Clinical Trials

Date: 2017-12-09

Type of information: Presentation of results at a congress

phase: 3

Announcement: presentation of results at The American Society of Hematology (ASH) 2017

Company: Roche (Switzerland)

Product: emicizumab (ACE910 - anti-factor IXa x anti-factor X humanized bispecific antibody)

Action mechanism:

bispecific antibody. Emicizumab is a bispecific antibody that mimics coagulation factor VIII. It is currently investigated as a therapy for people with hemophilia A. Emicizumab was designated as a Breakthrough Therapy by the FDA in September 2015.

Disease: hemophilia A

Therapeutic area: Rare diseases - Genetic diseases - Hematological diseases

Country: Australia, Costa Rica, France, Germany, Italy, Japan, Republic of Korea, New Zealand, Poland, South Africa, Spain, Taiwan, UK, USA

Trial details:

HAVEN 1 is a randomized, multi-center, open-label phase III clinical trial to evaluate the efficacy, safety and pharmacokinetics of prophylactic emicizumab versus no prophylaxis in hemophilia A patients with inhibitors previously treated with episodic or prophylactic bypassing agents. Episodic bypassing agent patients will be randomized in a 2:1 fashion to receive emicizumab prophylaxis (Arm A) versus no prophylaxis (Arm B) and will be stratified across Arms A and B according to the number of bleeds they experienced over the last 24 weeks prior to study entry (less than [<] 9 or greater than or equal to [>=] 9 bleeds); Arm B patients will have the opportunity to switch to emicizumab prophylaxis after 24 weeks on-study. Prophylactic bypassing agent patients will switch to emicizumab prophylaxis (Arm C) from the start of the trial; enrollment will be extended for 24 weeks after the last patient has enrolled in Arms A or B or until approximately 50 patients have enrolled in Arm C, whichever occurs first. Episodic bypassing agent patients who previously participated in a Non-Interventional Study BH29768 but were unable to enroll in Arms A or B prior to their closure will have the opportunity to enroll in Arm D until 24 weeks after the last patient has enrolled in Arms A or B or until approximately 35 patients have enrolled in Arm D, whichever occurs first. Like patients in Arms A and C, Arm D patients will receive emicizumab prophylaxis from the start of the trial. All patients will continue to receive standard of care/background treatment with their usual episodic bypassing agent therapy to treat breakthrough bleeds, as needed. (NCT02622321)

Latest news:

• On December 9, 2017, Roche announced that new data from the ongoing Hemlibra® (emicizumab) clinical development programme were presented at the 59th American Society of Hematology (ASH) Annual Meeting. These data include longer-term results from the pivotal HAVEN 1 and HAVEN 2 studies in people with haemophilia A with inhibitors to factor VIII, showing once-weekly subcutaneous Hemlibra prophylaxis demonstrated superior efficacy compared to prior treatment with bypassing agents (BPAs) as prophylaxis or on-demand. With nearly ten additional months of follow-up, updated results from the HAVEN 1 intra-patient analysis of adults and adolescents showed an 88% (risk rate [RR]=0.12, 95% CI: 0.05; 0.28) reduction in treated bleeds with Hemlibra® prophylaxis compared to prior BPA prophylaxis (n=24). The results also showed a 95% (RR=0.05, 95% CI: 0.02; 0.12) reduction in treated bleeds in patients who received Hemlibra® prophylaxis compared to prior on-demand BPA treatment (n=24). After more than one year, substantially more patients continued to experience zero bleeds with Hemlibra® prophylaxis compared to their prior prophylaxis or on-demand BPA treatment across bleed endpoints, including treated bleeds and all bleeds. The previously reported improvement in health status after 24 weeks, measured by the haemophilia-specific quality of life (Haem-A-QoL) and EuroQol 5-Dimensions 5-level (EQ-5D-5L) questionnaires, was also maintained with longer follow-up.
The most common adverse events (AEs) in the HAVEN 1 and HAVEN 2 studies at the time of these follow-up data were consistent with those observed previously in the studies. No unexpected safety findings were observed in the run-in cohort of the HAVEN 4 study. No new cases of thrombotic microangiopathy (TMA) or thrombotic events were observed in HAVEN 1, and no cases occurred in HAVEN 2 or HAVEN 4.
• On November 2, 2017, Chugai Pharmaceutical announced that oral and poster presentations will be given with regard to emicizumab at The American Society of Hematology (ASH) 2017 in Atlanta, Georgia, United States. Data from additional six-month follow-up of global Phase lll studies in hemophilia A with inhibitors to factor VIII, HAVEN 1 study and HAVEN 2 study will be shown at the conference.
• On July 10, 2017, Roche announced that data from HAVEN 1 evaluating emicizumab prophylaxis in adults and adolescents with haemophilia A with inhibitors, were published in The New England Journal of Medicine (NEJM). The primary endpoint showed a clinically meaningful and statistically significant reduction in treated bleeds of 87% (risk rate [RR]=0.13, p<0.0001) with emicizumab prophylaxis compared with on-demand (no prophylaxis; episodic use only) bypassing agents (BPAs). All 12 secondary endpoints were positive, including a statistically significant reduction of 79% (RR=0.21, p=0.0003) in treated bleeds in a first of its kind intra-patient analysis in a subset of patients comparing two prophylaxis regimens (emicizumab and BPAs). Data from HAVEN 1 are also being presented at the 26th International Society on Thrombosis and Haemostasis (ISTH) Congress.
Further data from HAVEN 1 showed that, after a median observation time of 31 weeks, substantially more patients experienced zero bleeds with emicizumab prophylaxis than with on-demand BPAs across all bleed measurements, including zero treated bleeds (62.9% vs 5.6%), zero treated spontaneous bleeds (68.6% vs 11.1%), zero treated joint bleeds (85.7% vs 50.0%), zero treated target joint bleeds (94.3% vs 50.0%) and zero bleeds overall, which includes all treated and non-treated bleeds (37.1% vs 5.6%). A clinically meaningful and statistically significant improvement in health-related quality of life (HRQoL) measured at 25 weeks, using two validated instruments (Haem-A-QoL and EQ-5D-5L), was also observed.
In an additional study arm (Arm C, n=49), patients who had previously received BPA prophylaxis were treated with emicizumab prophylaxis. A subset of patients in this arm (n=24) had previously participated in a non-interventional study (NIS), allowing for a first of its kind intra-patient analysis comparing two prophylaxis regimens. This analysis showed a 79% (RR=0.21, p=0.0003) reduction in treated bleeds in patients receiving emicizumab compared with their prior BPA prophylaxis during the NIS. Data also showed that 70.8% of patients in this subset experienced zero treated bleeds with emicizumab prophylaxis whereas only 12.5% of these patients had experienced zero bleeds with their prior BPA prophylaxis during the NIS.
Adverse events (AEs) occurring in 5% or more of patients treated with emicizumab were local injection site reactions, headache, fatigue, upper respiratory tract infection and joint pain (arthralgia). As previously reported, serious adverse events of thromboembolic events (TE) and thrombotic microangiopathy (TMA) occurred in two patients and three patients, respectively, while receiving emicizumab prophylaxis. The common aspect of these TMA and TE events is the patients were on emicizumab prophylaxis and received more than 100 u/kg/day of the BPA activated prothrombin complex on average for 24 hours or more before the onset of the event. Neither TE event required anti-coagulation therapy and one patient restarted emicizumab. The cases of TMA observed were transient, and one patient restarted emicizumab.
Data from both HAVEN 1 and HAVEN 2 have been submitted for approval consideration to the European Medicines Agency (EMA) and the FDA. • On June 26, 2017, Chugai Pharmaceutical and Genentech announced results from the primary analysis of HAVEN 1 study. The data will be presented on July 10 at the upcoming 26th International Society on Thrombosis and Haemostasis (ISTH) Meeting in Berlin, Germany (July 8 to 13).
The Phase III HAVEN 1 study compared emicizumab prophylaxis with on-demand (no prophylaxis; episodic use only) and prophylactic use of bypassing agents (BPAs) in adults and adolescents with hemophilia A with inhibitors. The primary endpoint was treated bleeds, and results showed a statistically significant and clinically meaningful reduction in bleed rate of 87 percent (RR [risk rate]=0.13, p<0.0001) with emicizumab prophylaxis compared to on-demand treatment with BPAs.
Patients previously treated with on-demand bypassing agents (BPAs) were randomised in a 2:1 fashion to Arm A or B:
Arm A (n=35): emicizumab once-weekly dosing
Arm B (n=18): no prophylaxis (on-demand BPA)
Patients previously treated with prophylactic BPA: Arm C (n=49): emicizumab once-weekly dosing
Patients who participated in a forgoing Non-Interventional Study (NIS) and previously on BPA (on-demand or prophylactic): Arm D: emicizumab once-weekly dosing
On-demand use of BPAs was allowed to treat breakthrough bleeds per protocol in all arms.
The primary endpoint was achieved with a statistically significant reduction in bleed rate of 87% (risk rate [RR]=0.13, p<0.0001) in treated bleeds with emicizumab (Arm A) compared with on-demand treatment with BPAs (Arm B). All secondary endpoints were also achieved with consistent reductions in bleed rates.
After a median observation time of 31 weeks, 62.9% of patients receiving emicizumab experienced zero treated bleeds (Arm A) compared to 5.6% of those receiving on-demand BPAs (Arm B). Results also showed a statistically significant improvement in health-related quality of life (HRQoL) measured at 25 weeks with emicizumab (Arm A) compared to on-demand BPAs (Arm B).
Among patients who had previously received prophylactic use of BPAs and then received emicizumab (Arm C), 24 patients had participated in the foregoing NIS, which was conducted without emicizumab. An intra-patient analysis in this group showed a 79% (RR=0.21, p=0.0003) reduction in treated bleeds receiving emicizumab compared to their prior prophylaxis with BPAs.
Adverse events (AEs) occurring in 5% or more of patients treated with emicizumab were injection site reactions, headache, fatigue, upper respiratory tract infection and arthralgia.
Serious adverse events were reported with thromboembolic events (TE) in two patients and thrombotic microangiopathy (TMA) in three patients (one patient experienced TMA after the clinical data cut off for primary analysis) while receiving emicizumab prophylaxis. The TE and TMA events were associated with repeated high doses of a BPA, activated prothrombin complex concentrate, when used to treat breakthrough bleeds.

Summary of the HAVEN 1 (NCT02622321) study results to be presented at ISTH

Treated bleeds ABR (primary endpoint)
Study Description	Phase III randomised, multicenter, open-label study evaluating the efficacy, safety, and pharmacokinetics of emicizumab prophylaxis versus no prophylaxis in people with haemophilia A with inhibitors to factor VIII.
Patients	Patients with haemophilia A with inhibitors aged ?12 years on episodic or prophylactic treatment with bypassing agent(s) N=109
Study group	No prophylaxis (prior episodic BPAs) (Arm B; n=18)	Emicizumab prophylaxis (prior episodic BPAs) (Arm A; n=35)
*Annualized bleeding rate [ABR] (95% CI)**	23.3 (12.33; 43.89)	2.9 (1.69; 5.02)
% reduction (RR, p-value)	87% reduction (RR= 0.13, p<0.0001)
Median ABR (Interquartile range; IQR)	18.8 (12.97; 35.08)	0.0 (0.00; 3.73)
% patients with zero bleeds (95% CI)	5.6 (0.1; 27.3)	62.9 (44.9; 78.5)

Treated bleeds ABR intra-patient comparison (Arm C patients who participated in NIS n=24; secondary endpoint)
Study group	Prior prophylaxis with BPAs	Emicizumab prophylaxis
*ABR (95% CI)**	15.7 (11.08; 22.29)	3.3 (1.33; 8.08)
% reduction (RR, p-value)	79% reduction (RR= 0.21, p=0.0003)
Median ABR (IQR)	12.0 [5.73; 24.22]	0.0 [0.00; 2.23]
% patients with zero bleeds	12.5 (2.7; 32.4)	70.8 (48.9; 87.4)

• On February 21, 2017, the European Haemophilia Consortium (EHC) announced that the consortium has been informed of the death of a person with haemophilia with inhibitors, who was on the clinical trial HAVEN 1 with emicizumab. The HEC requested information from Roche about this case. The company answered that it has received two new reports of Serious Adverse Events (SAE) in a patient who was enrolled in the HAVEN 1 study. This patient experienced a serious rectal haemorrhage (first reported SAE) and received bypassing agents, including repeated doses of activated prothrombin complex (aPCC), after which the patient developed signs of Thrombotic Microangiopathy (TMA) (second SAE). The preliminary assessment is that the clinical and laboratory characteristics of this case of TMA are consistent with what was observed in the two previously reported cases; however, our evaluation of the available information is ongoing.After aPCC was discontinued, laboratory values associated with TMA (platelet count and LDH) were improving. According to the report, treatment of the haemorrhage was complicated because the patient declined blood transfusions. The investigator’s assessment is that the cause of death was the rectal haemorrhage, and that this is not related to emicizumab. Roche is continuing to investigate the details of this patient case.

• On December 2, 2015, a Phase 3 trial sponsored by Roche was published on the NIH website ClinicalTrials.gov for emicizumab and is currently recruiting participants.

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