Eimerizumab for the prevention and treatment of hemophilia A: Long-term follow-up results of the HAVEN1-4 study

Patients with hemophilia A (HA) cause spontaneous or traumatic bleeding due to the lack of clotting factor VIII.

The most common bleeding sites include joints, muscles, and soft tissues.
Severe intracranial bleeding can be life-threatening.

Patients who do not receive preventive treatment will experience recurrent joint bleeding, leading to serious long-term complications such as hemophilic arthritis.

However, the preventive infusion of factor FVIII has a large treatment burden (≥2 infusions per week are required, and the infusion is usually affected by poor intravenous access), which affects the patient's treatment compliance.

25%-30% of severe HA patients will form FVIII inhibitors during preventive treatment, which further affects the efficacy of preventive treatment.

 Immexizumab is a bispecific monoclonal antibody that replaces inactivated FVIII by bridging activated FIX and FX to improve the hemostatic effect.

The HAVEN clinical study (HAVEN1: NCT02622321; HAVEN2: NCT02795767; HAVEN3: NCT02847637; HAVEN4: NCT03020160) initially confirmed the efficacy and safety of eimerizumab in adults and children with HA.

In the study, the annual bleeding rate (ABR) of HA patients was significantly reduced, and most (54%-90%) patients did not report bleeding.

 Iimerizumab is the first new type of non-factor therapy approved by the FDA for the preventive treatment of hemophilia, and its long-term safety and effectiveness are worthy of attention.

The results of the long-term efficacy and safety of imitizumab in the treatment of HA in the HAVEN1-4 clinical study have been announced recently.

The main results are summarized as follows for the reference of readers.

The key point is that long-term prophylaxis and treatment of iimerizumab can maintain a low ABR, significantly reduce target joint bleeding, and no new target joint formation.

Iimerizumab has good long-term safety, and no new safety issues and treatment-related deaths have been observed in the long-term follow-up.

Research method The study summarized the long-term follow-up data of the HAVEN1-4 study to evaluate the long-term efficacy and safety of Iimerizumab in the treatment of HA.

The HAVEN1-4 studies are all phase III multicenter, open-label studies.
A brief overview of each study is as follows: The primary endpoint of the HAVEN1-4 study is the treated bleeding rate, and the secondary endpoints include total bleeding rate, spontaneous bleeding rate, Treated joint bleeding rate, treated target joint (joint with ≥3 spontaneous bleeding in 6 months) bleeding rate.

The study also evaluated the proportion of patients with 0 bleeding, the proportion of patients with 0-3 bleeding after treatment, and the proportion of patients with target joint disappearance (≤2 spontaneous or traumatic bleeding in 52 weeks).

Results of the study: HAVEN1-4 study included a total of 401 patients, of which 400 patients were included in the efficacy analysis (1 patient was randomly assigned to the no preventive treatment group and then lost to follow-up), and 399 patients were included in the safety analysis (1 preventive treatment) Patients in the group withdrew from the study before treatment started).

244 patients have now completed the study, of which 242 patients are still receiving eimerizumab treatment.

 The 401 patients included 269 (67.
1%) adult (age ≥18 years) patients and 132 (32.
9%) children and adolescents.

FVIII inhibitors were present in 209 patients (52.
1%), and FVIII inhibitors were not present in 192 patients (47.
9%).

244 patients (61.
0%) had target joints at the time of enrollment, and 8.
0 bleeding events (IQR: 5.
0-15.
0) occurred in the median 24 weeks before enrollment.

 A total of 11 patients in the study discontinued treatment: 4 patients discontinued treatment due to adverse events (AE), 1 patient discontinued treatment due to poor efficacy and severe adverse events (SAE), and 6 patients discontinued treatment due to other reasons (such as loss to follow-up, personal Reason) The treatment was discontinued.

During the long-term follow-up, no other patients discontinued treatment due to adverse events.

The overall treated ABR of patients in the treated bleeding study was 1.
4% (95% CI: 1.
1%-1.
7%).

During the study period, the average treated ABR of patients decreased during each 24-week treatment cycle.

Throughout the study period, the median treated ABR remained at 0%.

During the 121-144 weeks of treatment (the last 24 weeks of treatment), 97.
6% of patients had bleeding times ≤3, and 82.
4% of patients had no bleeding times.

In addition, the efficacy of emeicilizumab has nothing to do with whether the patient has FVIII inhibitors.

Total bleeding Total bleeding includes untreated bleeding and bleeding treated with clotting factor products.

The total ABR of the patients in the study was 2.
6% (95%CI: 2.
2%-3.
1%).

During the study period, the average total ABR of patients decreased in each 24-week treatment cycle, and the number of patients with zero bleeding increased in each 24-week treatment cycle.

During the 121st-144th week of treatment, 97.
6% of the patients had bleeding times ≤3, and 74.
1% of the patients had no bleeding times.

The spontaneous ABR of patients in the spontaneous bleeding study was 0.
6% (95%CI: 0.
4%-0.
8%), and the average spontaneous BAR continued to decrease over time.

Patients in the study had a median spontaneous ABR of 0% during each 24-week treatment cycle.

The proportion of patients without spontaneous bleeding in the study increased, and the proportion during the treatment period was >91%.

During the 121st-144th week of treatment, 99.
4% of patients had spontaneous bleeding ≤ 3, and 91.
8% of patients had spontaneous bleeding 0.

The ABR of the treated joint during the study period was 0.
9% (95%CI: 0.
7%-1.
2%), and the ABR of the treated joint during the first to 24 weeks of treatment was 1.
4% (95%CI: 0.
1%).
-6.
2%), decreased to 0.
4% (95%CI: 0%-4.
5%) from 121 to 144 weeks of treatment.

In the study, the median treated joint ABR of the patients in each 24 week treatment cycle was 0%.

During the 121-144th week of treatment, 98.
2% of patients had treated joint bleeding ≤3, and 90.
0% of patients had treated joint bleeding of 0.

The ABR of the treated target joint of patients in the treated target joint bleeding study was 0.
5% (95% CI: 0.
4%-0.
7%).

The average treated ABR was 0.
8% (95%CI: 0%-5.
2%) in the first to 24 weeks of treatment, and the average treated ABR dropped to 0.
2% (95%CI: 0.
4%-1) in the 121-144 weeks of treatment.
%).

In the study, the median treated target joint ABR of the patients in each 24-week treatment cycle was 0%.

 Among the 226 patients whose target joint status can be assessed, 202 (89.
4%) patients received eimerizumab treatment without spontaneous or traumatic bleeding in the target joint.

During the 121-144th week of treatment, 160 of the 170 patients (94.
1%) had no target joint bleeding after treatment, and 169 (99.
4%) patients had target joint bleeding ≤3.

Among the 530 target joints observed at the baseline of the HAVEN1-4 study, 95.
1% disappeared after treatment with imitizumab.

Safety Among the 399 patients included in the safety analysis, 381 (95.
5%) patients had ≥1 AE during treatment.

The most common AE was nasopharyngitis (n=126), and the most common treatment-related AE was injection site reaction (ISR) (n=107).
Most ISRs were mild (93.
7%) and occurred during the first 24 weeks of treatment Within (83.
8%), none of the patients discontinued eimerizumab treatment due to ISR.

 93 patients had 144 SAEs, of which 32 patients had bleeding-related SAEs, and 6 patients had treatment-related SAEs (1 case each for cavernous sinus thrombosis, neutralizing antibodies, skin necrosis, and superficial thrombophlebitis, thrombotic microvascular 3 cases of disease).

Except for 1 patient who died of rectal bleeding in the HAVEN1 study, no other deaths were observed in the HAVEN1-4 study.

Research conclusions The long-term efficacy and safety of iimerizumab in the treatment of HA are consistent with the previous analysis results.
The treatment of HA by eimerizumab can improve the bleeding of patients and control the bleeding of the target joint.

Immexizumab also shows good safety in HA patients.

Except for the results of the previous main analysis of the study, no patients withdrew from the study due to AEs, and there were no new thrombotic microangiopathy (TMA) events and deaths.

Taking into account that the subcutaneous administration of immezizumab has better compliance, immezizumab is a better preventive treatment option for HA.

Reference: Michael U.
Callaghan, Claude Negrier, Ido Paz-Priel, Tiffany Chang, et al.
Long-term outcomes with emicizumabprophylaxis for hemophilia A with or without FVIII inhibitors from the HAVEN1-4 studies.
Blood (2021) 137 (16 ): 2231–2242.
; https://doi.
org/10.
1182/blood.
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