Cost-Effectiveness of Lovotibeglogene Autotemcel (Lovo-Cel) Gene Therapy for Patients with Sickle Cell Disease and Recurrent Vaso-Occlusive Events in the United States.

BACKGROUND AND OBJECTIVE: Gene therapies for sickle cell disease (SCD) may offer meaningful benefits for patients and society. This study evaluated the cost-effectiveness of lovotibeglogene autotemcel (lovo-cel), a one-time gene therapy administered via autologous hematopoietic stem cell transplantation, compared with common care for patients in the United States (US) with SCD aged ≥ 12 years with ≥ 4 vaso-occlusive events (VOEs) in the past 24 months. METHODS: We developed a patient-level simulation model accounting for lovo-cel and SCD-related events, complications, and mortality over a lifetime time horizon. The pivotal phase 1/2 HGB-206 clinical trial (NCT02140554) served as the basis for lovo-cel efficacy and safety. Cost, quality-of-life, and other clinical data were sourced from HGB-206 data and the literature. Analyses were conducted from US societal and third-party payer perspectives. Uncertainty was assessed through probabilistic sensitivity analysis and extensive scenario analyses. RESULTS: Patients treated with lovo-cel were predicted to survive 23.84 years longer on average (standard deviation [SD], 12.80) versus common care (life expectancy, 62.24 versus 38.40 years), with associated discounted patient quality-adjusted life-year (QALY) gains of 10.20 (SD, 4.10) and direct costs avoided of $1,329,201 (SD, $1,346,446) per patient. Predicted societal benefits included discounted caregiver QALY losses avoided of 1.19 (SD, 1.38) and indirect costs avoided of $540,416 (SD, $262,353) per patient. Including lovo-cel costs ($3,282,009 [SD, $29,690] per patient) resulted in incremental cost-effectiveness ratios of $191,519 and $124,051 per QALY gained from third-party payer and societal perspectives, respectively. In scenario analyses, the predicted cost-effectiveness of lovo-cel also was sensitive to baseline age and VOE frequency and to the proportion of patients achieving and maintaining complete resolution of VOEs. CONCLUSIONS: Our analysis of lovo-cel gene therapy compared with common care for patients in the US with SCD with recurrent VOEs estimated meaningful improvements in survival, quality of life, and other clinical outcomes accompanied by increased overall costs for the health care system and for broader society. The predicted economic value of lovo-cel gene therapy was influenced by uncertainty in long-term clinical effects and by positive spillover effects on patient productivity and caregiver burden.

Severity and burden of sickle cell disease in France: a nationwide real-world study.

The burden of sickle cell disease (SCD) in France has been difficult to apprehend due to the paucity of reliable nationwide epidemiological data. We aimed to describe the epidemiology of SCD and evaluate its burden and costs. Patients with SCD and most severely affected patients were identified between 2012 and 2018 from the French National Health Data System database (SNDS, Système national des données de santé). Outcomes of interest included rates of acute and chronic complications, healthcare resource utilization and associated costs, and were compared in subpopulations of patients before and after hematopoietic stem cell transplantation, initiating hydroxyurea or a chronic transfusion program. Between 2012 and 2018, 22,619 patients with SCD were identified, among which 4,270 patients were defined as most severely affected. Rates of vaso-occlusion episodes and acute chest syndrome were 86.29 (95% confidence interval [CI]: 85.75-86.83] and 12.90 (95% CI: 12.69-13.11) per 100 person years in the study population and 166.9 (95% CI: 165.4- 168.4) and 22.71 (95% CI: 22.16-23.27) per 100 person years in most severely affected patients. Median (Q1-Q3) annualized total costs were €5,073.63 (range, €1,633.74-14,000.94) and €13,295.67 (range, €5,754.67-26,385.23) in the study population and most severely affected patients. Median annualized costs were ten times lower after treatment intensification for hematopoietic stem cell transplantation (€29,011.75 vs. €2,465.98; P<0.001), they slightly decreased after hydroxyurea initiation (€13,057.79 vs. €12,752.44; P=0.003) and were five times higher after chronic transfusion program initiation (€4,643.11 vs. €22,715.85; P<0.001). SCD still places a significant demand on health resources, even after therapeutic intensification.

AXL Mediates Cetuximab and Radiation Resistance Through Tyrosine 821 and the c-ABL Kinase Pathway in Head and Neck Cancer.

PURPOSE: Radiation and cetuximab are therapeutics used in management of head and neck squamous cell carcinoma (HNSCC). Despite clinical success with these modalities, development of both intrinsic and acquired resistance is an emerging problem in the management of this disease. The purpose of this study was to investigate signaling of the receptor tyrosine kinase AXL in resistance to radiation and cetuximab treatment. EXPERIMENTAL DESIGN: To study AXL signaling in the context of treatment-resistant HNSCC, we used patient-derived xenografts (PDXs) implanted into mice and evaluated the tumor response to AXL inhibition in combination with cetuximab or radiation treatment. To identify molecular mechanisms of how AXL signaling leads to resistance, three tyrosine residues of AXL (Y779, Y821, Y866) were mutated and examined for their sensitivity to cetuximab and/or radiation. Furthermore, reverse phase protein array (RPPA) was employed to analyze the proteomic architecture of signaling pathways in these genetically altered cell lines. RESULTS: Treatment of cetuximab- and radiation-resistant PDXs with AXL inhibitor R428 was sufficient to overcome resistance. RPPA analysis revealed that such resistance emanates from signaling of tyrosine 821 of AXL via the tyrosine kinase c-ABL. In addition, inhibition of c-ABL signaling resensitized cells and tumors to cetuximab or radiotherapy even leading to complete tumor regression without recurrence in head and neck cancer models. CONCLUSIONS: Collectively, the studies presented herein suggest that tyrosine 821 of AXL mediates resistance to cetuximab by activation of c-ABL kinase in HNSCC and that targeting of both EGFR and c-ABL leads to a robust antitumor response.

Efficacy and safety of post-docetaxel therapies in metastatic castration-resistant prostate cancer: a systematic review of the literature.

OBJECTIVE: Prostate cancer is a highly prevalent form of cancer in older men and is one of the leading causes of death from cancer in men across the globe. Many therapeutic agents have been approved for patients with metastatic castration-resistant prostate cancer (mCRPC), particularly as a post-docetaxel treatment strategy. The objective of this systematic literature review was to assess published efficacy and safety data for select mCRPC therapies - such as abiraterone, cabazitaxel, and enzalutamide - in the post-docetaxel setting. METHODS: Database searches of MEDLINE, Embase, and Cochrane CENTRAL, in conjunction with hand searches of multiple congress abstracts, yielded 13 randomized studies and 107 non-randomized studies that met the inclusion criteria. RESULTS: Randomized studies demonstrated significant improvements in median overall survival (OS) outcomes over placebo for abiraterone (15.8 vs. 11.2 months) and enzalutamide (18.4 vs. 13.6 months), and similar significant improvements were noted for cabazitaxel over mitoxantrone (15.1 vs. 12.7 months). Differences in progression-free survival (PFS) were similarly significant, although variance in the criteria for measuring PFS may limit the extent to which these outcomes can be compared between studies. Non-randomized evidence included multiple publications from several early access and compassionate use programs with a primary objective to report safety outcomes. Results from these studies largely reflected the findings in randomized trials. CONCLUSIONS: Overall, there is a growing body of evidence for post-docetaxel treatment options available in patients with mCRPC. Further head-to-head trials or indirect treatment comparisons may be a valuable method to assess the comparative efficacy of these therapies.

Patient-reported visual function outcomes improve after ranibizumab treatment in patients with vision impairment due to diabetic macular edema: randomized clinical trial.

IMPORTANCE: Few data are available on relative changes in vision-related function after treatment for diabetic macular edema (DME). OBJECTIVE: To determine the impact of intravitreal ranibizumab, 0.5 mg, compared with laser on patient-reported visual function. DESIGN: Phase 3, randomized, double-masked, 12-month study (RESTORE). SETTING: Outpatient retina practices in Australia, Canada, and Europe. PARTICIPANTS: Patients 18 years or older with type 1 or 2 diabetes mellitus and visual impairment due to DME. INTERVENTIONS: Patients were randomized to ranibizumab plus sham laser (n = 116), ranibizumab plus laser (n = 118), or sham injections plus laser (n = 111). Ranibizumab and sham injections were given for 3 consecutive months then as needed; laser or sham laser treatment was given at baseline then as needed. MAIN OUTCOMES AND MEASURES: National Eye Institute Visual Functioning Questionnaire 25 (NEI VFQ-25) scores at 0, 3, and 12 months for patients receiving 1 or more study treatments with 1 or more postbaseline NEI VFQ-25 assessments and last observation carried forward for missing data. RESULTS: Mean baseline NEI VFQ-25 composite scores were 72.8, 73.5, and 74.1 in the ranibizumab, laser, and ranibizumab plus laser groups, respectively. At 12 months, the mean composite scores (95% CIs) improved by 5.0 (ranibizumab vs laser, 2.6 to 7.4; P = .01 vs laser) and 5.4 (ranibizumab plus laser vs laser alone, 3.3 to 7.4; P = .004 vs laser) from baseline in the ranibizumab and ranibizumab plus laser groups, respectively, compared with 0.6 (-1.8 to 3.0) for the laser group. Near activities scores improved by 9.0 (ranibizumab vs laser, 5.0 to 13.0; P = .01) and 9.1 (ranibizumab plus laser vs laser, 5.6 to 12.6; P = .006) compared with 1.1 (-3.0 to 5.2) for the laser group, whereas distance activities scores improved by 5.3 (ranibizumab vs laser, 1.8 to 8.9; P = .04) and 5.6 (ranibizumab plus laser vs laser, 2.3 to 9.0; P = .03) compared with 0.4 (-3.1 to 3.8) for the laser group. Patients with better baseline visual acuity or lower central retinal thickness had greater improvements with ranibizumab treatment compared with laser in composite and some subscale scores compared with patients with worse visual acuity or higher central retinal thickness. CONCLUSIONS AND RELEVANCE: These data provide vision-related, patient-reported outcome evidence that mirrors visual acuity outcomes and supports benefits from ranibizumab or ranibizumab plus laser treatment for patients with DME and characteristics similar to those enrolled in this randomized clinical trial. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00687804.

Cost-effectiveness of ranibizumab in treatment of diabetic macular oedema (DME) causing visual impairment: evidence from the RESTORE trial.

BACKGROUND/AIMS: To evaluate the cost-effectiveness of ranibizumab as either monotherapy or combined with laser therapy, compared with laser monotherapy, in the treatment of diabetic macular oedema (DME) causing visual impairment from a UK healthcare payer perspective. METHODS: A Markov model simulated long-term outcomes and costs of treating DME in one eye (BCVA ≤75 letters) based on data from the RESTORE Phase III trial. Outcomes measured in quality-adjusted life-years (QALYs) were simulated for a 15-year time horizon based on 12-month follow-up from RESTORE and published long-term data. Costs included treatment, disease monitoring, visual impairment and blindness (at 2010 price levels). RESULTS: Ranibizumab monotherapy resulted in a 0.17 QALY gain at an incremental cost of £4191 relative to laser monotherapy, yielding an incremental cost-effectiveness ratio (ICER) of £24 028. Probabilistic sensitivity analysis showed a 64% probability of being cost-effective at a threshold of £30 000 per QALY. Combined ranibizumab and laser therapy resulted in a 0.13 QALY gain at an incremental cost of £4695 relative to laser monotherapy (ICER £36 106; 42% probability of ICER <£30 000). CONCLUSIONS: Based on RESTORE 1-year follow-up data, ranibizumab monotherapy appears to be cost-effective relative to laser monotherapy, the current standard of care. Cost-effectiveness of combination therapy is less certain. Ongoing studies will further inform on disease progression and the need for additional ranibizumab treatment.

Burden of illness of diabetic macular edema: literature review.

OBJECTIVE: To provide an overview of the literature on the burden of diabetic macular edema (DME) in the United States and selected European countries. RESEARCH DESIGN AND METHODS: Computerized searches of English-language literature were conducted in PubMed/MEDLINE (1980-2009). The searches were supplemented with electronic and manual searches of relevant society/association proceedings and bibliographies of electronically identified sources. Abstracts were reviewed for relevance to any of the following topics: epidemiology, including prevalence and incidence; health outcomes; resource use and treatment patterns; and economic and humanistic burden associated with DME. Relevant full text articles were retrieved and major findings were synthesized and compared within and across countries. RESULTS: A total of 400 citations were included in the initial review. After abstract screening, 47 articles were deemed pertinent and summarized in this review. The prevalence of DME among diabetic patients ranged from 0.85% to 12.3% across the countries studied. The prevalence and incidence of DME vary depending on type of diabetes (1 vs. 2), insulin- vs. non-insulin-dependence, and duration of disease (years since diagnosis). Although literature findings are limited and indicate a need for further investigation, a synthesis of the available results indicates that DME has a negative impact on patients' health-related quality of life. In addition, patients with DME consume significantly more healthcare resources and incur higher costs compared to diabetic patients without retinal complications. CONCLUSIONS: There remains a need for consistent data capture and assessment within and between countries included in this analysis. Despite the limited evidence, DME appears to be a costly disease that has a negative impact on patients' quality of life.