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Although the trials included different doses of interferon beta-1a SC ® (Rebif ) diclofenac gel 20gm mastercard, the authors only pooled the standard dosing data of 44µg 3 times weekly cheap 20gm diclofenac gel with amex. Disease-modifying drugs for multiple sclerosis Page 30 of 120 Final Report Update 1 Drug Effectiveness Review Project Table 5. Interferon beta-1b and 1a compared with placebo: Efficacy measures Interferon beta-1b SC Interferon beta-1a Interferon beta-1a SC ® ® ® Outcome measure (Betaseron ) IM (Avonex ) (Rebif ) 44 µg Disability progression Progressed at 2 yrs 0. Overall, the data indicated that both interferon beta-1a products resulted in reductions in the proportions of patients having progressed at 2 years, while interferon beta-1b SC ® (Betaseron ) was not statistically significantly different to placebo (pooled analysis from the 50 review Rice et al). The mean change in Expanded Disability Status Scale was not different to placebo. The proportions of patients relapse-free and the annualized or mean relapse rates were 50 significantly lower in the interferon groups (pooled analysis from the review Rice et al). The ® shorter study of interferon beta-1a SC (Rebif ) using weekly instead of thrice weekly dosing was 54 unable to show a difference between the beta interferon and placebo at 48 weeks. Adjusted indirect comparison meta-analysis indicated no significant differences between the drugs for progression, the change in the Expanded Disability Status Scale (data available ® only for comparison of interferon beta-1a SC [Rebif ] 44 µg SC twice weekly and interferon ® beta-1b [Betaseron ]) or the proportion without relapse at 2 years (see Table 6). Inadequate data were available to conduct this analysis with annualized relapse rates. Disease-modifying drugs for multiple sclerosis Page 31 of 120 Final Report Update 1 Drug Effectiveness Review Project Table 6. Adjusted indirect analyses of placebo-controlled trials in relapsing- remitting multiple sclerosis ® ® Betaseron vs. Synthesis of direct and indirect evidence In the placebo-controlled trials, the rates of progression at 2 years ranged from 11. While the placebo-controlled ® trial of interferon beta-1b SC (Betaseron ) would indicate a lower potential for benefit in disease progression compared with the interferon beta-1a drugs, the head-to-head trials and our adjusted indirect analysis of placebo-controlled trial data contradict this conclusion. These differences could be attributed to differences in definition of progression, or baseline population characteristics, but the proportion of patients relapse-free at 2 years also showed some differences between head-to-head and placebo-controlled trials. For interferon beta-1b SC ® (Betaseron ) the rate in the placebo-controlled trial was 56%, while the head-to-head trial rates ® were somewhat lower (43% and 51%). Rates for interferon beta-1a SC (Rebif ) were better in head-to-head trials (57% and 56%) than in the placebo-controlled trial (31. The largest difference between placebo-controlled and head-to-head trial results lies in the rates of relapse- ® free patients with interferon beta-1a IM (Avonex ). Because there was only a small amount of evidence available from which to make these comparisons, we undertook an exploratory Bayesian analysis using the adjusted indirect analysis of the placebo-controlled trials as the “prior” assumptions and the direct evidence from head-to- ® head trials as the primary evidence. The dose of interferon beta-1a SC (Rebif ) 22 µg 3 times weekly was used in this analysis and resulted in no statistically significant differences for the ® ® comparison of interferon beta-1a SC (Rebif ) and interferon beta-1b SC (Betaseron ). For the ® ® comparison of interferon beta-1a IM (Avonex ) with either interferon beta-1b SC (Betaseron ) ® or interferon beta-1a SC (Rebif ) the results of our exploratory analysis was consistent with the ® findings of our direct and indirect analyses with both interferon beta-1a SC (Rebif ) and ® ® interferon beta-1b SC (Betaseron ) being superior to interferon beta-1a IM (Avonex ) in percent ® relapse-free, and with interferon beta-1b SC (Betaseron ) being superior to interferon beta-1a IM ® (Avonex ) in progression rates (see Table 7). Inadequate data were available to conduct this analysis with annualized relapse rates. Disease-modifying drugs for multiple sclerosis Page 32 of 120 Final Report Update 1 Drug Effectiveness Review Project Table 7. Exploratory Bayesian analysis of direct and indirect evidence in relapsing-remitting multiple sclerosis ® ® Betaseron vs. Glatiramer acetate Direct evidence ® Three trials directly comparing glatiramer acetate (Copaxone ) to another disease-modifying ® drug were identified, 2 comparing to interferon beta-1b (Betaseron ) and 1 comparing to ® 57-59 ® interferon beta-1a (Rebif ). The BEYOND trial comparing glatiramer acetate (Copaxone ) ® 59 to interferon beta-1b (Betaseron ) was a good-quality study while the other 2 trials were fair quality. The BECOME trial was small with a mixed population of patients with relapsing- remitting multiple sclerosis and clinically isolated syndrome and will be discussed under mixed populations. In both the double-blinded BEYOND trial, which lasted up to 3. The primary outcome in the REGARD trial was time to first relapse, however there were fewer relapses than expected which meant that the study was under-powered to show a significant difference. The results however are consistent with the BEYOND trial. Results of these trials are presented in Table 8 below. Relapse and progression outcomes: Glatiramer acetate compared with interferons Annualized Relapse- Proportion Study relapse free of steroid Disease a b N, Duration Intervention, dose rate (%) use progression Glatiramer actetate 0. Disease-modifying drugs for multiple sclerosis Page 33 of 120 Final Report Update 1 Drug Effectiveness Review Project The effectiveness results of the head-to-head trials were contrary to 2 observational ® studies that analyzed clinical databases to compare glatiramer acetate (Copaxone ) to the ® interferons: One compared with all 3 beta interferons (interferon beta-1a SC [Rebif ] 22 µg 60 ® 61 dose) and the other to interferon beta-1a SC (Rebif ), dose not reported. Castelli-Haley et al included both an intention-to-treat cohort of 845 patients as well as a continuous use cohort of 410 for which no other disease-modifying therapy was used during the 2-year period after the index date.

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Referral to mosis and cheap diclofenac gel 20 gm without prescription, on progression shown by cranial imaging order diclofenac gel 20 gm with visa, treatment for investigational studies for this purpose should be prioritized. In the cART era, this is not a medically sound strategy. Because risk of toxoplasmosis is high in these Kaposi sarcoma–associated herpes virus–associated patients and may occur concurrently with PCNSL, treatment for MCD both may sometimes be required. MCD is a neoplastic inflammatory condition with no standard therapy yet informed by adequate data. Patients with this condition The presence of EBV in AR-PCNSL and its nuclear medicine are clearly best served by referral to research studies. Rituximab can imaging avidity, thallium-201–based tomography or fluorodeoxyg- 18 be helpful, as well as novel therapies directed against human or viral lucose ( F) positron emission tomography (FDG-PET), offer an 29 IL-6. Because the Kaposi sarcoma–associated herpes virus encodes important diagnostic biomarker algorithm. If the CSF is positive for kinase that phosphorylate nucleoside analogs such as zidvoudine for EBV by PCR and the FDG-PET (or thallium-201 scan) is also and ganciclovir, these have been used as part of rationally designed positive, the positive predictive value for AR-PCNSL approaches 33 interventions with some success. Although biopsy is always preferred and should be per- formed in all cases if feasible, if it is not possible, lymphoma therapy may be initiated in certain cases without further delay. If Conclusion both tests are negative, lymphoma is ruled out with near 100% For the most part, hematologic cancer therapeutic prospects are predictive value. If the results of the FDG-PET and EBV PCR are equivalent in the HIV-related and HIV-unrelated settings. Appropri- discordant, the predictive values are too low to act on and biopsy ate assessment of HIV as a comorbid condition is essential to 386 American Society of Hematology optimizing therapeutic strategies. El-Sadr WM, Lundgren J, Neaton JD, et al; Strategies for enced the epidemiology of hematologic cancers in HIV, and those Management of Antiretroviral Therapy (SMART) Study Group. Pooled of malignancy and the specific therapy being administered. Off-label drug use: azidothymidine and ganciclo- 14. Rituximab plus vir for treatment of Kaposi sarcoma-associated herpes virus– concurrent infusional EPOCH chemotherapy is highly effective associated MCD. Relationship of Richard Little, National Cancer Institute, National Institutes of p53, bcl-2, and tumor proliferation to clinical drug resistance in Health, 31 Center Drive, MSC 2062, Bldg 31, Rm B1-W30, non-Hodgkin’s lymphomas. Bethesda, MD 20892; Phone: 240-276-6560; Fax: 240-276-7892; 16. Rituximab does not References improve clinical outcome in a randomized phase III trial of 1. Changes in AIDS-related CHOP with or without rituximab in patients with HIV- lymphoma since the era of highly active antiretroviral therapy. Dose-reduced with dose-adjusted EPOCH: impact of antiretroviral therapy busulfan, cyclophosphamide, and autologous stem cell transplan- suspension and tumor biology. MYC aggressive dense rituximab (SC-EPOCH-RR) in HIV-associated diffuse B-cell lymphomas: novel therapy of untreated Burkitt lym- large B-cell lymphoma. Swiss HIV Cohort Study: associations with immunodeficiency, Abstract 71. HIV-1-related Hodgkin outcome of lymphoma patients transferred to the intensive care lymphoma in the era of combination antiretroviral therapy: unit. Excellent immunological AIDS-defining cancers among HIV-infected patients compared recovery following CODOX-M/IVAC, an effective intensive with the general population in a large health district of northern chemotherapy for HIV-associated Burkitt’s lymphoma. Xicoy B, Ribera JM, Miralles P, et al; PETHEMA Group; non-Hodgkin lymphoma in the United States: disentangling the GESIDA Group; GMALL Group. Estimated HIV prevalence in the United combined antiretroviral therapy. Lymphocyte HIV-infected patients with plasmablastic lymphoma: results depletion during treatment with intensive chemotherapy for from the German AIDS-related lymphoma cohort study. Human immunodefi- and significance of severe toxicity in patients with human ciency virus-associated plasmablastic lymphoma. High-dose are the main cytogenetic alteration in plasmablastic lympho- zidovudine plus valganciclovir for Kaposi sarcoma herpesvirus- mas. Intensive ase chain reaction in CSF for the diagnosis of AIDS-related chemotherapy with cyclophosphamide, doxorubicin, high-dose primary CNS lymphoma. AIDS-associated (CODOX-M/IVAC) for human immunodeficiency virus- primary central nervous system lymphoma (AIDS-PCNSL) associated Burkitt lymphoma. Oriol A, Ribera JM, Brunet S, del Potro E, Abella E, Esteve J.

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The benefit of using fully human antibodies order diclofenac gel 20gm amex, as opposed to chimeric and humanized versions purchase diclofenac gel 20 gm mastercard, has not been evident from clinical trials, possibly because of the fact that cancer patients with advanced disease have impaired ability to form antitherapeutic antibodies. The roles of intrinsic antibody effector functions and Fc receptor binding in ADC activity have also not been established definitively. The 3 ADCs that achieved FDA approval had very different antibody characteristics: GO (IgG4 subtype) has no effector function activity,3 brentuximab vedotin (IgG1 subtype) has modest antibody-dependent cellular phagocyto- sis only,23 and ado-trastuzumab (IgG1 subtype) emtansine is highly active in effector function assays. The ADC binds to tumor cell none has been specifically engineered to enhance effector function. Upon entry into degradative antibody fragments such as diabodies or minibodies on ADC compartments such as lysosomes, the drug can be released by linker activity. Cell death occurs once the drug mor penetration but more rapid clearance. ADCs in clinical development Drug Status Therapeutic area Target Cytotoxic class Brentuximab vedotin Approved HL, ALCL CD30 Auristatin Ado-trastuzumab emtansine Approved MBC HER2 Maytansine Inotuzumab ozogamicin Phase 3 ALL CD22 Calicheamicin BT-062 Phase 2 Multiple myeloma CD138 Maytansine CDX-011 Phase 2 Breast cancer GPNMB Auristatin PSMA ADC Phase 2 Prostate PSMA Auristatin DCDT2980S (RG7593) Phase 2 NHL CD22 Auristatin DCDS4501A (RG7596) Phase 2 NHL CD79b Auristatin Lorvotuzumab mertansine Phase 2 SCLC CD56 Maytansine Milatuzumab-dox Phase 2 Multiple myeloma CD74 Anthracycline (doxorubicin) SAR3419 Phase 2 DLBCL, ALL CD19 Maytansine SGN-75 Phase 1b RCC CD70 Auristatin AGS-16M8F Phase 1 RCC AGS-16 Auristatin ASG-22ME Phase 1 Solid tumors Nectin-4 Auristatin BAY-94-9343 Phase 1 Solid tumors Mesothelin Maytansine BIIB015 Phase 1 Solid tumors Cripto Maytansine IMGN529 Phase 1 NHL, CLL CD37 Maytansine IMGN853 Phase 1 Solid tumors Folate receptor-1 Maytansine IMMU-130 Phase 1 Colorectal CEACAM5 Camptothecin analog (SN-38) DSTP3086S (RG7450) Phase 1 Prostate cancer STEAP1 Auristatin DMUC5754A (RG7458) Phase 1 Ovarian cancer MUC16 Auristatin DNIB0600A (RG7599) Phase 1 Ovarian, lung cancer NaPi2b Auristatin SAR566658 Phase 1 Solid tumors CA6 Maytansine MLN0264 Phase 1 Colorectal cancer GCC Auristatin AMG 595 Phase 1 GBM EGFRviii Maytansine AMG 172 Phase 1 RCC CD70 (CD27L) Maytansine SGN-CD19A Phase 1 ALL, NHL CD19 Auristatin SGN-CD33A Phase 1 AML CD33 PBD dimer PF-0626350 Phase 1 Solid tumors 5T4 Auristatin IMMU-132 Phase 1 Epithelial cancers TROP-2/EGP-1 Camptothecin analog (SN-38) SC16LD6. These molecules will have signifi- cant pharmacokinetic differences compared with ADCs, including In recent years, significant effort has been devoted to developing rapid clearance and larger volume of distribution, as well as a lack site-specific conjugation methods either by introducing novel un- of immune effector functions. An example of this approach is paired cysteine residues or nonnatural amino acids that allow for vintafolide, which uses folic acid to deliver a vinblastine analog to orthogonal chemistry methods. Linker technology and drug release An ADC linker should function as a highly stable bridge between Chemical conjugation the antibody and payload that allows efficient drug release upon Traditionally, drugs have been attached to antibodies using native delivery inside malignant cells. Early efforts to conjugate cytotoxic amino acids, taking advantage of the chemical reactivity of the agents to antibodies involved conditionally stable linkers, including ε-amino terminus of lysine residues or the sulfhydryl portion of a hydrazones that undergo cleavage under low pH conditions, such as reduced cysteine residue. GO was the first such ADC to demonstrate stoichiometry and location of the resulting adducts represents a significant clinical benefit, targeting the CD33 antigen expressed on distribution across many of the lysine residues in the antibody. The hydrazone linker in this contrast, conjugation to reduced cysteines results in even-numbered drug was shown to be unstable,33 which may have compromised drug additions (ie, 2, 4, 6, or 8), depending on how many of the overall activity and contributed to nontarget toxicity. These additions occur in the stability has been obtained with cleavable peptides in combination hinge region of the antibody and have no impact on antigen binding with self-immolative groups that undergo intracellular enzymatic and little impact on binding to Fc receptors on immune cells. The most advanced example incorporating such a date, most ADCs have targeted an average of 4 drugs per antibody. Conflict-of-interest disclosure: The authors are employed by and have equity ownership in Seattle Genetics. Off-label drug use: Data are presented from clinical trials of antibody-drug conjugates that Cytotoxic agents have not been approved. The released drug or “payload” of an ADC must be present in sufficient concentration inside the tumor cells to cause cell death. Correspondence Early attempts at ADCs included toxins such as ricin-A chain and 34 Jonathan Drachman, Seattle Genetics Inc, 21823 30th Dr SE, Pseudomonas exotoxin. These molecules posed challenges due to Bothell, WA 98021; Phone: 206-598-3300; Fax: 425-527-4315; immunogenicity. Subsequently, chemotherapy drugs such as Adria- 20 e-mail: jdrachman@seagen. However, these molecules proved to have insufficient single-agent activity to justify further develop- ment. In the last 2 decades, it has become apparent that highly potent References 1. Building better magic bullets–improving unconju- cytotoxic agents ranging from 100-10 000 times more potent than gated monoclonal antibody therapy for cancer. Continuous cultures of fused cells proteolytic cleavage or acid hydrolysis. However, the drug exerts its secreting antibody of predefined specificity. Identifying cytotoxic agents that are resistant to lysosomal proteases 3. Approval summary: gemtu- and are able to exit the lysosome (via diffusion or facilitated zumab ozogamicin in relapsed acute myeloid leukemia. Clin transport) are additional considerations for the design of ADCs. Final report of GO used calicheamicin, a DNA-damaging agent with highly potent 35 the efficacy and safety of gemtuzumab ozogamicin (Mylotarg) cytotoxicity, as the payload. Systemic administration of the free in patients with CD33-positive acute myeloid leukemia in first drug is not feasible due to toxicity, but by directing the drug to recurrence. A phase 3 study of achieve high concentrations in tumor cells. The 2 recently approved 11 12 gemtuzumab ozogamicin during induction and postconsolida- ADCs, brentuximab vedotin and ado-trastuzumab emtansine, tion therapy in younger patients with acute myeloid leukemia. This class of cytotoxic agents patients with acute myeloblastic leukemia who benefit from the has an additional level of specificity in that it preferentially kills addition of gemtuzumab ozogamicin: results of the MRC proliferating cells by disrupting the mitotic spindle apparatus. Furthermore, malignant cells frequently have disrupted cell cycle 7. Addition of gemtu- checkpoints, increasing the sensitivity to mitotic catastrophe com- zumab ozogamicin to induction chemotherapy improves sur- pared with healthy cells. ADCs may be subject to many of the same potential mechanisms of 36 8.

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Congestive heart failure events were higher with rosiglitazone than with glyburide (further details are presented in Key Question 8) order 20gm diclofenac gel fast delivery. The lower rates of cardiovascular events in the glyburide group were primarily due to lower rates of nonfatal myocardial infarction and congestive heart failure in this group order 20gm diclofenac gel mastercard. Several additional, smaller rosiglitazone trials were also identified in the updated 174, 176 search. In a very small (N=16), poor-quality, randomized controlled trial, subjects with coronary stent implantation were randomized to rosiglitazone 4-8 mg daily or placebo for 6 months. Rosiglitazone did not reduce in-stent restenosis and there were no differences in cardiac 174 events between the groups. Fixed-dose Combination Products (FDCPs) or Dual Therapy Summary of findings for FDCPs or Dual Therapy Evidence in children • We did not find any evidence meeting inclusion/exclusion criteria for children (insufficient strength of evidence). Evidence in adults • We found no studies that focused on health outcomes as the primary outcomes for any available FDCP. Two studies reported health outcomes among other secondary outcomes 183, 184 or in the adverse events section. Overall evidence was insufficient to determine how FDCPs compare with other treatments for their impact on health outcomes. Detailed Assessment for FDCPs and Dual Therapy We identified studies that have been conducted specifically using fixed-dose combination tablets 183, 185 comprised of rosiglitazone/metformin (Avandamet ), rosiglitazone/glimepiride 186 139 (Avandaryl ), and pioglitazone/metformin (Actoplus Met ). Two of these were new since 139, 183 the 2007 Drug Effectiveness Review Project report on FDCPs. For this report, dual therapy was defined as using the individual components of a FDCP in separate pills/tablets. Studies were required to randomize subjects to the components of a FDCP or to monotherapy with one of the components of the FDCP to be eligible for this report. No studies were identified that used the fixed-dose combination tablets comprised of 189 190 pioglitazone/glimepiride (Duetact ) or sitagliptin/metformin (Janumet ). The efficacy and safety of Duetact and Janumet have been established based on trials using the co- administration of their separate components. The majority of the trials were 4- to 6-month evaluations of glycemic control and general adverse events with FDCPs or dual therapy compared to component monotherapy when used as initial treatment for patients with type 2 diabetes. Studies that compared type 2 diabetes combination tablet products to co-administration of their components were few, nonrandomized, 191-193 and limited to analyses based on refill data from pharmacy claims databases. We found no evidence to address the effectiveness of combination tablet products in improving long-term health. Throughout this section, meta-analyses were not performed due to an insufficient number of studies or heterogeneity of study populations, outcomes, and designs. No comparative cohort studies, case-control studies or systematic reviews were identified reporting long-term benefits. Head-to-head trials We found no head-to-head trials of Avandamet or dual therapy with metformin and rosiglitazone comparing them with other FDCPs that met inclusion criteria. The dual therapy trial compared concurrent use of metformin and rosiglitazone with metformin monotherapy. Characteristics of Avandamet (metformin/rosiglitazone) and rosiglitazone plus metformin dual therapy trials in adults with type 2 diabetes a Age (years) (SD) a % Female a Sample size % White a Author, year (N) % Hispanic Country Follow-up Other population Quality (weeks) characteristics Intervention Control(s) Fixed-dose combination Rosenstock 50. In one of the trials, HbA1c was reduced by a mean of 2. In the other, mean HbA1c reduction in the Avandamet group (mean daily dose = 6. A 24-week trial of dual therapy (metformin plus rosiglitazone) compared with metformin monotherapy reported that dual therapy (8 mg rosiglitazone + 1,000 mg metformin daily) reduced HbA1c by a mean of 0. Change in HbA1c in Avandamet (metformin/rosiglitazone) or rosiglitazone plus metformin trials in adults with type 2 diabetes HbA1c (%) change from baseline HbA1c change Author, year (mean, SD) for from baseline P value of Country FDCP or dual (mean, SD) for between-group Quality Intervention therapy active control difference Fixed-dose combination Avandamet : 7. No comparative cohort studies, case-control studies or systematic reviews were identified reporting long-term benefits. Head-to-head trials We found no head-to-head trials of Avandaryl or dual therapy with rosiglitazone and glimepiride comparing them with other FDCPs that met inclusion criteria. One fair-quality dual therapy trial compared concurrent use of rosiglitazone and glimepiride with 187 rosiglitazone monotherapy. Characteristics of Avandaryl (rosiglitazone /glimepiride) and rosiglitazone plus glimepiride dual therapy trials in adults with type 2 diabetes a Age (years) (SD) a % Female a Sample size % White a Author, year (N) % Hispanic Country Follow-up Other population a Quality (weeks) characteristics Intervention Control(s) Fixed-dose combination Avandaryl : 4 mg/1 mg – 4 mg/4 Glimepiride: 186 53. The 186 trial comparing 2 dosages of Avandaryl with glimepiride or rosiglitazone monotherapy found that Avandaryl (4 mg/1 mg daily titrated to 4 mg/4 mg )reduced HbA1c levels by a greater amount (mean reduction 2. In the 4 mg/1 mg daily titrated to 8 mg/4 mg daily formulation of Avandaryl , mean HbA1c reduction was 2. This was also a significantly greater reduction compared with glimepiride and rosiglitazone monotherapies (P<0. In the other trial, dual therapy with rosiglitazone and glimepiride also resulted in greater 187 improvement in HbA1c than monotherapy. Dual therapy with 8 mg of rosiglitazone and 8 mg of glimepiride daily (titrated up from 8 mg/1 mg daily) was associated with a mean HbA1c reduction of 1.