Jill F.B. Altman

Rosiglitazone (a PPARγ agonist) has shown beneficial effects on memory and executive function tasks in Alzheimer's disease (AD)1. To examine the use of standard clinical measures (e.g ADAS–cog) and experimental measures of simple and choice reaction time (examining attention, visuospatial abilities, executive function) to detect cognitive decline and drug effects in a subset of mild to moderate AD patients involved in a 24 week phase 2b trial of rosiglitazone2. Simple reaction time (SRT) (mean time to respond to a change in colour of a centrally presented target), and choice reaction time (CRT) (the mean time to correctly respond to a target changing colour in either the left or right visual field) data were collected at baseline and 24 weeks in addition to ADAS–cog in a subset of 56 patients from the main trial. The subset was divided approximately equally between 2mg, 4mg, 8mg rosiglitazone and placebo treatments throughout the study. Across the study as whole (511 patients in ITT population), and in the subset, no differentiation was seen between placebo and rosiglitazone groups on the ADAS–cog at 24 weeks2. Similarly, in the subset studied, SRT remained stable and did not differentiate between groups. However, placebo treated patients showed increased reaction times (slower to respond) on the CRT task at 24 weeks, relative to rosiglitazone treated patients. Their deterioration in this measure of attention and executive functions over time was greater than that of all 3 rosiglitazone groups, with an exploratory analysis reaching statistical significance indicating the greatest effects with the 2 mg and 4 mg rosiglitazone. This effect was particularly marked for targets in the left visual field. Recent evidence suggests a link between reduced attention and preferential bias to the right side of space3,4. The left–right asymmetry in performance seen in our placebo group at 24 weeks but not at baseline, offers further evidence of reduced attention and executive functions with disease progression. Simple computerised tasks, e.g. choice reaction time task, may be useful to measure decline in placebo group and beneficial drug effects in small studies.

RSG (PPARγ agonist) is approved for type–2 diabetes treatment. Risner et al reported cognitive endpoints from a 24–week, double–blind, placebo–controlled monotherapy trial (N=511) in AD patients (baseline MMSE 16–26). No significant effects were observed on ADAS–Cog in the intention–to–treat (ITT) population; however, a significant interaction between treatment and APOE ϵ4 allele status on ADAS–Cog (P=0.014) was observed at Week 24 Last Observation Carried Forward (LOCF). Exploratory analyses suggested that APOE ϵ4 non–carriers showed significant clinical improvement whereas APOE ϵ4 allele carriers showed no improvement and some decline was noted. RSG was generally well tolerated. No new safety concerns were identified compared to the well–established safety profile of RSG. To report results of RSG on cognition, behavioral symptoms, and functional ability in mild–to–moderateAD patients in both the ITT population and by APOE ϵ4 carriage status. Patients were randomized to receive placebo or an unmarketed form of RSG 2, 4, or 8mg/day for 24 weeks. Cognitive symptoms, behavioral symptoms, and function were assessed using ADAS–Cog, NPI, and CIBIC–Plus and DAD, respectively. An analysis of covariance model was used based on the ITT and pharmacogenetic populations using an LOCF approach. Observed case (OC) analyses were also performed. No significant treatment effects were observed at Week 24 in the ITT population for CIBIC–Plus, NPI, DAD or MMSE. Exploratory analyses (not adjusted for multiplicity) of ADAS–Cog at Week 24 demonstrated improvement in the “Word recognition” item in RSG 8 mg group (P=0.046 OC; P=0.14 LOCF). At Week 24, RSG 8 mg group also showed significant improvement in CIBIC–Plus (P=0.021 OC; P=0.11 LOCF) and in the irritability/lability domain of NPI (P=0.018 LOCF). Exploratory analyses suggested that the pattern observed on ADAS–Cog (improvement in APOE ϵ4 non–carriers and lack of improvement or decline for APOE ϵ4 allele carriers) was also observed at Week 24 for CIBIC–Plus, DAD, and NPI (Figure). These exploratory findings cannot be used to inform clinical management of patients with AD. Further investigation of rosiglitazone for symptomatic treatment of patients with mild–to–moderate AD is warranted. Risner et al. The Pharmacogenomics Journal advance online publication, 31 January 2006; doi:10.1038/sj.tpj.6500369.

Background: Mutations in isocitrate dehydrogenase 1 (IDH1) are reported in 6–10% of patients with acute myeloid leukemia (AML). Ivosidenib (IVO; AG-120) is an oral, potent, targeted inhibitor of mutant IDH1 (mIDH1) that is approved for the treatment of adults with mIDH1 relapsed or refractory AML. In vitro, combination treatment of mIDH1 leukemic cell lines with IVO and azacitidine (AZA) enhanced cellular differentiation and apoptosis. Aims: We report results from an ongoing phase 1b study of patients with mIDH1 newly diagnosed (ND) AML who were ineligible for intensive treatment, and who received IVO in combination with AZA (NCT02677922). Methods: Patients received IVO 500 mg once daily continuously, and subcutaneous AZA 75 mg/m2 on Days 1–7 in 28-day cycles. Overall response rate (ORR) comprised complete remission (CR) + CR with incomplete hematologic or platelet recovery (CRi/CRp) + partial remission + morphologic leukemia-free state (MLFS). CR with partial hematologic recovery (CRh) was defined as CR with absolute neutrophil count >0.5 × 109/L (500/μL) and platelets >50 × 109/L (50,000/μL). Exploratory analysis included digital PCR assessment of mIDH1 allele frequency in bone marrow mononuclear cells (≤0.04% sensitivity). Results: As of Oct 9, 2018, 23 patients had received IVO+AZA (11 men; median age 76 years [range, 61–88]). Median duration of exposure was 11 months (range, 0.3–25.3); 12 patients remained on treatment at data cutoff. All-grade adverse events (AEs) regardless of cause in ≥30% of patients were thrombocytopenia (65%), nausea (61%), diarrhea (57%), anemia (52%), constipation (52%), febrile neutropenia (39%), pyrexia (39%), vomiting (35%), fatigue (35%), hypokalemia (35%), dizziness (35%), insomnia (35%), and neutropenia (30%). AEs of special interest included electrocardiogram (ECG) QT prolonged (26%), IDH differentiation syndrome (17%), and leukocytosis (13%). Grade 3/4 AEs in ≥10% of patients were thrombocytopenia (61%), anemia (44%), febrile neutropenia (39%), neutropenia (26%), sepsis (22%), and ECG QT prolonged (13%). ORR was 78% (n = 18), including a CR rate of 57%, a CRi/CRp rate of 13%, and an MLFS rate of 9%. The CR+CRh rate was 70% (n = 16). Median time to response was 1.8 months (range, 0.7–3.8) and to CR was 3.5 months (range, 0.8–6.0); median response duration not yet reached. mIDH1 clearance was seen in 10 of 16 patients (63%) with CR/CRh, including 9 of 13 (69%) with CR. Summary/Conclusion: IVO+AZA was well tolerated, and had a safety profile consistent with IVO or AZA monotherapy. All-grade cytopenia-related AEs were infrequent relative to other nonintensive therapies. CR rate and ORR exceeded those of AZA alone (Dombret et al. Blood 2015) and a majority of responders achieved mIDH1 mutation clearance. Based on these findings, a phase 3 double-blind placebo-controlled study of IVO+AZA (AGILE, NCT03173248) is actively enrolling patients.

Rosiglitazone (PPARγ agonist) approved for the treatment of type–2 diabetes is being tested in AD. Risner et al reported rosiglitazone was generally well–tolerated in a 24–week, double–blind, placebo–controlled monotherapy trial (N=511) in AD subjects (baseline MMSE 16–26). To report additional safety, tolerability, and biomarker results for RSG in AD patients. Subjects were randomized to receive placebo or an unmarketed formulation of RSG 2, 4, or 8 mg/day for 24 weeks. Safety and tolerability were assessed via patient–reported events, clinical chemistry, hematology, changes from baseline in fasting insulin and plasma glucose, homeostasis model assessment (HOMA) estimate of insulin resistance, and inflammatory markers. Adverse events (AEs) are summarized in Table below for overall safety population and by APOE ϵ4 carriage status. A small number of cases of edema were seen in RSG–treated subjects, and none were seen on placebo. One fatality owing to acute cardiac failure unrelated to study drug (RSG 8mg) was reported. With the exception of one report of atrial fibrillation and cardiac failure in a single subject (RSG 8 mg), other serious adverse events (SAEs) were not considered to be related to the study medication. No clinically significant trends were noted in the hematology, clinical chemistry, vital signs, or ECG parameters. Observed changes in insulin sensitivity and glycemic control parameters (fasting insulin, fasting plasma glucose, HbA1c, and HOMA IR) were within expected ranges and were typical of an older population who had a low level of insulin resistance and consistent with other recent AD studies. A significant linear trend in RSG dose response at Week 24 LOCF was noted for the expression of the CD40L protein marker, but the overall RSG treatment effect or individual RSG versus placebo treatment differences were not statistically significant. No major differences were observed between APOE ϵ4 negative and APOE ϵ4 positive subjects in the overall incidence of SAEs or AEs. The adverse events and tolerability profile observed in this AD population were comparable to the well established safety profile reported with rosiglitazone in type 2 diabetes.