Spleen tyrosine kinase (Syk) signaling is central to phagocytosis‐based, antibody‐mediated platelet destruction in adults with immune thrombocytopenia (ITP). Fostamatinib, an oral Syk inhibitor, produced sustained on‐treatment responses in a phase 2 ITP study. In two parallel, phase 3, multicenter, randomized, double‐blind, placebo‐controlled trials (FIT1 and FIT2), patients with persistent/chronic ITP were randomized 2:1 to fostamatinib (n = 101) or placebo (n = 49) at 100 mg BID for 24 weeks with a dose increase in nonresponders to 150 mg BID after 4 weeks. The primary endpoint was stable response (platelets ≥50 000/μL at ≥4 of 6 biweekly visits, weeks 14‐24, without rescue therapy). Baseline median platelet count was 16 000/μL; median duration of ITP was 8.5 years. Stable responses occurred in 18% of patients on fostamatinib vs. 2% on placebo (P = .0003). Overall responses (defined retrospectively as ≥1 platelet count ≥50 000/μL within the first 12 weeks on treatment) occurred in 43% of patients on fostamatinib vs. 14% on placebo (P = .0006). Median time to response was 15 days (on 100 mg bid), and 83% responded within 8 weeks. The most common adverse events were diarrhea (31% on fostamatinib vs. 15% on placebo), hypertension (28% vs. 13%), nausea (19% vs. 8%), dizziness (11% vs. 8%), and ALT increase (11% vs. 0%). Most events were mild or moderate and resolved spontaneously or with medical management (antihypertensive, anti‐motility agents). Fostamatinib produced clinically‐meaningful responses in ITP patients including those who failed splenectomy, thrombopoietic agents, and/or rituximab. Fostamatinib is a novel ITP treatment option that targets an important mechanism of ITP pathogenesis.

A phase I randomized, double-blind, placebo-controlled trial was done with a cytomegalovirus (CMV) vaccine based on the envelope glycoprotein, gB, combined with a novel adjuvant, MF59. Participants received CMV gB vaccine with MF59 or CMV gB with alum or placebo at 0, 1, and 6 months. A fourth vaccine was given at 12 months to a subgroup. Levels of neutralizing antibody and antibody to gB 2 weeks after the third dose of vaccine exceeded those in seropositive control subjects. the formulation with MF59 was more immunogenic than that with alum. The optimal dose of gB appeared to be between 5 and 30 microg. The fourth dose produced a prompt rise in antibody level. There were no serious adverse events associated with vaccine. Local and systemic reactions were generally mild and, except for pain at the injection site, occurred with similar frequency in recipients of placebo and CMV vaccine.

A fundamental goal of current strategies to develop an efficacious vaccine for AIDS is the elicitation of broadly reactive cytotoxic T lymphocyte (CTL) reactivities capable of destroying virally infected targets. Recent application of recombinant canarypox ALVAC͞HIV-1 vectors as vaccine immunogens in HIV-1,-noninfected volunteers has produced CTL responses in a significant number of vaccinees. Using a newly developed targeting strategy, we examined the capacity of vaccine-induced CTL to lyse autologous targets infected with a diverse group of viral isolates. CTL derived from recipients of a canarypox ALVAC͞HIV-1 gp160 (MN) vaccine were found capable of lysing autologous CD4 ؉ lymphoblasts infected with the prototypic LAI strain of HIV-1. When tested against autologous targets infected with primary HIV-1 isolates representing genetically diverse viral clades, CTL from ALVAC͞gp160 recipients showed both a broad pattern of cytolysis in which viruses from all clades tested were recognized as well as a highly restricted pattern in which no primary isolates, including clade B, were lysed. Differences in the HLA haplotypes of the volunteers immunized with the envelope vector might be a major determinant of the relative breadth of their CTL response. In contrast to ALVAC͞gp160 vaccinees, recipients of the ALVAC͞HIV-1 immunogen containing envelope as well as gag and protease genes consistently had CTL reactivities effective against a spectrum of primary isolate-infected targets. These studies demonstrate for the first time that clade B-based canarypox vaccines can elicit broad CTL reactivities capable of recognizing viruses belonging to genetically diverse HIV-1 clades. The results also reinforce the impact of viral core elements in the vaccine as well as the pattern of major histocompatibility complex class I allelic expression by the vaccine recipient in determining the relative breadth of the cellular response.

Two randomized, double‐blind, placebo‐controlled studies demonstrated responses (≥50 000/μL) to fostamatinib in adults with long‐standing immune thrombocytopenia (ITP). The long‐term safety and efficacy of fostamatinib were evaluated in a follow‐on, open‐label extension (OLE) study. Patients received double‐blind fostamatinib in the randomized trials, and responders continued the same dose, 100 to 150 mg BID, in the OLE study. Nonresponders received 100 mg BID for 4 weeks and could escalate to 150 mg BID at week 4. Endpoints included stable response, platelet count ≥50 000/μL at 4/6 biweekly (randomized trials) or 2/3 monthly visits (OLE), and overall response, ≥1 platelet count ≥50 000/μL during weeks 1 to 12. A total of 146 patients received fostamatinib including 123 in the OLE study. Median treatment duration was 6.7 months. Baseline median ITP duration was 8 years and median platelet count was 16 000/μL; prior treatments included thrombopoietic (TPO) agents (47%), splenectomy (35%), and rituximab (32%). Twenty‐seven (18%) patients achieved a stable response with median duration of >28 months and a median platelet count of 89 000/μL. Sixty‐four (44%) patients achieved an overall response (including stable responders) with a median platelet count of 63 000/μL and a median response duration of >28 months. Twenty‐four of 71 (34%) patients who had failed TPO agents achieved overall responses to fostamatinib. The most common adverse events (AEs) were diarrhea, hypertension, nausea, epistaxis, and abnormal liver function tests. Most AEs were mild/moderate and resolved or were managed with dose reduction, dose interruption, and/or secondary medication. Almost half of the patients achieved an overall response, and most of these maintained their responses for >2 years. No new or increased frequency of AEs was seen at up to 31 months of treatment.

The live canarypox vector was safe, stimulated cytotoxic T-cells and primed for a vigorous neutralizing antibody response upon boosting with subunit gp120 vaccine. This vaccine combination should be evaluated further for inducing protection against HIV infection.

Live attenuated viral vectors that express human immunodeficiency virus (HIV) antigens are being developed as potential vaccines to prevent HIV infection. The first phase 2 trial with a canarypox vector (vCP205, which expresses gp120, p55, and protease) was conducted in 435 volunteers with and without gp120 boosting, to expand the safety database and to compare the immunogenicity of the vector in volunteers who were at higher risk with that in volunteers at lower risk for HIV infection. Neutralizing antibodies to the MN strain were stimulated in 94% of volunteers given vCP205 plus gp120 and in 56% of volunteers given vCP205 alone. CD8(+) cytotoxic T lymphocyte cells developed at some time point in 33% of volunteers given vCP205, with or without gp120. Phase 3 field trials with these or similar vaccines are needed, to determine whether efficacy in preventing HIV infection or in slowing disease progression among vaccinees who become infected is associated with the level and types of immune responses that were induced by the vaccines in this study.

A safety and immunogenicity trial was conducted in vaccinia-immune and vaccinia-naive human immunodeficiency virus (HIV) -uninfected adults who were randomized to receive 10 6 or 10 7 TCID 50 of canarypox (ALVAC) vector expressing HIV-1 MN gp160 or 10 5.5 TCID 50 of ALVAC -rabies virus glycoprotein control at 0 and 1 or 2 months and ALVAC-gp160 or 50 mg of HIV-1 SF2 recombinant (r) gp120 in microfluidized emulsion at 9 and 12 months; others received rgp120 at 0, 1, 6, and 12 months. All vaccines were well-tolerated. Neither vaccinia-immune status before vaccination nor ALVAC dose affected HIV immune responses. HIV-1 MN and HIV-1 SF2 neutralizing antibodies were detected more often (100%) in ALVAC-gp160/rgp120 recipients than in recipients of ALVAC-gp160 (õ65%) or rgp120 (89%) alone. ALVAC-gp160/rgp120 also elicited more frequent HIV V3 -specific and fusion-inhibition antibodies, antibody-dependent cellular cytotoxicity, lymphoproliferation, and cytotoxic CD8 / T cell activity than did either vaccine alone. Trials with ALVAC expressing additional HIV components and rgp120 are underway. AIDS, caused by infection with the human immunodefi-duce the transmission of HIV-1 infection and to prevent or ameliorate disease are needed, especially for developing counciency virus type 1 (HIV-1), is associated with enormous mortries, where ú90% of infections occur [1] and where antiretbidity and mortality worldwide. Safe, effective vaccines to reroviral drugs are not affordable.To prevent chronic HIV-1 infection, it is thought that a vaccine To circumvent the safety issues associated with vaccinia virusThe study protocol was reviewed and approved by the institutional review boards at each site. Informed consent was obtained from each volunteer in recombinants, an avipox vector, canarypox virus (referred to as accordance with guidelines of the US Department of Health and Human Ser-ALVAC), has been used to express genes encoding human vacvices and those of the authors' institutions.cine antigens, such as rabies virus glycoprotein, measles virus

Hematide is an investigational pegylated synthetic peptide that stimulates erythropoiesis in animal models and is being developed for the treatment of anemia associated with chronic renal failure and cancer. This study evaluated the safety and pharmacodynamics of single, intravenous doses (0.025, 0.05, and 0.1 mg/kg) of Hematide in 28 healthy male volunteers. All doses of Hematide were well tolerated, with safety profiles similar to those of placebo. Hematide showed a dose-dependent increase in reticulocytes. The 0.1-mg/kg dose was associated with a statistically significant increase in hemoglobin (Hgb) from baseline compared to the placebo group (13.6 ؎ 3.9 g/L [1. 36 IntroductionThere are several common clinical situations in which anemia is the result of hypoproliferation of red blood cell (RBC) precursors secondary to erythropoietin (EPO) deficiency. These include anemias associated with chronic kidney disease (CKD), chronic inflammation, and cancer, with or without myelosuppressive therapy. In these situations, recombinant human EPO (rHuEPO) has been used successfully to increase hemoglobin (Hgb) levels, reduce fatigue, and improve daily function.Hematide is a synthetic, dimeric peptidic erythropoiesisstimulating agent (ESA) covalently linked to polyethylene glycol (PEG) and is being developed for the treatment of anemia associated with chronic renal failure and cancer. Because its primary amino acid sequence is unrelated to that of rHuEPO, Hematide is unlikely to induce a cross-reactive immune response against endogenous EPO. 1 This potentially reduces the risk of pure red cell aplasia (PRCA), a rare complication caused by an immune response to rHuEPO. PRCA reached a peak incidence outside of the United States in 2001 to 2002, largely related to a change in formulation of the product. 2,3 Hematide binds to and activates the human EPO receptor, stimulating the proliferation and differentiation of human red cell precursors in vitro in a manner similar to ESAs. 1 A predictable, dose-related effect on reticulocyte and Hgb levels has been observed in rats and monkeys. 1 The design of this first study of Hematide in humans was based on these nonclinical data and the published reports of ESAs in approximately 400 healthy volunteers. [4][5][6][7][8][9][10][11][12][13] This study was designed to evaluate the safety and pharmacokinetic and pharmacodynamic profiles of single intravenous dose levels of the drug and to determine the minimum pharmacologic active dose (PAD) in healthy subjects. Results of the pharmacokinetic analysis will be published separately. Subjects, materials, and methods EligibilityEligible subjects were men, 18 to 40 years of age, with a body mass index (BMI) of 18 to 30 kg/m 2 , without any clinically significant medical condition. At study entry, subjects were to have a Hgb value of 160 g/L (16 g/dL) or less, and normal values for ferritin, white blood cell count, and platelet count. All subjects were informed of the investigational nature of this study and signed informed consent. The stud...