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Chugai Presents Results of Two Pivotal Phase lll Studies for its Bispecific Antibody HEMLIBRA® at WFH 2018

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Chugai
Pharmaceutical Co., Ltd.
(TYO:4519) today announced that full
results from HAVEN 3 study (NCT02847637) and HAVEN 4 study (NCT03020160)
evaluating Chugai's hemophilia A treatment HEMLIBRA® [generic
name: emicizumab (genetical recombination)] are being presented at the
World Federation of Hemophilia 2018 World Congress held in Glasgow,
Scotland from May 20 to 24. HAVEN 3 study is conducted in people with
hemophilia A without inhibitors, and HAVEN 4 study is conducted in
people with hemophilia A with or without inhibitors. Results from both
studies will be presented as late-breaking abstracts.

"The results from HAVEN 3 study demonstrate that HEMLIBRA, which was
created with Chugai's proprietary antibody engineering technologies, can
reduce the bleeding risk in people with hemophilia A without inhibitors.
The intra-patient comparison in this study also shows a statistically
significant reduction in bleeding by HEMLIBRA prophylaxis compared to
factor VIII therapy, the current standard treatment," said Chugai's
President & CEO, Tatsuro Kosaka. "In addition, HAVEN 4 data indicates
that regardless of the presence of inhibitors, HEMLIBRA administration
once every four weeks can reduce the risk of bleeding in people with
hemophilia A compared with existing treatments. We will closely work
with Roche to obtain approval of HEMLIBRA for the treatment of
hemophilia A without inhibitors as early as possible."

HAVEN 3 Study

Study description

HAVEN 3 study is a randomized, multicentre, open-label phase III study
evaluating the efficacy, safety and pharmacokinetics of HEMLIBRA
prophylaxis subcutaneous injection once a week and once every two weeks.
The study enrolled 152 patients with hemophilia A, 12 years of age or
older without inhibitors to factor VIII, who were previously treated
with episodic or prophylactic factor VIII therapy.

  • Primary endpoint: number of treated bleeds over time with HEMLIBRA
    prophylaxis (Arm A and Arm B) versus no prophylaxis (Arm C).
  • Secondary endpoints: all bleed rate, treated spontaneous bleed rate,
    treated joint bleed rate, treated target joint bleed rate,
    health-related quality of life (HRQoL) / health status with HEMLIBRA
    prophylaxis (Arm A and Arm B) versus no prophylaxis (Arm C);
    intra-patient comparison of bleed rate and safety on their prior
    prophylactic factor VIII therapy (Arm D); and safety etc.

Study design    n=152

  • Patients previously treated with episodic factor VIII therapy were
    randomized in a 2:2:1 fashion to either Arm A, B or C
         

Arm A

(n=36)

  Received HEMLIBRA prophylaxis at 3 mg/kg by once-weekly subcutaneous
injection for 4 weeks, followed by 1.5 mg/kg once-weekly
subcutaneous injection
Arm B

(n=35)

Received HEMLIBRA prophylaxis at 3 mg/kg by once-weekly subcutaneous
injection for 4 weeks, followed by 3 mg/kg once every two weeks
subcutaneous injection
Arm C

(n=18)

  No prophylaxis control arm
 
  • Patients previously treated with factor VIII prophylactic were
    enrolled in:
         
Arm D

(n=63)

  Received HEMLIBRA prophylaxis at 3 mg/kg by once-weekly subcutaneous
injection for 4 weeks, followed by 1.5 mg/kg once-weekly
subcutaneous injection
 

Episodic treatment of breakthrough bleeds with factor VIII therapy was
allowed per protocol.

Summary of results

  • HEMLIBRA achieved a statistically significant reduction in treated
    bleeds by 96% (Wald test, p <0.0001) with once-weekly prophylaxis of
    HEMLIBRA (Arm A) and 97% (p <0.0001) with once every two weeks
    prophylaxis respectively, compared with no prophylaxis control arm
    (Arm C).
       

 [Major secondary endpoints and reduction rate (%)]  (Wald test)

    Arm A   Arm B
All bleeds 95%

(p <0.0001)

94%

(p <0.0001)

Treated spontaneous bleeds 94%

(p <0.0001)

98%

(p <0.0001)

Treated joint bleeds 96%

(p <0.0001)

97%

(p <0.0001)

Treated target joint bleeds   95%

(p <0.0001)

  95%

(p <0.0001)

  • 55.6% (95% CI: 38.1, 72.1) of patients receiving once-weekly
    prophylaxis of HEMLIBRA (Arm A) experienced zero treated bleeds and
    60% (95% CI: 42.1, 76.1) of patients receiving once every two weeks
    prophylaxis of HEMLIBRA (Arm B) compared to 0% (95% CI: 0.0, 18.5) of
    those not receiving prophylaxis treatment (Arm C).
  • An intra-patient comparison (n=48) in patients who had previously
    treated with factor VIII prophylaxis prior to the study (Arm D) and
    participated in the foregoing non-interventional study (NIS) showed
    that 68% (RR=0.32, p <0.0001) reduction of treated bleeds with
    once-weekly prophylaxis of HEMLIBRA.
  • Adverse events (AEs) occurring in 5% or more of patients treated with
    HEMLIBRA were injection site reactions, joint pain (arthralgia),
    common cold symptoms (nasopharyngitis), headache, upper respiratory
    tract infection and influenza.
  • There were no unexpected or serious adverse events (AEs) related to
    HEMLIBRA and most common AE profiles appeared consistent with the
    known safety profile of the medicine.

HAVEN 4 Study

Study Description

HAVEN 4 study is a single-arm, multicentre, open-label, phase III study
evaluating the efficacy, safety, and pharmacokinetics of subcutaneous
administration of HEMLIBRA dosed every four weeks. The study included 48
patients (12 years of age or older) with hemophilia A with or without
inhibitors to factor VIII who were previously treated with either
on-demand or prophylactic factor VIII or bypassing agents, depending on
their inhibitor status.

  • Primary endpoint: treated bleed rate with HEMLIBRA prophylaxis
  • Secondary endpoints: all bleed rate, treated spontaneous bleed rate,
    treated joint bleed rate, treated target joint bleed rate,
    health-related quality of life (HRQoL) / health status, and safety etc.

Study design    n=48

Patients with or without inhibitors to factor VIII previously treated
with either on-demand or prophylactic factor VIII or bypassing agents
were enrolled in two cohorts. The study was conducted in two stages as
follows;

         
Cohort   Objective   Treatment Regimen
Pharmacokinetic (PK) run-in cohort

(n=7)

Evaluate pharmacokinetics Received HEMLIBRA prophylaxis at 6 mg/kg once every 4 weeks
Expansion cohort

(n=41)

  Evaluate efficacy and safety   Received HEMLIBRA prophylaxis at 3 mg/kg once every week for 4
weeks, followed by 6 mg/kg once every 4 weeks
 

All patients in the PK run-in cohort (n=7) were previously treated with
on-demand treatment and then received HEMLIBRA prophylaxis in the study.
The evaluation of pharmacokinetics was conducted after monitoring all
seven patients in the PK run-in cohort for at least six weeks since they
had initiated the administration of HEMLIBRA, followed by an expansion
cohort study. Episodic treatment of breakthrough bleeds with factor VIII
therapy was allowed per protocol.

Summary of results

  • Patients receiving HEMLIBRA prophylaxis in Expansion cohort had a
    median annualized bleeding rate (ABR) for treated bleeds of 0.0 (IQR:
    0.0; 2.1).
  • 56.1% (95% CI: 39.7, 71.5) of patients in Expansion cohort achieved
    zero treated bleeds and 90.2% (95% CI: 76.9, 97.3) of patients
    experienced three or fewer treated bleeds.
 

 

   

[Major secondary endpoints and achievement rate (%) of zero bleeds]

  All bleeds:   29.3% (95% CI: 16.1, 45.5)
Treated spontaneous bleeds: 82.9% (95% CI: 67.9, 92.8)
Treated joint bleeds: 70.7% (95% CI: 54.5, 83.9)
Treated target joint bleeds: 85.4% (95% CI: 70.8, 94.4)
  • Results from HAVEN 4 study is consistent with results obtained from
    other phase III studies of HEMLIBRA. These data show that once every 4
    weeks prophylaxis of HEMLIBRA can provide clinically meaningful
    control of bleeding in patients with hemophilia A with or without
    factor VIII inhibitors.
  • There were no unexpected or serious adverse events (AEs) related to
    HEMLIBRA and the most common AEs were consistent with previous studies.
  • Injection site reaction was the most common AE, occurring in nine
    people.
 

Summary of the HAVEN 3 (NCT02847637) study results presented at
WFH

Study Description   A randomized, multicentre, open-label phase III study evaluating the
efficacy, safety and pharmacokinetics of HEMLIBRA prophylaxis
subcutaneous injection once a week and once every two weeks.
Patients

Patients with hemophilia A, 12 years of age or older without
inhibitors to factor VIII, who were previously treated with
episodic or prophylactic factor VIII therapy.

  N=152
Primary endpoint Number of bleeds over time with HEMLIBRA prophylaxis (Arm A and Arm
B) versus no prophylaxis (Arm C)
Study group   No prophylaxis

(Arm C; n=18)

  Once weekly HEMLIBRA prophylaxis

(Arm A; n=36)

  Once every 2 weeks HEMLIBRA prophylaxis

(Arm B; n=35)

Treated bleeds (primary endpoint)
Median efficacy period, weeks

(min–max)

24.0

(14.4–25.0)

  29.6

(17.3–49.6)

  31.3

(7.3–50.6)

Model-based ABR (95% CI)* 38.2

(22.9; 63.8)

1.5

(0.9; 2.5)

1.3

(0.8; 2.3)

% reduction vs arm C

(RR, Wald test; p-value)

N/A 96% reduction

(0.04, p <0.0001)

97% reduction

(0.03, p <0.0001)

Median ABR

(Interquartile range; IQR)

40.4

(25.3; 56.7)

0.0

(0.0; 2.5)

0.0

(0.0; 1.9)

% patients with zero bleeds

(95% CI)

0.0

(0.0; 18.5)

55.6

(38.1; 72.1)

60

(42.1; 76.1)

% patients with zero to three bleeds

(95% CI)

  5.6

(0.1; 27.3)

  91.7

(77.5; 98.2)

  94.3

(80.8; 99.3)

 
Treated bleeds ABR intra-patient comparison

(Arm D patients who participated in NIS, n=48; secondary
endpoint)

Study group   Prior factor VIII prophylaxis

(Arm C; n=48)

  Once-weekly HEMLIBRA prophylaxis

(Arm D; n=48)

Median efficacy period, weeks

(min–max)

30.1

(5.0–45.1)

33.7

(20.1–48.6)

Model-based ABR*

(95% CI)

4.8

(3.2; 7.1)

1.5

(1.0; 2.3)

% reduction vs NIS Factor VIII

(RR, p-value)

68% reduction

(0.32, p <0.0001)

Median ABR (IQR) 1.8

(0.0; 7.6)

0.0

(0.0; 2.1]

% patients with zero bleeds 39.6

(25.8; 54.7)

54.2

(39.2; 68.6)

% patients with zero to three bleeds   72.9

(58.2; 84.7)

  91.7

(80.0; 97.7)

*Negative binomial regression model

 

Summary of the HAVEN 4 (NCT03020160) study results presented at
WFH

Study Description   A single-arm, multicentre, open-label, phase III study evaluating
the efficacy, safety, and pharmacokinetics of subcutaneous
administration of HEMLIBRA dosed every four weeks.
Patients

12 years of age or older patients with hemophilia A with or
without inhibitors to factor VIII who were previously treated with
either on-demand or prophylactic factor VIII or bypassing agents,
depending on their inhibitor status.
N=48

Primary endpoint bleed rate with HEMLIBRA prophylaxis
Study group   HEMLIBRA prophylaxis (n=48 total; n=41 included in efficacy analyses)
Treated bleeds (primary endpoint)
ABR, model based

(95% CI)

2.4

(1.4; 4.3)

Median ABR,

calculated

(IQR)

0.0

(0.0; 2.1)

% patients with zero bleeds

(95% CI)

56.1

(39.7; 71.5)

% patients with zero to three bleeds

(95% CI)

  90.2

(76.9; 97.3)

 

About Chugai

Chugai Pharmaceutical is one of Japan's leading research-based
pharmaceutical companies with strengths in biotechnology products.
Chugai, based in Tokyo, specializes in prescription pharmaceuticals and
is listed on the 1st section of the Tokyo Stock Exchange. As an
important member of the Roche Group, Chugai is actively involved in R&D
activities in Japan and abroad. Specifically, Chugai is working to
develop innovative products which may satisfy the unmet medical needs,
mainly focusing on the oncology area.
In Japan, Chugai's research
facilities in Gotemba and Kamakura are collaborating to develop new
pharmaceuticals and laboratories in Ukima are conducting research for
technology development for industrial production. Overseas, Chugai
Pharmabody Research
based in Singapore is engaged in research
focusing on the generation of novel antibody drugs by utilizing Chugai's
proprietary innovative antibody engineering technologies. Chugai
Pharma USA
and Chugai
Pharma Europe
are engaged in clinical development activities in the
United States and Europe.
The consolidated revenue in 2016 of
Chugai totalled 491.8 billion yen and the operating income was 80.6
billion yen (IFRS Core basis).
Additional information is available
on the internet at https://www.chugai-pharm.co.jp/english.

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