Bleeding risk in hemophilia A and B carriers: comparison of factor levels determined using chronometric and chromogenic assays.

BACKGROUND: Predicting the bleeding risk in hemophilia A and B carriers (HAC, HBC) is challenging. OBJECTIVE: The objectives of this study were to describe the bleeding phenotype in HAC and HBC using the standardized Tosetto bleeding score (BS); to determine whether the BS correlates better with factor levels measured with a chromogenic assay than with factor levels measured with chronometric and thrombin generation assays; and to compare the results in HAC and HBC. METHODS: This ambispective, noninterventional study included obligate and sporadic HAC and HBC followed at a hemophilia treatment center between 1995 and 2019. RESULTS AND CONCLUSION: The median BS (3, range 0-21 vs. 3.5, range 0-15, P  = ns, respectively) and the abnormal BS rate (35.6% vs. 38.2%, P  = ns) were not significantly different in 104 HAC and 34 HBC (mean age: 38 years, 6-80 years). However, some differences were identified. The risk of factor deficiency was higher in HBC than HAC. Specifically, Factor VIII activity (FVIII):C/Factor IX activity (FIX):C level was low (<40 IU/dl) in 18.3% (chronometric assay) and 17.5% (chromogenic assay) of HAC and in 47% and 72.2% of HBC ( P  < 0.001). Moreover, the FIX:C level thresholds of 39.5 IU/dl (chronometric assay) and of 33.5 IU/dl (chromogenic assay) were associated with very good sensitivity (92% and 100%, respectively) and specificity (80% for both) for bleeding risk prediction in HBC. Conversely, no FVIII:C level threshold could be identified for HAC, probably due to FVIII:C level variations throughout life.

Decitabine Versus Hydroxyurea for Advanced Proliferative Chronic Myelomonocytic Leukemia: Results of a Randomized Phase III Trial Within the EMSCO Network.

PURPOSE: Hydroxyurea (HY) is a reference treatment of advanced myeloproliferative neoplasms. We conducted a randomized phase III trial comparing decitabine (DAC) and HY in advanced myeloproliferative chronic myelomonocytic leukemias (CMML). PATIENTS AND METHODS: Newly diagnosed myeloproliferative CMML patients with advanced disease were randomly assigned 1:1 to intravenous DAC (20 mg/m2/d days 1-5) or HY (1-4 g/d) in 28-day cycles. The primary end point was event-free survival (EFS), events being death and acute myelomonocytic leukemia (AML) transformation or progression. RESULTS: One-hundred seventy patients received DAC (n = 84) or HY (n = 86). Median age was 72 and 74 years, and median WBC count 32.5 × 109/L and 31.2 × 109/L in the DAC and HY arms, respectively. Thirty-three percent of DAC and 31% of HY patients had CMML-2. Patients received a median of five DAC and six HY cycles. With a median follow-up of 17.5 months, median EFS was 12.1 months in the DAC arm and 10.3 months in the HY arm (hazard ratio [HR], 0.83; 95% CI, 0.59 to 1.16; P = .27). There was no significant interaction between treatment effect and blast or platelet count, anemia, CMML Prognostic Scoring System, Groupe Francophone des Myelodysplasies, or CMML Prognostic Scoring System-mol risk. Fifty-three (63%) DAC patients achieved a response compared with 30 (35%) HY patients (P = .0004). Median duration of response was similar in both arms (DAC, 16.3 months; HY, 17.4 months; P = .90). Median overall survival was 18.4 months in the DAC arm and 21.9 months in the HY arm (P = .67). Compared with HY, DAC significantly reduced the risk of CMML progression or transformation to acute myelomonocytic leukemia (cause-specific HR, 0.62; 95% CI, 0.41 to 0.94; P = .005) at the expense of death without progression or transformation (cause-specific HR, 1.55; 95% CI, 0.82 to 2.9; P = .04). CONCLUSION: Compared with HY, frontline treatment with DAC did not improve EFS in patients with advanced myeloproliferative CMML (ClinicalTrials.gov identifier: NCT02214407).

Identification of New DR5 Agonistic Nanobodies and Generation of Multivalent Nanobody Constructs for Cancer Treatment.

Current cancer therapeutics suffer from a lack of specificity in targeting tumor cells and cause severe side effects. Therefore, the design of highly specialized drugs comprising antibody derivatives inducing apoptosis in targeted cancer cells is considered to be a promising strategy. Drugs acting on death receptor 5 (DR5) such as DR5 agonist antibodies replacing "TNF-related apoptosis-inducing ligand" (TRAIL) offer feasible opportunities in this direction. Although such agonists provided good antitumor activity in preclinical studies, they were less effective in clinical studies, possibly due to a disturbed Fc interaction with Fc-γ receptors. Thus, multimerized antigen binding fragments without Fc have been proposed to increase their efficacy. We generated nanobodies (Nbs), recombinant variable domains of heavy chain-only antibodies of camelids, against the DR5 ectodomain. Nb24 and Nb28 had an affinity in the nM and sub-nM range, but only Nb28 competes with TRAIL for binding to DR5. Bivalent, trivalent, and tetravalent constructs were generated, as well as an innovative pentameric Nb complex, to provoke avidity effects. In our cellular assays, these trimeric, tetrameric, and pentameric Nbs have a higher apoptotic capacity than monomeric Nbs and seem to mimic the activity of the natural TRAIL ligand on various cancer cells.

Structural Basis for the Specific Neutralization of Stx2a with a Camelid Single Domain Antibody Fragment.

BACKGROUND: Shiga toxin-producing Escherichia coli (STEC) are a subset of pathogens leading to illnesses such as diarrhea, hemolytic uremic syndrome and even death. The Shiga toxins are the main virulence factors and divided in two groups: Stx1 and Stx2, of which the latter is more frequently associated with severe pathologies in humans. RESULTS: An immune library of nanobodies (Nbs) was constructed after immunizing an alpaca with recombinant Shiga toxin-2a B subunit (rStx2aB), to retrieve multiple rStx2aB-specific Nbs. The specificity of five Nbs towards rStx2aB was confirmed in ELISA and Western blot. Nb113 had the highest affinity (9.6 nM) and its bivalent construct exhibited a 100-fold higher functional affinity. The structure of the Nb113 in complex with rStx2aB was determined via X-ray crystallography. The crystal structure of the Nb113-rStx2aB complex revealed that five copies of Nb113 bind to the rStx2aB pentamer and that the Nb113 epitope overlaps with the Gb3 binding site, thereby providing a structural basis for the neutralization of Stx2a by Nb113 that was observed on Vero cells. Finally, the tandem-repeated, bivalent Nb1132 exhibits a higher toxin neutralization capacity compared to monovalent Nb113. CONCLUSIONS: The Nb of highest affinity for rStx2aB is also the best Stx2a and Stx2c toxin neutralizing Nb, especially in a bivalent format. This lead Nb neutralizes Stx2a by competing for the Gb3 receptor. The fusion of the bivalent Nb1132 with a serum albumin specific Nb is expected to combine high toxin neutralization potential with prolonged blood circulation.

Changing the Way We Pay for Health Care: Is Value the New Plastic?

DISCLOSURES: Navarro is a clinical professor in the College of Pharmacy at the University of Florida, Gainesville, and is an assistant editor with the Journal of Managed Care and Specialty Pharmacy. Navarro reports consulting fees from Analysis Group, Amgen, Novartis, and Allergan.

Performance-Based Risk-Sharing Arrangements: U.S. Payer Experience.

BACKGROUND: As a result of global concern about rising drug costs, many U.S. payers and European agencies such as the National Health Service have partnered with pharmaceutical companies in performance-based risk-sharing arrangements (PBRSAs) by which manufacturers share financial risk with health care purchasing entities and authorities. However, PBRSAs present many administrative and legal challenges that have minimized successful contract experiences in the United States. OBJECTIVE: To (a) identify drug and disease characteristics and contract components that contribute to successful PBRSA experiences and the primary barriers to PBRSA execution and (b) explore solutions to facilitate contract negotiation and execution. METHODS: A 37-item, web-based survey instrument (Qualtrics), approximately 20 minutes in duration, was open during July and August 2016. The survey was emailed to 90 pharmacy and medical directors of various health care organizations. Statistical analysis included the Kruskal-Wallis test and chi-square tests to examine differences among payer responses. Survey responses were anonymized and data were aggregated. RESULTS: Twenty-seven individuals completed the survey (30% completion rate). The majority of respondents worked for regional health plans (52%, n = 14), covering at least 1 million lives (63%, n = 17), with at least 7 years of managed care experience (81%, n = 22). A total of 51 PBRSAs were active among respondents at the time of the survey. Easily obtainable and evaluable drug data and medical data were the most important drug and disease attributes for successful PBRSAs, respectively. Pharmacy claims and patient demographic data were assessed as "very easy and inexpensive" to collect. Type and amount of manufacturer payment for drug outcome performance failure, endpoint measurement, and necessary clinical data for drug performance measurement were all critical factors for successful PBRSAs. Standardized contract templates and transparent contract financial risk evaluation and modeling ranked highest among methods of manufacturer facilitation of PBRSAs. This study was limited by sample size and survey questions were limited to explanation of PBRSAs at the disease state level. CONCLUSIONS: On the basis of PBRSA experiences, respondents noted that drug use in chronic medical conditions and objective drug outcome performance measurements were favorable drug characteristics and serve as the primary source of satisfaction for these types of contracts. Third parties and manufacturers can facilitate the uptake and success of PBRSAs by developing standardized contracting templates in addition to other methods that increase their stake in the arrangement. Looking forward, mounting perceptions of success in this realm of contracting for pharmaceuticals may contribute in the quest for value-based payments in the U.S. health care system. DISCLOSURES: The construction of the survey and payment for survey respondents were supported by Charles River Associates. Parece is an employee of Charles River Associates. Goble and Ung are completing fellowship training sponsored by Novartis and Celgene, respectively, but do not have any conflicts of interest and did not receive any funding related to this study. Navarro reports consulting fees from Analysis Group, TEVA, and Amgen, unrelated to this study. Van Boemmel-Wegmann declares no conflict of interest. Study concept and design were contributed by Navarro, Goble, Ung, and Parece. Navarro took the lead in data collection, along with Goble and Ung, and data interpretation was performed by van Boemmel-Wegmann, Goble, and Ung. The manuscript was written by Goble, Ung, Navarro, and van Boemmel-Wegmann and revised by all of the authors.

Outcomes-Based Contracting Experience: Research Findings from U.S. and European Stakeholders.

BACKGROUND: Outcomes-based contracts (OBCs), a type of risk-sharing arrangement (RSA), have emerged as a promising avenue for payers to engage with pharmaceutical manufacturers to share risk and improve patient access to medicines via evaluation of real-world outcomes. OBJECTIVE: To assess the level of recent OBC activity and stakeholder perceptions of these arrangements, as well as the outlook for future OBC activity from a payer and manufacturer perspective in the United States and EU-5 (France, Germany, Italy, Spain, and the United Kingdom). METHODS: Using a structured questionnaire, interviews were conducted with 27 experts, including 14 U.S. payers, 5 EU-5 national payers, and 8 manufacturer pricing/market access executives (4 U.S., 4 EU-5). We also used the University of Washington's Performance Based Risk-Sharing (PBRS) database and other targeted publicly available information. RESULTS: Publicly disclosed information on OBCs understates the level of OBC activity, since many arrangements are confidential. Overall, U.S. and EU-5 interviewees generally expected that 2 to 3 times more OBCs would be implemented in the next 5 years than in the previous 5 years. Key drivers included the introduction of a national OBC framework in Spain, potentially a similar framework in the United Kingdom, a growing sickness fund activity in Germany, and a U.S. movement towards accountable care. Motivation for OBCs varied markedly across markets and stakeholders, with operational feasibility noted as a significant hurdle in the United States and France. Along with improving health outcomes, cost and financial risk reduction were the primary OBC motivators for payers, while potential access or reimbursement gains were key factors for manufacturers. CONCLUSIONS: Using direct input from U.S. and EU-5 payer and pharmaceutical manufacturer decision makers, this research suggests that high OBC growth is expected in the EU-5 and, to a more moderate extent, in the United States, particularly if clear, simpler OBC frameworks can be developed. DISCLOSURES: This study was funded by Novartis Pharmaceuticals. Novartis employees were involved in all aspects of this study. Vegesna and Sasane are employed by and own stock in Novartis. Nazareth and Ko were employees of Novartis at the time of this study. Frois, Demean, Carpenter, and Wu are or have been employed by Analysis Group, which received a grant from Novartis for this research. Navarro received consulting fees from Novartis for his involvement in this research. Study concept and design were contributed by Sasane, Frois, Nazareth, and Wu. Navarro, Demean, and Frois took the lead in data collection, assisted by Carpenter, Ko, and Nazareth. Data interpretation was provided by Frois, Carpenter, Nazareth, and Ko, along with Sasane, Demean, Wu, and Navarro. The manuscript was written by Frois, Demean, Nazareth, and Ko, along with Sasane, Carpenter, Wu, and Navarro, and revised by Frois, Ko, and Vegesna, along with Sasane, Nazareth, Wu, and Navarro.

Cytomegalovirus Infection With Retinitis After Brentuximab Vedotin Treatment for CD30+ Lymphoma.

Brentuximab vedotin is an antibody-conjugated chemotherapy targeting CD30 indicated in treatment of several lymphomas. We report the first 3 cases of cytomegalovirus severe infections with retinitis following this treatment. Evolution was favorable, but relapse occurred after treatment rechallenge. We suggest vigilance about cytomegalovirus in patients treated with brentuximab vedotin.

Primary Biliary Cholangitis: Medical and Specialty Pharmacy Management Update.

BACKGROUND: Chronic liver disease and cirrhosis are a leading cause of morbidity and mortality in the United States. Primary biliary cholangitis (PBC), previously known as primary biliary cirrhosis and which has been designated an orphan condition, is a chronic autoimmune disease resulting in the destruction of the small bile ducts in the liver. Without effective treatment, disease progression frequently leads to liver failure and death. Until May 2016, the only FDA-approved treatment for PBC was ursodiol (UDCA), an oral hydrophilic bile acid, which can slow progression of liver damage due to PBC. However, 1 out of 3 patients taking UDCA has an inadequate biochemical response, leading to increased risk of disease progression, liver transplantation, and mortality. Given this unmet clinical need, new therapies are in development for the treatment of PBC. To provide pharmacists with an overview of the latest research on the pathophysiology of PBC and potential new treatment options and to highlight medical and specialty pharmacy approaches to managing access to drugs to treat orphan diseases such as PBC, a 2-hour satellite symposium was presented in conjunction with the 2015 Academy of Managed Care Pharmacy (AMCP) Nexus meeting. Although obeticholic acid was approved by the FDA for the treatment of PBC in May 2016, this development occurred after the symposium presentation. The symposium was supported by an independent educational grant from Intercept Pharmaceuticals and was managed by Analysis Group. Robert Navarro, PharmD, moderated the CPE-accredited symposium titled "Medical and Specialty Pharmacy Management Update on Primary Biliary Cirrhosis." Expert panelists included Christopher L. Bowlus, MD; James T. Kenney, RPh, MBA; and Gary Rice, RPh, MS, MBA, CSP. OBJECTIVE: To summarize the educational satellite symposium presentations and discussions. SUMMARY: Autoimmune liver diseases, including PBC, are responsible for 15% of all liver transplants performed and an equal percentage of deaths related to liver disease. UDCA is the only FDA-approved therapy for treatment of PBC and is considered the standard of care. Nevertheless, many patients do not respond to UDCA, creating the need for new therapeutic options to improve clinical outcomes for PBC patients with inadequate response to treatment. While several agents are being studied in combination with UDCA, monotherapy with the novel agent obeticholic acid, a farnesoid X receptor agonist, has also shown promising results. Health plans are anticipated to assign any newly introduced therapy for the treatment of PBC to specialty pharmacy given its orphan disease status. This assignment enables the health plan to receive disease education, which is particularly important when new drugs are indicated for orphan diseases, and assistance with designing appropriate prior authorization criteria. The clinical value of any new therapeutic options that will inform formulary decisions and prior authorization criteria will be assessed based on evidence of efficacy, safety, and tolerability, among other factors, such as the potential to reduce or delay medical resource utilization (e.g., liver transplant). Key considerations for prior authorization of a new therapy will be determining which PBC patients are appropriate candidates for the new therapy and developing criteria for that determination. These are likely to include clinical diagnostic criteria and degree of response to prior treatment with UDCA. Initially, any new therapy would likely be positioned as noncovered until appropriate prior authorization criteria are established. CONCLUSIONS: PBC is a chronic liver disease with significant morbidity and mortality, as well as a significant burden on the health care system if the disease progresses to the point at which a liver transplant is needed. Although UDCA, the current standard of care, has improved outcomes for many patients, others have an inadequate response to this treatment. This symposium discussed these issues and also addressed the overall treatment paradigm for orphan drug therapies, key implications for patient management, and the role of specialty pharmacy management and any associated needs both in general and specifically for new therapeutic options for PBC.

A phase II, single-arm, multicentre study of coltuximab ravtansine (SAR3419) and rituximab in patients with relapsed or refractory diffuse large B-cell lymphoma.

In this phase II, multicentre, single-arm study, 52 patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) received the anti-CD19 antibody-drug conjugate coltuximab ravtansine (55 mg/m(2) ) and rituximab (375 mg/m(2) ) weekly for 4 weeks, then every 2 weeks for 8 weeks. The primary endpoint was objective response rate (ORR) by International Working Group Criteria. The primary objective was to reject the null hypothesis of an ORR of ≤40%. Among 45 evaluable patients, the ORR was 31·1% (80% confidence interval [CI]: 22·0-41·6%) and the primary objective was not met. The ORR appeared higher in patients with relapsed disease (58·3% [80% CI: 36·2-78·1%]) versus those refractory to their last (42·9% [80% CI: 17·0-72·1%]) or first-line therapy (15·4% [80% CI: 6·9-28·4%]). Median progression-free survival, overall survival and duration of response were 3·9 [80% CI: 3·22-3·98], 9·0 [80% CI: 6·47-13·67] and 8·6 (range: 0-18) months, respectively. The pharmacokinetics of both drugs were unaffected by co-administration. Common adverse events included gastrointestinal disorders (52%) and asthenia (25%). No patients discontinued due to adverse events. In conclusion, coltuximab ravtansine with rituximab was well tolerated and yielded clinical responses in a subset of patients with relapsed/refractory DLBCL.

Assessment of the Level of Satisfaction and Unmet Data Needs for Specialty Drug Formulary Decisions in the United States.

BACKGROUND: Formulary management within a limited budget is critical, especially for specialty drugs, which are used for serious medical conditions and are very expensive. Despite attempts to summarize the pertinent evidence, it is uncertain whether data needs of formulary decision makers for specialty drugs are satisfied. OBJECTIVE: To assess the level of satisfaction of specialty drug formulary decision makers with regards to the strength of current available data sources and unmet needs regarding clinical, economic, and unpublished evidence. METHODS: This study targeted pharmacists and physicians involved with formulary decision making at health plans or pharmacy benefit management companies at the national, large regional, and local levels. 95 individuals were invited to participate (without compensation) in a 21-item, web-based survey (Qualtrics), which was open from June 14 to July 31, 2014. The responses were coded for descriptive and statistical analysis. Statistical analyses included the Kruskal-Wallis test, analysis of variance, and the Mann-Whitney-Wilcoxon test. RESULTS: Of 95 pharmacists or physicians, 40 respondents initiated the survey, and 33 respondents completed the survey (response rate = 34.7%). Drug formulary decision makers infrequently rated data evidence strength (17.1% "always"). Clinical data evidence strength was rated highest with published randomized controlled trials (RCTs; mean [SD] = 4.06 [0.87] of 5.0), while participant organizations' internal data were rated highest for economic data evidence strength (mean [SD] = 3.91 [1.07] of 5.0). Decision makers rated the highest unmet need as more data generated from head-to-head RCTs (mean [SD] = 2.94 [0.25] of 3.0) and cost-effectiveness analyses (mean [SD] = 2.53 [0.67] of 3.0). The participants believed manufacturers might be in the best position to satisfy their desire for head-to-head RCTs (mean [SD] = 4.31 [1.09] of 5.0). CONCLUSIONS: Despite a variety of data sources, drug formulary decision makers continue to rely on published RCTs or internal economic analyses as having the strongest evidence strength. The study respondents believed that pharmaceutical manufacturers would be best able to satisfy the greatest clinical data unmet need, that is, head-to-head RCTs in specialty drug formulary decisions. DISCLOSURES: This study was not funded by any company or pharmaceutical manufacturer. Navarro has worked as a consultant for Biogen, Purdue Pharma, and Novartis and has offered expert testimony on behalf of AstraZeneca. The authors declare no other potential conflicts of interest. Study design was contributed primarily by Navarro, along with Choi. Choi took the lead in data collection and interpretation, assisted by Navarro. Both authors contributed equally to manuscript writing and revision.

Cytotoxic factor secreted by Escherichia coli associated with sepsis facilitates transcytosis through human umbilical vein endothelial cell monolayers.

Culture supernatant of sepsis-associated Escherichia coli (SEPEC) isolated from patients with sepsis caused loss of intercellular junctions and elongation of human umbilical vein endothelial cells (HUVEC). The cytotoxic factor was purified from culture supernatant of SEPEC 15 (serogroup O153) by liquid chromatography process. PAGE (polyacrylamide gel electrophoresis) showed that the purified SEPEC cytotoxic factor had a molecular mass of ∼150kDa and consisted of at least two subunits. At the concentration of 1 CD50 (40µg/mL) did facilitate transcytosis through the HUVEC cells monolayer of SEPEC 15 as much as E. coli K12 within 30min without affecting cell viability. These results suggest that this cytotoxic factor, named as SPF (SEPEC's permeabilizing factor), may be an important SEPEC virulence factor that facilitates bacterial access to the bloodstream.

Phage display and Shiga toxin neutralizers.

The current work presents an overview of the use of phage display technology for the identification and characterization of potential neutralizing agents for Shiga toxins. The last major Shiga toxin-associated disease outbreak, which took place in Germany in 2011, showed the international community that Shiga toxins remain a serious threat to public health. This is also demonstrated by the lack of specific therapies against Shiga toxin-induced Hemolytic Uremic Syndrome (HUS). Since its inception, phage display technology has played a key role in the development of antigen-specific (poly)-peptides or antibody fragments with specific biological properties. Herein, we review the current literature regarding the application of phage display to identify novel neutralizing agents against Shiga toxins. We also briefly highlight reported discoveries of peptides and heavy chain antibodies (VHH fragments or nanobodies) that can neutralize the cellular damage caused by these potent toxins.

Translating clinical guidelines into practice: the effective and appropriate use of human growth hormone.

There are 9 recombinant human growth hormone (rhGH) products currently available for 10 US Food and Drug Administration-approved indications; each rhGH product is approved for 1 or more indications. Adult and pediatric patients with the various conditions for which rhGH is indicated, from idiopathic short stature (ISS) and growth hormone (GH) deficiency to short bowel syndrome and HIV/AIDS wasting, may benefit from rhGH treatment. In clinical practice, pediatric patients with GH deficiency or ISS make up the majority of the population receiving treatment with rhGH. Most rhGH products are provided through specialty pharmacies that often have to balance the needs of the patient, their own utilization objectives, and the availability of the rhGH on formulary from a particular payer. Often, a payer will prefer only 2 or 3 rhGH products to cover all 10 indications. As such, managed care professionals need to be more informed about the options available and should be familiar with the different indications to help educate patients about treatment. Additionally, healthcare providers should endeavor to identify and manage the care of appropriate patients who would potentially benefit from rhGH therapy, and should be aware of formulary options. Because many of the patients are children and young adults, adherence to treatment is a concern; patient education on the importance of treatment adherence should be ongoing. Various mechanisms are in place (eg, prior authorization requirements and case manager follow-up) to help ensure that rhGH products are used, and used appropriately. This publication includes highlights from a roundtable discussion by key opinion leaders (clinicians and managed care professionals) on how managed care policies and clinical guidelines on appropriate use of rhGH translate into real-world practice. Also discussed are the efficacy and safety of rhGH therapy for its pediatric indications, and the role of specialty pharmacies in managing patient access to therapy.