Contemporary Accounts in Drug Discovery and Development. Группа авторов

Чтение книги онлайн.

Читать онлайн книгу Contemporary Accounts in Drug Discovery and Development - Группа авторов страница 33

Contemporary Accounts in Drug Discovery and Development - Группа авторов

Скачать книгу

LEPHT study [25, 26, 46], patients with symptomatic worsening chronic HF were enrolled irrespective of documented elevations in pulmonary artery pressure. Since very high mortality and morbidity rates persist in patients who experience HF events despite receiving optimal medical therapy, these studies specifically enrolled patients within a one month window after a preceding HF hospitalization, or alternatively after a HF event that had to be treated with i.v. diuretics in an outpatient setting [47]. Rather than transient management with additional i.v. therapy, long‐term treatment with an oral sGC stimulator was deemed to carry promise [48] to meet this medical need in patients suffering from HF events despite available therapies [49].

      Primary endpoint in SOCRATES‐REDUCED was reduction in NT‐proBNP at 12 weeks, and the study was powered to detect a decrease in the 10 mg arm as previously observed in patients with HFrEF and concomitant PH in the 2 mg riociguat target dose arm of the LEPHT study [47]. Although the primary analysis of the pooled three higher dose arms did not reach statistical significance, the pre‐specified secondary analysis of the primary endpoint NT‐proBNP comparing the individual dose arms versus placebo showed a statistically and clinically significant reduction in NT‐proBNP in the 10 mg target dose arm at 12 weeks [50]. Based upon the established association of short‐term NT‐proBNP lowering with long‐term decreases in clinical events in patients with HFrEF, the Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction (VICTORIA) phase 3 event‐driven outcome trial was designed to study whether vericiguat at a target dose of 10 mg once daily reduces mortality and morbidity in patients with worsening chronic HFrEF [18]. Different from other previous trials in patients with stable HFrEF, patients enrolled in the VICTORIA trial represent a broadly generalizable high‐risk population suffering from worsening chronic HFrEF despite very good HF therapy [51].

      In parallel with the development in HFrEF, vericiguat was also studied in patients with worsening chronic HFpEF. Conducted back‐to‐back with the phase 2 HFrEF study, the SOCRATES‐PRESERVED trial enrolled patients within one month after an HF event who had a preserved ejection fraction (LVEF >45%) [47]. Opposed to the clinically meaningful reduction observed in patients with HFrEF in SOCRATES‐REDUCED, the same dose and duration of treatment with vericiguat did not reduce NT‐proBNP in patients with HFpEF, and changes in the other primary endpoint, left atrial volume, did not differ between treatment arms [52]. However, exploratory analyses showed an improved health status assessed by the Kansas City Cardiomyopathy Questionnaire (KCCQ) and QoL measured with the EQ‐5D in patients treated with vericiguat [53]. Therefore, the phase 2b study VITALITY‐HFpEF has been designed to determine the efficacy and safety of vericiguat on QoL and exercise tolerance in patients with HFpEF [54], and results of this study showed that vericiguat did not improve the physical limitation score (KCCQ PLS) at 24 weeks [55].

      Vericiguat belongs to a novel class of drugs termed sGC stimulators. Vericiguat selectively and specifically binds to sGC leading to concentration‐dependent production of the second messenger cGMP. Since NO/sGC signaling is impaired in CV diseases and HF, vericiguat can restore this dysfunctional NO/sGC signaling. Preclinical and clinical data strongly suggest that vericiguat as confirmed in the recent VICTORIA phase 3 trial does improve clinical outcomes in patients with HF and maybe other CV diseases.

      1 1 Butler, J., Yang, M., Manzi, M.A. et al. (2019). J. Am. Coll. Cardiol. 73: 935–944.

      2 2 Vos, T., Abajobir, A.A., Abate, K.H. et al. (2017). The Lancet 390: 1211–1259.

      3 3 Roger, V.L. (2013). Circ. Res. 113: 646–659.

      4 4 Packer, M., Anker, S.D., Butler, J. et al. (2020). N. Engl. J. Med. 383: 1413–1424.

      5 5 Armstrong, P.W., Pieske, B., Anstrom, K.J. et al. (2020). N. Engl. J. Med. 382: 1883–1893.

      6 6 Burnett, J.C. Jr. (2020). N. Engl. J. Med. 382: 1952–1953.

      7 7 Evgenov, O.V., Pacher, P., Schmidt, P.M. et al. (2006). Nat. Rev. Drug Discov. 5: 755–768.

      8 8 Follmann, M., Griebenow, N., Hahn, M.G. et al. (2013). Angew. Chem. Int. Ed. Engl. 52: 9442–9462.

      9 9 Murad, F. (2006). N. Engl. J. Med. 355: 2003–2011.

      10 10 Greene, S.J., Gheorghiade, M., Borlaug, B.A. et al. (2013). J. Am. Heart Assoc. 2: e000536.

      11 11 Gheorghiade, M., Marti, C.N., Sabbah, H.N. et al. (2013). Heart Fail. Rev. 18: 123–134.

      12 12 Breitenstein, S., Roessig, L., Sandner, P., and Lewis, K.S. (2017). Handb. Exp. Pharmacol. 243: 225–247.

      13 13 Sandner, P., Zimmer, D.P., Milne, G.T. et al. (2018). Soluble guanylate cyclase stimulators and activators. In: Reactive Oxygen Species, Handbook of Experimental Pharmacology, vol. 264 (eds. H.H.H.W. Schmidt, P. Ghezzi and A. Cuadrado). Cham: Springer https://doi.org/10.1007/164_2018_197.

      14 14 McMurray, J.J., Packer, M., Desai, A.S. et al. (2014). N. Engl. J. Med. 371: 993–1004.

      15 15 Packer, M., McMurray, J.J., Desai, A.S. et al. (2015). Circulation 131: 54–61.

      16 16 Nougué, H., Pezel, T., Picard, F. et al. (2019). Eur. J. Heart Fail. 21: 598–605.

      17 17 Goetze, J.P., Bruneau, B.G., Ramos, H.R. et al. (2020). Nat. Rev. Cardiol. 17 (11): 698–717.

      18 18 Armstrong, P.W., Roessig, L., Patel, M.J. et al. (2018). JACC Heart Fail. 6: 96–104.

      19 19 Felker, G.M., Adams, K.F. Jr., Konstam, M.A. et al. (2003). Am. Heart J. 145: S18–S25.

      20 20 Gheorghiade, M. and Pang, P.S. (2009). J. Am. Coll. Cardiol. 53: 557–573.

      21 21 Gheorghiade, M., De Luca, L., Fonarow, G.C. et al. (2005). Am. J. Cardiol. 96: 11g–17g.

      22 22 Solomon, S.D., Dobson, J., Pocock, S. et al. (2007). Circulation 116: 1482–1487.

      23 23 Abrahamsson, P., Swedberg, K., Borer, J.S. et al. (2013). Eur. J. Heart Fail. 15: 885–891.

      24 24 Bello, N.A., Claggett, B., Desai, A.S. et al. (2014). Circ. Heart Fail. 7: 590–595.

      25 25 Ghio, S., Bonderman, D., Felix, S.B. et al. (2012). Eur. J. Heart Fail. 14: 946–953.

      26 26 Bonderman, D., Ghio, S., Felix, S.B. et al. (2013). Circulation 128: 502–511.

      27 27 Bonderman, D., Ghio, S., Felix, S.B. et al. (2014). J. Card. Fail. 20:

Скачать книгу