AKR‐501 (YM477) a novel orally‐active thrombopoietin receptor agonist

Fukushima-Shintani, Mari; Suzuki, Kenichi; Iwatsuki, Yoshiyuki; Abe, Masaki; Sugasawa, Keizo; Hirayama, Fukushi; Kawasaki, Tomihisa; Nakahata, Tatsutoshi

doi:10.1111/j.1600-0609.2008.01198.x

Cited by 62 publications

(43 citation statements)

References 24 publications

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“…Compared with the orally active eltrombopag they have fewer drug or dietary interactions, and as yet have no significant toxicities. AKR-501/E5501 is an orally active small molecule with no dietary interactions and encouraging laboratory data in vitro and in augmenting human platelet counts in mice engrafted with human progenitor cells [115,116]. Human studies indicate no adverse events with a dose-dependant rise in platelet counts.…”

Section: Future Perspectives and Other Tpo Agonists In Developmentmentioning

confidence: 98%

Immune thrombocytopenia – what are the new treatment options?

Hallam

Newland

2013

Expert Opinion on Biological Therapy

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There is an increasing understanding of the natural history of ITP and an increasing evidence-based approach to the disease and its management. Treatment should be aimed at the patient with a bleeding risk and should minimise the risk of adverse effects while maximising the chances of response. Few, if any, treatments are curative and treatment strategies need to be designed in ITP that manage patients with what can be a life-long condition with periodic relapses.

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Section: Future Perspectives and Other Tpo Agonists In Developmentmentioning

confidence: 98%

Immune thrombocytopenia – what are the new treatment options?

Hallam

Newland

2013

Expert Opinion on Biological Therapy

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“…It is believed to mimic the biological effects of TPO in vitro and in vivo and was shown to increase PC in both animal models and healthy human volunteers. [13][14][15] Like eltrombopag, avatrombopag is thought to bind to the transmembrane domain of the TPO receptor, which is different from the binding site of native TPO and romiplostim.…”

Section: Introductionmentioning

confidence: 99%

A randomized trial of avatrombopag, an investigational thrombopoietin-receptor agonist, in persistent and chronic immune thrombocytopenia

Bussel

Kuter

Aledort

et al. 2014

Blood

120

109

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• Once-daily oral avatrombopag dose-dependently raised PCs over 28 days, with stable counts maintained over a 24-week extension.• Low rates of severe AEs and study drug discontinuations due to AEs occurred despite dose increases in maintenance.Stimulation of platelet production by thrombopoietin-receptor agonists (TPO-RAs) is an effective second-line treatment in immune thrombocytopenia (ITP). This 28-day phase 2 study assigned subjects with ITP of ‡3 months to once-daily oral avatrombopag (2.5, 5, 10, or 20 mg), an investigational nonpeptide TPO-RA active in humans, or placebo; subjects completing randomized treatment could enroll in a 24-week extension study. Of 64 randomized subjects, 13% (avatrombopag 2.5 mg), 53% (5 mg), 50% (10 mg), and 80% (20 mg), vs 0% for placebo, achieved a platelet count (PC) response of ‡50 3 10 9 /L with ‡20 3 10 9 /L increase above baseline at day 28. Fifty-three subjects (83%) entered the extension: 52% and 76% had a durable (PC response at ‡75% of their platelet assessments over the last 14 weeks) and overall (stable response or response at any ‡2 consecutive visits) response, respectively. All subjects experienced ‡1 adverse event (AE) (most commonly fatigue, headache, and epistaxis); 19% (n 5 12) reported ‡1 serious AE; 10 (16%) withdrew due to an AE (5 due to increased PC). Avatrombopag was active and generally well tolerated, with PC response rates and AE incidence comparable with other TPO-RAs. These studies were registered at www.clinicaltrials.gov as #NCT00441090 and

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“…Clinical trials of these agents were discontinued in the United States several years ago (Basser et al, 2002; Li et al, 2001). Since then, a peptide mimetic (romiplostim), and a few non-peptide, small molecule c-Mpl agonists have been developed as alternatives to recombinant TPO (Erickson-Miller et al, 2009; Fukushima-Shintani et al, 2009; Inagaki et al, 2004; Nakamura et al, 2006; Nogami et al, 2008). Among these, eltrombopag (SB-497115) is an oral thrombopoietic receptor agonist, which interacts with the transmembrane domain of the c-Mpl .…”

Section: Introductionmentioning

confidence: 99%

Eltrombopag, a thrombopoietin receptor agonist, enhances human umbilical cord blood hematopoietic stem/primitive progenitor cell expansion and promotes multi-lineage hematopoiesis

Sun¹,

Tsai²,

Nowak³

et al. 2012

Stem Cell Research

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Umbilical cord blood (UCB) transplantation has emerged as promising therapy, but is challenged by scarcity of stem cells. Eltrombopag is a non-peptide, thrombopoietin (TPO) receptor agonist, which selectively activates c-Mpl in humans and chimpanzees. We investigated eltrombopag’s effects on human UCB hematopoietic stem cell (HSC) and hematopoietic progenitor cell (HPC) expansion, and its effects on hematopoiesis in vivo. Eltrombopag selectively augmented the expansion of human CD45+, CD34+, and CD41+ cells in bone marrow compartment without effects on mouse bone marrow cells in the NOD/SCID mice xenotransplant model. Consequently, eltrombopag increased peripheral human platelets and white blood cells. We further examined effects in the STAT and AKT signaling pathways in serum-free cultures. Eltrombopag expanded human CD34+CD38−, CD34+, and CD41+ cells. Both eltrombopag and recombinant human TPO (rhTPO) induced phosphorylation of STAT5 of CD34+CD41−, CD34−CD41+, and CD34−CD41− cells. rhTPO preferentially induced pSTAT3, pAKT, and more pSTAT5 in CD34−C41+ cells, while eltrombopag had no effects on pSTAT3. In conclusion, eltrombopag enhanced expansion of HSCs/HPCs of human UCB in vivo and in vitro, and promoted multi-lineage hematopoiesis through the expansion of bone marrow HSCs/HPCs of human UCB in vivo. Eltrombopag differed somewhat from rhTPO in the signal transduction pathways by favoring earlier HSC/HPC populations.

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AKR‐501 (YM477) a novel orally‐active thrombopoietin receptor agonist

Cited by 62 publications

References 24 publications

Immune thrombocytopenia – what are the new treatment options?

Immune thrombocytopenia – what are the new treatment options?

A randomized trial of avatrombopag, an investigational thrombopoietin-receptor agonist, in persistent and chronic immune thrombocytopenia

Eltrombopag, a thrombopoietin receptor agonist, enhances human umbilical cord blood hematopoietic stem/primitive progenitor cell expansion and promotes multi-lineage hematopoiesis

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