Efficacy and Safety of K-877 (Pemafibrate), a Selective PPARα Modulator, in European Patients on Statin Therapy.

OBJECTIVE: High plasma triglyceride (TG) is an independent risk factor for cardiovascular disease. Fibrates lower TG levels through peroxisome proliferator-activated receptor α (PPARα) agonism. Currently available fibrates, however, have relatively low selectivity for PPARα. The aim of this trial was to assess the safety, tolerability, and efficacy of K-877 (pemafibrate), a selective PPARα modulator, in statin-treated European patients with hypertriglyceridemia. RESEARCH DESIGN AND METHODS: A total of 408 statin-treated adults were recruited from 68 European sites for this phase 2, randomized, double-blind, placebo-controlled trial. They had fasting TG between 175 and 500 mg/dL and HDL-cholesterol (HDL-C) ≤50 mg/dL for men and ≤55 mg/dL for women. Participants were randomly assigned to receive placebo or one of six pemafibrate regimens: 0.05 mg twice a day, 0.1 mg twice a day, 0.2 mg twice a day, 0.1 mg once daily, 0.2 mg once daily, or 0.4 mg once daily. The primary end points were TG and non-HDL-C level lowering at week 12. RESULTS: Pemafibrate reduced TG at all doses (adjusted P value <0.001), with the greatest placebo-corrected reduction from baseline to week 12 observed in the 0.2-mg twice a day treatment group (54.4%). Reductions in non-HDL-C did not reach statistical significance. Reductions in TG were associated with improvements in other markers for TG-rich lipoprotein metabolism, including reductions in apoB48, apoCIII, and remnant cholesterol and an increase in HDL-C levels. Pemafibrate increased LDL-cholesterol levels, whereas apoB100 was unchanged. Pemafibrate was safe and well-tolerated, with only minor increases in serum creatinine and homocysteine concentrations. CONCLUSIONS: Pemafibrate is effective, safe, and well-tolerated for the reduction of TG in European populations with hypertriglyceridemia despite statin treatment.

Effects of halogenated WNA derivatives on sequence dependency for expansion of recognition sequences in non-natural-type triplexes.

Triplex-forming oligonucleotides (TFOs) are sequence-specific DNA-binding agents, but their target duplexes are limited to homopurine/homopyrimidine sequences because of interruption of the pyrimidines bases in the purine region. This problem has not been fully solved despite a wide variety of studies. Recently, we have developed a bicyclic system as a novel scaffold for nucleoside analogues (WNA, W-shaped nucleoside analogues) and determined two useful compounds, WNA-betaT (2) and WNA-betaC (5), for highly stable and selective triplex formation at a TA and a CG interrupting site, respectively. However, subsequent investigations have shown that the triplex formation using WNA is dependent on the neighboring bases of the TFOs. In this study, we have synthesized new WNA derivatives having halogenated recognition bases or benzene rings and evaluated the effects of the modifications on the triplex stability as well as selectivity. It has been found that the WNA-betaT analogues holding 5-halogenated pyrimidine bases (WNA-beta(Br)U (3) and WNA-beta(F)U (4)) exhibit high CG-selectivity. On the other hand, the WNA-betaT derivatives having the bromo-substituted benzene ring (mBr-WNA-betaT (10) and oBr-WNA-betaT (11)) have shown high selectivity to a TA interrupting site with high stability in the sequences to which the original WNA-betaT do not bind. Thus, sequence-dependency has been overcome by the sequence-dependent use of WNA-betaT, mBr-WNA-betaT, and oBr-WNA-betaT.

Expansion of triplex recognition codes by the use of novel bicyclic nucleoside derivatives (WNA).

Recently, we have developed new base analogs (WNA) and demonstrated that WNA-[see text];T with thymine and WNA-[see text];C with cytosine stabilize n on-natural antiparallel triplexes with a TA or CG interrupting site, respectively. However, limitations in recognizable sequences with the WNA-containing TFO were also found. The objective of this study is to search better WNA analogs for expansion of triplex recognition codes to general duplex sequences. In this study, we designed new WNA analogs by systematic modification of the aromatic part and the recognition part. The new WNA analogs with the benzene ring substituted with bromide or cyanide have determined for selective stabilization of triplexes at a TA interrupting site, and general formation of triplexes having a TA interrupting site has been achieved.

Selective formation of stable triplexes including a TA or a CG interrupting site with new bicyclic nucleoside analogues (WNA).

Triplex-forming oligonucleotides (TFOs) are potential DNA-targeting molecules and would become powerful tools for genomic research. As the stabilization of the TFO is partially provided by hydrogen bonds to purine bases, the most stable triplexes form with homopurine/homopyrimidine sequences, and a pyrimidine base in the purine strand of the duplex interrupts triplex formation. If a TFO can recognize sequences including such an interrupting site, the target regions in the genome would be expanded to a greater extent. However, this problem has not been generally solved despite extensive studies. We have previously reported a new base analogue (WNA) constructed of three parts, a benzene ring, a heterocyclic ring, and a bicyclic skeleton to hold these two parts. In this study, we have further investigated modification of WNA systematically and determined two useful WNA analogues, WNA-beta T and WNA-beta C, for selective stabilization of triplexes at a TA and a CG interrupting site, respectively. The triplexes with WNA analogues have exhibited an interesting property in that they are more stable than natural-type triplexes even at low Mg(2+) concentration. From comparison of the results with H-WNA-beta T lacking benzene and those with WNA-H without thymine, it has been suggested that benzene is a major contributor for triplex stability and thymine provides selectivity. Thus, it has been successfully demonstrated that WNA-beta T/TA and WNA-beta C/CG combinations may expand triplex recognition codes in addition to the natural A/AT and G/GC base triplet codes. The results of this study will provide useful information for the design of new WNA analogues to overcome inherent problems for further expansion of triplex recognition codes.

Effects of 5-substituted pyrimidine nucleoside bases of WNA on stability of triplex DNA.

Triplex-forming oligonucleotides (TFOs) are potential DNA-targeting molecules, but their recognizable duplexes are limited to homopurine:homopyrimidine sequences by interruption of pyrimidine bases in the purine strand. Despite numerous studies, this problem has not been generally solved. We have recently demonstrated that the new nucleoside analogues, WNA-betaT and WNA-betaC exhibit selective stabilization of the triplexes at a TA and a CG interrupting site, respectively. However, subsequent investigations have shown that there are limitations in recognizable sequences by these analogs. In this study, we performed further systematic investigation on WNA analogs by synthesizing a variety of WNA analogs having 5-substituted cytosine and uracil, and found that WNA-betaFU exhibit high CG-selectivity.

Design and evaluation of novel nucleoside analogs (WNA) for specific formation of non-natural type triplexes containing a TA or CG interrupting site.

In a search of suitable recognition molecules for the formation of stable non-natural triplex DNA, we have developed the new nucleoside analogs (WNA, W-shape nucleoside analog) bearing an aromatic ring, a recognition base and a bicyclic skeleton to hold them. A successful result with WNA-betaT that recognizes a TA base pair selectively has suggested that the basic structure of the WNA is useful as a scaffold for search of other candidates for the formation of triplex containing a TA or a CG interrupting site. In this study, we have synthesized and investigated binding property of a variety of WNA candidates. As a result, we have determined new potential analog, WNA-betaC for a CG interrupting site. It should be noted that the triplexes containing a WNA-betaT:TA or a WNA-betaC:CG base triplet have exhibited higher stability than the natural anti-parallel triplexes constructed of A:AT and G:GC triplets. The results that H-WNA-betaT lacking a benzene ring did not show stabilization effect to any base pairs have clearly indicated that a benzene ring plays a key role in stability of triplexes.

Selective formation of non-natural type triplexes containing TA interrupting sites with the TFO incorporating W-shape nucleic acid (WNA) analogs.

Novel nucleoside analogs have been desired for selective formation of non-natural type triplexes containing TA or CG interrupting sites. We have previously reported that the W-shaped nucleic acid (WNA) would be a useful skeleton to develop new base analog for the formation of non-natural triplexes of antiparallel motif. In this study, we have found that triplex forming oligonucleotide (TFO) incorporating the new WNA analog, WNA-beta T, formed more stable triplex than natural triplex with high selectivity to the TA site. It is also noted that the TFO containing WNA-beta T did not form aggregates at the physiological condition of K+.