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International Society of Thrombosis and Haemostasis Annual Congress (ISTH 2024) | 2024 |News | Updates | iPharmaCeter

Takeda Unveils Promising Phase 2b Study Results for Mezagitamab in Treating Primary Immune Thrombocytopenia

Takeda has revealed findings from its Phase 2b study of mezagitamab (TAK-079), showcasing its potential to revolutionize the treatment of primary immune thrombocytopenia (ITP).

Patients treated with mezagitamab exhibited swift and sustained increases in platelet counts that lasted up to eight weeks post-treatment, continuing through to week 16.

Takeda is planning to commence a global Phase 3 trial for mezagitamab in ITP in the latter half of FY2024.




The Phase 2b trial, randomized, double-blind, and placebo-controlled, assessed the safety, tolerability, and efficacy of mezagitamab in patients with chronic or persistent ITP, a rare disorder where accelerated platelet destruction leads to significantly reduced platelet counts and increased bleeding risks.



The TAK-079-1004 study (NCT04278924) explored three doses of subcutaneous mezagitamab (100mg, 300mg, and 600mg) compared to a placebo, administered weekly for eight weeks followed by more than eight weeks of safety follow-up. The primary endpoint focused on the percentage of patients experiencing Grade 3 or higher treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and adverse events (AEs) leading to discontinuation of mezagitamab. Secondary endpoints evaluated various platelet response metrics, including complete, clinically meaningful, and hemostatic platelet responses.


The trial results showed that mezagitamab significantly improved platelet response at all tested doses compared to placebo. The highest platelet response rates were observed with the 600mg dose of mezagitamab, where 81.8% achieved complete platelet response, 90.9% achieved clinically meaningful platelet response, and 100% achieved hemostatic platelet response.

Moreover, fewer patients treated with mezagitamab reported disease-related bleeding adverse events compared to those on placebo (17.9% versus 46.2%). The safety and tolerability profile of mezagitamab was consistent with prior studies, with no new safety signals.



Mezagitamab is a fully human immunoglobulin IgG1 monoclonal antibody that targets CD38-expressing cells, such as plasmablasts, plasma cells, and natural killer cells, leading to their depletion. This therapy aims to provide rapid and sustained platelet count improvements, restoring them to functional levels.


These positive outcomes from the Phase 2b study pave the way for further clinical development of mezagitamab, with Takeda set to launch a global Phase 3 trial in ITP patients in the second half of FY2024.

 

Mim8 Shows Promising Results in Reducing Bleeding Rates in Hemophilia A Patients

FRONTIER2 Trial Data Presented at ISTH 2024 Demonstrates Significant Benefits of Mim8

Novo Nordisk has shared promising results from the phase 3 FRONTIER2 trial, which included 254 adults and adolescents aged 12 and older with hemophilia A, both with and without inhibitors. This trial evaluated the effectiveness of once-weekly and once-monthly prophylactic treatments with the investigational drug Mim8.



In the trial subgroup without prior prophylactic treatment, Mim8 achieved remarkable reductions in the mean annualized bleeding rate (ABR) of treated bleeds, with a 97.1% reduction for the once-weekly regimen and a 98.7% reduction for the once-monthly regimen. These regimens resulted in mean ABRs of 0.45 and 0.20 bleeds per patient-year, respectively, compared to a mean ABR of 15.75 for patients who did not receive prophylaxis. Impressively, 85.7% of patients on the weekly regimen and 95.0% on the monthly regimen experienced no bleeds.




For participants with prior coagulation factor prophylaxis, Mim8 also demonstrated superior outcomes. The mean ABR was reduced by 48% with the weekly regimen and by 42.6% with the monthly regimen. Specifically, the mean ABRs were 2.51 bleeds per patient-year for the weekly regimen (compared to 4.83 with previous prophylaxis) and 1.78 bleeds per patient-year for the monthly regimen (compared to 3.10 with previous prophylaxis). Additionally, zero bleeds were observed in 66.3% of those on the weekly regimen and 65.3% on the monthly regimen.



Mim8, a next-generation Factor VIIIa (FVIIIa) mimetic bispecific antibody, is designed to provide sustained hemostasis. It is being developed for weekly or monthly prophylactic treatment for hemophilia A patients, including those with inhibitors. Administered subcutaneously, Mim8 bridges Factor IXa and Factor X, effectively replacing the missing FVIII and restoring the body's thrombin generation capacity to facilitate blood clotting. In this trial, Mim8 was well-tolerated with no significant safety concerns, including thromboembolic events or serious adverse effects, consistent with previous studies.


Hemophilia is a rare genetic bleeding disorder that affects the body’s ability to form blood clots. Approximately 1,125,000 people worldwide are estimated to have hemophilia, with hemophilia A accounting for 80-85% of cases. Due to its X-linked recessive inheritance pattern, hemophilia predominantly affects males, with about 88% of diagnosed cases being male. Hemophilia A is caused by a deficiency or defect in clotting Factor VIII (FVIII). Some patients with hemophilia develop inhibitors, which are immune responses that neutralize the effectiveness of replacement therapies, affecting up to 30% of those with severe hemophilia A.



About the FRONTIER2 Clinical Trial

The FRONTIER2 trial is part of a broader phase 3 program investigating Mim8 as a prophylactic treatment for hemophilia A patients, with or without inhibitors. The program includes multiple trials: FRONTIER2, FRONTIER3, FRONTIER4, and FRONTIER5.


FRONTIER2 is a 52-week efficacy and safety trial comparing weekly and monthly Mim8 regimens against no prophylaxis and previous coagulation factor prophylaxis over a 26-52 week period in patients aged 12 and older with hemophilia A. The main 26-week phase is complete, with a 26-week extension phase ongoing.


Participants were divided into five treatment groups:

  • For those who had previously received on-demand treatment:

  • Group 1: Continued without prophylaxis and did not receive Mim8 during the main phase.

  • Group 2a: Received once-weekly Mim8 prophylaxis.

  • Group 2b: Received once-monthly Mim8 prophylaxis.

  • For those with prior prophylaxis treatment:

  • Standard coagulation factor prophylaxis was recorded over a 26-52 week run-in period.

  • Group 3: Randomized to receive once-weekly Mim8 prophylaxis.

  • Group 4: Randomized to receive once-monthly Mim8 prophylaxis.




 

Sanofi Strengthens Hemophilia Leadership with New Findings for ALTUVIIIO and Fitusiran


Sanofi is bolstering its position in hemophilia treatment with fresh data on ALTUVIIIO and fitusiran. The company’s commitment to pioneering top-tier treatments for rare blood disorders is highlighted by seven oral presentations covering its hemophilia portfolio.


Interim results from the XTEND-ed phase 3 study reveal that ALTUVIIIO continues to offer highly effective bleed protection with once-weekly doses. Additionally, new findings from the ATLAS phase 3 study underscore fitusiran’s potential as a prophylactic treatment for individuals with hemophilia A or B, regardless of inhibitor status. The US FDA has accepted a New Drug Application for fitusiran, with a review date set for March 28, 2025.



Sanofi will showcase new data at the 32nd Congress of the International Society on Thrombosis and Haemostasis (ISTH) in Bangkok, Thailand, from June 22-26, 2024. Presentations on ALTUVIIIO [Antihemophilic Factor (Recombinant), Fc-VWF-XTEN Fusion Protein] will include long-term interim phase 3 data focusing on efficacy and safety in both adults and children with severe hemophilia A. Data on fitusiran will cover surgical experiences and long-term safety from the ATLAS phase 3 clinical program involving both hemophilia A and B patients, with or without inhibitors.





ALTUVIIIO Highlights

Interim analyses from the XTEND-ed phase 3 study indicate that ALTUVIIIO provides sustained bleed prevention in both adults and children, maintaining or improving joint health over two years, and showing a consistent safety profile. Key presentations include:

  • Clinical Outcomes in Adults and Adolescents: Patients (≥12 years) from the XTEND-1 trial reported mean annualized bleed rates (ABR) of 0.72 (SD=1.26) for arm A and 0.42 (SD=0.89) for arm B, with no factor VIII inhibitors detected.

  • Joint Health Outcomes: Continued use of ALTUVIIIO (50 IU/kg) improved or maintained joint health in adults and adolescents over two years.

  • Children's Long-term Outcomes: In previously treated children, the mean ABR was 0.70 (SD=1.27), comparable to rates observed in the XTEND-Kids study.

Additionally, ALTUVIIIO has shown effective bleed protection during perioperative management in patients undergoing major surgeries.



Fitusiran Insights

The latest analyses for fitusiran indicate its potential as a groundbreaking treatment offering reliable bleed protection for hemophilia A or B patients, with or without inhibitors. Data on perioperative management show that fitusiran enables safe and effective major surgeries.

  • Surgical Experience: Major surgeries were successfully performed on patients using fitusiran, following bleed management protocols, irrespective of inhibitor status.

  • Safety Profile: Fitusiran’s revised antithrombin-based dosing regimen (AT-DR) has led to reduced thrombotic events and lower incidences of liver enzyme elevation and gallbladder issues.

The findings further support earlier phase 3 study results showing that maintaining antithrombin activity levels between 15-35% provides effective bleed control and enhances the treatment’s benefit-risk profile.



Regulatory Developments

Regulatory submissions for fitusiran have been made in China, Brazil, and the US, with a US FDA target action date of March 28, 2025. The FDA granted fitusiran Breakthrough Therapy Designation for hemophilia B with inhibitors in December 2023.


About ALTUVIIIO

ALTUVIIIO [Antihemophilic Factor (Recombinant), Fc-VWF-XTEN Fusion Protein] is a high-sustained factor VIII therapy, designed for once-weekly prophylactic use in hemophilia A patients. It offers extended protection from bleeds and has a longer half-life compared to standard factor VIII therapies, breaking through the von Willebrand factor ceiling that limits other treatments. ALTUVIIIO is approved in the US, Taiwan, Japan, and recently by the European Commission under the name Altuvoct.


About the XTEND-ed Study

The XTEND-ed phase 3 study (NCT04644575) evaluates the long-term efficacy and safety of ALTUVIIIO (50 IU/kg) in severe hemophilia A patients. It includes participants from previous phase 3 studies, encompassing both adult and adolescent patients from the XTEND-1 study and children from the XTEND-Kids study. Participants received ALTUVIIIO prophylaxis over 100 exposure days, combining the initial and extension study periods.

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