akr-501 and Purpura--Thrombocytopenic--Idiopathic

The aim of the study was to conduct a network meta-analysis to assess the efficacy and incidence of treatment-related adverse events (TRAEs) of eltrombopag, romiplostim, avatrombopag, recombinant human thrombopoietin (rhTPO), and hetrombopag for adult immune thrombocytopenia (ITP).. Randomized controlled trials (RCTs) of the five therapies from inception to June 1, 2022, were included. The efficacy outcome was the rate of platelet response, defined as the achievement of platelet counts above 50 × 109/L. Pairwise odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. The surface under the cumulative ranking (SUCRA) was used to rank the included therapies for each outcome.. In total, 1,360 participants were analyzed in 14 eligible RCTs. All of the therapies showed a significantly better platelet response than the placebo, and avatrombopag (OR, 7.42; 95% CI: 1.74-31.69) and rhTPO (OR, 3.86; 95% CI: 1.62-9.18) were better than eltrombopag. Regarding TRAEs, no significant differences were found between patients receiving eltrombopag, romiplostim, and avatrombopag. Avatrombopag carried the highest platelet response rate with SUCRA value of 87.5, and carried the least TRAEs risk with SUCRA value of 37.0.. These findings indicated that avatrombopag appeared to be the optimal choice as the second-line therapy for adult ITP.

Topics: Adult; Benzoates; Humans; Hydrazines; Incidence; Network Meta-Analysis; Purpura, Thrombocytopenic, Idiopathic; Randomized Controlled Trials as Topic; Receptors, Fc; Receptors, Thrombopoietin; Recombinant Fusion Proteins; Thrombocytopenia; Thrombopoietin

In this review, the recently approved drugs avatrombopag and fostamatinib, which were not extensively covered within 2019 international recommendations for ITP, will be discussed in some detail. Avatrombopag appears more convenient than eltrombopag as it does not require dietary restrictions or subcutaneous administration like romiplostim. However, data on quality of life (QoL) are lacking and the rate of thromboembolic events in exposed patients is not negligible. Efficacy of fostamatinib, an inhibitor of macrophagic activity, is supported by placebo-controlled trials in patients refractory to several therapies, including TPO-RA. While hypertension and diarrhea have been reported, only one minor thrombotic event occurred in 146 exposed patients. In addition, several new treatment combinations and new agents entered clinical investigation in recent years. In a UK trial, combining mycophenolate mofetil with corticosteroids as first line therapy was more effective than corticosteroids alone, but at the cost of worse QoL. No combination, including oseltamivir or all-trans retinoic acid or danazol, resulted in convincing evidence of superior efficacy and safety when used in first or later lines of treatment. Agents targeting specific mechanisms are also discussed: sutimlimab (complement inhibitor); rilzabrutinib (BTK inhibitor) and efgartigimod (modified Fc fragment inhibiting FcRn). Only efgartigimod has completed phase 3 investigation.

Topics: Clinical Trials as Topic; Humans; Purpura, Thrombocytopenic, Idiopathic; Quality of Life; Receptors, Fc; Recombinant Fusion Proteins; Thiazoles; Thrombopoietin

In this paper, we systematically review the efficacy and safety of thrombopoietin receptor agonists (TPORAs) for treatment of persistent and chronic immune thrombocytopenia (ITP) in children and adults.. We searched PubMed, MEDLINE, ScienceDirect, Scopus, EMbase and the Cochrane Library to collect randomized controlled trials (RCTs) of TPO-RAs which including avatrombopag hetrombopag eltrombopag and romiplostim treated persistent and chronic ITP from their earliest records to February 2022.. We included 15 RCTs with a total of 1563 patients. There were ten trials of adults and five trials of children. The results of meta-analysis showed that in adult patients, patients treated with TPO-RAs had longer duration of platelet response, higher platelet response rate, lower use of rescue therapy, and lower incidence of bleeding events, and similar incidence of adverse events compared with placebo. Except for the incidence of any bleeding, the results in children were consistent with those in adults. The network meta-analysis of data on overall platelet response rates in adults showed that avatrombopag was more effective than eltrombopag and hetrombopag.. TPO-RAs has better efficacy and higher safety in the treatment of ITP. And the overall response rate of avatrombopag in adults was higher than that in eltrombopag and hetrombopag.

Topics: Adult; Benzoates; Child; Hemorrhage; Humans; Hydrazines; Purpura, Thrombocytopenic, Idiopathic; Receptors, Thrombopoietin; Recombinant Fusion Proteins

Avatrombopag (Doptelet

Topics: Adult; Animals; Chronic Disease; Humans; Liver Diseases; Purpura, Thrombocytopenic, Idiopathic; Receptors, Thrombopoietin; Thiazoles; Thiophenes; Thrombocytopenia

A network meta-analysis (NMA) was performed to assess the efficacy and safety of avatrombopag, relative to eltrombopag, romiplostim, and fostamatinib, for patients with chronic immune thrombocytopenia (ITP) not responding adequately to corticosteroids.. A systematic search of publication and clinical trial databases was conducted to identify relevant randomized controlled trials (RCTs) and observational studies. Data from eligible studies were extracted and analyzed in a Bayesian framework using relative effect sizes vs placebo. Outcomes included durable platelet response; need for rescue therapy; reduction in use of concomitant ITP medication; incidence of any or World Health Organization (WHO) grade 2-4 bleeding events, and any adverse events. Results were reported as odds ratios or incidence rate ratios (IRR) with 95% credible intervals (CrIs).. The NMA included seven phase 3 RCTs. Compared with placebo, avatrombopag was associated with statistically significant improvements in durable platelet response, reduction in use of concomitant ITP medication, and incidence of any bleeding events. Statistically significant differences vs placebo were also observed for durable platelet response and need for rescue therapy (eltrombopag, romiplostim, and fostamatinib); reduction in use of concomitant ITP medication (eltrombopag and romiplostim); incidence of any bleeding events (fostamatinib); and incidence of WHO grade 2-4 bleeding events (romiplostim and fostamatinib). No statistically significant differences were observed for any adverse events. Avatrombopag was associated with a statistically significant lower incidence of any bleeding events vs eltrombopag (IRR 0.38 [95% CrI 0.19, 0.75]) and romiplostim (IRR 0.38 [95% Crl 0.17, 0.86]); no other between-treatment differences were observed.. In this NMA, avatrombopag significantly increased the chance of achieving durable platelet response and reducing the use of concomitant ITP medication vs placebo, and significantly reduced the incidence of any bleeding events compared with placebo, eltrombopag, and romiplostim. The study aims to help guide clinicians managing patients with chronic ITP and insufficient response to previous treatment.

Topics: Benzoates; Humans; Network Meta-Analysis; Purpura, Thrombocytopenic, Idiopathic; Randomized Controlled Trials as Topic; Recombinant Fusion Proteins; Thiazoles; Thiophenes

Immune thrombocytopenia is a haematological, autoimmune disorder characterized by elevated platelet demolition due to the presence of antiplatelet autoantibodies derived from B cells and to an irregular, deficient process of platelets production in bone marrow. In this review, after a brief presentation of 'old' strategies used nowadays yet, we focused on new drugs used in the treatment of immune thrombocytopenia and their mechanism of action and posology, basing on the last scientific literature. The observation that CoViD-19 can be associated with immune thrombocytopenia is also put in evidence. Particular attention will be dedicated on the concept that the ideal treatment should represent a solution not only for the failure of normal processes of production and survival of platelets, but also it should improve quality of life of patients, with minimum adverse events. Anyway, despite enormous advances of the last years, further investigations are necessary in order to define scrupulously long-term efficacy of new molecules proposed.

Topics: Aminopyridines; Antibodies, Monoclonal, Humanized; COVID-19; Histocompatibility Antigens Class I; Humans; Immunosuppressive Agents; Morpholines; Protein Kinase Inhibitors; Purpura, Thrombocytopenic, Idiopathic; Pyrimidines; Receptors, Fc; Receptors, Thrombopoietin; SARS-CoV-2; Syk Kinase; Thiazoles; Thiophenes

Topics: Animals; Blood Platelets; Clinical Trials as Topic; Humans; Platelet Count; Purpura, Thrombocytopenic, Idiopathic; Receptors, Thrombopoietin; Thiazoles; Thiophenes; United States; United States Food and Drug Administration

Thrombopoietin (TPO) is the major regulator of both megakaryopoiesis and platelet production. TPO is a glycoprotein primarily produced in the liver. TPO, when binding to its receptor (c-Mpl), triggers a signaling cascade that leads to the differentiation and proliferation of megakaryocytes, with a concomitant increase in platelets. The cloning and characterization of TPO in 1994 led to the production of a full length, glycosylated recombinant human TPO (rhTPO) and a pegylated, truncated protein (PEGrHuMGDF). These first-generation TPO drugs stimulated megakaryocyte production and increased platelet counts in healthy volunteers. Successful clinical trials followed in cancer patients, patients with immune thrombocytopenic purpura (ITP), and cancer patients receiving non-myeloablative chemotherapy. Neither rhTPO nor PEG-rHuMGDF raised platelet counts in myeloablated chemotherapy patients, probably due to a lack of megakaryocyte progenitor cells in their bone marrow. Unfortunately, neutralizing antibodies developed against TPO in 13 subjects who had received multiple injections of PEG-rHuMGDF. The resulting thrombocytopenia in these individuals ended all clinical trials with both drugs. A second generation of TPO growth factors have been developed and are in clinical trials. Researchers screened peptide libraries to find random, unrelated peptides that could stimulate TPO-dependent cell lines without also causing neutralizing antibody production. These peptides were then conjugated to various carrier molecules to increase their half-lives. This strategy led to the synthesis of romiplostim (AMG-531), with 2 sets of identical peptides linked to the Fc moiety of an Immunoglobulin G (IgG) antibody. This TPO peptide mimetic has shown success in clinical trials with healthy volunteers and individuals with ITP. No neutralizing antibodies have developed against AMG-531, however some thromboembolic events have occurred in high risk patients, and potentially reversible increases in bone marrow reticulin have been reported. Other TPO nonpeptide mimetics have been created by using a similar strategy with libraries of nonpeptide molecules that can stimulate TPO-dependent cell lines. Eltrombopag and AKR-501 are two drugs of this type that have shown positive results in clinical trials. In addition, antibodies that can stimulate the c-Mpl receptor are being engineered to act as potent TPO agonists. These and other drugs in preclinical development represent a new line of the

Topics: Animals; Carrier Proteins; Humans; Purpura, Thrombocytopenic, Idiopathic; Receptors, Fc; Recombinant Fusion Proteins; Thiazoles; Thiophenes; Thrombopoiesis; Thrombopoietin

Topics: Humans; Platelet Count; Purpura, Thrombocytopenic, Idiopathic; Thiazoles; Thrombocytopenia

Topics: Benzoates; Humans; Hydrazines; Platelet Count; Purpura, Thrombocytopenic, Idiopathic

Topics: Double-Blind Method; Female; Humans; Male; Purpura, Thrombocytopenic, Idiopathic; Receptors, Thrombopoietin; Thiazoles; Thiophenes

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 × 10(9)/L with ≥20 × 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 = 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 #NCT00625443.

Topics: Administration, Oral; Adult; Aged; Chronic Disease; Dose-Response Relationship, Drug; Double-Blind Method; Drugs, Investigational; Epistaxis; Fatigue; Female; Headache; Humans; Male; Middle Aged; Platelet Count; Purpura, Thrombocytopenic, Idiopathic; Receptors, Thrombopoietin; Thiazoles; Thiophenes; Time Factors; Treatment Outcome

Topics: Adult; Humans; Platelet Count; Purpura, Thrombocytopenic, Idiopathic; Receptors, Thrombopoietin; Recombinant Fusion Proteins; Thrombocytopenia; Thrombopoietin

We present a case of a 30-year-old man suffering from chronic refractory immune thrombocytopenia (ITP) from early childhood. The patient was treated with all the therapeutic methods available in Poland, without platelet response: corticosteroids, intravenous immunoglobulins, splenectomy, cyclophosphamide, vinblastine, azathioprine, mycophenolate mofetil, rituximab, ciclosporin A, romiplostim, and eltrombopag. He continued to function persistently with deep thrombocytopenia, symptoms of hemorrhagic diathesis, and one episode of spontaneous subarachnoid bleeding. In April 2022, at the age of 29, the patient received avatrombopag. Within 4 weeks of starting avatrombopag 20 mg daily for 2 weeks and then 40 mg daily, he reached a platelet (PLT) count of 67 x 10 9 /l. In the next month, platelets fell below 30 x 10 9 /l, but subsequently the count increased to 47 x 10 9 /l, then to 52 x 10 9 /l, and remained stable. The symptoms of cutaneous hemorrhage diathesis have resolved completely since avatrombopag was introduced and did not reappear despite the decrease in PLT count.

Topics: Adult; Child, Preschool; Humans; Male; Platelet Count; Purpura, Thrombocytopenic, Idiopathic; Thiazoles; Thrombocytopenia

Multiple agents are available for the management of chronic immune thrombocytopenia (ITP), including thrombopoietin-receptor agonists (TPO-RAs), rituximab, and fostamatinib. Although TPO-RAs are often selected as treatments for chronic ITP, when choosing between the TPO-RAs, clinicians must balance safety profile, dosing restrictions, and method of administration incorporating patient preference.. We provide an overview of the thrombopoietin receptor agonists with a particular focus on avatrombopag, the newest agent in this class. In phase II and III clinical trials, avatrombopag was shown to offer durable improvement in platelet counts. We also include recent real-world evidence describing avatrombopag effectiveness in patients with poor response to prior treatments (including other TPO-RAs).. Compared with other TPO-RAs used to treat ITP, avatrombopag offers practical oral dosing with a single pill strength, does not require long-term dietary restrictions, and has no warning for hepatotoxicity. It is frequently effective after use of other TPO-RAs in ITP. The primary downside with avatrombopag use at present is the lack of longer-term safety data in ITP that presently exists for romiplostim and eltrombopag.

Topics: Humans; Purpura, Thrombocytopenic, Idiopathic; Receptors, Thrombopoietin; Recombinant Fusion Proteins; Thiazoles; Thiophenes

BACKGROUND First-line treatments for patients with immune thrombocytopenia include corticosteroids, intravenous immunoglobulin, and anti-D. These may be followed by second- and third-line options, including thrombopoietin receptor agonists and the tyrosine kinase inhibitor fostamatinib. These treatments have different mechanisms and divergent adverse event profiles. We show that fostamatinib-associated adverse events can be mitigated with fostamatinib dose reduction and the introduction of avatrombopag, and that response can be maintained with avatrombopag monotherapy. CASE REPORT A 61-year-old woman with a history of chronic refractory immune thrombocytopenia since 2006 had previously received steroids, rituximab, splenectomy, and eltrombopag without achieving platelet count stability. The patient reported flu-like symptoms in February 2020, with platelet counts ranging from 25×10⁹/L to 50×10⁹/L and isolated occurrences <10×10⁹/L. Platelet counts did not respond to eltrombopag 75 mg/day, 2 courses of rituximab, or multiple courses of prednisone. Within 2 weeks of starting fostamatinib 150 mg twice daily, she reached a platelet count of 523×10⁹/L. She experienced new-onset diarrhea associated with fostamatinib, so the dose was reduced to 75 mg twice daily, and avatrombopag 20 mg/day was added to augment platelet recovery. Platelet levels remained in the supratherapeutic range. She was transitioned to avatrombopag 40 mg/day monotherapy and then 20 mg/day owing to continued supratherapeutic platelet counts. CONCLUSIONS Avatrombopag can be used in combination with fostamatinib to augment platelet response and reduce the severity of adverse events associated with fostamatinib, while maintaining adequate therapeutic response in chronic immune thrombocytopenia. Avatrombopag 40 mg/day monotherapy was quite effective in achieving and maintaining high platelet counts.

Topics: Female; Humans; Middle Aged; Platelet Count; Protein Kinase Inhibitors; Purpura, Thrombocytopenic, Idiopathic; Thiazoles; Thiophenes

Topics: Humans; Liver Diseases; Purpura, Thrombocytopenic, Idiopathic; Thiazoles; Thiophenes; Thrombocytopenia

Topics: Benzoates; Dose-Response Relationship, Drug; Female; Hematologic Agents; Humans; Hydrazines; Middle Aged; Platelet Count; Purpura, Thrombocytopenic, Idiopathic; Pyrazoles; Receptors, Fc; Receptors, Thrombopoietin; Recombinant Fusion Proteins; Thiazoles; Thiophenes; Thrombopoietin; Treatment Outcome

Topics: Humans; Purpura, Thrombocytopenic, Idiopathic; Thiazoles; Thiophenes

Predictive biomarkers are needed in immune thrombocytopenia (ITP). Single nucleotide polymorphisms (SNPs) in beta 1 tubulin are potential candidates, as beta 1 tubulin is integral for platelet production and function, and SNPs in beta 1 tubulin have been associated with distinct phenotypes in platelets. We investigated the most prevalent beta 1 tubulin SNP (R307H) as a biomarker in patients with ITP via a retrospective chart review. Allelic frequencies between a group of 191 ITP patients and a healthy control group showed no difference, suggesting no direct aetiological role for the SNP in ITP. However, over similar periods of follow-up, both heterozygote and homozygote minor allele ITP patients were treated with significantly more treatment modalities and had significantly higher risk of failure to immune-modulatory therapies [relative risk (RR) = 1·5, 95% confidence interval (CI) = 1·1-2·1; P = 0·01]; with rituximab, in particular, ITP patients with the SNP experienced a 58% failure rate (RR = 1·6, 95%CI = 1·03-2·5; P = 0·04). Analysis of the absolute immature platelet fraction (A-IPF) as a marker of platelet production showed that SNP patients had significantly higher median A-IPFs compared to non-SNP patients when complete responses were achieved using immune modulatory therapies. The data suggest that the beta 1 tubulin R307H SNP has potential for use as a biomarker in ITP and may affect platelet turnover.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Alleles; Antibodies, Monoclonal, Murine-Derived; Benzoates; Biomarkers; Child; Child, Preschool; Female; Gene Frequency; Genotype; Humans; Hydrazines; Immunologic Factors; Infant; Male; Middle Aged; Phenotype; Platelet Count; Polymorphism, Single Nucleotide; Purpura, Thrombocytopenic, Idiopathic; Pyrazoles; Receptors, Fc; Receptors, Thrombopoietin; Recombinant Fusion Proteins; Retrospective Studies; Rituximab; Thiazoles; Thiophenes; Thrombopoiesis; Thrombopoietin; Treatment Failure; Tubulin