Application of systems biology to identify pharmacological mechanisms of thrombotic microangiopathy evoked by combined activated prothrombin complex concentrate and emicizumab.

Emicizumab is a bispecific monoclonal antibody that substitutes for the function of missing or deficient factor VIII (FVIII) in people with hemophilia A (PwHA). Long-term safety and efficacy of emicizumab have been demonstrated in several clinical trials. Nevertheless, in the first of these, three cases of thrombotic microangiopathy (TMA) occurred in PwHA treated with emicizumab receiving high doses of activated prothrombin complex concentrate (aPCC), a bypassing agent used for treating breakthrough bleeds when FVIII neutralizing antibodies (inhibitors) make FVIII replacement ineffective. The aim of the present work is to offer a method to elucidate the pathophysiological and pharmacological mechanisms involved in this treatment-induced TMA. Systems biology and machine learning-based Therapeutic Performance Mapping System is a validated in silico technology that allowed us to construct models of potential mechanisms behind induced TMA. Two drug combinations were modeled and assessed: emicizumab plus aPCC and emicizumab plus recombinant activated factor VII (another bypassing agent). Our models showed that both combinations were related to activation of the coagulation cascade. However, mechanisms involved mainly in platelet activation and possibly in complement activation were detected only for emicizumab plus aPCC, potentially explaining the occurrence of TMA only in this combination.

Mitigating Drug-Target-Drug Complexes in Patients With Paroxysmal Nocturnal Hemoglobinuria Who Switch C5 Inhibitors.

Drug-target-drug complexes (DTDCs) are phenomena newly observed in patients who switch from the complement component 5 (C5) inhibitor eculizumab to crovalimab, a novel, anti-C5 antibody in development for paroxysmal nocturnal hemoglobinuria (PNH), because these agents bind to different C5 epitopes. In Part 3 of the four-part, phase I/II COMPOSER study, 19 patients with PNH switching from eculizumab received 1,000-mg crovalimab intravenously, then subcutaneous maintenance doses from Day 8 (680 mg every 4 weeks (q4w), 340 mg every 2 weeks, or 170 mg every week). Crovalimab exposure was transiently reduced, and size-exclusion chromatography and crovalimab-specific enzyme-linked immunosorbent assays revealed DTDCs in all 19 patients' sera. Additionally, self-limiting mild to moderate symptoms suggestive of type III hypersensitivity reactions occurred in two patients. Mathematical modeling simulations of DTDC kinetics and effects of dosing on DTDC size distribution using Part 3 data predicted that increased crovalimab concentrations could reduce the proportion of large, slow-clearing DTDCs in the blood. A simulation-guided, optimized crovalimab regimen (1,000 mg intravenously; four weekly, subcutaneous 340-mg doses; then 680 mg q4w from Day 29) was evaluated in Part 4. Confirming the model's predictions, mean proportions of large DTDCs in patients who switched from eculizumab to this optimized regimen decreased by > 50% by Day 22, and target crovalimab concentrations were maintained. No type III hypersensitivity reactions occurred in Part 4. Optimizing crovalimab dosing thus reduced the proportion of large DTDCs, ensured adequate complement inhibition, and may improve safety. Model-based dosing optimization to mitigate DTDC formation offers a useful strategy for patients switching to novel antibody treatments targeting soluble epitopes.

Surgical outcomes in people with hemophilia A taking emicizumab prophylaxis: experience from the HAVEN 1-4 studies.

Many people with hemophilia A (PwHA) undergo surgery in their lifetime, often because of complications of their disease. Emicizumab is the first bispecific monoclonal antibody prophylactic therapy for PwHA, and its efficacy and safety have been previously demonstrated; however, there is a need to build an evidence base on the management of PwHA on emicizumab undergoing surgery. Data from the HAVEN 1-4 phase 3 clinical trials were pooled to provide a summary of all minor and major surgeries in PwHA with or without factor VIII (FVIII) inhibitors who were receiving emicizumab prophylaxis. Overall, 233 surgeries were carried out during the HAVEN 1-4 trials: 215 minor surgeries (including minor dental and joint procedures, central venous access device placement or removal, and endoscopies) in 115 PwHA (64 with FVIII inhibitors) and 18 major surgeries (including arthroplasty and synovectomy) in 18 PwHA (10 with FVIII inhibitors). Perioperative hemostatic support was at the discretion of the treating physician. Overall, the median (interquartile range [IQR]) age was 33.5 (13.0-49.0) years and the median (IQR) emicizumab exposure time before surgery was 278.0 (177.0-431.0) days. Among the 215 minor surgeries, 141 (65.6%) were managed without additional prophylactic factor concentrate, and of those, 121 (85.8%) were not associated with a postoperative bleed. The majority (15 of 18 [83.3%]) of major surgeries were managed with additional prophylactic factor concentrate. Twelve (80.0%) of these 15 surgeries were associated with no intraoperative or postoperative bleeds. The data demonstrate that minor and major surgeries can be performed safely in PwHA receiving emicizumab prophylaxis. These trials are registered at www.clinicaltrials.gov as #NCT02622321, #NCT02795767, #NCT02847637, and #NCT03020160.

Effect of emicizumab prophylaxis on bone and joint health markers in people with haemophilia A without factor VIII inhibitors in the HAVEN 3 study.

INTRODUCTION: Emicizumab prophylaxis significantly reduces bleeding events; however, the associated impact on bone/joint health is unknown. AIM: To explore the effect of emicizumab prophylaxis on bone/joint health in people with haemophilia A (PwHA) without FVIII inhibitors enrolled in HAVEN 3 (NCT02847637). METHODS: Haemophilia joint health scores (HJHS; v2.1) were evaluated at baseline and Weeks 49 and 97 in PwHA receiving emicizumab (n = 134), and at baseline and Weeks 49, 73 and 97 in PwHA who switched to emicizumab after 24 weeks of no prophylaxis (n = 17). Bone and joint biomarkers were measured in 117 PwHA at baseline and at Weeks 13, 25, 49 and 73. RESULTS: HJHS was lower for PwHA who were previously on FVIII prophylaxis, aged <40 years or had no target joints at baseline compared with PwHA who were receiving no prophylaxis, aged ≥40 years or with target joints. Clinically significant mean (95% confidence interval) improvements from baseline of -2.13 (-3.96, -.29) in HJHS joint-specific domains were observed at Week 49 in PwHA with at least one target joint at study entry (n = 71); these changes were maintained through Week 97. Improvements in HJHS from baseline were also observed for PwHA aged 12-39 years. Biomarkers of bone resorption/formation, cartilage degradation/synthesis, and inflammation did not change significantly during emicizumab prophylaxis. CONCLUSIONS: Clinically relevant improvements in HJHS were observed in younger PwHA and those with target joints after 48 weeks of emicizumab in HAVEN 3. Biomarkers of bone/joint health did not show significant changes during 72 weeks of emicizumab prophylaxis.

Low immunogenicity of emicizumab in persons with haemophilia A.

INTRODUCTION: Emicizumab is a humanised, bispecific monoclonal antibody mimicking the cofactor function of activated factor (F)VIII. It is indicated for routine prophylaxis of bleeding episodes in persons with haemophilia A (PwHA) with/without FVIII inhibitors. AIM: To evaluate the development of anti-emicizumab antibodies and their impact on pharmacokinetics (PK), pharmacodynamics (PD), efficacy and safety in PwHA. METHODS: Data from seven completed or ongoing phase 3 studies were pooled. The assessment of the immunogenicity profile of emicizumab included anti-drug antibody (ADA) measurement and the association of ADAs with PK, PD, bleeding events, and adverse events. RESULTS: Of 668 PwHA evaluable for immunogenicity analysis, 34 (5.1%) developed ADAs after exposure to emicizumab. ADAs were transient in 14/34 PwHA (41.2%). ADAs were neutralising in vitro in 18/34 PwHA (52.9%) and associated with decreased emicizumab concentration in 4/668 evaluable PwHA (.6%); of those, one (.1%) discontinued emicizumab due to loss of efficacy. ADAs without decreased exposure did not impact emicizumab efficacy. The proportion of PwHA who had injection-site reactions (ISRs) was higher in ADA-positive PwHA (29.4% vs. 20.8%); however, the safety profile was similar between ADA-positive and ADA-negative PwHA, overall. No cases of anaphylaxis or hypersensitivity were reported in ADA-positive participants. CONCLUSION: The immunogenicity risk of emicizumab in phase 3 studies was low. ADAs, including in vitro neutralising ADAs, were not associated with a change in safety profile. Routine surveillance is, therefore, not warranted; however, in cases where a loss and/or waning of efficacy are observed, prompt evaluation by a healthcare provider should be sought.

The effect of emicizumab prophylaxis on long-term, self-reported physical health in persons with haemophilia A without factor VIII inhibitors in the HAVEN 3 and HAVEN 4 studies.

INTRODUCTION: Severe haemophilia A (HA) has a major impact on health-related quality of life (HRQoL). AIM: Assess the impact of emicizumab on HRQoL in persons with severe HA (PwHA) without factor VIII (FVIII) inhibitors in the phase 3 HAVEN 3 and 4 studies. METHODS: This pooled analysis examines the HRQoL of PwHA aged ≥ 18 years treated with emicizumab prophylaxis via Haemophilia-Specific Quality of Life Questionnaire for Adults (Haem-A-QoL) and EuroQoL 5-Dimensions 5-levels (EQ-5D-5L). In particular, changes from baseline in Haem-A-QoL 'Physical Health' (PH) domain and 'Total Score' (TS) are evaluated. RESULTS: Among 176 evaluable participants, 96 (55%) had received prior episodic treatment and 80 (45%) prophylaxis; 70% had ≥ 1 target joint and 51% had experienced ≥ 9 bleeds in the previous 24 weeks. Mean Haem-A-QoL PH and TS improved after emicizumab initiation. Mean (standard deviation) -12.0 (21.26)- and -8.6 (12.57)-point improvements were observed in PH and TS from baseline to Week 73; Week 73 scores were 27.9 (24.54) and 22.0 (14.38), respectively. Fifty-four percent of participants reported a clinically meaningful improvement in PH scores (≥ 10 points) by Week 73. Subgroups with poorer HRQoL prior to starting emicizumab (i.e. receiving episodic treatment, ≥ 9 bleeds, target joints) had the greatest improvements in PH scores, and corresponding reductions in missed workdays; change was not detected among those previously taking prophylaxis. No change over time was detected by the EQ-5D-5L questionnaire. CONCLUSIONS: Emicizumab prophylaxis in PwHA without FVIII inhibitors resulted in persistent and meaningful improvements in Haem-A-QoL PH and less work disruption than previous treatment.

Long-term outcomes with emicizumab prophylaxis for hemophilia A with or without FVIII inhibitors from the HAVEN 1-4 studies.

Prophylaxis with emicizumab, a subcutaneously administered bispecific humanized monoclonal antibody, promotes effective hemostasis in persons with hemophilia A (PwHAs). The primary efficacy, safety, and pharmacokinetics of emicizumab were reported previously, but long-term data were limited. Here, data from 401 pediatric and adult PwHAs with/without factor VIII (FVIII) inhibitors who were enrolled in the phase 3 HAVEN 1, HAVEN 2, HAVEN 3, and HAVEN 4 studies (NCT02622321, NCT02795767, NCT02847637, NCT03020160) have been pooled to establish a long-term efficacy, safety, and pharmacokinetics profile. Across a median efficacy period of 120.4 weeks (interquartile range, 89.0-164.4) (data cutoff 15 May 2020), the model-based treated annualized bleed rate (ABR) was 1.4 (95% confidence interval [CI], 1.1-1.7). ABRs declined and then stabilized at <1 in an analysis of 24-week treatment intervals; at weeks 121 to 144 (n = 170), the mean treated ABR was 0.7 (95% CI, 0-5.0). During weeks 121 to 144, 82.4% of participants had 0 treated bleeds, 97.6% had ≤3 treated bleeds, and 94.1% reported no treated target joint bleeds. Bleeding into target joints decreased substantially. Emicizumab was well tolerated, and no participant discontinued because of adverse events beyond the 5 previously described. This data cutoff includes the previously reported 3 thrombotic microangiopathies (one in the PwHA with fatal rectal hemorrhage) and 2 thromboembolic events, all associated with activated prothrombin complex concentrate use, as well as a myocardial infarction and a venous device occlusion. With 970.3 patient-years of exposure, emicizumab prophylaxis maintained low bleed rates in PwHAs of all ages with/without FVIII inhibitors and remains well tolerated, with no new safety concerns identified.

Development and testing of the Satisfaction Questionnaire with Intravenous or Subcutaneous Hemophilia Injection and results from the Phase 3 HAVEN 3 study of emicizumab prophylaxis in persons with haemophilia A without FVIII inhibitors.

INTRODUCTION: Emicizumab is a subcutaneously (SC) administered prophylactic agent for persons with haemophilia A (PwHA). As part of its clinical development, a new instrument was required to measure treatment satisfaction. AIM: Describe development of the Satisfaction Questionnaire with Intravenous or Subcutaneous Hemophilia Injection (SQ-ISHI) and its subsequent testing with HAVEN 3 study participants to measure patient satisfaction with emicizumab. METHODS: To develop the SQ-ISHI, we conducted four rounds of in-person interviews at five qualitative research facilities. Participants aged ≥12 years with moderate or severe haemophilia A, receiving intravenous factor VIII (FVIII) prophylaxis, provided feedback to optimize content understanding, ease of completion and item relevance. The final SQ-ISHI was completed by HAVEN 3 participants who previously received FVIII prophylaxis; baseline scores were compared with those at Week 21 or 25 of emicizumab prophylaxis. RESULTS: Sixty-three HAVEN 3 participants were eligible to complete the questionnaire and rate their satisfaction on a scale of 0 ('not at all satisfied') to 10 ('extremely satisfied'). Mean 'overall satisfaction' with previous FVIII prophylaxis at baseline was 6.9 (95% confidence interval [CI]: 6.2 to 7.7) increasing to 8.8 (95% CI: 8.4 to 9.3) at follow-up (Week 21/25 of treatment with emicizumab). The greatest improvement was observed in satisfaction with treatment half-life (mean score at baseline: 5.8 [95% CI: 4.9 to 6.6] vs 8.6 [95% CI: 8.0 to 9.2] at follow-up). CONCLUSION: These results demonstrate that emicizumab prophylaxis leads to greater treatment satisfaction compared with FVIII prophylaxis, reflecting in part the low treatment burden of emicizumab associated with its infrequent, SC administration.