscale (FACIT-F)'s individual questions to speak more directly to patients' experience and clinicians' day-to-day practice. Methods. The PEGASUS trial compared Peg with Ecu in patients who remained anemic on Ecu over 16 weeks (n = 41 and 39, for Peg and Ecu, respectively), after which all patients received Peg open label for 32 weeks ("Peg" vs. "Ecu-to-Peg" at Week 48). Hb normalization was defined as ≥12-16 g/dL for females and ≥13.6-18 g/dL for males. The FACIT-F assessed fatigue. Using the complete-case data set, Cohen's d summarized the effect sizes of the mean FACIT-F item change for both study arms from the baseline to week 16 (n = 36 and 37, for Peg and Ecu, respectively) and from the baseline to week 48 (n = 30 and 29, for Peg and Ecu-to-Peg, respectively), and for Hb-normalized patients in each study arm from the baseline to week 16 (n = 14 and 0, for Peg and Ecu, respectively) and from the baseline to week 48 (n = 10 and 12, for Peg and Ecu-to-Peg, respectively). Results. The FACIT-F scores for both arms were worse at the baseline compared to later in the trial. Peg patients reported improvements on all fatigue items at Week 16, but Ecu patients reported improvement in only one item. At Week 48, the improvement in fatigue was maintained in Peg patients, and Ecu-to-Peg patients' fatigue improved on all FACIT-F items. Hb normalization was achieved in 14 Peg patients but no Ecu patients at Week 16, and in 10 Peg and 12 Ecu-to-Peg patients, respectively, at week 48. The FACIT-F single items showing the largest change overall, and particularly in Hb-normalized patients across the study arms, were related to symptoms and social limitations. Conclusions. Peg patients reported lasting improvements in fatigue. Patients who were anemic on Ecu reported sustained improvements in fatigue with Peg treatment. Patients who had Hb normalization generally had large, clinically important improvements in fatigue items.

Prevalence of Nonalcoholic Steatohepatitis and Associated Fibrosis Stages Among US Adults Using Imaging-Based vs Biomarker-Based Noninvasive Tests.

Introduction: Nonalcoholic fatty liver disease (NAFLD) is believed to be the most common chronic liver disease worldwide. Therapies are under development for nonalcoholic steatohepatitis (NASH), the progressive form of NAFLD, such that the prevalence of NASH with liver fibrosis, which is likely to require treatment, may be of interest to healthcare decision makers. Noninvasive tests are used in initial screening for NASH, as well as in observational studies of NASH prevalence. However, existing evidence does not address how estimated prevalence varies with different noninvasive tests. This analysis estimated the prevalence of NASH among US adults and assessed variation with different noninvasive tests. Methods: A cross-sectional analysis was conducted using the 2017-March 2020 National Health and Nutrition Examination Survey cycle. Participants with presumed NAFLD (steatosis and without alternative causes of liver disease) were identified, among whom NASH was predicted based on FAST score, Fibrosis-4 (FIB-4), and AST-to-Platelet Ratio Index (APRI) cutoffs across 11 scenarios. Among NASH participants, fibrosis stages were explored based on distribution across the spectrum of liver-stiffness measurements. Results: Among participants with complete data for the analysis (N=6969), prevalence of presumed NAFLD was 25.6%. Within presumed NAFLD, prediction of NASH using imaging-based NIT cutoffs yielded estimated prevalence of 1.3%-4.8% (3.3 million-12.2 million) based on FAST score cutoffs from 0.35-0.67. Using biomarker-based NIT cutoffs yielded estimated prevalence of 0.4%-12.3% (1.0 million-14.5 million) based on FIB-4 cutoffs from 0.90-2.67, and 0.1%-1.9% (0.2-5.0 million) based on APRI cutoffs from 0.50-1.50. Conclusion: Prevalence of NASH among US adults was estimated to range from 1.3% to 4.8% when predicted using imaging-based noninvasive test values for participants with presumed NAFLD, generally aligning with estimates in the literature of prevalence of biopsy-confirmed NASH. Use of biomarker-based noninvasive test values for prediction of NASH yielded a wider range of estimates with FIB-4, and a considerably lower range of estimates with APRI.

Dosing Patterns of Patients with Paroxysmal Nocturnal Hemoglobinuria Treated with Ravulizumab in the United States: A Retrospective Claims-Based Analysis.

INTRODUCTION: Complement factor 5 inhibitors eculizumab and, recently, ravulizumab are standard therapies for paroxysmal nocturnal hemoglobinuria (PNH). However, some patients experience suboptimal response and may benefit from dosage adjustments. Ravulizumab is administered less frequently than eculizumab on the basis of patient's body weight. This retrospective analysis of insurance claims investigated ravulizumab dosing patterns among patients with PNH from the USA. METHODS: Patients aged ≥ 12 years with ≥ 2 ravulizumab infusions between June 21, 2019 and May 6, 2021, and ≥ 6 months of continuous clinical activity prior to first ravulizumab infusion (index date) were identified from the Symphony Health Integrated Dataverse (IDV®) database. Observed mean (standard deviation, SD) ravulizumab doses administered were reported and stratified by previous eculizumab use. Scenarios adjusting for patients' body weights (unavailable in Symphony Health IDV) based on the US general population distribution were performed to estimate percentages of patients receiving label-recommended doses. RESULTS: Among 433 patients (mean [SD] age 47 [17] years), the mean (SD) loading dose was 3316.3 (2931.7) mg, greater than the maximal label-recommended loading dose (3000 mg for patients ≥ 100 kg). The mean (SD) loading doses were 3581.3 (3673.7) mg for eculizumab-naive versus 3093.1 (2096.8) mg for eculizumab-experienced patients. Over a mean (SD) treatment period of 11.8 (6.9) months, the mean (SD) average maintenance dose was 3403.7 (1024.4) mg, falling between label-recommended maintenance dose categories (3300 mg for ≥ 60 to < 100 kg; 3600 mg for ≥ 100 kg). Estimated percentages of patients receiving label-recommended loading and maintenance doses were 23.1% and 39.2%, respectively; 59.1% and 28.4% were estimated to receive above label-recommended loading and average maintenance doses, respectively. CONCLUSION: Although limited by missing clinical characteristics including body weight, this study of ravulizumab dosing patterns in patients with PNH identified potential deviations from label-recommended dosing, warranting further investigations of treatment response to complement inhibitors in PNH.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare blood disease. Complement factor 5 (C5) inhibitors can help treat PNH symptoms; health care providers administer C5 inhibitors to patients during clinic or office visits. Eculizumab was the first C5 inhibitor approved for PNH. Some patients still experience symptoms with approved eculizumab doses and may need to receive larger or more frequent doses than recommended. The new C5 inhibitor ravulizumab offers reduced dosing frequency and is dosed on the basis of patients' body weights. This study assessed ravulizumab doses administered to patients with PNH in the USA using insurance claim records. Studied patients were 12 years or older and received two or more ravulizumab doses between June 21, 2019 and May 6, 2021. Researchers assessed ravulizumab doses administered to patients on the basis of body weight distribution of the US general population. The average first (loading) ravulizumab dose administered to 433 patients was 3316 mg. This was above the largest recommended loading dose of 3300 mg for patients weighing 100 kg (220 pounds) or more. Over nearly 12 months on average, the average maintenance dose administered was 3403 mg. Researchers estimated that larger loading doses than recommended were administered to almost 6 out of 10 patients and larger maintenance doses than recommended were administered to almost 3 out of 10 patients. This study found that larger than recommended ravulizumab doses may have been administered to some patients with PNH. More studies are needed to evaluate treatment response to complement inhibitors in patients with PNH.

Pegcetacoplan in paroxysmal nocturnal haemoglobinuria: Its use, its clinical effectiveness, and its influence on health-related quality of life and productivity.

OBJECTIVES: To describe real-world use/effectiveness of pegcetacoplan (PEG) in paroxysmal nocturnal haemoglobinuria (PNH). METHODS: Data were drawn from the Adelphi PNH Disease Specific Programme™, a cross-sectional survey conducted in France, Italy, Germany, Spain and the United States from January to November 2022. Patients had a confirmed PNH diagnosis and received PEG for ≥1 month. Physicians reported patient characteristics, treatment use/satisfaction and their perception of patients' fatigue and health-related quality of life (HRQoL). Patients reported treatment satisfaction and completed questionnaires assessing fatigue, HRQoL and productivity. Descriptive statistics were reported. RESULTS: Overall, 14 physicians provided data for 61 patients who had received 1080 mg/dose PEG for 1.3-14.8 months. At data collection compared to PEG initiation: haemoglobin was 2.5 g/dL higher on average; proportion of patients with lactate dehydrogenase (LDH) ≥1.5 × upper limit of normal was reduced by 27.4%; physician-perceived fatigue was lower and HRQoL better. Physician- and patient-reported treatment satisfaction was high for >90% of patients. Physicians and patients were more satisfied with PEG than previously prescribed C5 complement inhibitors. Mean work impairment and activity impairment in the 7 days prior to data collection were 32.9% and 22.4%, respectively. CONCLUSIONS: These real-world data support the effectiveness of PEG through positive effects on haemoglobin, LDH, fatigue and HRQoL.

Analysis of Costs per Responder in US Adults with Paroxysmal Nocturnal Hemoglobinuria with a Suboptimal Response to Prior Eculizumab Treatment.

European Society for Blood and Marrow Transplantation (EBMT) hematologic response categories comprehensively assess complement inhibitor responses in patients with paroxysmal nocturnal hemoglobinuria (PNH). Using data from the 16-week randomized controlled period of the phase 3 PEGASUS trial (N = 80), we estimated the treatment cost per responder by the EBMT response category for pegcetacoplan and eculizumab in adults with PNH and a suboptimal response to eculizumab. Average drug costs per responder, number needed to treat, and incremental drug costs per responder were estimated using dosages administered during the trial (base case). A US payer perspective (2020 US dollars) was used. Scenario analyses were conducted for various costs, dosages, treatment durations, patient populations, and settings. In total, 30 of 41 (73%) who switched to pegcetacoplan and 2 of 39 (5%) patients who continued eculizumab had a good, major, or complete response (good-to-complete responders) at Week 16. Average weekly drug costs per good-to-complete responder were USD 15,923 with pegcetacoplan and USD 216,100 with eculizumab; average weekly drug costs per patient were USD 11,651 and USD 11,082, respectively. Average drug costs per good-to-complete responder with pegcetacoplan were similar across complement inhibitor-naïve populations and were consistently lower than with eculizumab. Switching from eculizumab to pegcetacoplan allowed more patients with a suboptimal response to attain a good-to-complete response at lower costs. These results apply to patients with a suboptimal response to prior eculizumab treatment only.

Cross-walk of the Chronic Liver Disease Questionnaire for Nonalcoholic Steatohepatitis (CLDQ-NASH) and the EuroQol EQ-5D-5L in patients with NASH.

BACKGROUND: Nonalcoholic steatohepatitis (NASH) is a chronic progression of nonalcoholic fatty liver disease, which can negatively impact the health-related quality of life (HRQoL) of affected individuals. HRQoL in NASH has been assessed using the disease-specific Chronic Liver Disease Questionnaire for NASH (CLDQ-NASH) and the generic EuroQol EQ-5D-5L. As the performance of these instruments relative to each other is unknown, we performed a cross-walk analysis of CLDQ-NASH to EQ-5D-5L using data from a real-world NASH population. METHODS: Data were drawn from the Adelphi Real World 2019 NASH Disease Specific Programme, a cross-sectional survey of physicians and their patients in the United States. Patients with physician-diagnosed NASH completed a questionnaire that included the CLDQ-NASH and EQ-5D-5L. Mapping from CLDQ-NASH to EQ-5D-5L was done using tenfold cross-validation; performance was assessed using root-mean squared error as accuracy measure. Subgroup analyses compared performance of the models in obese versus non-obese patients and patients with versus without type 2 diabetes (T2D). RESULTS: Data from 347 patients were included in this analysis. Overall, 2172 models were tested for predicting EQ-5D-5L index score from CLDQ-NASH score. The best model for this mapping was a generalized linear model using Gaussian distribution and a power link. The best model for mapping from CLDQ-NASH domains to the EQ-5D-5L was a fractional logistic model. Models performed better at predicting upper versus lower values of EQ-5D-5L, for non-obese versus obese patients, and for patients without versus with T2D. CONCLUSION: We describe a scoring algorithm for cross-walking the CLDQ-NASH to the EQ-5D-5L enabling health status comparisons of HRQoL across studies.

The cost-effectiveness of pegcetacoplan in complement treatment-naïve adults with paroxysmal nocturnal hemoglobinuria in the USA.

Aim: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare blood disorder characterized by hemolytic anemia, bone marrow failure and thrombosis, and is associated with high healthcare burden. We evaluated the cost-effectiveness of pegcetacoplan, a proximal complement-3 inhibitor (C3i), compared with the C5i, eculizumab and ravulizumab, in complement treatment-naive adults with PNH, from the US healthcare payer perspective. Materials & methods: A de novo cost-effectiveness model based on a Markov cohort structure evaluated lifetime (55-year) PNH costs and outcomes. The 6-month cycles of the model reflected the follow-up period of PRINCE (NCT04085601), an open-label trial of pegcetacoplan compared with eculizumab in C5i-naive patients. Data from PRINCE informed the clinical, safety and health-related quality of life outcomes in the model. Results: Pegcetacoplan was associated with lifetime cost savings of USD1,176,808 and USD213,062 relative to eculizumab and ravulizumab, respectively (largely attributed to reduced drug costs and blood transfusions), and additional quality-adjusted life years (QALYs) of 0.25 and 0.24. Conclusion: In patients with PNH who are treatment-naive, the base-case cost-effectiveness analysis, scenario analysis and sensitivity analysis showed both lifetime cost savings and increased QALYs associated with pegcetacoplan compared with eculizumab or ravulizumab in the USA.

The incremental cost of non-alcoholic steatohepatitis and type 2 diabetes in the United States using real-world data.

BACKGROUND: Non-alcoholic steatohepatitis (NASH) and type 2 diabetes (T2D) are both linked to substantial healthcare costs and are often co-occurring. We aim to quantify the incremental cost of NASH and T2D using real-world data. METHODS: Adults (≥18 years old) with ≥2 diagnosis codes for NASH and/or ≥2 diagnosis codes for T2D between 1/1/2016 and 12/31/2021 and ≥24 months of continuous claims enrollment (study period) were identified in electronic health records or claims in the Veradigm Integrated Dataset. Patients were stratified into 3 cohorts: NASH-only, T2D-only, and NASH + T2D. We calculated annualized costs for the 24-month study period and fit a generalized linear model (excluding the most expensive 1%) that controlled for disease cohort, age, sex, and modified Charlson comorbidity index to estimate the per year all-cause healthcare costs and incremental cost of adding T2D to a NASH diagnosis (or vice versa). RESULTS: We identified 23,111 patients diagnosed with NASH-only, 3,548,786 patients with T2D-only, and 30,339 patients with NASH + T2D. The model-predicted mean costs per year were $7,668 for patients with NASH-only, $11,226 for patients with T2D-only, and $16,812 for patients with NASH + T2D. The incremental increase in costs per year of adding T2D to NASH was 63% (+$4,846), and the incremental increase in costs per year of adding NASH to T2D was 42% (+$4,692). CONCLUSIONS: Both NASH and T2D contribute to the high healthcare costs among patients with a dual diagnosis. Results from our analysis indicate that NASH comprises a high portion of total healthcare costs among patients with NASH and T2D.

Descriptive, real-world treatment patterns, resource use, and total cost of care among eculizumab- and ravulizumab-treated members with paroxysmal nocturnal hemoglobinuria.

BACKGROUND: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, genetic, chronic, and life-threatening blood disease with an estimated prevalence of 13 per 1,000,000 persons reported in the United States. Available at analysis, PNH treatment included the use of C5 inhibitors (C5is), which prevent formation of membrane attack complex and consequently intravascular hemolysis. Limited real-world evidence suggests some individuals with PNH continue to experience anemia and breakthrough hemolysis (BTH) after C5i treatment, indicating unmet needs. OBJECTIVE: To describe real-world treatment patterns and outcomes among individuals treated with C5is, eculizumab (ECU), and ravulizumab (RAV), focusing on affordability challenges and therapy unmet needs from a US payer perspective. METHODS: This retrospective cohort study was conducted using deidentified data from Prime Therapeutics' approximately 15 million commercially insured US members with integrated medical and pharmacy claims data. Members were identified between January 1, 2018, and December 31, 2020. Inclusion criteria for cohort identification were adults aged 18 years or older at ECU or RAV index date requiring 2 or more claims for ECU or 1 or more claims for RAV. ECU and RAV users were excluded if they had a claim indicating treatment for a US Food and Drug Administration (FDA)-approved non-PNH indication. Members were required to be continuously enrolled 6 months before and 12 months after their index ECU or RAV claim. Real-world C5i claims-based treatment dosage and frequency patterns were compared with FDA-labeled dosing. Clinical outcomes, including transfusions and BTH events, were identified in the pre-index and post-index periods. Health care resource use and costs were calculated after network discounts, including member share. RESULTS: A total of 86 commercial members met analysis criteria: 34 in the ECU cohort and 52 in the RAV cohort. The mean age was 42.6 years, and 54.6% were female. Estimated higher-than-label PNH-recommended dosage occurred in 38.2% of ECU and 9.6% of RAV members. In total, 29.4% of ECU and 17.3% of RAV members had 4 or more transfusions in the post-index period. Additionally, 29.4% of ECU and 13.5% of RAV members had 1 or more BTH episodes. Post-index period mean per member total health care costs were $711,785 among ECU members and $624,911 among RAV members, and C5i costs accounted for 79.7% and 85.6% of total health care costs, respectively. CONCLUSIONS: Although all members received at minimum FDA-approved dosages, transfusions and BTH events continue to occur for some members. These findings indicate potentially inadequate therapy responses in a substantial subset of C5i users, adding additional therapy costs to an already extremely expensive therapy. DISCLOSURES: This study was funded by Apellis Pharmaceuticals. Drs Broderick and Fishman report employment by Apellis Pharmaceuticals and own stock options. Dr Burke reports employment by Prime Therapeutics, LLC, which has received research funding from Apellis Pharmaceuticals. Dr Gleason reports employment by Prime Therapeutics, LLC, which has received research funding from Apellis Pharmaceuticals; serves on the advisory committee at the Institute for Clinical and Economic Review; and has served on the Board of Directors at the Academy of Managed Care Pharmacy.

Changes in Hematologic Lab Measures Observed in Patients with Paroxysmal Nocturnal Hemoglobinuria Treated with C5 Inhibitors, Ravulizumab and Eculizumab: Real-World Evidence from a US Based EMR Network.

Paroxysmal nocturnal hemoglobinuria (PNH), a rare acquired hematologic disorder, can be treated with C5 inhibitors (C5i) such as eculizumab or ravulizumab. This retrospective study is the first to describe real-world treatment patterns and changes in hematologic PNH-monitoring laboratory tests among C5i-treated US patients. Data were extracted from TriNetX Dataworks Network and included patients with a PNH diagnosis between 1 January 2010, and 20 August 2021. Patients were stratified into three cohorts based on their C5i usage: eculizumab, ravulizumab (prior eculizumab), and ravulizumab (eculizumab naïve). Hematological markers (hemoglobin [Hb], lactate dehydrogenase [LDH], and absolute reticulocyte count [ARC]) and relevant clinical events (e.g., breakthrough hemolysis [BTH], complement-amplifying conditions [CAC], thrombosis, infection, and all-cause mortality) were captured any time within 12 months post-index treatment. Of the 143 (eculizumab), 43 (ravulizumab, prior eculizumab), and 33 (ravulizumab, eculizumab naïve) patients, mean age across cohorts was 42-51 years, 55-61% were female, 63-73% were White, and 33-40% had aplastic anemia. Among all cohorts 12 months post-C5i treatment, 50-82% remained anemic, 8-32% required ≥1 transfusion, and 13-59% had BTH, of which 33%-54% had CACs. Additionally, thrombosis was seen in 7-15% of patients, infection in 20-25%, and mortality in 1-7%. These findings suggest many C5i-treated patients experience suboptimal disease control.

Mapping the EORTC QLQ-C30 onto the EQ-5D-5L index for patients with paroxysmal nocturnal hemoglobinuria in France.

Aim: To map patient-level data collected on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC) QLQ-C30 to EQ-5D-5L data for estimating health-state utilities in patients with paroxysmal nocturnal hemoglobinuria (PNH). Materials & methods: European cross-sectional PNH patient survey data populated regression models mapping EORTC QLQ-C30 domains (covariates: sex and baseline age) to utilities calculated with the EQ-5D-5L French value set. A genetic algorithm allowed selection of the best-fitting between a set of models with and without interaction terms. We validated the selected algorithm using EQ-5D-5L utilities converted from EORTC QLQ-C30 data collected in the PEGASUS phase III, randomized controlled trial of pegcetacoplan versus eculizumab in adults with PNH. Results: Selected through the genetic algorithm, the ordinary least squares model without interactions provided highly stable results across study visits (mean [±SD] utilities 0.58 [±0.42] to 0.89 [±0.10]), and showed the best predictive validity. Conclusion: The new PNH EQ-5D-5L direct mapping developed using a genetic algorithm enabled calculation of reliable health-state utility data required for cost-utility analysis in health technology assessments supporting treatments of PNH.

Healthcare resource utilization and costs of care in the United States for patients with non-alcoholic steatohepatitis.

AIMS: This retrospective, observational cohort study aimed to determine the burden of comorbidities, hospitalization, and healthcare costs among patients with non-alcoholic steatohepatitis (NASH) in the United States stratified by fibrosis-4 (FIB-4) or body mass index (BMI). METHODS: Adults with NASH were identified in the Veradigm Health Insights Electronic Health Record Database and linked Komodo claims data. The index date was the earliest coded NASH diagnosis between 1 January 2016 and 31 December 2020 with valid FIB-4 and ≥6 months of database activity and continuous enrollment pre- and post-index. We excluded patients with viral hepatitis, alcohol-use disorder, or alcoholic liver disease. Patients were stratified by FIB-4: FIB-4 ≤ 0.95, 0.95 < FIB-4 ≤ 2.67, 2.67 < FIB-4 ≤ 4.12, FIB-4 > 4.12) or BMI (BMI <25, 25 ≤ BMI ≤30, BMI > 30). Multivariate analysis was used to assess the relationship of FIB-4 with costs and hospitalizations. RESULTS: Among 6,743 qualifying patients, index FIB-4 was ≤0.95 for 2,345 patents, 0.95-2.67 for 3,289 patients, 2.67-4.12 for 571 patients, and >4.12 for 538 patients (mean age 55.8 years; 62.9% female). Mean age, comorbidity burden, cardiovascular disease risk, and healthcare utilization increased with increasing FIB-4. Mean ± SD annual costs increased from $16,744±$53,810 to $34,667±$67,691 between the lowest and highest FIB-4 cohorts and were higher among patients with BMI <25 ($24,568±$81,250) than BMI >30 ($21,542±$61,490). A one-unit increase in FIB-4 at index was associated with a 3.4% (95%CI: 1.7%-5.2%) increase in mean total annual cost and an 11.6% (95%CI: 8.0%-15.3%) increased likelihood of hospitalization. CONCLUSIONS: A higher FIB-4 was associated with increased healthcare costs and risk of hospitalization in adults with NASH; however, even patients with FIB-4 ≤ 0.95 presented a significant burden.

Fatigue and health-related quality of life in paroxysmal nocturnal haemoglobinuria: A post hoc analysis of the pegcetacoplan PEGASUS trial data.

OBJECTIVES: Paroxysmal nocturnal haemoglobinuria (PNH) is a rare, non-malignant haematological disorder associated with disabling fatigue and reduced health-related quality of life. Post hoc analysis of PEGASUS phase 3 trial (NCT03500549) characterised improvements in patient-reported fatigue measured by functional assessment of chronic illness therapy-fatigue (FACIT-fatigue) instrument item-level ratings for pegcetacoplan and eculizumab for the treatment of PNH. METHODS: Item-level responder analysis was conducted on a ≥2-level change from baseline (CFB) clinically important response (CIR) for the FACIT-fatigue 13 individual items rated on a 5-level Likert scale. We evaluated ≥2-level change against the minimal clinically important difference (MCID) of the FACIT-fatigue total score (≥5 points) and clinical parameters, haemoglobin (Hb; ≥1 g/dL) and normalised absolute reticulocyte count (ARC; 30-100 pg/cells). Logistic regressions estimated baseline-to-Week-16 FACIT-fatigue item-level transitional probabilities; Kaplan-Meier analysis estimated time to FACIT-fatigue item CIR. RESULTS: Pegcetacoplan versus eculizumab was associated with significantly greater odds of Week 16 CIR across 8/13 items and on total score MCID (OR [CI] = 11.19 [3.73, 33.57]) and faster times to responses. The item-level CIR threshold also showed clinical relevance on Hb level and ARC normalization. CONCLUSIONS: Compared with eculizumab, pegcetacoplan was associated with clinically meaningful greater improvements on a majority of FACIT-fatigue items.

Comparative Effectiveness of Pegcetacoplan Versus Ravulizumab and Eculizumab in Complement Inhibitor-Naïve Patients with Paroxysmal Nocturnal Hemoglobinuria: A Matching-Adjusted Indirect Comparison.

INTRODUCTION: In the absence of head-to-head trials, this study compared treatment outcomes with the C3 complement inhibitor pegcetacoplan versus the C5 complement inhibitor eculizumab or ravulizumab in complement inhibitor-naïve patients with paroxysmal nocturnal hemoglobinuria (PNH). METHODS: A matching-adjusted indirect comparison was conducted using individual patient data from the pegcetacoplan arm of the PRINCE trial (NCT04085601; n = 34) and aggregate data from the ravulizumab (n = 125) and eculizumab (n = 121) arms of the ALXN1210-PNH-301 trial (NCT03056040). Clinical and quality of life endpoints were evaluated after matching patients in the two trials on baseline characteristics. The weighted Wald test with 95% confidence interval was used to compare categorical and continuous variables (i.e., weighted chi-squared and z tests, respectively). Bias factor analysis was performed to quantify the extent of residual bias from unmeasured confounders. RESULTS: After weighting, treatment with pegcetacoplan was associated with statistically significant improvements in most clinical endpoints compared with ravulizumab or eculizumab treatment. These included: greater absolute and percent reductions in lactate dehydrogenase (LDH) level and increase in hemoglobin level from baseline; shorter time to first occurrence of LDH normalization; larger proportions of patients achieving hemoglobin stabilization and avoiding transfusion, with fewer packed red blood cell units transfused; and a smaller proportion of patients experiencing breakthrough hemolysis (all p < 0.05). Patients receiving pegcetacoplan also had a greater increase in general health status score from baseline compared with those receiving C5 complement inhibitors. CONCLUSION: Pegcetacoplan provides clinical benefits as first-line treatment for complement inhibitor-naïve patients with PNH. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT04085601.

Early Cost-Effectiveness and Price Threshold Analyses of Resmetirom: An Investigational Treatment for Management of Nonalcoholic Steatohepatitis.

BACKGROUND: Nonalcoholic steatohepatitis (NASH) is characterized by inflammation and hepatocellular damage caused by accumulation of fat in the liver. Resmetirom (MGL-3196) is an orally administered, small-molecule, liver-targeted, selective thyroid hormone receptor-ß agonist. This early analysis explored the potential cost effectiveness of resmetirom for the treatment of NASH from a US commercial payer perspective. METHODS: An early economic model was developed to reflect the clinical pathways typically followed by patients with NASH and liver fibrosis. Use of resmetirom, compared with placebo, was assessed. The Markov model structure was informed by a previous modeling study and a randomized, double-blind, placebo-controlled, phase II trial of resmetirom. Costs and outcomes were assessed over a lifetime time horizon with results presented in terms of cost per quality-adjusted life-year (QALY) gained. RESULTS: Resmetirom treatment resulted in increased costs of US$66,764 per patient, while increasing QALYs by 1.24. The incremental cost-effectiveness ratio was US$53,929 per QALY gained, indicating resmetirom treatment would potentially be cost effective at a willingness-to-pay (WTP) threshold of US$100,000. Results indicated that resmetirom would reduce the lifetime number of cases of decompensated cirrhosis (- 87), hepatocellular carcinoma (- 59), and liver transplants (- 30) per 1,000 patients compared with placebo. Resmetirom treatment remained cost effective at a US$100,000 WTP threshold up to a daily price point of US$72.00. CONCLUSION: Resmetirom is a potentially cost-effective treatment option for patients with NASH and liver fibrosis based on an analysis performed from a US commercial payer perspective. Future economic analyses of the technology should, however, focus on overcoming the limitations of existing modeling methodology.

The burden of illness of patients with paroxysmal nocturnal haemoglobinuria receiving C5 inhibitors: clinical outcomes and medical encounters from the patient perspective.

OBJECTIVES: To assess the clinical and healthcare resource burden among C5 inhibitor (C5i)-treated patients with paroxysmal nocturnal haemoglobinuria (PNH), using patient-reported data. METHODS: This web-based, cross-sectional survey (01FEB2021-31MAR2021) of adults with PNH treated with eculizumab (France, Germany, UK) or ravulizumab (Germany) included: patient characteristics; treatment patterns/dosage; haematological outcomes (haemoglobin [Hb] levels, transfusions, thrombotic events, breakthrough haemolysis); and medical encounters. Treatment and Hb-level subgroup differences were assessed with statistical significance tests. RESULTS: Among 71 patients, 98.6% were C5i-treated for ≥3 months. The majority (with reported Hb levels) had levels ≤12.0 g/dL (85.7%; n = 54/63). The mean Hb level was 10.2 g/dL (standard deviation [SD]: 2.0; median 10.0 g/dL). Treatment with above label-recommended doses was reported by 30.4% (eculizumab) and 5.3% (ravulizumab) of patients. Within the past 12 months among patients treated with C5i for ≥1 year: 24.1% had ≥1 transfusion; 3.2% had ≥1 thrombosis; and 28.6% had ≥1 breakthrough haemolysis. Among all patients, 26.8% and 31.0% reported emergency department/room [ER] and inpatient visits, respectively. Mean annual, per-patient all-cause medical encounters were: 0.5 (ER); 1.9 (inpatient); and overall outpatient visits ranged by setting from 2.0 to 6.4. Most encounters were PNH-related, with means of 0.4 (ER); 1.8 (inpatient); and 1.6-5.4 (outpatient). Primary haematological and medical encounter outcomes were similar between treatment as well as Hb-level subgroups, with almost no statistically significant differences. CONCLUSIONS: Despite at least 3 months of C5i treatment, high proportions of patients with PNH reported low haemoglobin levels and required transfusions and hospitalizations, which suggests remaining unmet needs.

Changes in hemoglobin and clinical outcomes drive improvements in fatigue, quality of life, and physical function in patients with paroxysmal nocturnal hemoglobinuria: post hoc analyses from the phase III PEGASUS study.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, chronic, acquired, hematologic, life-threatening disease characterized by thrombosis, impaired bone marrow function, and complement-mediated hemolysis. The PEGASUS phase III clinical trial demonstrated superiority of pegcetacoplan over eculizumab regarding improvements in hemoglobin levels in patients with suboptimal response to prior eculizumab treatment. The objective of this post hoc analysis was to compare the patient-reported outcome (PRO) response rates observed among PEGASUS participants and the relationships between their PRO scores with clinical and hematological parameters. Data from the 16-week randomized, controlled (1:1 to pegcetacoplan or eculizumab) period of the PEGASUS trial included comparisons of weekly PRO measurements taken using the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) scale and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 (EORTC QLQ-C30) scales. A clinically meaningful FACIT-F response was defined as an increase from baseline of ≥5 points. Convergent validity was assessed using conventional threshold correlations between FACIT-F, EORTC QLQ-C30, and laboratory parameters. A clinically meaningful improvement in FACIT-F score was seen in 72.2% of pegcetacoplan-treated patients compared to 22.9% of eculizumab-treated patients. At week 16, the FACIT-F total score correlated with hemoglobin levels (r=0.47, p< 0.0001), absolute reticulocyte count (r=-0.37, p<0.01), and indirect bilirubin levels (r=-0.25, p<0.05). Clinically meaningful improvements in pegcetacoplan-treated patients were also observed for multiple EORTC scales. Fatigue and other self-reported outcomes were correlated with clinically meaningful improvements in clinical and hematological parameters. Clinical trial registration: NCT03500549.

The burden of illness of patients with paroxysmal nocturnal haemoglobinuria receiving C5 inhibitors in France, Germany and the United Kingdom: Patient-reported insights on symptoms and quality of life.

OBJECTIVES: To assess the clinical, humanistic and economic burden of paroxysmal nocturnal haemoglobinuria (PNH) among C5 inhibitor (C5i)-treated patients with PNH. METHODS: This was a web-based, cross-sectional survey (01FEB2021-31MAR2021) of adults with PNH treated with eculizumab (France, Germany, United Kingdom) or ravulizumab (Germany). Self-reported outcomes included: patient characteristics; patient-reported symptoms; and standardised patient-reported outcomes (e.g. Functional Assessment of Chronic Illness Therapy [FACIT]-Fatigue, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 [EORTC QLQ-C30]). RESULTS: Among 71 included patients, 98.6% were C5i-treated for ≥3 months (88.7% ≥12 months); among those with self-reported haemoglobin (Hb) levels (n = 63), most (85.7%) were anaemic (defined as ≤12.0 g/dL). Fatigue was the most common symptom at both diagnosis (73.2%) and survey time (63.4%); there were no statistically significant differences in symptom prevalence between treatment subgroups (eculizumab vs. ravulizumab). Total FACIT-Fatigue and EORTC QLQ-C30 scores were substantially lower than European general population references, but there were no statistically significant differences between treatment subgroups. Hb-level subgroups (<10.5 g/dL vs. ≥10.5 d/dL) followed similar trends for all measures, with few significant subgroup differences. CONCLUSIONS: Results suggest that there remains a considerable burden and unmet need among C5i-treated patients with PNH that requires improved therapies.

The burden of illness in patients with paroxysmal nocturnal hemoglobinuria receiving treatment with the C5-inhibitors eculizumab or ravulizumab: results from a US patient survey.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare and life-threatening disease with symptoms of hemolysis and thrombosis. Current therapies for this complement-mediated disease rely predominantly on inhibition of the C5 complement protein. However, data on treatment responses and quality of life in C5-inhibitor (C5i)-treated PNH patients are scarce. The objective of this study was to determine C5i treatment effects on clinical parameters, PNH symptoms, quality of life, and resource use for PNH patients. This cross-sectional study surveyed 122 individuals in the USA receiving treatment for PNH with C5-targeted monoclonal antibodies, eculizumab (ECU) or ravulizumab (RAV). Despite most patients receiving C5i therapy for ≥ 3 months (ECU 100%, n = 35; RAV 95.4%, n = 83), many patients remained anemic with hemoglobin levels ≤ 12 g/dL in 87.5% (n = 28/32) and 82.9% (n = 68/82) of ECU and RAV recipients, respectively. A majority of patients on ECU (88.6%; n = 31/35) and RAV (74.7%; n = 65/87) reported fatigue symptoms. Among PNH patients receiving C5i therapy for ≥ 12 months, some still reported thrombotic events (ECU, 10.0%, n = 1/10; RAV, 23.5%, n = 4/17) and required transfusions within the past year (ECU, 52.2%, n = 12/23; RAV, 22.6%, n = 7/31). Other patient-reported PNH symptoms included breakthrough hemolysis, shortness of breath, and headaches. Patients reported scores below the average population norms on the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) scales. Overall, this study found that PNH patients receiving ECU or RAV therapy demonstrated a significant burden of illness, highlighting the need for improved PNH therapies.