Saturday, Dec 9, 2017

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

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

South San Francisco, CA -- December 9, 2017 --

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

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

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.