Market Overview

Genentech's HEMLIBRA (emicizumab-kxwh) Continued to Substantially Reduce Bleeds in People with Hemophilia A with Inhibitors

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– Newly approved HEMLIBRA demonstrated superior efficacy compared to
prior treatment with bypassing agents as prophylaxis or on-demand –

– Nearly 95 percent of children who received HEMLIBRA experienced
zero treated bleeds –

Genentech, a member of the Roche Group ((SIX: RO, ROG, OTCQX:RHHBY),
announced today that new data from the ongoing HEMLIBRA®
(emicizumab-kxwh) clinical development program 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 hemophilia 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. These new data from the largest pivotal
studies in people with hemophilia A with inhibitors further support
HEMLIBRA as an important new treatment option for these adults,
adolescents and children.

In updated results from the HAVEN 2 study with six additional months of
data and 40 more children (younger than 12 years of age), 94.7 percent
(95 percent CI: 85.4; 98.9) of children with hemophilia A with
inhibitors who received HEMLIBRA prophylaxis had zero treated bleeds
(n=57). The intra-patient analysis comparing the effects of different
therapies in the same child (n=13) showed a 99 percent reduction in
treated bleeds with HEMLIBRA prophylaxis compared to prior treatment
with a BPA, either as prophylaxis (n=12) or on-demand (n=1). Substantial
improvements in health-related quality of life and aspects of caregiver
burden, measured by the haemophilia-specific quality of life short form
(Haemo-QoL-SF) and adapted health-related quality of life in hemophilia
patients with inhibitors (Inhib-QoL) questionnaires, were also observed
with HEMLIBRA prophylaxis compared to prior BPA prophylaxis. These data
were featured today in the official press program of the ASH Annual
Meeting.

With nearly 10 additional months of follow-up, updated results from the
HAVEN 1 intra-patient analysis of adults and adolescents showed an 88
percent (risk rate [RR]=0.12, 95 percent 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 percent (RR=0.05, 95
percent 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.

"These data demonstrate the continued reduction in bleeds over time with
HEMLIBRA prophylaxis and reinforce the potential of this medicine,
recently approved by the FDA for hemophilia A with inhibitors, to
redefine the standard of care," said Sandra Horning, M.D., chief medical
officer and head of Global Product Development. "We are continuing to
study HEMLIBRA in a robust clinical development program to help advance
care for all people with hemophilia A, regardless of age or inhibitor
status, and provide even less frequent dosing options."

Data from the run-in cohort of the ongoing Phase III HAVEN 4 study
showed that HEMLIBRA prophylaxis dosed once every four weeks in people
12 years of age or older with hemophilia A, with or without inhibitors,
resulted in levels of HEMLIBRA in the blood (pharmacokinetics) that were
consistent with predictions. These data supported opening the expansion
cohort of the study to further evaluate this dosing regimen. After a
median observation time of eight weeks, 85.7 percent of patients (six
out of seven) had zero bleeds while receiving HEMLIBRA prophylaxis once
every four weeks. These data follow the recent announcement that an
interim analysis of the Phase III HAVEN 4 study showed a clinically
meaningful control of bleeding in people 12 years of age or older with
hemophilia A who received HEMLIBRA prophylaxis once every four weeks.

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.

Based on earlier results from the HAVEN 1 and HAVEN 2 studies, HEMLIBRA
was approved by the U.S. Food and Drug Administration (FDA) for routine
prophylaxis to prevent or reduce the frequency of bleeding episodes in
adults and children with hemophilia A with inhibitors. Data from HAVEN 1
and HAVEN 2 are also being reviewed under accelerated assessment by the
European Medicines Agency (EMA) and submissions to health authorities
around the world are ongoing. The clinical development program also
includes the ongoing Phase III HAVEN 4 study and the Phase III HAVEN 3
study, which showed a statistically significant and clinically
meaningful reduction in the number of treated bleeds over time in people
aged 12 years or older with hemophilia A without inhibitors who received
HEMLIBRA prophylaxis every week or every other week, compared to those
receiving no prophylaxis.

About HAVEN 1 (NCT02622321)

HAVEN 1 is a randomized, multicenter, open-label, Phase III study
evaluating the efficacy, safety and pharmacokinetics of once-weekly
subcutaneous administration of HEMLIBRA prophylaxis compared to no
prophylaxis in adults and adolescents with hemophilia A with inhibitors
to factor VIII. The study included 113 patients (12 years of age and
older) with hemophilia A with inhibitors to factor VIII, who were
previously treated with BPAs on-demand or as prophylaxis. Patients
previously treated with on-demand BPAs were randomized in a 2:1 ratio to
receive HEMLIBRA prophylaxis (Arm A) or no prophylaxis (Arm B). Patients
previously treated with BPAs as prophylaxis received HEMLIBRA
prophylaxis (Arm C). Additional patients previously treated with
on-demand BPAs were also enrolled in a separate arm (Arm D). On-demand
treatment of breakthrough bleeds with BPAs was allowed per protocol in
all arms.

The updated HAVEN 1 intra-patient analysis data presented at ASH
comparing treatment with HEMLIBRA prophylaxis to prior BPAs as
prophylaxis or on-demand showed:

 
HAVEN 1 (NCT02622321)
Phase III randomized, multicenter, open-label study evaluating the
efficacy, safety and pharmacokinetics of HEMLIBRA prophylaxis versus
no prophylaxis in patients with hemophilia A with inhibitors to
factor VIII
Patients with hemophilia A with inhibitors aged ≥12 years on
bypassing agent(s) (BPAs) on-demand (episodic) or as prophylaxis
Endpoint   Arm A (n=24)   Arm C (n=24)
   

HEMLIBRA
prophylaxis

 

Prior episodic
BPAs

 

HEMLIBRA
prophylaxis

 

Prior prophylactic
BPAs

Median (range) duration of efficacy period (weeks)   76.3

(0.1-94.3)

  21.1

(10.6-33.9)

  75.6

(24.1-90.7)

  32.1

(8.1-49.3)

Treated bleeds
ABR

(95% CI)

  1.0

(0.4; 2.4)

  21.4

(15.2; 30.1)

  1.8

(0.7; 4.6)

  15.7

(11.2; 22.0)

% reduction

(RR [95% CI]), p-value

  95%

(0.05 [0.02; 0.12]), p<0.0001

  88%

(0.12 [0.05; 0.28]), p<0.0001

% patients with 0 bleeds

(95% CI)

  62.5

(40.6; 81.2)

  8.3

(1.0; 27.0)

  58.3

(36.6; 77.9)

  12.5

(2.7; 32.4)

% patients with 1-3 bleeds (95% CI)   33.3

(15.6; 55.3)

  25.0

(9.8; 46.7)

  25.0

(9.8; 46.7)

  16.7

(4.7; 37.4)

% of patients with ≥4 bleeds (95% CI)   4.2

(0.1; 21.1)

  66.7

(44.7; 84.4)

  16.7

(4.7; 37.4)

  70.8

(48.9; 87.4)

All bleeds
ABR

(95% CI)

  3.1

(1.6; 6.2)

  37.8

(28.6; 50.1)

  3.6

(1.9; 6.7)

  24.6

(18.4; 32.9)

% reduction

(RR [95% CI]), p-value

  92%

(0.08 [0.04; 0.17]), p<0.0001

  85%

(0.15 [0.08; 0.28]), p<0.0001

% patients with 0 bleeds

(95% CI)

  45.8

(25.6; 67.2)

  0

(0.0; 14.2)

  33.3

(15.6; 55.3)

  0

(0.0; 14.2)

% patients with 1-3 bleeds (95% CI)   25.0

(9.8; 46.7)

  4.2

(0.1; 21.1)

  29.2

(12.6; 51.1)

  16.7

(4.7; 37.4)

% of patients with ≥4 bleeds (95% CI)   29.2

(12.6; 51.1)

  95.8

(78.9; 99.9)

  37.5

(18.8; 59.4)

  83.3

(62.6; 95.3)

ABR, annualized bleeding rate; BPA, bypassing agent; NIS,
non-interventional study; RR, risk ratio

 

No new AEs resulted in treatment discontinuation. No new cases of TMA or
thrombotic events were observed. As previously reported, three people
experienced TMA events and two people experienced serious thrombotic
events in the HAVEN 1 study when on average a cumulative amount of >100
U/kg/24 hours of activated prothrombin complex concentrate (aPCC) was
administered for 24 hours or more to patients receiving HEMLIBRA
prophylaxis.

About HAVEN 2 (NCT02795767)

HAVEN 2 is a single-arm, multicenter, open-label, clinical study in
children younger than 12 years of age with hemophilia A with inhibitors
to factor VIII. The study is evaluating the efficacy, safety and
pharmacokinetics of once-weekly subcutaneous administration of HEMLIBRA
prophylaxis.

The updated HAVEN 2 analysis after a median of nine weeks of treatment
(range 1.6-41.6 weeks) included 60 children with hemophilia A with
inhibitors to factor VIII. The updated data presented at ASH showed:

 
HAVEN 2 (NCT02795767)
Pivotal, single-arm, multicenter, open-label, study evaluating the
efficacy, safety and pharmacokinetics of once-weekly subcutaneous
administration of HEMLIBRA
Patients with hemophilia A with inhibitors aged <12 years old (or
12-17 if <40 kg) previously treated with BPAs
Endpoint  

% zero bleeds
(95% CI)
N=57

 

% zero bleeds
(95% CI)
n=23

 

ABR*
(95% CI)
n=23

 

Median ABR
(IQR)
n=23

Treated bleeds   94.7

(85.4; 98.9)

  87.0

(66.4; 97.2)

  0.2

(0.06; 0.62)

  0.0

(0.00; 0.00)

All bleeds   64.9

(51.1; 77.1)

  34.8

(16.4; 57.3)

  2.9

(1.75; 4.94)

  1.5

(0.00; 4.53)

Treated spontaneous bleeds   98.2

(90.6; 100.0)

  95.7

(78.1; 99.9)

  0.1

(0.01; 0.47)

  0.0

(0.00; 0.00)

Treated joint bleeds   98.2

(90.6; 100.0)

  95.7

(78.1; 99.9)

  0.1

(0.01; 0.47)

  0.0

(0.00; 0.00)

Treated target joint bleeds   100

(93.7; 100.0)

  100

(85.2; 100.0)

  Not estimable   0.0

(0.00; 0.00)

*Negative binomial regression model. Primary efficacy
results (ABR analysis) based only on patients aged <12 years on study
for ≥12 weeks. ABR, annualized bleeding rate; IQR, interquartile range

The most common AEs related to HEMLIBRA were injection-site reactions.
Six patients experienced serious AEs, including bleeding in the muscles
(muscle hemorrhage), eye pain, catheter site infection, device-related
infection, bleeding of the mouth or gums (mouth hemorrhage) and
appendicitis. No cases of TMA or thrombotic events occurred in the study.

About HAVEN 4 (NCT03020160)

HAVEN 4 is a single-arm, multicenter, open-label, Phase III study
evaluating the efficacy, safety and pharmacokinetics (PK) 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 factor VIII or bypassing agents, on-demand or as
prophylaxis. The study was conducted in two parts: a PK run-in; and an
expansion cohort. All patients in the PK run-in (n=7) were previously
treated on-demand, and received subcutaneous HEMLIBRA at 6 mg/kg to
fully characterize the PK profile after a single dose during four weeks,
followed by 6 mg/kg every four weeks for at least 24 weeks. Patients in
the expansion cohort (n=41) received subcutaneous HEMLIBRA prophylaxis
at 3 mg/kg/wk for four weeks, followed by 6 mg/kg every four weeks for
at least 24 weeks. Episodic treatment of breakthrough bleeds with factor
VIII therapy or bypassing agents, depending on a patient's inhibitor
status, was allowed per study protocol.

About HEMLIBRA

HEMLIBRA is a bispecific factor IXa- and factor X-directed antibody. It
is designed to bring together factor IXa and factor X, proteins required
to activate the natural coagulation cascade and restore the blood
clotting process for hemophilia A patients. HEMLIBRA is a prophylactic
(preventative) treatment that can be administered by an injection of a
ready-to-use solution under the skin (subcutaneously) once weekly.
HEMLIBRA was created by Chugai Pharmaceutical Co., Ltd. and is being
co-developed by Chugai, Roche and Genentech.

HEMLIBRA U.S. Indication

HEMLIBRA is a prescription medicine used for routine prophylaxis to
prevent or reduce the frequency of bleeding episodes in adults and
children with hemophilia A with factor VIII inhibitors.

Important Safety Information

HEMLIBRA increases the potential for blood to clot. Discontinue
prophylactic use of bypassing agents the day before starting HEMLIBRA
prophylaxis. Carefully follow the healthcare provider's instructions
regarding when to use an on-demand bypassing agent, and the dose and
schedule one should use. Cases of thrombotic microangiopathy and
thrombotic events were reported when on average a cumulative amount of
>100 U/kg/24 hours of activated prothrombin complex concentrate (aPCC)
was administered for 24 hours or more to patients receiving HEMLIBRA
prophylaxis.

HEMLIBRA may cause the following serious side effects when used with
aPCC (FEIBA
®), including:

  • Thrombotic microangiopathy (TMA). This is a condition involving
    blood clots and injury to small blood vessels that may cause harm to
    one's kidneys, brain, and other organs. Patients should get medical
    help right away if they have any of the following signs or symptoms
    during or after treatment with HEMLIBRA:
    • confusion
    • weakness
    • swelling of arms and legs
    • yellowing of skin and eyes
    • stomach (abdomen) or back pain
    • nausea or vomiting
    • feeling sick
    • decreased urination
  • Blood clots (thrombotic events). Blood clots may form in blood
    vessels in one's arm, leg, lung or head. Patients should get medical
    help right away if they have any of these signs or symptoms of blood
    clots during or after treatment with HEMLIBRA:
    • swelling in arms or legs
    • pain or redness in the arms or legs
    • shortness of breath
    • chest pain or tightness
    • fast heart rate
    • cough up blood
    • feel faint
    • headache
    • numbness in the face
    • eye pain or swelling
    • trouble seeing

If aPCC (FEIBA®) is needed, patients should
talk to their healthcare provider in case they feel they need more than
100 U/kg of aPCC (FEIBA
®) total.

How should patients use HEMLIBRA?

HEMLIBRA may interfere with laboratory tests that measure how well blood
is clotting and may cause a false reading. Patients should talk to their
healthcare provider about how this may affect their care.

What are the other possible side effects of HEMLIBRA?

The most common side effects of HEMLIBRA include: redness,
tenderness, warmth, or itching at the site of injection; headache; and
joint pain.

These are not all of the possible side effects of HEMLIBRA. Patients
should call their doctor for medical advice about side effects.

Side effects may be reported to the FDA at (800) FDA-1088 or http://www.fda.gov/medwatch.
Side effects may also be reported to Genentech at (888) 835-2555.

Please see the HEMLIBRA full Prescribing
Information
and the Medication
Guide
, including Serious Side Effects, for more important
safety information.

About hemophilia A

Hemophilia A is an inherited, serious disorder in which a person's blood
does not clot properly, leading to uncontrolled and often spontaneous
bleeding. Hemophilia affects around 20,000 people in the United States,
with hemophilia A being the most common form and approximately 50-60
percent of people living with a severe form of the disorder.

People with hemophilia A either lack or do not have enough of a clotting
protein called factor VIII. In a healthy person, when a bleed occurs,
factor VIII brings together the clotting factors IXa and X, which is a
critical step in the formation of a blood clot to help stop bleeding.
Depending on the severity of their disorder, people with hemophilia A
can bleed frequently, especially into their joints or muscles. These
bleeds can present a significant health concern as they often cause pain
and can lead to chronic swelling, deformity, reduced mobility and
long-term joint damage.

A serious complication of treatment is the development of inhibitors to
factor VIII replacement therapies. Inhibitors are antibodies developed
by the body's immune system that bind to and block the efficacy of
replacement factor VIII, making it difficult, if not impossible, to
obtain a level of factor VIII sufficient to control bleeding.

About Genentech in hemophilia

In 1984, Genentech scientists were the first to clone recombinant factor
VIII in response to the contaminated hemophilia blood supply crisis of
the early 1980s. For more than 20 years, Genentech has been developing
medicines to bring innovative treatment options to people with diseases
of the blood within oncology, and in hemophilia A. Genentech is
committed to improving treatment and care in the hemophilia community by
delivering meaningful science and clinical expertise. For more
information visit http://www.gene.com/hemophilia.

About Genentech

Founded more than 40 years ago, Genentech is a leading biotechnology
company that discovers, develops, manufactures and commercializes
medicines to treat patients with serious or life-threatening medical
conditions. The company, a member of the Roche Group, has headquarters
in South San Francisco, California. For additional information about the
company, please visit http://www.gene.com.

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