Cost-effectiveness of brentuximab vedotin plus chemotherapy as frontline treatment of stage III or IV classical Hodgkin lymphoma.

OBJECTIVE: The ECHELON-1 trial demonstrated efficacy and safety of brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine (A + AVD) vs doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) as frontline therapy for stage III/IV classical Hodgkin lymphoma. This analysis evaluated the cost-effectiveness of A + AVD from a US healthcare payer perspective. METHODS: The incremental cost-effectiveness ratio (ICER), defined as the incremental costs per quality-adjusted life year (QALY) gained, was estimated using a non-homogenous semi-Markov cohort model with health states defined on progression following frontline treatment, and for those with progression, receipt of autologous stem-cell transplant (ASCT), and progression after ASCT. Patients undergoing ASCT were classified as refractory or relapsed based on timing of progression. Probabilities of progression/death with frontline therapy were based on parametric survival distributions fit to data on modified progression-free survival (mPFS) from ECHELON-1. Duration of frontline treatment and incidence of adverse events were from ECHELON-1. Utility values for patients in the frontline mPFS state were based on EQ-5D data from ECHELON-1. Other inputs were from published sources. A lifetime time horizon was used. Costs and QALYs were discounted at 3%. Analyses were conducted alternately using data on mPFS for the overall and North American populations of ECHELON-1. RESULTS: The ICER for A + AVD vs ABVD was $172,074/QALY gained in the analysis using data on mPFS for the overall population and $69,442/QALY gained in the analysis using data on mPFS for the North American population of ECHELON-1. The ICER is sensitive to estimated costs of ASCT and frontline failure. CONCLUSION: The ICER for A + AVD vs ABVD based on ECHELON-1 is within the range of threshold values for cost-effectiveness in the US. A + AVD is, therefore, likely to be a cost-effective frontline therapy for patients with stage III/IV classical Hodgkin lymphoma from a US healthcare payer perspective.

Using Health Care Claims Data to Assess the Prevalence of Hodgkin Lymphoma and Relapsed or Refractory Hodgkin Lymphoma in the United States.

PURPOSE: Although most patients with Hodgkin lymphoma (HL) respond to primary therapy, some patients experience relapses or are refractory to treatment (RR-HL). The objectives of this study were to investigate the prevalence of HL and RR-HL in the United States by using a large health care claims database. METHODS: Patients with ≥1 diagnosis for HL between January 1, 2013, and September 30, 2014 (prevalence assessment period), in the MarketScan Commercial and Medicare databases were identified. RR-HL patients were identified as any HL patient with any record for either an autologous stem cell transplantation (ASCT) or brentuximab vedotin (BV) treatment between January 1, 2010, and September 30, 2014 (entire study period). Prevalence rates of HL and RR-HL were calculated as the number of patients with HL or RR-HL divided by the total number of persons with insurance enrollment during the prevalence assessment period (January 1, 2013-September 30, 2014) in the MarketScan databases. Age- and sex-specific prevalence rates for HL and RR-HL were estimated. The estimated prevalence rates based on the claims database analysis were applied to the US national population estimates from the US Census Bureau to project the national prevalence of HL and RR-HL in the United States. FINDINGS: Of persons with any insurance enrollment in the MarketScan databases during the prevalence assessment period (N = 58,968,235), 24,812 (0.04%) were identified as having HL (mean age, 48.6 years) between January 1, 2013, and September 30, 2014. Of this HL population, 712 (2.87%) were identified as RR-HL patients, with 432 (1.74%) having received ASCT, 199 (0.80%) having received BV, and 81 (0.33%) having received both ASCT and BV treatments during the study period. According to the national projection according to the US Census population estimate, the overall number of persons with HL in the United States was estimated at 149,615 (469.2 per 1 million) in 2014, with 2.72% (N = 4077; 12.8 per 1 million) having RR-HL. IMPLICATIONS: Among patients in the United States with HL, the proportion of RR-HL patients during the study period was estimated at <3% of the HL population.

Brentuximab vedotin activity in diffuse large B-cell lymphoma with CD30 undetectable by visual assessment of conventional immunohistochemistry.

This phase 2 study evaluated brentuximab vedotin monotherapy in CD30-expressing DLBCL; after several patients with little to no CD30 achieved a complete remission (CR), the study evaluated treatment of DLBCL with undetectable CD30 (CD30u) by local visual immunohistochemistry (vIHC). Sixteen of 52 CD30u DLBCL patients (31%) had an objective response (6 CRs [12%]). Median progression-free survival (PFS) was 1.4 months (range, 0.4-15.6) and median overall survival (OS) was 7.5 months (range, 0.7-18.6+). Subsequent CD30 expression quantitated by computer-assisted digital image analysis (cIHC) showed that 11 of 16 CD30u DLBCL responders had ≥1% CD30. Correlative analyses of CD30u and CD30-expressing DLBCL combined demonstrated that ≥1% CD30 expression by cIHC resulted in a trend toward a higher response rate and significantly longer median PFS and OS. A minimum CD30 expression threshold appears to be required for antitumor activity in DLBCL; however, other factors also likely contribute to activity. (NCT01421667).

Development of Lu-177-trastuzumab for radioimmunotherapy of HER2 expressing breast cancer and its feasibility assessment in breast cancer patients.

HER2/neu is over expressed in 20-25% of breast cancers. HER2 breast cancers are aggressive and are associated with poor prognosis. The aim of this study was to develop the clinical grade Lu-177-trastuzumab and its preliminary evaluation for specific tumor targeting in HER2 positive breast cancer patients. Trastuzumab was conjugated to bifunctional chelator, DOTA, and characterized for integrity and the number of molecules conjugated. Radiolabeling of DOTA-conjugated trastuzumab was optimized using Lu-177. Quality control parameters including radiochemical purity, stability, sterility, pyrogenicity and immunoreactivity were assessed. A preliminary pilot study was conducted on breast cancer patients (n = 6 HER2 positive and n = 4 HER2 negative) to evaluate the ability of Lu-177-trastuzumab for HER2 specific tumor targeting. The conjugates were efficiently labeled with Lu-177 with high radiochemical purity (up to 91%) and specific activity (6-13 µCi/µg). Lu-177-trastuzumab was stable up to 12 hr post labeling. The radioimmunoassay demonstrated good antigen binding ability and specificity for HER2 receptor protein. The patient studies showed the localization of Lu-177-trastuzumab at primary as well as metastatic sites (HER2 positive) in the planar and SPECT/CT images. No tracer uptake was observed in HER2 negative patients that indicated the specificity of Lu-177-trastuzumab. The study demonstrated that in-house developed Lu-177-trastuzumab has specific targeting ability for HER2 expressing lesions and may in future become a palliative treatment option in the form of targeted radionuclide therapy for disseminated HER2 positive breast cancer.

The European Medicines Agency Review of Brentuximab Vedotin (Adcetris) for the Treatment of Adult Patients With Relapsed or Refractory CD30+ Hodgkin Lymphoma or Systemic Anaplastic Large Cell Lymphoma: Summary of the Scientific Assessment of the Committee for Medicinal Products for Human Use.

BACKGROUND: On October 25, 2012, a conditional marketing authorization valid throughout the European Union (EU) was issued for brentuximab vedotin for the treatment of adult patients with relapsed or refractory CD30+ Hodgkin lymphoma (HL) and for the treatment of adult patients with relapsed or refractory systemic anaplastic large cell lymphoma (sALCL). For HL, the indication is restricted to treatment after autologous stem cell transplantation (ASCT) or after at least two previous therapies when ASCT or multiagent chemotherapy is not a treatment option. MATERIALS AND METHODS: Brentuximab vedotin is an antibody-drug conjugate (ADC) composed of a CD30-directed monoclonal antibody (recombinant chimeric IgG1) that is covalently linked to the antimicrotubule agent monomethyl auristatin E (MMAE). Binding of the ADC to CD30 on the cell surface initiates internalization of the MMAE-CD30 complex, followed by proteolytic cleavage that releases MMAE. The recommended dose is 1.8 mg/kg administered as an intravenous infusion over 30 minutes every 3 weeks. RESULTS: Brentuximab vedotin as a single agent was evaluated in two single-arm studies. Study SG035-003 included 102 patients with relapsed or refractory HL. An objective response was observed in 76 patients (75%), with complete remission in 34 (33%). Study SG035-004 included 58 patients with relapsed or refractory sALCL. An objective response was observed in 50 patients (86%), with complete remission in 34 (59%). The most frequently observed toxicities were peripheral sensory neuropathy, fatigue, nausea, diarrhea, neutropenia, vomiting, pyrexia, and upper respiratory tract infection. CONCLUSION: The present report summarizes the scientific review of the application leading to approval in the EU. The detailed scientific assessment report and product information, including the summary of the product characteristics, are available on the European Medicines Agency website (http://www.ema.europa.eu). IMPLICATIONS FOR PRACTICE: Brentuximab vedotin was approved in the European Union for the treatment of adult patients with relapsed or refractory CD30+ Hodgkin lymphoma or systemic anaplastic large cell lymphoma. For Hodgkin lymphoma, brentuximab vedotin should only be used after autologous stem cell transplantation or following at least two prior therapies when transplantation or multiagent chemotherapy is not a treatment option. In two studies involving 160 patients, partial or complete responses were observed in the majority of patients. Although there was no information on the survival of patients treated in the studies at the time of approval, the responses were considered a clinically relevant benefit.

Preclinical Efficacy and Safety Assessment of an Antibody-Drug Conjugate Targeting the c-RET Proto-Oncogene for Breast Carcinoma.

PURPOSE: The RET proto-oncogene has been implicated in breast cancer, and the studies herein describe the preclinical and safety assessment of an anti-RET antibody-drug conjugate (ADC) being developed for the treatment of breast cancer. EXPERIMENTAL DESIGN: RET protein expression was analyzed in breast tumor samples using tissue microarrays. The fully human anti-RET antibody (Y078) was conjugated to the DM1 and DM4 derivatives of the potent cytotoxic agent maytansine using thioether and disulfide linkers, respectively. The resulting compounds, designated Y078-DM1 and Y078-DM4, were evaluated for antitumor activity using human breast cancer cell lines and established tumor xenograft models. A single-dose, 28-day, safety study of Y078-DM1 was performed in cynomolgus monkeys. RESULTS: By immunohistochemistry, RET expression was detected in 57% of tumors (1,596 of 2,800 tumor sections) and was most common in HER2-positive and basal breast cancer subtypes. Potent in vitro cytotoxicity was achieved in human breast cancer cell lines that have expression levels comparable with those observed in breast cancer tissue samples. Dose-response studies in xenograft models demonstrated antitumor activity with both weekly and every-3-weeks dosing regimens. In cynomolgus monkeys, a single injection of Y078-DM1 demonstrated dose-dependent, reversible drug-mediated alterations in blood chemistry with evidence of on-target neuropathy. CONCLUSIONS: RET is broadly expressed in breast cancer specimens and thus represents a potential therapeutic target; Y078-DM1 and Y078-DM4 demonstrated antitumor activity in preclinical models. Optimization of the dosing schedule or an alternate cytotoxic agent with a different mechanism of action may reduce the potential risk of neuropathy. Clin Cancer Res; 21(24); 5552-62. ©2015 AACR.

Practical considerations for the pharmacokinetic and immunogenic assessment of antibody-drug conjugates.

Currently, the most bioanalytically challenging drugs are antibody-drug conjugates (ADCs), constructs comprising a monoclonal antibody and a cytotoxic drug connected by a linker. The bioanalytical challenges arise from the heterogeneous nature of ADCs and their complex in vivo behavior, resulting in a high number of analytes to be measured. Measuring the concentration of biologics in blood/plasma/serum is a necessity to properly assess their pharmacokinetic (PK)/pharmacodynamic behaviors in vivo. An additional bioanalytical challenge is to monitor the stability of the ADCs, as cytotoxic drugs released from the ADC in blood circulation may pose a potential safety risk because of their high cytotoxic potency. The nature of ADCs does not only complicate bioanalysis, but also immunogenicity assessment. Questions, such as 'Which part of the ADCs is the anti-drug antibodies directed against?' may arise, and their answer normally includes several immunogenicity risk assessment strategies. This review will focus on the bioanalytical challenges of ADCs, current approaches involving ligand-binding assays (LBAs), liquid chromatography and mass spectrometry platforms, and recommendations on which approach to use for which stage of drug development, and will close with immunogenicity assessment. In order to appropriately tackle the bioanalytical and immunogenic challenges of ADCs and consider every angle, the authors of this review have expertise in ligand binding and liquid chromatography-mass spectrometry.

Cost-effectiveness of abatacept for moderate-to-severe rheumatoid arthritis.

Abatacept, a selective T-cell costimulation modulator, has become a valuable treatment option for those with moderately to severely active rheumatoid arthritis. Given new clinical evidence, for the first time guidelines from the American College of Rheumatology and Canadian Rheumatology Association are promoting the consideration of abatacept as the first biologic added to initial traditional disease-modifying antirheumatic drugs once an inadequate response to disease-modifying antirheumatic drug monotherapy has been established, putting abatacept at the same line of treatment options as TNF-α inhibitors or rituximab. Since the advent of the subcutaneous formulation of abatacept, positive results from its clinical trials have further increased its appeal. In light of these changes, a review of the literature was conducted on the cost-effectiveness of abatacept for moderate-to-severe rheumatoid arthritis. Here we discuss current evidence, gaps in the literature and abatacept's future outlook.

18-Fluorodeoxyglucose positron emission tomography/computed tomography for assessment of response to brentuximab vedotin treatment in relapsed and refractory Hodgkin lymphoma.

Brentuximab vedotin has emerged as a possible treatment option in patients suffering from relapsed and refractory Hodgkin lymphoma (HL). We investigated the role of 18-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) for monitoring treatment response to brentuximab vedotin in patients with relapsed and refractory HL. Twelve consecutive, heavily pretreated patients with relapsed and refractory HL treated with brentuximab vedotin were available for analysis. FDG-PET/CT studies were performed early during treatment after a median of 3 cycles (range, 2-5 cycles), and were analyzed visually using a 5-point scale (5PS) and quantitatively using the maximum standardized uptake value (SUV(max)) and the three-dimensional (3D) isocontour at 50% of the maximum pixel value (SUV(50)) in the hottest single lesion. The median follow-up in our study cohort was 16 months (range, 5-30 months). The median progression-free survival (PFS) was 12.5 months and PFS at 12 months was 58%. Patients treated with brentuximab vedotin and negative interim FDG-PET/CT assessed by visual or quantitative analysis demonstrated a significantly prolonged PFS compared to patients with positive interim FDG-PET/CT. The 1-year PFS was 100% in patients with negative interim FDG-PET/CT assessed by visual analysis, whereas patients with positive interim FDG-PET/CT had a worse outcome with a 1-year PFS of 38% (p = 0.033). The 1-year PFS was 75% in patients with negative interim FDG-PET/CT assessed by quantitative analysis using the SUV(50), whereas patients with positive interim FDG-PET/CT had a worse outcome with a 1-year PFS of 25% (p = 0.017) Interim FDG-PET/CT might be a suitable diagnostic approach to predict response to brentuximab vedotin in relapsed and refractory HL.

Abatacept or infliximab for patients with rheumatoid arthritis and inadequate response to methotrexate: an Italian trial-based and real-life cost-consequence analysis.

OBJECTIVES: In the 1-year, double-blind, placebo-controlled ATTEST trial, efficacy of abatacept or infliximab versus placebo was reported in patients with rheumatoid arthritis (RA) and an inadequate response to methotrexate (MTX). The current study estimated trial-based and real-life costs of abatacept and infliximab for achieving pre-defined remission or low disease activity state (LDAS). METHODS: Quantity of drug, serious adverse event (SAE) rates and time (months) in remission or LDAS were taken from ATTEST for the trial-based calculation to derive a cost per remitting/LDAS patient and a cost per patient-month in remission/LDAS. Trial-based and real-life scenarios were performed. RESULTS: The annual trial-based costs per remitting/LDAS patient were €70.238/€37.208 for abatacept and €85.565/€46.602 for infliximab. In the first 6 months of the ATTEST trial, costs per patient-month in remission/LDAS were higher for abatacept (€11.024 and €6.018, respectively), relative to infliximab (€8.347 and €4.174, respectively). Over the full 12-month trial period cost per month in remission/LDAS estimates were only slightly in favour of infliximab (€6.959/€3.625) relative to abatacept (€7.297/€3.909). Assuming extension of treatment under real life conditions the cost per month in remission/LDAS turned substantially in favour of abatacept (€5.321/€2.819), as compared to infliximab (€7.189/€3.916). The higher initiation cost for abatacept to achieve remission/LDAS would be offset after a total 14.6 and 16.1 months of treatment, respectively, if treatment extended beyond 6 months under real-life conditions. These results proved to be robust when it was assumed that the (i) sharing of vials across patients completely averted infliximab wastage, (ii) AE risks were similar and (iii) onset of response was slower for abatacept. CONCLUSIONS: Our findings suggest a lower cost-consequence for abatacept during real-life treatment.

Contraceptive vaccines based on the zona pellucida glycoproteins for dogs and other wildlife population management.

Zona pellucida (ZP) glycoproteins, by virtue of their critical role in fertilization, have been proposed as candidate antigens for the development of contraceptive vaccines. In this review, the potential of a ZP-based contraceptive vaccine for the management of wildlife population, with special reference to street dogs, is discussed. Immunization of various animal species, including female dogs, with native porcine ZP led to inhibition of fertility, which was associated with the ovarian dysfunction. Immunization of female dogs with Escherichia coli-expressed recombinant dog ZP glycoprotein-3 (ZP3) either coupled to diphtheria toxoid or expressed as fusion protein with 'promiscuous' T non-B-cell epitope of tetanus toxoid also led to inhibition of fertility. To improve the contraceptive efficacy of ZP-based contraceptive vaccine, various groups are working on improving the immunogen, use of DNA vaccine as prime-boost strategy, and delivering the zona proteins/peptides presented on either virus-like particles or entrapped in microsphere. Host-specific live vectors such as ectromelia virus and cytomegalovirus have also been used to deliver mouse ZP3 in mice. Various studies show the enormous potential of the ZP-based vaccine for the management of wildlife population, where permanent sterilization may be desirable.

Contraceptive vaccines for the humane control of community cat populations.

Free-roaming unowned stray and feral cats exist throughout the world, creating concerns regarding their welfare as well as their impact on the environment and on public health. Millions of healthy cats are culled each year in an attempt to control their numbers. Surgical sterilization followed by return to the environment is an effective non-lethal population control method but is limited in scope because of expense and logistical impediments. Immunocontraception has the potential to be a more practical and cost-effective method of control. This is a review of current research in immunocontraception in domestic cats. Functional characteristics of an ideal immunocontraceptive for community cats would include a wide margin of safety for target animals and the environment, rapid onset and long duration of activity following a single treatment in males and females of all ages, and sex hormone inhibition. In addition, product characteristics should include stability and ease of use under field conditions, efficient manufacturing process, and low cost to the user. Two reproductive antigens, zona pellucida and GnRH, have been identified as possible targets for fertility control in cats. Zona pellucida, which is used successfully in multiple wildlife species, has achieved little success in cats. In contrast, immunization against GnRH has resulted in long-term contraception in both male and female cats following a single dose. GnRH is an ideal contraceptive target because it regulates pituitary and gonadal hormone responses in both males and females, thus suppressing nuisance behaviors associated with sex hormones in addition to preventing pregnancy. The responsiveness of cats to fertility control via GnRH suppression should encourage researchers and cat control stakeholders to continue efforts to optimize vaccines that induce multiyear contraception following a single dose in a high proportion of treated cats.

Comparative analysis of nanoparticle-antibody conjugations: carbodiimide versus click chemistry.

The ability to modify the physical, chemical, and biologic properties of nanoparticles has led to their use as multifunctional platforms for drug delivery and diagnostic imaging applications. Typically, these applications involve functionalizing the nanoparticles with targeting agents. Antibodies remain an attractive choice as targeting agents because of their large epitope space and high affinity; however, implementation of antibody-nanoparticle conjugates is plagued by low coupling efficiencies and the high cost of reagents. Click chemistry may provide a solution to this problem, with reported coupling efficiencies nearing 100%. Although click chemistries have been used to functionalize nanoparticles with small molecules, they have not previously been used to functionalize nanoparticles with antibodies. Concerns associated with extending this procedure to antibodies are that reaction catalysts or the ligands required for cross-linking may result in loss of functionality. We evaluated the efficiency of conjugations between antibodies and superparamagnetic iron oxide nanoparticles using click chemistry as well as the functionality of the product. The results were compared with conjugates formed through carbodiimide cross-linking. The click reaction allowed for a higher extent and efficiency of labeling compared with carbodiimide, thus requiring less antibody. Further, conjugates prepared via the click reaction exhibited improved binding to target receptors.

Patient and physician perception of the infusion process of the biologic agents abatacept, infliximab, and rituximab for the treatment of rheumatoid arthritis.

OBJECTIVES: To assess the process related to each infusible biologic used in rheumatoid arthritis (RA) with regard to patient and physician engagement in the infusion process, ancillary services required, and participant preferences. METHODS: This was a cross-sectional survey of patients with RA and their physicians. Biologic-naïve patients with RA starting abatacept, infliximab, or rituximab were included. Both patients and physicians completed detailed questionnaires related to the infusion and satisfaction with the process. RESULTS: A total of 205 patients were enrolled: abatacept (n=102), infliximab (n=74), rituximab (n=29). Patients were primarily female (75%), Caucasian (85%), with a mean age of 58 years. Patients had a mean disease duration of approximately 8 years and had typically failed multiple DMARDs. Rituximab required the most pre-infusion preparation and the longest infusion time. Abatacept was associated with a shorter mean infusion time (42 minutes) than infliximab (131 minutes; p<0.0001) or rituximab (274 minutes; p<0.0001) and required less time away from work/home (p=0.01 and p<0.0001, respectively). Abatacept patients reported significantly less discomfort than rituximab patients (p=0.03), while discomfort was similar between abatacept and infliximab. From the physicians' perspective, compared to infliximab and rituximab abatacept was very easy to administer (57% vs. 27% and 5%, respectively), caused no pain/discomfort (52% vs. 42% and 31%), and had very infrequent infusion reactions (75% vs. 30% and 44%). CONCLUSION: The process involved in infusion administration, as perceived by both the patient and physician, seems to differ across the three infusible biologic agents and may have an impact on the decision-making process regarding which infusible biologic to use.