Kurt J. Griffin

Targeting of memory T cells with alefacept in new-onset type 1 diabetes (T1DAL study): 12 month results of a randomised, double-blind, placebo-controlled phase 2 trial

BACKGROUND Type 1 diabetes results from autoimmune targeting of the pancreatic β cells, likely mediated by effector memory T (Tem) cells. CD2, a T cell surface protein highly expressed on Tem cells, is targeted by the fusion protein alefacept, depleting Tem cells and central memory T (Tcm) cells. We postulated that alefacept would arrest autoimmunity and preserve residual β cells in patients newly diagnosed with type 1 diabetes. METHODS The T1DAL study is a phase 2, double-blind, placebo-controlled trial in patients with type 1 diabetes, aged 12-35 years who, within 100 days of diagnosis, were enrolled at 14 US sites. Patients were randomly assigned (2:1) to receive alefacept (two 12-week courses of 15 mg intramuscularly per week, separated by a 12-week pause) or a placebo. Randomisation was stratified by site, and was computer-generated with permuted blocks of three patients per block. All participants and site personnel were masked to treatment assignment. The primary endpoint was the change from baseline in mean 2 h C-peptide area under the curve (AUC) at 12 months. Secondary endpoints at 12 months were the change from baseline in the 4 h C-peptide AUC, insulin use, major hypoglycaemic events, and HbA1c concentrations. This trial is registered with ClinicalTrials.gov, number NCT00965458. FINDINGS Of 73 patients assessed for eligibility, 33 were randomly assigned to receive alefacept and 16 to receive placebo. The mean 2 h C-peptide AUC at 12 months increased by 0.015 nmol/L (95% CI -0.080 to 0.110) in the alefacept group and decreased by 0.115 nmol/L (-0.278 to 0.047) in the placebo group, and the difference between groups was not significant (p=0.065). However, key secondary endpoints were met: the mean 4 h C-peptide AUC was significantly higher (mean increase of 0.015 nmol/L [95% CI -0.076 to 0.106] vs decrease of -0.156 nmol/L [-0.305 to -0.006]; p=0.019), and daily insulin use (0.48 units per kg per day for placebo vs 0.36 units per kg per day for alefacept; p=0.02) and the rate of hypoglycaemic events (mean of 10.9 events per person per year for alefacept vs 17.3 events for placebo; p<0.0001) was significantly lower at 12 months in the alefacept group than in the placebo group. Mean HbA1c concentrations at week 52 were not different between treatment groups (p=0.75). So far, no serious adverse events were reported and all patients had at least one adverse event. In the alefacept group, 29 (88%) participants had an adverse event related to study drug versus 15 (94%) participants in the placebo group. In the alefacept group, 14 (42%) participants had grade 3 or 4 adverse events compared with nine (56%) participants in the placebo group; no deaths occurred. INTERPRETATION Although the primary outcome was not met, at 12 months, alefacept preserved the 4 h C-peptide AUC, lowered insulin use, and reduced hypoglycaemic events, suggesting efficacy. Safety and tolerability were similar in the alefacept and placebo groups. Alefacept could be useful to preserve β-cell function in patients with new-onset type 1 diabetes.Background Type 1 diabetes (T1D) results from autoimmune targeting of the pancreatic beta cells, likely mediated by effector memory T cells (Tems). CD2, a T cell surface protein highly expressed on Tems, is targeted by the fusion protein alefacept, depleting Tems and central memory T cells (Tcms). We hypothesized that alefacept would arrest autoimmunity and preserve residual beta cells in newly diagnosed T1D.

Sleep, glucose, and daytime functioning in youth with type 1 diabetes.

UNLABELLED STUDY HYPOTHESES: 1) Youth with evidence of SDB (total apnea-hypopnea index [Total-AHI] ≥ 1.5) would have significantly worse glucose control than those without SDB; 2) Elevated self-reported sleepiness in youth with T1DM would be related to compromised psychosocial functioning; and 3) Youth with T1DM would have significantly less slow wave sleep (SWS) than controls. DESIGN The study utilized home-based polysomnography, actigraphy, and questionnaires to assess sleep, and continuous glucose monitors and hemoglobin A1C (HbA1C) values to assess glucose control in youth with T1DM. We compared sleep of youth with T1DM to sleep of a matched control sample. SETTING Diabetic participants were recruited in a pediatric endocrinology clinic. PARTICIPANTS Participants were youth (10 through 16 years) with T1DM. Controls, matched for sex, age, and BMI percentile, were from the Tucson Childrens Assessment of Sleep Apnea study. RESULTS Participants with a Total-AHI ≥ 1.5 had higher glucose levels. Sleepiness and/or poor sleep habits correlated with reduced quality of life, depressed mood, lower grades, and lower state standardized reading scores. Diabetic youth spent more time (%) in stage N2 and less time in stage N3. Findings related to sleep architecture included associations between reduced SWS and higher HbA1C, worse quality of life, and sleepiness. More time (%) spent in stage N2 related to higher glucose levels/hyperglycemia, behavioral difficulties, reduced quality of life, lower grades, depression, sleep-wake behavior problems, poor sleep quality, sleepiness, and lower state standardized math scores.

A Coccidioides posadasii CPS1 Deletion Mutant Is Avirulent and Protects Mice from Lethal Infection

ABSTRACT The CPS1 gene was identified as a virulence factor in the maize pathogen Cochliobolus heterostrophus. Hypothesizing that the homologous gene in Coccidioides posadasii could be important for virulence, we created a Δcps1 deletion mutant which was unable to cause disease in three strains of mice (C57BL/6, BALB/c, or the severely immunodeficient NOD-scid,γc null [NSG]). Only a single colony was recovered from 1 of 60 C57BL/6 mice following intranasal infections of up to 4,400 spores. Following administration of very high doses (10,000 to 2.5 × 107 spores) to NSG and BALB/c mice, spherules were observed in lung sections at time points from day 3 to day 10 postinfection, but nearly all appeared degraded with infrequent endosporulation. Although the role of CPS1 in virulence is not understood, phenotypic alterations and transcription differences of at least 33 genes in the Δcps1 strain versus C. posadasii is consistent with both metabolic and regulatory functions for the gene. The in vitro phenotype of the Δcps1 strain showed slower growth of mycelia with delayed and lower spore production than C. posadasii, and in vitro spherules were smaller. Vaccination of C57BL/6 or BALB/c mice with live Δcps1 spores either intranasally, intraperitoneally, or subcutaneously resulted in over 95% survival with mean residual lung fungal burdens of <1,000 CFU from an otherwise lethal C. posadasii intranasal infection. Considering its apparently complete attenuation of virulence and the high degree of resistance to C. posadasii infection when used as a vaccine, the Δcps1 strain is a promising vaccine candidate for preventing coccidioidomycosis in humans or other animals.

Targeting of memory T cells with alefacept in new-onset type 1 diabetes (T1DAL study)

This article of the yearbook of Advanced Technology and Treatments in Diabetes reviews several clinical studies that have appeared between July 2013 and August 2014 in the area of immune intervention in type 1 diabetes (T1D). The first article discussed is the first results from the Trial to Reduce IDDM in the Genetically at Risk (TRIGR), a much anticipated primary prevention trial. Hydrolyzed infant formula and early β-cell autoimmunity: a randomized clinical trial Knip M1, Akerblom HK1, Becker D2, Dosch HM3, Dupre J4, Fraser W5, Howard N6, Ilonen J7, Krischer JP8, Kordonouri O9, Lawson ML10, Palmer JP11, Savilahti E1, Vaarala O12, Virtanen SM12; TRIGR Study Group 1University of Helsinki, Helsinki, Finland; 2University of Pittsburgh, Pittsburgh, PA; 3University of Toronto, Toronto, Ontario, Canada; 4University of Western Ontario, London, Canada; 5University of Montreal, Montreal, Quebec, Canada; 6Childrens Hospital of Westmead, Sydney, Australia; 7University of Turku, Turku, Finland; 8University of South Florida, Tampa; 9Kinder- und Jugendkrankenhaus AUF DER BULT, Hannover, Germany; 10Childrens Hospital of Eastern Ontario, Ottawa, Ontario, Canada; 11University of Washington, Seattle, WA; and 12National Institute for Health and Welfare, Helsinki, Finland JAMA 2014; 311: 2279–87 Background Short duration of breast-feeding and/or early exposure to complex dietary proteins have been implicated as potential risk factors for β-cell autoimmunity and T1D. Extensively hydrolyzed formulas do not contain intact proteins. The Trial to test Reduce IDDM in the Genetically at Risk (TRIGR) Study was designed to test the hypothesis that weaning to an extensively hydrolyzed formula decreases the cumulative incidence of T1D in young children. Presentation of clinical T1D by age 10 years is the primary outcome of TRIGR, while positivity for 2 or more diabetes-associated autoantibodies by age 6 years is a secondary outcome, presented in this article.

2. Durable Efficacy of Alefacept in New-Onset Type 1 Diabetes: Evidence for Lasting Modulation of Effector and Regulatory T Cells (231-OR)

SamenvattingType 1 diabetes (T1D) results from destruction of pancreatic beta cells by autoreactive effector T cells. We hypothesized that a combination of targeted depletion and modulation of effector T cell activity by alefacept would result in prolonged preservation of endogenous insulin secretion in patients with newly diagnosed T1D. In a multicenter, randomized, double-blind, placebo-controlled trial we compared alefacept (two 12-week courses of 15 mg intramuscularly per week, separated by a 12-week pause) with placebo in patients with new-onset T1D. Endpoints assessed at 24 months included meal-stimulated C-peptide area under the curve (AUC), insulin use, hypoglycemic events, and immunologic responses.

Targeting of memory T cells with alefacept in new-onset type 1 diabetes (T1DAL study): 12 month results of a randomized, double-blind, placebo-controlled phase 2 trial

This article of the yearbook of Advanced Technology and Treatments in Diabetes reviews several clinical studies that have appeared between July 2013 and August 2014 in the area of immune intervention in type 1 diabetes (T1D). The first article discussed is the first results from the Trial to Reduce IDDM in the Genetically at Risk (TRIGR), a much anticipated primary prevention trial. Hydrolyzed infant formula and early β-cell autoimmunity: a randomized clinical trial Knip M1, Akerblom HK1, Becker D2, Dosch HM3, Dupre J4, Fraser W5, Howard N6, Ilonen J7, Krischer JP8, Kordonouri O9, Lawson ML10, Palmer JP11, Savilahti E1, Vaarala O12, Virtanen SM12; TRIGR Study Group 1University of Helsinki, Helsinki, Finland; 2University of Pittsburgh, Pittsburgh, PA; 3University of Toronto, Toronto, Ontario, Canada; 4University of Western Ontario, London, Canada; 5University of Montreal, Montreal, Quebec, Canada; 6Childrens Hospital of Westmead, Sydney, Australia; 7University of Turku, Turku, Finland; 8University of South Florida, Tampa; 9Kinder- und Jugendkrankenhaus AUF DER BULT, Hannover, Germany; 10Childrens Hospital of Eastern Ontario, Ottawa, Ontario, Canada; 11University of Washington, Seattle, WA; and 12National Institute for Health and Welfare, Helsinki, Finland JAMA 2014; 311: 2279–87 Background Short duration of breast-feeding and/or early exposure to complex dietary proteins have been implicated as potential risk factors for β-cell autoimmunity and T1D. Extensively hydrolyzed formulas do not contain intact proteins. The Trial to test Reduce IDDM in the Genetically at Risk (TRIGR) Study was designed to test the hypothesis that weaning to an extensively hydrolyzed formula decreases the cumulative incidence of T1D in young children. Presentation of clinical T1D by age 10 years is the primary outcome of TRIGR, while positivity for 2 or more diabetes-associated autoantibodies by age 6 years is a secondary outcome, presented in this article.

Targeting effector memory T cells with alefacept in new onset type 1 diabetes: 12 month results from the T1DAL study

BACKGROUND Type 1 diabetes results from autoimmune targeting of the pancreatic β cells, likely mediated by effector memory T (Tem) cells. CD2, a T cell surface protein highly expressed on Tem cells, is targeted by the fusion protein alefacept, depleting Tem cells and central memory T (Tcm) cells. We postulated that alefacept would arrest autoimmunity and preserve residual β cells in patients newly diagnosed with type 1 diabetes. METHODS The T1DAL study is a phase 2, double-blind, placebo-controlled trial in patients with type 1 diabetes, aged 12-35 years who, within 100 days of diagnosis, were enrolled at 14 US sites. Patients were randomly assigned (2:1) to receive alefacept (two 12-week courses of 15 mg intramuscularly per week, separated by a 12-week pause) or a placebo. Randomisation was stratified by site, and was computer-generated with permuted blocks of three patients per block. All participants and site personnel were masked to treatment assignment. The primary endpoint was the change from baseline in mean 2 h C-peptide area under the curve (AUC) at 12 months. Secondary endpoints at 12 months were the change from baseline in the 4 h C-peptide AUC, insulin use, major hypoglycaemic events, and HbA1c concentrations. This trial is registered with ClinicalTrials.gov, number NCT00965458. FINDINGS Of 73 patients assessed for eligibility, 33 were randomly assigned to receive alefacept and 16 to receive placebo. The mean 2 h C-peptide AUC at 12 months increased by 0.015 nmol/L (95% CI -0.080 to 0.110) in the alefacept group and decreased by 0.115 nmol/L (-0.278 to 0.047) in the placebo group, and the difference between groups was not significant (p=0.065). However, key secondary endpoints were met: the mean 4 h C-peptide AUC was significantly higher (mean increase of 0.015 nmol/L [95% CI -0.076 to 0.106] vs decrease of -0.156 nmol/L [-0.305 to -0.006]; p=0.019), and daily insulin use (0.48 units per kg per day for placebo vs 0.36 units per kg per day for alefacept; p=0.02) and the rate of hypoglycaemic events (mean of 10.9 events per person per year for alefacept vs 17.3 events for placebo; p<0.0001) was significantly lower at 12 months in the alefacept group than in the placebo group. Mean HbA1c concentrations at week 52 were not different between treatment groups (p=0.75). So far, no serious adverse events were reported and all patients had at least one adverse event. In the alefacept group, 29 (88%) participants had an adverse event related to study drug versus 15 (94%) participants in the placebo group. In the alefacept group, 14 (42%) participants had grade 3 or 4 adverse events compared with nine (56%) participants in the placebo group; no deaths occurred. INTERPRETATION Although the primary outcome was not met, at 12 months, alefacept preserved the 4 h C-peptide AUC, lowered insulin use, and reduced hypoglycaemic events, suggesting efficacy. Safety and tolerability were similar in the alefacept and placebo groups. Alefacept could be useful to preserve β-cell function in patients with new-onset type 1 diabetes.Background Type 1 diabetes (T1D) results from autoimmune targeting of the pancreatic beta cells, likely mediated by effector memory T cells (Tems). CD2, a T cell surface protein highly expressed on Tems, is targeted by the fusion protein alefacept, depleting Tems and central memory T cells (Tcms). We hypothesized that alefacept would arrest autoimmunity and preserve residual beta cells in newly diagnosed T1D.