Limitations of standard cost-effectiveness methods for health technology assessment of treatments for rare, chronic diseases: a case study of treatment for cystic fibrosis.

OBJECTIVES: Cost-effectiveness analysis (CEA) is useful to assess the value of health care interventions based on clinical effectiveness and costs. However, standard CEA methods make important assumptions that may significantly increase the incremental cost-effectiveness ratio (ICER) for lifelong treatments for rare, chronic diseases. We used the cost-effectiveness of elexacaftor/tezacaftor/ivacaftor and ivacaftor (ELX/TEZ/IVA) for the treatment of cystic fibrosis as a case study to explore how alternative assumptions for (1) discounting, (2) utility measures, (3) disease management costs, and (4) static drug pricing impact cost-effectiveness outcomes. MATERIALS AND METHODS: Cost-effectiveness of ELX/TEZ/IVA was evaluated using base-case inputs and assumptions reflecting standard CEA methods and was then compared with cost-effectiveness estimates obtained with alternate assumptions: (1) applying a lower discount rate to health benefits (1.5%) than costs (3%); (2) including a treatment-specific utility increment; (3) excluding disease management costs incurred during the period of extended survival attributable to ELX/TEZ/IVA treatment; and (4) decreasing the price of ELX/TEZ/IVA following loss of exclusivity. RESULTS: Modifying assumptions for these four factors together reduced the ICER by 75% from the base case, with the largest reduction (45%) occurring when the price trajectory was modified to allow for generic entry. Differential discounting, use of a treatment-specific utility increment, and exclusion of additional disease management costs each individually reduced the ICER by 36%, 14%, and 10%, respectively, from the base case. CONCLUSIONS: This study illustrates the impact that modifications to standard CEA methods may have on measures of cost-effectiveness for rare, chronic diseases.

Disease burden in people with cystic fibrosis heterozygous for F508del and a minimal function mutation.

BACKGROUND: People with cystic fibrosis (CF) heterozygous for F508del-CFTR and a minimal function CFTR mutation (F/MF) that results in no CFTR protein or results in CFTR protein that is not responsive to tezacaftor, ivacaftor, and tezacaftor/ivacaftor in vitro comprise a sizeable percentage of the US CF population. This retrospective, cross-sectional, observational study aimed to characterize CF burden in this subpopulation. METHODS: People ≥2 years of age in the US CF Foundation Patient Registry with a CF diagnosis, F/MF genotype, and ≥1 encounters in 2017 were included. Descriptive analyses assessed lung function, nutritional parameters, microbiology, hospitalization and pulmonary exacerbation rates, and CF-related complications. Results were stratified by age group; select characteristics were summarized by percent predicted FEV1 (ppFEV1) and ethnicity. RESULTS: 5348 people met inclusion criteria. Rates of positive bacterial cultures, pulmonary exacerbations, and hospitalizations were generally higher in older age groups. Prevalence of prescribed symptomatic CF therapies was substantial and also generally higher in older age groups. ppFEV1 was lower in older age groups. A greater percentage of adolescents and adults reported complications, including cirrhosis, osteoporosis, osteopenia, and sinus disease, than younger age groups. Increased prevalence of cultured Pseudomonas aeruginosa and prescribed chronic therapy was seen with decreasing ppFEV1. In each age group, ppFEV1 was slightly higher in the non-Hispanic cohort than in the Hispanic cohort. CONCLUSIONS: People with F/MF genotypes have substantial disease burden that worsened in older age groups consistent with the progressive nature of CF, indicating need for additional treatment options in this subpopulation.

A Retrospective Observational Study of Rurioctocog Alfa Pegol in Clinical Practice in the United States.

BACKGROUND: Research describing patient experience and outcomes with extended half-life recombinant factor VIII (EHL rFVIII) outside of clinical trials is limited. Real-world rFVIII consumption studies, when people with hemophilia A (PWHA) switch from standard half-life (SHL) to EHL rFVIII, may help payers and clinicians make more informed treatment choices. OBJECTIVE: To conduct a retrospective, observational, U.S.-based analysis to describe clinical and demographic profiles of PWHA who switched to prophylactic rurioctocog alfa pegol. METHODS: Data were obtained from PWHA treated by 38 prescribers across 21 states using specialty pharmacy database case report forms, electronic medical records, and direct communication with providers, PWHA, or their guardians. Assessments included disease severity, pain severity, number and location of target joints, prior HA therapy, reasons for switching, treatment duration, dosing frequency, adherence, and annualized bleeding rates (ABRs) before and after switching to rurioctocog alfa pegol from SHL or another EHL rFVIII. RESULTS: Data were collected from 56 PWHA. The mean age was 26 years (range = 5-88); median age was 24 years (interquartile range = 14-34); 20% were aged < 12 years; and 89% (50/56) had severe HA. All PWHA had ≥ 12 months of rFVIII treatment before switching to rurioctocog alfa pegol. The population had a mean 1.8 target joints. Baseline subjective pain assessment was mild to moderate for 68% (38/56) of respondents. Before receiving rurioctocog alfa pegol, most PWHA received antihemophilic factor (recombinant) for prophylaxis (73%, 41/56) or breakthrough bleeding (59%, 33/56). Mean dosing frequency for prior prophylaxis was 2.8 per week for SHL rFVIII and 1.8 per week for EHL rFVIII, and 2.2 per week for all PWHA after switching to rurioctocog alfa pegol prophylaxis. The median time on rurioctocog alfa pegol prophylaxis was 12.0 months versus 80.8 months on previous SHL rFVIII and 13.5 months on previous EHL rFVIII. Mean ABRs on prior prophylaxis were 5.9 for SHL rFVIII (n = 35) and 4.7 for EHL rFVIII (n = 3). After switching to rurioctocog alfa pegol, the overall mean ABR reduced by 71% (5.8 to 1.7, P < 0.001) and 20/56 PWHA had no bleeding events. There was also a 20.9% reduction in the mean days per week of factor administration (P < 0.001) after switching to prophylactic rurioctocog alfa pegol. For 47 PWHA who switched from SHL rFVIII, their weekly dose decreased from 109.8 to 100.6 IU per kg with rurioctocog alfa pegol (P = 0.094). The proportion of PWHA with good/complete treatment adherence increased from 68% (38/56) on any prior rFVIII to 80% (45/56) on rurioctocog alfa pegol. The most common reason PWHA switched to rurioctocog alfa pegol was to reduce treatment infusions. CONCLUSIONS: Switching from either an SHL or EHL rFVIII to rurioctocog alfa pegol is associated with fewer bleeding episodes owing to more effective prophylaxis and improved adherence. Those who switched from an SHL rFVIII reported reduced factor consumption with rurioctocog alfa pegol. This long-acting factor is an important additional option for the care of PWHA. DISCLOSURES: This study was funded by Shire Development LLC, a Takeda company, Lexington, MA. Trio Health was involved in study design and acquisition, analysis, and interpretation of data and was funded by Shire Development LLC, a Takeda company. Aledort serves on the data and safety monitoring boards of Baxalta U.S. Inc., a Takeda company, and Octapharma; is chair of the scientific advisory board of Kedrion; and receives consultancy fees and honoraria from Baxalta U.S. Inc., a Takeda company. Milligan is an employee of Trio Health and reports research support from AbbVie, Gilead, Merck, Sanofi, and ViiV, unrelated to this study. Watt is an employee of Shire International GmbH, a Takeda company, and owns stock in the company. Booth was an employee of Baxalta U.S. Inc., a Takeda company, at the time of this study and owns stock in the company. Data from this study were presented at the AMCP Managed Care and Specialty Pharmacy Annual Meeting; April 23-28, 2018; Boston, MA; SETH (2018) Sociedad Espanola de Trombosis y Hemostasia-XXXIV Congreso Nacional; October 11-13, 2018; Grenada, Espana; and Blood 2018 Annual Scientific Meeting; October 21-24, 2018; Brisbane, Australia.

Real-world comparative analysis of bleeding complications and health-related quality of life in patients with haemophilia A and haemophilia B.

INTRODUCTION: Clinical severity and impact of haemophilia on quality of life have been generally considered to be lower for haemophilia B (HB) compared with haemophilia A (HA) patients. AIMS: To compare annual bleeding rate (ABR), target joint development and health-related quality of life (HRQoL) between adult (≥18 years) severe HA and HB patients using recent data from the Cost of Haemophilia in Europe: a Socioeconomic Survey (CHESS) study. METHODS: Multivariate generalized linear models (GLM) were constructed to assess the relationship between haemophilia type, ABR, HRQoL (derived from EQ-5D index scores) and the presence of target joints while controlling for covariates. RESULTS: Of the 1225 patients included, 77% (n = 949) had HA and 23% (n = 278) had HB. Of the 514 patients who completed the EQ-5D, 78% (n = 405) had HA, and 22% (n = 110) had HB. Unadjusted mean ABR was 3.79 in HA and 4.60 in HB. The presence of ≥1 target joint was reported in 59% and 54% of patients with HA and HB, respectively. Unadjusted mean EQ-5D index score was 0.78 in HA and 0.76 in HB. Haemophilia type was not a significant predictor of ABR, target joints or HRQoL when adjusted for confounding factors such as BMI, age and replacement therapy regimen. CONCLUSION: Data suggest comparable ABR, incidence of target joints and HRQoL between patients with HB and HA indicating comparable clinical severity and disease impact on patient quality of life.

Synthesis of building blocks and oligonucleotides with {G}O6-alkyl-O6{G} cross-links.

This unit describes two methods for preparing oligonucleotides containing an O(6)-2'-deoxyguanosine-alkyl-O(6)-2'-deoxyguanosine interstrand cross-link by a solid-phase synthesis approach. Depending on the desired orientation of the cross-link in the DNA duplex, either a bis- or a mono-phosphoramidite synthesis strategy can be employed. Both procedures require the preparation of a protected 2'-deoxyguanosine-containing dimer where the two nucleosides are attached at the O(6)-atoms by an alkyl linker. This linker is introduced as a protected diol using two successive Mitsunobu reactions to produce a cross-linked amidite that is incorporated into an oligonucleotide via solid-phase synthesis. The use of a protected diol lends versatility to this method, as cross-links of variable chain length may be prepared. The bis-phosphoramidite approach is a direct method to preparing the cross-linked duplex, whereas the mono-phosphoramidite strategy requires additional manipulation of the solid support to prepare cross-linked oligonucleotides. Once all synthetic steps are completed, these oligonucleotides can then be removed from the solid support and deprotected, and then purified via ion-exchange HPLC to produce sufficient quantities of substrates that can be used in DNA repair studies.

Synthesis and characterization of an O(6)-2'-deoxyguanosine-alkyl-O(6)-2'-deoxyguanosine interstrand cross-link in a 5'-GNC motif and repair by human O(6)-alkylguanine-DNA alkyltransferase.

O(6)-2'-Deoxyguanosine-alkyl-O(6)-2'-deoxyguanosine interstrand DNA cross-links (ICLs) with a four and seven methylene linkage in a 5'-GNC- motif have been synthesized and their repair by human O6-alkylguanine-DNA alkyltransferase (hAGT) investigated. Duplexes containing 11 base-pairs with the ICLs in the center were assembled by automated DNA solid-phase synthesis using a cross-linked 2'-deoxyguanosine dimer phosphoramidite, prepared via a seven step synthesis which employed the Mitsunobu reaction to introduce the alkyl lesion at the O(6) atom of guanine. Introduction of the four and seven carbon ICLs resulted in no change in duplex stability based on UV thermal denaturation experiments compared to a non-cross-linked control. Circular dichroism spectra of these ICL duplexes exhibited features of a B-form duplex, similar to the control, suggesting that these lesions induce little overall change in structure. The efficiency of repair by hAGT was examined and it was shown that hAGT repairs both ICL containing duplexes, with the heptyl ICL repaired more efficiently relative to the butyl cross-link. These results were reproducible with various hAGT mutants including one that contains a novel V148L mutation. The ICL duplexes displayed similar binding affinities to a C145S hAGT mutant compared to the unmodified duplex with the seven carbon containing ICLs displaying slightly higher binding. Experiments with CHO cells to investigate the sensitivity of these cells to busulfan and hepsulfam demonstrate that hAGT reduces the cytotoxicity of hepsulfam suggesting that the O(6)-2'-deoxyguanosine-alkyl-O(6)-2'-deoxyguanosine interstrand DNA cross-link may account for at least part of the cytotoxicity of this agent.

Effect of linker length on DNA duplexes containing a mismatched O6-2'-deoxyguanosine-alkyl interstrand cross-link.

DNA duplexes containing a directly opposed O(6)- alkyl-2'-deoxyguanosine interstrand cross-link were synthesized to serve as structural mimics of lesions formed by the bifunctional chemotherapeutic alkylating agents busulfan and hepsulfam. One of the key steps to prepare the necessary bis-phosphoramidites involved the Mitsunobu reaction between a diol linking two protected 2'-deoxyguanosine nucleosides at the O(6) position. These bis-phosphoramidites were incorporated into 11-bp DNA duplexes by solid phase synthesis to produce cross-linked DNA probes in high yields. UV thermal denaturation studies revealed that these interstrand cross-linked containing oligonucleotides were stabilized compared to a DNA duplex containing a central 2'-deoxyguanosine mismatch. The duplex containing the four carbon cross-link was stabilized by 10 degrees C relative to the seven carbon linker. Molecular models of these duplexes that were geometry optimized by the AMBER force field suggest that the seven carbon cross-link was less efficiently accommodated in the major groove of the duplex relative to the four carbon linker, accounting for the observed destabilization.

A comparison of torque required to fracture three different nickel-titanium rotary instruments around curves of the same angle but of different radius when bound at the tip.

Instrument fracture is an unfortunate but possible sequela of instrumentation of canals, especially when the instrument is bound at the tip. The purpose of this study was to compare the torque required to fracture three file sizes of three different rotary file types around two simulated canal curvatures, gradual or acute, when the tip of the working end of the file was bound. Profile Series 29 0.04 and 0.06 taper and Profile 0.06 ISO rotary files were placed passively into simulated canal curvatures of the same angle but of different radii. The file tips were bound 2 mm from the working end and a measurable torque was applied until fracture. ANOVA with Tamhane post-hoc comparison showed that the 0.06 Series 29 did not differ from the ISO 0.06 taper or the 0.04 Series 29 but there was statistical difference (p < 0.01) showing that the 0.04 Series 29 broke with less force than did the 0.06 ISO files. Statistical tests (p < 0.01) also showed smaller files failed with less torque, as did files in more acute canal curvatures.