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Introduction: Hematide™ a novel, synthetic, PEGylated peptidic compound, binds to and activates the erythropoietin receptor. It is in development for treatment of anemia associated with chronic renal failure and cancer. Objective: To assess the subcutaneous (SC) Hematide™ dose required to increase hemoglobin (Hb) by ≥ 1 g/dL in ≥ 50% of anemic cancer patients (pts) on chemotherapy. Safety, pharmacodynamics and pharmacokinetics were also assessed. Method: In a phase 2, open label, multi-center, dose finding study, up to four doses of Hematide™ were given SC every 3 wks (Q3W) to 4 cohorts of fifteen pts at 0.05, 0.10, 0.15 or 0.2 mg/kg each. Entry criteria included confirmed solid tumor malignancy or lymphoma, >9 weeks of chemotherapy, baseline (BL) H ≥ 8 and Results: Sixty patients were enrolled (45% male). Preliminary data show that across cohorts 0.05, 0.10, 0.15 and 0.20 mg/kg, mean (BL) Hb values were 10.1(±1.07), 10.0(±0.89), 9.8(±0.67), 10.1(±0.69); the % of pts completing the study were approximately 79%, 50%, 60%, and 92%. An increase in mean Hb from BL of ≥ 1g/dL in the pharmacodynamic dataset (forty two pts) at Week 7 occurred in approximately 20%, 70%, 55% and 55% of patients. Three pts withdrew due to AEs and six due to SAEs (none attributed to study drug). Three deaths occurred (two disease progression, one renal insufficiency) none attributed to study drug. One SAE, thrombophlebitis, was considered to be possibly/probably related to study drug. Final safety and efficacy data will be provided at the meeting. Conclusion: In this study, HematideTM dosed SC Q3W resulted in an increase from BL of ≥ 1 g/dL of Hgb in ≥ 50% of patients in the 0.10, 0.15 and 0.20 mg/kg cohorts in the pharmacodynamic analysis. HematideTM appeared to be well tolerated at all doses studied.

Hematide is a PEGylated synthetic peptidic ESA that binds to and activates the erythropoietin (EPO) receptor. It has demonstrated potent and sustained dose dependent erythropoietic activity in healthy volunteers (HV). Methods: A randomized double-blind placebo controlled dose escalation study is being conducted to assess safety, pharmacokinetics (PK) and pharmacodynamics (PD) of Hematide administered as a single intravenous (IV) injection in EPO-naïve patients with Chronic Kidney Disease (CKD) pre-dialysis. Cohorts of 9 patients each (7 on Hematide and 2 on placebo) are planned with escalating doses. The results of this study are compared with those of a recently completed Phase 1 dose escalating study of Hematide in 4 cohorts of HV in which the pharmacologically active dose (PAD; i.e., the dose resulting in a statistically and clinically significant increase in hemoglobin) of Hematide was defined. Results: 28 day follow up of the 9 patients in Cohort 1 is complete. As of this date, the study remains blinded and we assume that increases in reticulocytes and hemoglobin (Hgb) are due to Hematide. Injections were well tolerated with no adverse events reported as related to study drug injection. In 7 patients whose reticulocytes increased, counts peaked at 7–10 days with a mean change from baseline of 151.4 ± 18.4 x 109/L before returning within baseline at 21 days post-injection. A Hgb increase was also observed in these 7 patients with a mean difference in change from baseline Hgb between these 7 responding and the 2 non-responding subjects of 0.80 g/dL at Day 10 (p = 0.028) and 1.16 g/dL (p = 0.08) at Day 28 post-injection. The PD profile of these 7 responding patients is comparable to that of the 10 HV receiving a PAD of Hematide. For example, the average maximum Hgb increase from baseline was 1.22 g/dL (SD: 0.37) in patients versus 1.36 g/dL (SD: 0.39) in HV. However, the PAD for CKD patients was half the Hematide dose that was required to obtain a similar Hgb effect in HV. Unblinded results from the complete study, including dose responses, follow-up after 28 days, PK data, additional PD data, EPO levels and iron status assessment will be presented and compared to the results in HV. Conclusion: A single IV injection of Hematide administered to patients with CKD was well tolerated and demonstrated potent and sustained erythropoietic activity of the same magnitude as that observed in HV. The PAD in patients with CKD was half of that observed in HV. These preliminary data suggest that patients with CKD may be more sensitive to Hematide and/or might have a different PK profile compared to HV. The sustained increases in Hgb levels for at least one month following a single dose of Hematide are compatible with anticipated monthly dosing of Hematide to maintain Hgb in target range. This is a reduced frequency of administration compared to that of currently available ESAs. These results serve as a basis to plan studies of repeat doses of Hematide in patients with anemia related to cancer or CKD and this plan will be outlined.

8180 Background: Hematide is an innovative, synthetic, pegylated, peptidic ESA that binds to and activates the erythropoietin (EPO) receptor. Although its amino acid sequence is unrelated to that o...

ContextWhile interleukin 2 (IL-2) is capable of inducing a marked expansion of the CD4 T-lymphocyte pool, limited data exist on whether IL-2 treatment can add significantly to the immunologic and virologic effects of potent antiretroviral therapy (ART).ObjectiveTo determine the rate and magnitude of CD4 cell recovery and viral suppression when using a combination therapy of IL-2 and ART compared with ART alone.Design and SettingRandomized, controlled multicenter trial conducted from April 1996 through April 1998 at 8 clinical sites in the United States.PatientsEighty-two adult outpatients who were infected with human immunodeficiency virus (HIV) and had baseline CD4 cell counts of 200 × 106/L to 500 × 106/L and baseline RNA levels of fewer than 10,000 copies/mL were randomized; 78 completed the study.InterventionsThirty-nine patients were randomly assigned to receive a combination therapy of subcutaneous IL-2 (administered in 5-day courses every 8 weeks at a starting dosage of 7.5 mIU twice per day) and ART; 43 were to receive ART therapy alone.Main Outcome MeasuresInterleukin 2 safety and differential effects on CD4 cell counts, CD4 cell percentages, and plasma HIV RNA levels.ResultsThe mean (SD) percentage increase in CD4 cell counts at 1 year for patients who received IL-2 was 112% (113%) compared with 18% (35%) in recipients of ART alone (P

Background: Effective immunization of young children against CMV may decrease transmission from children to adults and prevent severe sequelae including congenital birth defects. Objective: To evaluate the reactogenicity and immunogenicity of CHIRON CMV gB vaccine in toddlers. Methods: We conducted a Phase I trial in which 18 CMV-seronegative children, 12-35 months of age, received either 20μg of CMV gB/MF59 vaccine, a purified recombinant gB protein produced in Chinese hamster ovary cell culture combined with MF59, oil and water adjuvant, (n=15) or a control Hepatitis A vaccine from SmithKline Beecham (n=3) at 0,1, and 6 months. The study was open-label for the first 6 children, and then double-blinded and randomized. Children were monitored for local and systemic reactions for 7 days following each injection. Serologic tests for CMV anti-gB antibody by ELISA and CMV neutralizing antibodies were obtained pre-immunization, 1 month after dose 2 in 50% of subjects, and 1 month after.dose 3 in all subjects. Results: No pattern of reactogenicity was observed; 5 post-immunization reactions were seen in 4 subjects. The GMTs (95% CI) of antibody to gB by ELISA were: 0 pre-immunization (n=18), 27,457 (13,794-54,653) after dose 2 (n=6), and 98,264(39,896-242,025) after dose 3 (n=5). Neutralizing antibody reciprocal GMTs(95% CI) were: 0 pre-immunization (n=18), 90 (51-158) after dose 2 (n=6), and 638 (415-982) after dose 3 (n=13). After dose 3, all children had titers greater than those observed in naturally infected adults.Conclusion: Antibody responses of toddlers were notably higher than among 149 adults given 3 doses of the same vaccine in other trials(neutralization GMT=133). CHIRON CMV gB vaccine is well tolerated and highly immunogenic in toddlers.Supported by Chiron Vaccines, Emeryville, CA

In Reply. —We fully agree with the comments by Drs Katz and McNamara regarding the various types of disease progressions in children infected with (HIV). Indeed, some patients with a "borderline" or an unusual progression might not perfectly fit into our description of a "bimodal population" of children according to the progression of the disease. 1 We followed up a child, perinatally infected with HIV, who, at age 4 months, developed Pneumocystis carinii pneumonia. Three years later she was well, with no neurologic impairment or secondary infection. Her most recent CD4 cell count was over 1.5× 109/L, and the results of her in vitro lymphocyte proliferation tests became progressively normal, showing an association between the clinical and immunologic improvements. In most cases of HIV-infected children, there is a correlation between the severity of the symptoms and the impairment of the immune system or the intensity of the viral load. However

• To better define the clinical and biological evolution of infants after vertical human immunodeficiency virus type 1 infection, we analyzed 94 consecutive infected patients followed up after their first clinical symptoms. The expression of clinical symptoms and biological abnormalities followed a bimodal distribution, some patients having an early and severe disease and the others having a slowly progressive one. One third of our patients suffered from early onset of opportunistic infection (OI). These patients had a significantly higher incidence of severe encephalopathy compared with patients without OI. The rate of survival at 3 years was 48% ± 24%. In contrast, the patients without early OI or severe encephalopathy had a probability of survival at 3 years of 97%±3%. This probability was not modified by the occurrence of bacterial infection or lymphoid interstitial pneumonitis. Lymphoid interstitial pneumonitis occurred at a mean age of 29 months, significantly later than OI or severe encephalopathy. Laboratory results at initial examination were correlated with clinical symptoms. Thus, when the number of CD4 lymphocytes was less than 500/mm 3 , children suffered more frequently from life-threatening symptoms (OI and severe encephalopathy): 15 of 22 vs 14 of 69. The same was true when the lymphocytes did not proliferate after antigenic stimulation, when anti-p18 and/or anti-p25 antibodies were absent in the serum, and when p24 antigen was detected in serum. Finally, severe encephalopathy was associated with low anti–human immunodeficiency virus cerebrospinal fluid antibody titer, whereas 88% of patients with moderate or no encephalopathy had signs of intrathecal anti–human immunodeficiency virus antibody synthesis. In conclusion, a subgroup of patients expressed very early signs of severe immunodeficiency and encephalopathy, whereas the majority of patients had a longer survival and less severe clinical symptoms during their first years of life than previously thought. ( AJDC . 1990;144:1210-1215)

Recombinant CD4-immunoglobulin G (rCD4-IgG) is a 98-kDa human immunoglobulin-like protein that is produced by fusing the gp120 binding domain of CD4 to the Fc portion of the human IgG1 heavy chain. This hybrid molecule was given to human immunodeficiency virus (HIV)-infected pregnant women at the onset of labor by intravenous bolus at 1 mg/kg of body weight (group A; n = 3) and 1 week prior to and at the onset of labor by the same route and at the same dose (group B; n = 3). In addition to pharmacokinetic studies, safety in the mothers and infants was determined through routine chemistries, hematology, and urinalysis; immunologic and HIV infection statuses in the infants were assessed through lymphocyte cultures, p24 antigen level determination, culture of HIV from plasma, PCR, lymphocyte subset enumeration, quantitative immunoglobulin analysis, and lymphocyte proliferation. Thirty minutes after the rCD4-IgG injection, concentrations in maternal serum were 12 to 23 micrograms/ml. These concentrations declined slowly, with initial and terminal half-lives (mean +/- standard deviation) of 9.95 +/- 3.23 and 47.6 +/- 22.3 h, respectively. Infants were born 2.6 to 46.5 h after rCD4-IgG administration; concentrations of rCD4-IgG in cord blood ranged from 28 to 107 ng/ml. The half-life of rCD4-IgG in infants ranged from 5 to 29 h. These data demonstrate that the transfer of rCD4-IgG from the mother to the fetus is rapid and that newborns do not appear to have any difficulty eliminating rCD4-IgG. No safety concerns in mothers or infants were encountered. Although the study did not address the question of efficacy, none of the infants was HIV type 1 infected 36 months later. In summary, these findings document that bifunctional immune molecules can be transported across the placenta, and this general approach may be used in the future to block vertical transmission of HIV type 1.

This report describes the one-year results of a noncomparative study designed to assess the safety and tolerance of low-dose zidovudine (azidothymidine) given orally to 60 human immunodeficiency virus type 1-infected infants and children. At baseline, the mean age was 1.9 years (±1.4), and all were symptomatic: 43% were P2A and 57% were P2B to F according to the Centers for Disease Control classification. All the patients received zidovudine for at least 6 months, and 52 of them (87%) completed a full year of therapy. The mean duration of follow-up was 346 days (±42) (range, 183 to 366 days). The initial therapy consisted of four daily doses of 100 mg/m2 (400 mg/m2 per day, equivalent to 20 mg/kg per day). However, this treatment was modified when neutropenia or anemia was observed. Twenty-nine children (48%) remained at the initial therapy for the entire study. Zidovudine dosage was adjusted 92 times in the other 31 children (52%), mostly due to neutropenia (83%). Altogether, the time under full-dose therapy represented 81% of the total duration of the protocol for all patients. Children with mild symptoms, P2A at study entry, were more likely to remain under full-dose therapy than children with severe symptoms, P2B to F: the time under full-dose therapy represented 91% of the duration of the protocol for the former group and only 74% for the latter one (P < .02). No clinical adverse experiences were attributed directly to zidovudine. Thirty-seven children were prescribed trimethoprim-sulfametoxazole as a prophylaxis for Pneumocystis carinii pneumonia. In a multivariate analysis, this comedication had no influence on the hematologic tolerance of zidovudine.