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Summary Background Guadecitabine (SGI-110) is a novel hypomethylating dinucleotide of decitabine (DAC) and deoxyguanosine that is resistant to degradation by cytidine deaminase. Methods This is a first-in-human pharmacokinetic (PK)- and pharmacodynamic (PD)-guided Phase 1 dose-escalation study in adults with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Patients with MDS or AML refractory to, or relapsed after, standard treatment were randomly assigned to one of two regimens of subcutaneous (SC) guadecitabine: Daily×5 or Once Weekly for three weeks. Stratification was based on disease (MDS vs. AML). Treatment assignment was not blinded. A Twice Weekly for three weeks regimen was later added to the study. All regimens were given in 28-day cycles. The primary objective was the safety profile of all regimens and the recommended dose and schedule for phase 2 by either maximum tolerated dose (MTD) or biologically effective dose (BED). All patients who received at least one treatment were included in the analyses. Enrollment is complete and all patients have finished treatment. This study is registered with ClinicalTrials.gov, number NCT01261312. Findings 93 patients were treated (74 AML and 19 MDS): 44 on Daily×5 (3–125 mg/m2/d), 34 on Once Weekly (6–125 mg/m2/d), and 15 on Twice Weekly (60 and 90 mg/m2/d). Guadecitabine SC produced a longer exposure window and half-life, and lower Cmax, of plasma DAC than intravenous DAC. The MTD was 90 mg/m2 in MDS on the Daily×5 regimen but was not reached in AML or on the other regimens. The most common Grade ≥3 adverse events were febrile neutropenia (38/93, 41%), pneumonia (27/93, 29%), thrombocytopenia and anemia (23/93, 25% each), and sepsis (16/93, 17%). The most common serious adverse events (SAEs) were febrile neutropenia (29/93, 31%), pneumonia (26/93, 28%), and sepsis (16/93, 17%). Potent dose-related DNA demethylation occurred on the daily regimen, reaching a plateau at 60 mg/m2 Daily×5 (designated as BED). Responses were seen in heavily pretreated patients including six responders (two complete response [CR], two CR with incomplete blood count recovery [CRi], one CR with incomplete platelet recovery [CRp], and one partial response [PR]) in AML patients and two marrow complete response (mCR) in MDS patients. Responders showed significantly more demethylation than non-responders. Interpretation Guadecitabine SC at 60 mg/m2 Daily×5 is well-tolerated, easily administered, and biologically and clinically active in both MDS and AML; it warrants testing in phase 2 studies.

This phase 2 study was designed to compare systemic decitabine exposure, demethylation activity, and safety in the first 2 cycles with cedazuridine 100 mg/decitabine 35 mg vs standard decitabine 20 mg/m2 IV. Adults with International Prognostic Scoring System intermediate-1/2- or high-risk myelodysplastic syndromes (MDS), or chronic myelomonocytic leukemia (CMML) were randomized 1:1 to receive oral cedazuridine/decitabine or IV decitabine in cycle 1, followed by crossover to the other treatment in cycle 2. All patients received oral cedazuridine/decitabine in subsequent cycles. Cedazuridine and decitabine were given initially as separate capsules in a dose-confirmation stage and then as a single fixed-dose combination (FDC) tablet. Primary endpoints: mean decitabine systemic exposure (geometric least-squares mean [LSM]) of oral/IV 5-day area under curve from time 0 to last measurable concentration (AUClast), % long interspersed nuclear element 1 (LINE-1) DNA demethylation for oral cedazuridine/decitabine vs IV decitabine, and clinical response. Eighty patients were randomized and treated. Oral/IV ratios of geometric LSM 5-day AUClast (80% confidence interval) were 93.5% (82.1%, 106.5%) and 97.6% (80.5%, 118.3%) for the dose-confirmation and FDC stages, respectively. Differences in mean %LINE-1 demethylation between oral and IV were ≤1%. Clinical responses were observed in 48 patients (60%), including 17 (21%) with complete response. The most common grade ≥3 adverse events regardless of causality were neutropenia (46%), thrombocytopenia (38%), and febrile neutropenia (29%). Oral cedazuridine/decitabine (100/35 mg) produced similar systemic decitabine exposure, DNA demethylation, and safety vs decitabine 20 mg/m2 IV in the first 2 cycles, with similar efficacy. ClinicalTrials.gov NCT02103478.

The presenilin containing ␥-secretase complex is responsible for the regulated intramembraneous proteolysis of the amyloid precursor protein (APP), the Notch receptor, and a multitude of other substrates. ␥-Secretase catalyzes the final step in the generation of A␤ 40 and A␤ 42 peptides from APP. Amyloid ␤-peptides (A␤ peptides) aggregate to form neurotoxic oligomers, senile plaques, and congophilic angiopathy, some of the cardinal pathologies associated with Alzheimer's disease. Although inhibition of this protease acting on APP may result in potentially therapeutic reductions of neurotoxic A␤ peptides, nonselective inhibition of the enzyme may cause severe adverse events as a result of impaired Notch receptor processing. Here, we report the preclinical pharmacological profile of GSI-953 (begacestat), a novel thiophene sulfonamide ␥-secretase inhibitor (GSI) that selectively inhibits cleavage of APP over Notch. This GSI inhibits A␤ production with low nanomolar potency in cellular and cell-free assays of ␥-secretase function, and displaces a tritiated analog of GSI-953 from enriched ␥-secretase enzyme complexes with similar potency. Cellular assays of Notch cleavage reveal that this compound is approximately 16-fold selective for the inhibition of APP cleavage. In the human APP-overexpressing Tg2576 transgenic mouse, treatment with this orally active compound results in a robust reduction in brain, plasma, and cerebral spinal fluid A␤ levels, and a reversal of contextual fear-conditioning deficits that are correlated with A␤ load. In healthy human volunteers, oral administration of a single dose of GSI-953 produces dosedependent changes in plasma A␤ levels, confirming pharmacodynamic activity of GSI-953 in humans.This research was supported by Wyeth Research. Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

The amyloid hypothesis states that a variety of neurotoxic ␤-amyloid (A␤) species contribute to the pathogenesis of Alzheimer's disease. Accordingly, a key determinant of disease onset and progression is the appropriate balance between A␤ production and clearance. Enzymes responsible for the degradation of A␤ are not well understood, and, thus far, it has not been possible to enhance A␤ catabolism by pharmacological manipulation. We provide evidence that A␤ catabolism is increased after inhibition of plasminogen activator inhibitor-1 (PAI-1) and may constitute a viable therapeutic approach for lowering brain A␤ levels. PAI-1 inhibits the activity of tissue plasminogen activator (tPA), an enzyme that cleaves plasminogen to generate plasmin, a protease that degrades A␤ oligomers and monomers. Because tPA, plasminogen and PAI-1 are expressed in the brain, we tested the hypothesis that inhibitors of PAI-1 will enhance the proteolytic clearance of brain A␤. Our data demonstrate that PAI-1 inhibitors augment the activity of tPA and plasmin in hippocampus, significantly lower plasma and brain A␤ levels, restore long-term potentiation deficits in hippocampal slices from transgenic A␤-producing mice, and reverse cognitive deficits in these mice.Alzheimer ͉ plasminogen activator inhibitor ͉ tissue plasminogen activator A lzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the presence of intracellular neuronal tangles and extracellular parenchymal and vascular amyloid deposits containing ␤-amyloid peptide (A␤). A␤ is a 39-to 42-aa peptide derived from the proteolytic processing of the amyloid precursor protein (APP) (1). The ''amyloid hypothesis'' of AD postulates a central causal role for A␤ in AD pathogenesis and is supported by genetic and physiological evidence. All known early onset familial AD mutations result in enhanced levels of cytotoxic A␤ species, amyloid plaque deposition, and dementia. Furthermore, A␤ peptide is reported to be neurotoxic and synaptotoxic in vitro and in vivo, inhibiting long-term potentiation (LTP), a physiological correlate of memory (2). Based on these observations, a number of strategies to reduce brain A␤ levels are being pursued as therapeutic approaches to treat AD (3, 4).If the amyloid hypothesis of AD is correct and A␤ levels are pivotal to disease etiology, then the balance between A␤ production and catabolism is likely to be a key determinant of disease progression. It has been suggested that insufficient clearance of A␤ may account for elevated A␤ levels in the brain and the accumulation of pathogenic amyloid deposits in sporadic AD (5). A number of proteases have been implicated in the proteolytic clearance of A␤ from the CNS, including neprilysin, insulin-degrading enzyme, endothelin converting enzyme, and plasmin (3, 6-8). The relative contribution of these enzymes to A␤ catabolism remains unclear, but each protease may play a significant role in the degradation and clearance of A␤, resulting in a slowing of A␤ accumulation and aggregation and u...