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Acquired thrombotic thrombocytopenic purpura (aTTP) is a rare immune-mediated thrombotic microangiopathy.
After plasma exchange therapy (TPE) and immunosuppressive therapy, its acute mortality rate is still 8%-20%.
Up to 42% of patients will develop refractory disease and may lead to a poor prognosis.
Therefore, targeted quick-acting treatments are still needed to prevent poor prognosis and early death.
Caplacizumab is a humanized bivalent anti-von Willebrand factor (vWF) nanobody that can block the interaction between vWF multimers and platelets.
The TITAN Phase 2 study evaluated the efficacy and safety of caplacizumab in patients with aTTP.
Patients were randomly assigned to receive subcutaneous caplacizumab (10 mg per day) or placebo during plasma exchange and 30 days later.
The primary endpoint is the time to normalization of the platelet count.
A total of 75 patients received randomization (36 in the caplacizumab group and 39 in the placebo group).
Compared with the placebo group, patients in the caplacizumab group had a significantly shorter time to remission (median time reduced by 39%, p=0.
005).
Three patients in the caplacizumab group got worse, and 11 patients in the placebo group got worse.
Most of the bleeding-related adverse events (AE) were mild to moderate, and the caplacizumab group was more common than the placebo group (54% vs 38%).
The incidence of other AEs was similar between the two groups.
The HERCULES Phase 3 study is a double-blind, randomized, multi-center controlled study that evaluated the efficacy and safety of caplacizumab in patients with aTTP.
A total of 145 patients with aTTP were randomized to receive caplacizumab (10 mg intravenously before the first plasma exchange, then 10 mg subcutaneously every day until 30 days after the last plasma exchange) or placebo treatment during plasma exchange.
The main study endpoint is the time to normalization of platelet counts.
108 patients completed the study.
The median time of platelet count normalization in the Caplacizumab group was shorter than that in the placebo group (2.
69 days [95% CI: 1.
89-2.
83] vs 2.
88 days [95% CI: 2.
68-3.
56], P=0.
01).
The most common AE was mucosal and skin bleeding.
65% of patients in the caplacizumab group and 48% of patients in the placebo group had mucosal and skin bleeding.
Both the placebo-controlled Phase 2 TITAN study and the Phase 3 HERCULES study demonstrated the efficacy and safety of Caplacizumab in the treatment of TTP.
Recently, the researchers conducted a comprehensive analysis of the TITAN study and the HERCULES study to evaluate the possible undiscovered efficacy and safety results of caplacizumab in the treatment of aTTP.
Research methods In addition to TPE and immunosuppressive treatment, participants were randomly assigned to receive Caplacizumab or placebo treatment.
During TPE treatment, 30 days after TPE treatment was stopped in the TITAN study, and 30 to 58 days after TPE treatment was stopped in the HERCULES study, The treatment is extended up to 4 weeks to resolve autoimmune diseases (such as ADAMTS13<10%).
The comprehensive analysis included all randomly assigned participants (intent-to-treat [ITT] population) in the two studies.
The time to remission of the platelet count (primary endpoint) was evaluated during the blinded study.
Secondary endpoints include the time for organ damage indicators to return to normal, TPE treatment time, TTP-related mortality, TTP recurrence rate, and the incidence of major thromboembolic events (MTE) that occurred during ≥1 treatment period, and during blind treatment and The recurrence of TTP during the entire study period and the occurrence of refractory TTP as defined by international consensus.
The comprehensive safety analysis included all participants who received ≥1 dose of study medication.
Research Results and Discussion This comprehensive analysis of 220 participants in the TITAN and HERCULES studies (108 in the caplacizumab group; 112 in the placebo group) provides information on the benefits of caplacizumab in reducing mortality and refractory diseases in patients with aTTP New evidence of incidence and no new safety issues.
During the treatment period, compared with placebo, the number of patients who died (0 vs 4; P<0.
05) and refractory TTP (0 vs 8; P<0.
01; see Table 1) were significantly reduced with Caplacizumab (time of death from treatment 7 to 11 days after the start).
One patient in the Caplacizumab group and one patient in the placebo group died outside the treatment period.
Researchers believe that all deaths are related to TTP.
Table 1 Comprehensive efficacy endpoints of the ITT population A real-world study showed that compared with the historical cohort, the combined incidence of death and refractory disease in aTTP patients receiving first-line caplacizumab, TPE, and immunosuppressive therapy was significantly reduced (2.
2% vs.
12.
2%; P=0.
01), reaching the main endpoint of the study.
Overall, these data consistently highlight the significant impact of caplacizumab treatment on mortality and the incidence of refractory diseases.
Consistent with the results of the TITAN study and the HERCULES study, caplacizumab can significantly shorten the time for platelet count normalization (HR: 1.
65; 95% CI: 1.
24-2.
20; P<0.
001). In addition, caplacizumab significantly reduced the normalization time of organ damage marker lactate dehydrogenase (HR: 1.
43; 95% CI: 1.
04-1.
96; P=0.
03), and accelerated troponin (HR: 1.
32; 95% CI : 0.
86-2.
04; P=0.
29) and serum creatinine (HR: 1.
68; 95% CI: 0.
89-3.
15; P=0.
14) recovery time.
During the entire treatment period, the median TPE treatment time of caplacizumab and placebo was reduced by 33.
3% (5.
0 days [1-35 days] and 7.
5 days [2-46 days], respectively).
Compared with placebo, caplacizumab significantly reduced the combined incidence of TTP-related death, disease deterioration, or MTE during treatment (a decrease of 72.
6%; P<0.
001; Table 1).
Compared with placebo, caplacizumab reduced the incidence of MTE by 40.
8% (7.
4% vs 12.
5%).
During the blind treatment, the incidence of deterioration in the Caplacizumab group was reduced by 84.
0% (6 vs 39; P<0.
001; Table 1).
In the TITAN study and the HERCULES study, compared with the placebo group, the number of relapses in the Caplacizumab group was higher (14 vs 0).
The recurrence of 13/14 patients occurred within 10 days of discontinuing caplacizumab, highlighting the importance of continuing caplacizumab treatment.
Importantly, the total recurrence (worsening or recurrence) rate in the caplacizumab group decreased by 49.
4% (19 vs 39; P<0.
01; Table 1) during the entire study period of the comprehensive analysis.
The comprehensive safety analysis included a total of 216 participants (106 in the caplacizumab group; 110 in the placebo group).
In the Caplacizumab group and the placebo group, 40.
6% (43/106) and 45.
5% (50/11) had TPE-related adverse events (TEAE) during treatment; the incidence of serious TPE-related TEAEs were respectively 3.
8% (4/106) and 6.
4% (7/110).
Bleeding events are the most common AE in caplacizumab treatment.
Bleeding events are mainly mucosal and skin bleeding (nasal bleeding and gum bleeding), most of which are mild to moderate and self-limiting.
Severe TEAEs are rare, and no new safety issues have been discovered.
Summary This comprehensive analysis provides some important new insights that can complement the results from the HERCULES and TITAN studies.
Caplacizumab treatment can prevent the death of aTTP patients and the occurrence of refractory diseases, and is generally well tolerated.
AEs are mainly manifested as mild mucosal and skin bleeding.
This comprehensive analysis of a large population and recent real-world research data further shows that Caplacizumab may be able to solve the serious unmet clinical needs of aTTP.
Reference source: Flora Peyvandi, Spero Cataland, Marie Scully, et al.
Caplacizumab prevents refractoriness and mortality in acquired thrombotic thrombocytopenic purpura: integrated analysis.
Blood Adv (2021) 5 (8): 2137-2141.
Stamp "read the original text", we improve together
After plasma exchange therapy (TPE) and immunosuppressive therapy, its acute mortality rate is still 8%-20%.
Up to 42% of patients will develop refractory disease and may lead to a poor prognosis.
Therefore, targeted quick-acting treatments are still needed to prevent poor prognosis and early death.
Caplacizumab is a humanized bivalent anti-von Willebrand factor (vWF) nanobody that can block the interaction between vWF multimers and platelets.
The TITAN Phase 2 study evaluated the efficacy and safety of caplacizumab in patients with aTTP.
Patients were randomly assigned to receive subcutaneous caplacizumab (10 mg per day) or placebo during plasma exchange and 30 days later.
The primary endpoint is the time to normalization of the platelet count.
A total of 75 patients received randomization (36 in the caplacizumab group and 39 in the placebo group).
Compared with the placebo group, patients in the caplacizumab group had a significantly shorter time to remission (median time reduced by 39%, p=0.
005).
Three patients in the caplacizumab group got worse, and 11 patients in the placebo group got worse.
Most of the bleeding-related adverse events (AE) were mild to moderate, and the caplacizumab group was more common than the placebo group (54% vs 38%).
The incidence of other AEs was similar between the two groups.
The HERCULES Phase 3 study is a double-blind, randomized, multi-center controlled study that evaluated the efficacy and safety of caplacizumab in patients with aTTP.
A total of 145 patients with aTTP were randomized to receive caplacizumab (10 mg intravenously before the first plasma exchange, then 10 mg subcutaneously every day until 30 days after the last plasma exchange) or placebo treatment during plasma exchange.
The main study endpoint is the time to normalization of platelet counts.
108 patients completed the study.
The median time of platelet count normalization in the Caplacizumab group was shorter than that in the placebo group (2.
69 days [95% CI: 1.
89-2.
83] vs 2.
88 days [95% CI: 2.
68-3.
56], P=0.
01).
The most common AE was mucosal and skin bleeding.
65% of patients in the caplacizumab group and 48% of patients in the placebo group had mucosal and skin bleeding.
Both the placebo-controlled Phase 2 TITAN study and the Phase 3 HERCULES study demonstrated the efficacy and safety of Caplacizumab in the treatment of TTP.
Recently, the researchers conducted a comprehensive analysis of the TITAN study and the HERCULES study to evaluate the possible undiscovered efficacy and safety results of caplacizumab in the treatment of aTTP.
Research methods In addition to TPE and immunosuppressive treatment, participants were randomly assigned to receive Caplacizumab or placebo treatment.
During TPE treatment, 30 days after TPE treatment was stopped in the TITAN study, and 30 to 58 days after TPE treatment was stopped in the HERCULES study, The treatment is extended up to 4 weeks to resolve autoimmune diseases (such as ADAMTS13<10%).
The comprehensive analysis included all randomly assigned participants (intent-to-treat [ITT] population) in the two studies.
The time to remission of the platelet count (primary endpoint) was evaluated during the blinded study.
Secondary endpoints include the time for organ damage indicators to return to normal, TPE treatment time, TTP-related mortality, TTP recurrence rate, and the incidence of major thromboembolic events (MTE) that occurred during ≥1 treatment period, and during blind treatment and The recurrence of TTP during the entire study period and the occurrence of refractory TTP as defined by international consensus.
The comprehensive safety analysis included all participants who received ≥1 dose of study medication.
Research Results and Discussion This comprehensive analysis of 220 participants in the TITAN and HERCULES studies (108 in the caplacizumab group; 112 in the placebo group) provides information on the benefits of caplacizumab in reducing mortality and refractory diseases in patients with aTTP New evidence of incidence and no new safety issues.
During the treatment period, compared with placebo, the number of patients who died (0 vs 4; P<0.
05) and refractory TTP (0 vs 8; P<0.
01; see Table 1) were significantly reduced with Caplacizumab (time of death from treatment 7 to 11 days after the start).
One patient in the Caplacizumab group and one patient in the placebo group died outside the treatment period.
Researchers believe that all deaths are related to TTP.
Table 1 Comprehensive efficacy endpoints of the ITT population A real-world study showed that compared with the historical cohort, the combined incidence of death and refractory disease in aTTP patients receiving first-line caplacizumab, TPE, and immunosuppressive therapy was significantly reduced (2.
2% vs.
12.
2%; P=0.
01), reaching the main endpoint of the study.
Overall, these data consistently highlight the significant impact of caplacizumab treatment on mortality and the incidence of refractory diseases.
Consistent with the results of the TITAN study and the HERCULES study, caplacizumab can significantly shorten the time for platelet count normalization (HR: 1.
65; 95% CI: 1.
24-2.
20; P<0.
001). In addition, caplacizumab significantly reduced the normalization time of organ damage marker lactate dehydrogenase (HR: 1.
43; 95% CI: 1.
04-1.
96; P=0.
03), and accelerated troponin (HR: 1.
32; 95% CI : 0.
86-2.
04; P=0.
29) and serum creatinine (HR: 1.
68; 95% CI: 0.
89-3.
15; P=0.
14) recovery time.
During the entire treatment period, the median TPE treatment time of caplacizumab and placebo was reduced by 33.
3% (5.
0 days [1-35 days] and 7.
5 days [2-46 days], respectively).
Compared with placebo, caplacizumab significantly reduced the combined incidence of TTP-related death, disease deterioration, or MTE during treatment (a decrease of 72.
6%; P<0.
001; Table 1).
Compared with placebo, caplacizumab reduced the incidence of MTE by 40.
8% (7.
4% vs 12.
5%).
During the blind treatment, the incidence of deterioration in the Caplacizumab group was reduced by 84.
0% (6 vs 39; P<0.
001; Table 1).
In the TITAN study and the HERCULES study, compared with the placebo group, the number of relapses in the Caplacizumab group was higher (14 vs 0).
The recurrence of 13/14 patients occurred within 10 days of discontinuing caplacizumab, highlighting the importance of continuing caplacizumab treatment.
Importantly, the total recurrence (worsening or recurrence) rate in the caplacizumab group decreased by 49.
4% (19 vs 39; P<0.
01; Table 1) during the entire study period of the comprehensive analysis.
The comprehensive safety analysis included a total of 216 participants (106 in the caplacizumab group; 110 in the placebo group).
In the Caplacizumab group and the placebo group, 40.
6% (43/106) and 45.
5% (50/11) had TPE-related adverse events (TEAE) during treatment; the incidence of serious TPE-related TEAEs were respectively 3.
8% (4/106) and 6.
4% (7/110).
Bleeding events are the most common AE in caplacizumab treatment.
Bleeding events are mainly mucosal and skin bleeding (nasal bleeding and gum bleeding), most of which are mild to moderate and self-limiting.
Severe TEAEs are rare, and no new safety issues have been discovered.
Summary This comprehensive analysis provides some important new insights that can complement the results from the HERCULES and TITAN studies.
Caplacizumab treatment can prevent the death of aTTP patients and the occurrence of refractory diseases, and is generally well tolerated.
AEs are mainly manifested as mild mucosal and skin bleeding.
This comprehensive analysis of a large population and recent real-world research data further shows that Caplacizumab may be able to solve the serious unmet clinical needs of aTTP.
Reference source: Flora Peyvandi, Spero Cataland, Marie Scully, et al.
Caplacizumab prevents refractoriness and mortality in acquired thrombotic thrombocytopenic purpura: integrated analysis.
Blood Adv (2021) 5 (8): 2137-2141.
Stamp "read the original text", we improve together
